By Kreipe, Richard E

Somatoform disorders constitute a group of disorders within the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV] that have two features in common: (1) physical (somatic) symptoms that suggest a medical condition, but that are not explained fully by a medical or mental disorder or the direct effects of a substance, and (2) the symptoms “must cause clinically significant distress or impairment in social, occupational or other areas of functioning” [1]. Because of the physical nature of symptoms, somatoform disorders are more likely to present to a primary care provider or medical specialist than to a mental health provider. Six distinct diagnoses are included in this category: somatization disorder, undifferentiated somatoform disorder, conversion disorder, pain disorder, hypochondriasis, and body dysmorphic disorder. Factitious disorder and malingering can present with similar symptoms, and often are considered in the differential diagnosis, but each is placed in a separate category in DSM-IV.

In clinical practice, psychiatric symptoms that are associated with somatoform disorders often are assumed by adolescent patients and their parents to be the result of a physical illness, whereas physicians tend to interpret underlying mental health problems as causing the symptoms. Somatic symptoms present challenges to medical providers who attempt to distinguish a physical source from a psychiatric source, not only because the two domains are inseparably interactive, but also because a diagnostic work-up that is guided by this often proceeds along a path that leads to conflict and dissatisfaction for all parties involved (adolescent patients, their parents, and their physician).

Adolescents present special challenges in the diagnosis and treatment of somatic symptoms that are associated with psychiatric dysfunction. Usually, the second decade of life is characterized by significant changes in biologic, psychologic, and social domains, which blurs the distinctions between function and dysfunction. Primary and specialty care providers for adolescents recognize the significant interactions across these domains in all adolescents, but may not be equipped to meet the challenges that patients present when psychologic problems rise to the level of a psychiatric diagnosis as they do in somatoform disorders. As noted by Spratt and DeMaso [2], the somatoform disorders represent the extreme end of a continuum of somatic symptoms (the other end of which are the mild and self-limited symptoms of unknown etiology that frequently present to primary care physicians) with recurrent complaints that present puzzling diagnostic dilemmas and even more difficult treatment barriers. Adding to the difficulty, after being informed that no medical/surgical illness has been found and that the symptoms cannot be explained fully by a medical diagnosis, adolescents or their parents may continue to seek repeated medical/ surgical evaluation and treatment.

This article addresses the shortcomings of commonly used diagnostic categories and therapeutic strategies, counterbalanced by the advantages of the biopsychosocial approach in the context of somatoform disorders. It also includes practical suggestions and clinical pearls for primary care providers who evaluate and treat adolescents who have somatic symptoms. Following a description of the present DSM-IV diagnostic algorithm in the somatoform spectrum, a discussion of an alternative approach that applies the biopsychosocial approach to adolescents is described. By offering strategies that can be applied to all adolescents, regardless of their symptoms, this article presents an approach that is especially useful in the diagnosis and management of adolescents who have psychiatric problems, with or without somatic symptoms. Each of the following scenarios represents an actual case that was referred to the author for an adolescent medicine consultation at some point in the course of a somatoform illness. They highlight some potential pitfalls in the management of these challenging conditions, and are used to emphasize the value of the biopsychosocial approach for all of the conditions that are addressed in this issue.

Case scenarios

A 16-year-old girl had been evaluated by an ophthalmologist, an allergist, and an otolaryngologist, and was admitted to the hospital by a neurologist because of unrelenting headaches that made it impossible for her to attend school regularly. She had a history of abdominal pain, vomiting, and diarrhea that were attributed to “food allergies”; chronic fatigue and rheumatic symptoms that were attributed to “fibromyalgia”; and recurrent chest pain that was attributed to “costochondritis.” The adolescent medicine consultant returns to the patient’s room as she is being transported for a repeat electroencephalogram (EEG), now with nasopharyngeal leads. Her mother turns to him and says “I hope that they find something…”

A 12-year-old boy had “seizures” while playing soccer. Treatment for asthma had been initiated 4 months earlier, but without improvement in his wheezing. EEG with video monitoring is normal and pulmonary function tests reveal flow-volume loops with inspiratory flattening, which is characteristic of vocal cord dysfunction.

A 15-year-old girl was evaluated for chronic midepigastric pain. After extensive inpatient testing, she was transferred to a university hospital, where repeat tests remained normal and endoscopy failed to identify the cause of her pain. Adolescent medicine consultation revealed that her estranged father had remarried recently and taught at her school. He had not visited her during hospitalization, but had shown much attention to his stepdaughter when she was ill with abdominal pain. The patient described herself as “much more mature than my classmates” and as a “drama queen.” Regular outpatient visits with the adolescent medicine specialist, using a somatically oriented cognitive behavioral approach to symptomatic relief and resolution of ongoing family conflicts, resulted in gradual improvement.

Two years later, she presented to her primary care physician with acute lower abdominal pain. Because of her history of somatoform pain disorder, he focused on stressors and learned that she had not resolved her conflict with family members, but was planning to move to New York City to become an actress. Brief palpation of her abdomen revealed tenderness, but she seemed to “overreact” to the physical examination. She was prescribed antacids, and was recommended to work on family relationships. Five days later, she presented to the Emergency Department because of worsening pain. When a pelvic examination was performed, 75 mL of pus from a ruptured pyosalpinx spontaneously drained from her posterior vaginal vault.

A 17-year-old boy was evaluated for recurrent back pain that was worse at night, but which responded quickly to ibuprofen. He was a well-known scholarathlete from a small rural town, who was feeling “overwhelmed” by stress. The best player on a winless football team, he mentioned to his physician that it would be good to have an “excuse” not to be on the team. He said, “Could you give me an excuse, Doc?.. Just kidding.” He reported trouble sleeping because of the pain and “all the things on my mind.” Physical examination and standard radiographs of the spine were unremarkable; fluoxetine was added to the ibuprofen because of symptoms of depression and anxiety. When the pain did not improve, he was referred to an adolescent medicine specialist for counseling. Because of his history, a CT scan was obtained first, which revealed a suspected small vertebral osteoid osteoma. After this was removed, his pain did not return, but he continued to work on coping with stress, and expressed relief that his pain was not “all in his head,” as he had presumed when prescribed fluoxetine.

Potential pitfalls in diagnosing somatoform spectrum disorders in adolescents

Limitations of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition in somatoform disorders

The classification scheme that is applied to psychiatric conditions, the DSM, now in its fourth edition and published by the American Psychiatric Association, highlights characteristics or unique features of various mental health diagnoses. Mayou and colleagues [3] recently concluded that the “existing category of somatoform disorders may be regarded to have failed” because (1) the terminology is unacceptable to patients, because interpreting symptoms as merely a mental disorder in somatic form raises doubt about the genuineness of their suffering; (2) dichotomizing symptoms into those that reflect disease or are psychogenic in origin is theoretically questionable, incompatible with cultures that do not dichotomize mind-body issues, and countertherapeutic; (3) somatoform disorders do not form a coherent category and overlap with other psychiatric disorders (eg, depression, anxiety) that include somatic symptoms; and (4) the medical condition exclusion criteria are ambiguous-a patient could be assigned axis III (irritable bowel syndrome) and axis I (undifferentiated somatoform disorder or pain disorder) diagnoses for identical somatic symptoms.

In addition, the DSM-IV has limitations when applied to adolescents who have somatoform disorders because many primary care providers are not familiar with the intrica\cies and subtleties of a formal psychiatric diagnostic evaluation and the application of the five DSM “axes” (I = mental disorders; II = personality disorders and mental retardation; III = physical conditions and disorders; IV = psychosocial and environmental factors; V=global assessment functioning). In addition, most adolescents do not meet full criteria threshold, but fall to an “undifferentiated” or “not otherwise specified” level of specificity within a diagnostic category. Finally, diagnostic criteria for some conditions (eg, somatization disorder), are intended for adult populations, although a pattern of somatic symptoms is established clearly by adolescence.

Diagnostic and Statistical Manual for Primary Care, Child and Adolescent Version

To respond to these and other limitations in the DSM-IV, the American Academy of Pediatrics published a companion document in 1996. The Diagnostic and Statistical Manual for Primary Care (DSM- PC), Child and Adolescent Version takes into account the developmental issues that are considered in pdiatrie primary care [4]. With respect to somatizing and other symptoms that are assumed to have some relationship to emotional issues, the major advantage of this classification scheme is the creation of two hierarchical subthreshold categories for patients who have symptoms: those that do not interfere with everyday functioning, but that might benefit from intervention (somatic complaint variation V65.49), and those that cause distress or impairment (somatic complaint problem V40.3). The formal DSM-IV criteria are retained in DSM-PC for the most symptomatic patients. Some health insurers do not reimburse visits that are labeled only with “V-codes,” although the recognition of such may lead to significant cost savings in the avoidance of unnecessary diagnostic tests. Thus, the DSM-IV remains the standard coding system that is used most commonly in practice and in research; however, rigid adherence to any of the criteria in DSM-IV can be counterproductive clinically. As Morrison noted [5], “diagnoses are not decided by criteria; diagnoses are decided by clinicians, who use criteria as guidelines.”

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic algorithm for somatoform disorders: potential problems at every step

Ruling out underlying medical conditions

The first step in the diagnostic algorithm in somatoform disorders that is suggested in DSM-IV [1] is to rule out an underlying medical condition that might explain the symptoms. This usually involves diagnostic testing that might include: (1) analysis of blood, urine, stool or spinal fluid; (2) indirect imaging by ultrasound, radiographs, CT, or MRI; (3) direct imaging of internal organs by endoscopy or laparoscopy; or (4) procedures that are related to the function of the heart (eg, ECG or echocardiograms), lungs (eg, pulmonary function tests), brain (eg, EEG), metabolism (eg, breath hydrogen), or other targets that are suggested by the symptoms. When presented with symptoms that are not accounted for by history or physical examination, physicians may perform a battery of tests, some of which will be uninformative and unnecessary either “to be complete” and to reassure themselves, or to respond to pressures by the patient or parents to “find out what is wrong.” Because diagnostic tests rarely have 100% sensitivity to detect pathology, some amount of residual uncertainty remains with negative results. Because of false positivity, the more tests that are performed, the greater is the likelihood that some “abnormality” will be detected.

Although such a strategy may satisfy an individual physician’s required level of diagnostic certainty that a medical condition has been “ruled out,” a series of negative tests may lead to requests or demands from the adolescent or parents for additional tests. Often, these consumers arrive at an office visit armed with misinformation that has been gleaned from the Internet. Sometimes the requests are for unusual tests, such as to detect “dysbiosis” that is related to “yeast overgrowth,” which is diagnosed by the presence of antibodies of unknown significance. Often, the sources of such information are for-profit entities (a web address ending in “.com”). Thus, in practice, a physician often is faced with the dilemma of diagnostic testing that confuses, rather than clarifies, “what is wrong.” On the one hand, “absence of proof does not constitute proof of absence. ” Conversely, the presence of abnormal findings (eg, gallstones) does not necessarily account for symptoms (abdominal pain), and the presence of a medical diagnosis may be distracting and cause a psychiatric condition to go unrecognized.

Thus, “normal” findings may not be reassuring, because they are interpreted by the adolescent as “my doctor thinks that nothing is wrong” or “the symptoms are all in my head” (eg, the boy who had osteoid osteoma). This is especially true if a physician follows a report of negative test results (“good news, everything is normal”) with questions about underlying stress or emotional problems that might be causing symptoms. When a physician reports negative test results and then inquires about stress, a linear cause-effect relationship reasonably can be inferred. It is understandable why an adolescent might conclude that the physician believes that symptoms are being “faked,” are due to “emotional instability,” or are used to get “attention.”

Thus, when adolescent patients or their parents seem to be disappointed when they learn of “normal” test results, the reason may be iatrogenic. When diagnostic tests are preceded by a statement such as, “we will do some tests to see what is wrong,” the implication is that the tests will result in a diagnosis. From the patient’s perspective, normal tests mean that the diagnosis remains unknown and the prognosis is uncertain, so the logical next step would be to obtain more tests. Negative test results also are distressing because adolescents may infer that without a positive test, there will not be any effective treatment and the symptoms may continue indefinitely. This only exacerbates the suffering that is being caused by the symptoms. Such was the case with the 16-year- old girl in the case scenarios, who already had established a pattern of bodily symptoms that was well on its way to somatization disorder.

If the physician indicates that no further studies are indicated because “everything has been normal so far,” the patient or parents often become resentful because the severity of the symptoms is often not perceived as being appreciated by the physician. Likewise, there may be a sense of abandonment when the patient hears statements like “there is nothing more I can do for you,””you will just have to learn to live with it” or, “you need to see a psychiatrist, because I cannot find anything wrong with you physically.” These are additional ways in which a rift in the patient-physician relationship occurs. Obtaining more tests may mend this rift temporarily, but when more negative test results are returned, a vicious cycle has already been set in motion. Some practitioners believe that performing “too many” tests only may reinforce the belief that a medical condition exists, which “feeds into the illness.” Not performing “enough tests” may indicate to the adolescent or parents that the symptoms are not being taken seriously, which often leads to “doctor shopping.” The medical care of patients who have somatoform disorders requires a balance of art and science that can help to avoid some of these pitfalls.

Involuntary versus voluntary (intentional) symptoms

The second step in the DSM-IV diagnostic algorithm is to determine if the adolescent is producing symptoms intentionally. The purpose of this step is to distinguish somatoform disorders from factitious disorder (Munchausen syndrome) or malingering, in which symptoms are produced intentionally to assume the sick role, or for some external gain, respectively. Although the somatoform disorders are characterized by symptoms that are not under voluntary control, attempting to determine if symptoms are produced intentionally tends to be counterproductive in clinical practice; it undermines the trust that is required in a therapeutic partnership between a physician and an adolescent patient. Furthermore, it is nearly impossible to determine if symptoms are being feigned; attempts to do so are inferred as the physician believing that symptoms are being produced to avoid something negative (primary gain), to obtain something positive (secondary gain), for attention, or because of psychologic illness. . i

If an adolescent perceives that his/her physician believes that he/she might be “faking it,” the formation of a therapeutic alliance is extremely difficult. In practice, there is little clinical advantage to identifying symptoms as being under voluntary control in the early phases of assessment. Either side of the clinical algorithm presents a slippery slope. Adolescents who are not intentionally producing symptoms are offended and suffer further because they are not believed, or worse, are believed to be “crazy”; adolescents who are producing symptoms intentionally may become indignant, or escalate or modify their symptoms. This dynamic tends to produce resentment on the part of physicians (suspicious of being duped) and defensiveness on the part of patients (for not being believed).

Additionally, it can lead to splitting of parents, if one parent/ stepparent believes that the adolescent is “making up” symptoms, while the other parent/stepparent believes that a medical condition is “being missed” by the physician. Such was the case with the 12- year-old boy in the case scenarios. Because conversion disorder was suspected before the video-EEG was performed, adolescent medicine consultation was obtained early in the course of the illness, and the normal EEGwas interpreted as reassuring. In addition, because a positive diagnosis of conversion disorder was made, the diagnosis of asthma also was reconsidered and was changed to vocal cord dysfunction, based on inspiratory flow-volume loops. Because of this process, his mother and father were unified in the approach to treatment. Of course, if the diagnosis of factitious disorder is being entertained, it is important to corroborate data from numerous sources, but not to confront the adolescent or parent directly until confirmatory data have been obtained. The production of signs or symptoms to assume the sick role-whether by the adolescent or by a proxy-can be associated with significant harm, including death, and always represents significant psychiatric illness. It must be approached cautiously, and should not be avoided.

Symptoms caused by unresolved conflict or stress

The third step in the DSM-IV diagnostic algorithm is to determine if unconscious, unresolved conflict or stress is related to the symptom pattern. In conversion disorder, stress or unresolved conflict that cannot be dealt with on a conscious level is interpreted to submerge below the level of awareness, but emerge as (is converted into) somatic-often neurologic-symptoms. Thus, the symptom often has symbolic meaning, and reflects a “model” [6]. Classically, primary and secondary gains can be identified that represent something that the adolescent is avoiding and is approaching, respectively. The avoidance-approach dynamic is not unique to conversion dynamics, but it provides homeostatic balance by allowing the adolescent to avoid the source of stress or unresolved conflict (primary) and to approach something desirable, such as attention (secondary). As is true of the other elements in the DSM-IV algorithm, this criterion is difficult to apply clinically because it is not clear how one can determine if psychologic factors are related etiologically to the somatic symptoms.

Similar to the dilemma regarding attempts to determine if symptoms are produced intentionally, there is little advantage to make a definitive cause-effect linkage between emotional distress and physical symptoms in conversion or pain disorder. Recognizing that the proposed dynamic reflects the emergence of somatic symptoms because of stress or conflict that could not be dealt with on a conscious level, it is clinically useless and potentially countertherapeutic to bring these issues to conscious awareness during symptom assessment. Treatment is directed at helping the adolescent to resolve the conflict or develop alternative coping skills and to gain insight into how future problems might cause their bodies to function improperly. A physician who merely points out the link between somatic symptoms and emotional distress does not make affected adolescents competent to deal with underlying problems.

Likewise, the presence of significant stress or unresolved conflict does not mean necessarily that the symptoms are causally related. Although the 17-year-old in the case scenarios had acknowledged not coping well with life stressors that deserved attention, their presence caused his physician to miss the symptoms of osteoid osteoma. The history of somatoform pain disorder in the 15-year-old girl sidetracked her physician, and precluded an interval history and physical examination, which caused her pelvic inflammatory disease to be overlooked.

Failure of the biomedical model in somatoform disorders

Faced with all of these problems, it is understandable that Silber and Pao [7] noted that many clinicians are “baffled by the onslaught of symptoms, become annoyed by the time consumed in caring for patients who are ‘not really sick,’ or feel frustrated by the never-ending recurrent complaints.” Fabrega [8] emphasized that the biomedical paradigm espoused by Western medicine, is in part responsible for this situation, because it reduces a patient’s subjective distress and impairment to objective disease and pathophysiologic processes understood only in terms of biophysical or chemical processes.

The prevalence of these conditions adds to the challenge to clinicians. Somatic complaints are common in primary care [9-13]; recurrent abdominal pain accounts for up 5% of pediatric office visits, and headaches, nausea, chest pain, or fatigue are reported by 10% of adolescents [7]. Some somatizing adolescents have coexisting psychopathology, family conflict, school absenteeism, and increased use of health and mental health services [14], as well as emotional problems [15,16] and persistent physical symptoms later in adulthood [17], which compounds this situation. Therefore, a different paradigm is needed for diagnosis and treatment. The biopsychosocial approach offers many advantages with respect to somatizing adolescents and their families.

The biopsychosocial approach in adolescent medicine

Proposed by Engel [18] in a landmark article in the journal Science in 1977 [18], the biopsychosocial approach offers a means of incorporating existing, as well as emerging and new areas (eg, psychoneuroimmunology), that better explain the cause and treatment of all symptoms that might present in health care settings than does the traditional dualistic approach in which illness is dichotomized into two domains: the body or the mind (Fig. 1). Thus, it “supplements and enriches the discoveries of biomedicine, rather than undermining them” [19]. Central to the biopsychosocial model is an appreciation of the continuum of hierarchical natural systems that always are interacting at any point in time in a patient’s experience of symptoms. Engel noted that “each level of hierarchy represents an organized dynamic whole. . .(with) qualities and relationships distinctive for that level of organization. . .In no way can the methods and rules appropriate for the study and understanding of the cell as cell be applied to the study of the person as person or the family as family” [19]. Furthermore, “each system as a whole has its own unique characteristics and dynamics; as a part it is a component of a higher-level system” [20]; however, “neither the cell nor the person can be fully characterized as a dynamic system without characterizing the larger system(s) (environment) of which it is a part” [20]. Thus, “with the systems hierarchy as a guide, the physician from the outset considers all information in terms of systems levels and the possible relevance and usefulness of data from each level for the patient’s further study and care” [20]. In practice, Frankel and colleagues [21] noted that “a comprehensive understanding of every aspect of care from diagnosis to treatment depends upon an appreciation of both linear and nonlinear processes associated with disease and illness.”

Fig. 1. Biopsychosocial model. (From Engel GL. The clinical application of the biopsychosocial model. Am J Psychiatry 1980;137:537; with permission.)

Another important contribution to the literature was Medical Choices, Medical Chances, a book that was published in 1981 by Bursztajn and colleagues [22], which was based on the fact that the practice of medicine inevitably involves probabilities and uncertainties. The way in which uncertainty is handled by a physician can increase suffering or promote healing. Although often considered distinct and separate, subjective domains (eg, patient- reported history, symptoms) and objective domains (eg, physical examination, laboratory findings) are continuous and interactive in this viewpoint. As Cassell [23] pointed out, regardless of the diagnosis or the underlying emotional issues “the patient does not have the option, nor the interest, to relate things objectively where illness is concerned.” Although the diagnostic process traditionally begins with the history, he also noted that “taking a history is unavoidably and actually an exchange of information” [23]. Therefore, issues of cross-systems relationships, trust, and therapeutic partnerships become central to the suffering that the adolescent and family is experiencing and to the healing process. Nowhere is this truer than with adolescent “psychiatric” issues, not only because of the intrinsically subjective nature of the suffering, but because psychiatric diagnoses tend to be highly stigmatized in many cultures. Within psychiatric diagnoses there probably is no greater risk of doing unintentional harm-as well as the potential for doing good-than in the somatoform disorders. The emphasis of the remainder of this article is on the latter.

The recent emergence of biologic psychiatry, with its focus on neurotransmitters and neural circuitry, also runs the risk of being reductionistic. For example, simplifying adolescent depression to the level of a “chemical imbalance in the brain,” addresses only the molecular contribution to the illness. Although such a framework may minimize stigmatization and enhance the acceptance by patients or parents to use medications that “restore balance,” it ignores the other contexts and systems in an adolescent’s life. This is especially true if a 15-minute medication check with a psychiatrist only targets symptom reduction and medication side effects. As pointed out by Sharf and Williams in the article on psychopharmacology elsewhere in this issue, medication can be a useful tool in the treatment of adolescents who have psychiatric symptoms; however, its optimal effect is realized when it is used as a component of a multi-pronged therapeutic approach. Addressing the molecular systems level is important, but the larger view biopsychosocial approach must be integrated into the other systems that are operating in an adolescent’s life.

Communication in adolescent somatoform disorders

Language in communication

The word “communication” is derived from the Latin communicare (to share, or to have in common). Most adolescents see themselves as having little in common with their physicians, so communicat\ion may be limited. Patients who have somatoform symptoms may have additional difficulties communicating, based on the diagnostic approaches that sometimes are used. If a patient and his/her physician share the goal of understanding the likely cause of symptoms and developing a treatment plan that is likely to restore function and promote healing, then successful outcomes are possible. The best way to establish shared goals is through spoken language.

Spoken language in clinical interactions has two dimensions that are relevant to the patient and the provider: receptive and expressive. Although adolescent patients rarely are aware of these issues, clinicians who treat adolescents must attend to receptive and expressive language for the patient and the provider. To emphasize the importance of this concept, Cassell [23] noted that “spoken language is our most important diagnostic and therapeutic tool, and we must be as precise in its use as is a surgeon with a scalpel.”

During diagnosis, language can be an impediment in working with adolescents who have somatoform symptoms. Several examples were illustrated, but others can be considered. For example, seizurelike activity may be labeled as “psychogenic,” whereas abdominal pain is called “psychosomatic.” Regardless of the root term that follows, many adolescents and their parents regard the prefix “psych” as a negative and nonvalidating term. “I cannot find anything wrong with you” is not helpful on several levels. Depending on where the emphasis is placed (or perceived) in this comment, an adolescent might infer that: (1) another physician might be able to find something wrong, (2) there is nothing wrong, (3) the symptoms are being imagined, (4) the symptoms are being falsified intentionally, or (5) there is nothing that can be done. Silber and Pao [7] noted that the concept of “functional versus organic” misses the mark, because it does not reflect the current thinking that symptoms are the result of a complex interplay of several factors.

Identifying pain as “real”

Traditional wisdom teaches the importance of clinicians acknowledging explicitly to the patient who has somatoform pain disorder their belief that the pain is “real”; however, patients often realize that this is a forced and unnatural response. Adolescents who have a broken arm, appendicitis, or strep throat are not informed that their pain is real; explicitly validating symptoms can have the unintended effect of invalidating them. Patients who are referred to adolescent medicine specialists by organ-based specialists note, not uncommonly, “The doctor who sent me here said that he knows that my pain is real, but I think that he was just saying that and did not really believe it.”

Therein lies a subtle, but critical, point with respect to communication, which is applicable to somatoform disorders. In addition to the actual words of spoken language that are expressed and received in communicating, there is an unspoken need for the words to be authentic and truly express what the physician and the adolescent patient truly believe. Pellegrino [24] pointed out that, “a person becomes a patient when, in his perception of his own existence, he passes some point of tolerance for a symptom or debility and seeks out another person who has professed to help. The patient bears and suffers something, and his expectation is that every act of the physician will be to relieve him of that burden and restore his lost wholeness-which is, incidentally, the meaning of the AngloSaxon word heal.”

“Believing” reported symptoms

Physicians may not believe that the symptoms (eg, pain) that are experienced by a patient who has somatoform disorder are real, when “all of the tests are negative.” A significant amount of time may be invested by clinicians to determine if an adolescent is trying to: (1) avoid something (primary gain), (2) seek attention (secondary gain), or (3) feign symptoms for an internal or external reward. Although adolescents who have somatoform disorders may lack interceptive awareness, they usually are extremely sensitive and aware of any lack of authenticity. Scrupulous attention to honesty requires the physician to acknowledge uncertainty.

Therefore, beliefs about the symptoms are more important than what is spoken about the symptoms; acknowledging that pain is real can cause an adolescent to suffer more if the words expressed say “1 believe you,” but the message received says “I do not believe you.” As a basic principle, Cassell [23] suggested that physicians “accept that physical symptoms always have a physical basis no matter what the underlying cause.” Understanding the significance and meaning of symptoms is important in the diagnosis and in planning treatment.

Changing our understanding of symptoms based on scientific knowledge

Dysmenorrhea provides an excellent example of the limitations of the language and our understanding of adolescent somatic symptoms and their relationship to psychologic issues. Between 1972 and 1989, a highly respected quarterly pediatric series published three articles on adolescent dysmenorrhea. In 1972, primary dysmenorrhea was defined by Sloan [25] as “the presence of painful menstruation in the absence of any somatic or pelvic lesion. The term intrinsic. . .was derived from the belief, sometimes still held, that the etiology for the pain lay in the uterus itself.” Based on this understanding, he stated “the cause. . .that can account for the vast number of cases is and remains psychogenic. As stated, this is almost 100% true in the patient in her teens or younger” [25].

By 1981, advances in our understanding of menstrual physiology led Gantt and McDonough [26] to define primary dysmenorrhea as “painful menstruation without significant pelvic pathology.” Citing scientific findings over the previous 5 years based on microtransducer techniques, and studies of pain receptor physiology and a variety of prostaglandins and their metabolites, they concluded that “the common denominator in most women with primary dysmenorrhea is excess myometrial activity” and “the importance of psychological factors in dysmenorrhea is dubious” [26]. In the 1972 article, the focus was on the patient almost to the exclusion of the pain, whereas in the 1981 article, the focus was more on the pain, with less attention on the patient.

A more balanced approach than either of these dualistic conceptualizations was offered in 1989 by Coupey and Ahlstrom [27], who synthesized knowledge about the physiology and psychology of dysmenorrhea and noted that “some adolescent girls will be found to have disability related to menstrual cramps that seems out of proportion to the severity of the pain. Occasionally, an underlying psychosocial problem,. . .personal or family problem may be contributing to the decreased pain tolerance and heightened anxiety centered around the menses in these girls.” This formulation considers the pain in the context of the patient and the various domains that affect pain.

In addition to spoken language, the astute diagnostician interprets the body language of the adolescent patient as part of the evaluation, and makes use of body language and other techniques to facilitate the adolescent’s expressive language. These techniques include: (1) giving the patient undivided attention (writing as little as possible and making direct eye contact), (2) using reflective language to clarify traditional elements of the history (eg, timing, location, radiation, quality, severity, precipitants, and relievers of pain as well as any associated symptoms), (3) using a conversational style to identify things that the patient is unable to do as a result of the symptoms, (4) developing a differential diagnosis that include specific diagnoses or diseases that the patient (and parents) might be worried about. All of these are directed at helping the clinician to understand the story and the meaning of the illness, as well as the suffering that is caused by it. As Cassell [23] pointed about, “thinking about symptoms, attaching meaning to them, searching for explanations, are a much a part of the illness as are its physical expressions. These thoughts are not caused by the illness, they are part of the illness.”

Using reflective listening to establish a therapeutic partnership

Reflective listening goes beyond not talking. It requires being attentive to subtle nuances of verbal and body language. The physician should not expect to get “facts” from the patient and parents, but an “understanding of what it is like for the patient to be sick.” Central to this process should be an exploration of the fears, worries, or concerns that might be evoked by the symptoms- for the adolescent or the parents. Because what may be stressful to one adolescent may be inconsequential to another, it is important not to make assumptions. There are two major fears that adolescents who have somatoform symptoms often have: an unrecognized physical illness or unrelenting symptoms. The somatizing 16-year-old in the case scenarios had both. These can lead to adolescents seeing themselves as vulnerable, and they may be “overprotected” by parents. As Epstein and colleagues [28] noted, in determining any previous assessment or treatment, the emphasis needs to be on the “experience of the illness.” One also must be aware that circumstances change over time. The 15-year-old girl who had somatoform pain disorder had initiated unprotected intercourse and had developed pelvic inflammatory disease.

Nonverbal communication

Communicating with adolescents who have somatic symptoms need not occur only through spoken or body language. Specifically, asking the patient to keep a detailed daily journal that includes all activities and symptoms can provide written documentation of patterns that are impossible to capture in conversation. This also emphasizes to the adolescent that the symptoms are being taken seriou\sly. Alternatively, patients may find it easier to communicate about their illness through poems or drawings. All of these nonverbal formats serve the dual purpose of aiding in the diagnostic process by adding dimensions that usually are not included in traditional medicine, and being therapeutic, because they give the patients an opportunity to express themselves by a means other than through somatic symptoms.

Applied principles of the biopsychosocial approach in adolescent somatoform disorders

There is not a large evidence base regarding the treatment of somatoform disorders in adolescence. In the literature, the sequence of events often is described as assessment, followed by diagnosis, followed by treatment. In practice, these are not discrete processes, but are highly iterative. Rather than address the specific diagnoses separately as occurs in the DSM-IV, the approach that is used by family physicians [29,30] is more applicable in the primary care of adolescents. Campo and colleagues [9,14,15,31] have translated what is known about adult somatoform disorders into pediatrics; their contributions form the basis of many of the principles regarding the management of somatizing adolescents that follow.

Fig. 2. Somatoform disorders: functional gastrointestinal disorders as a model. (Modified from Drossman DA, editor. Rome II: The functional gastrointestinal disorders. McLean (VA): Degnon Associates; 2000. p. 4; with permission.)

The functional gastrointestinal disorders as a model

The gastrointestinal (GI) system is among the most vulnerable to dysfunction, based on psychosocial influences (Fig. 2). Thus, the criteria for the diagnosis of somatization disorder includes two GI symptoms other than pain. Recognizing the profound interaction between the gut and the brain, the biopsychosocial conceptualization was defined clearly and broadly by an international group of GI specialists that developed a compendium, now it its second edition, entitled Rome II: The functional gastrointestinal disorders: diagnosis, pathophysiology and treatment: a multinational consensus [32]. This 764-page monograph focuses on helping the clinician and investigator to: (1) make a positive diagnosis of disorders that result in pain, nausea, vomiting, diarrhea, constipation, or any combination of these-after metabolic, infectious, neoplastic, and other structural abnormalities have been excluded; (2) understand the pathophysiology of these conditions; and (3) make effective treatment decisions. Rome II is a model for all other organ-based specialties to address functional symptoms that are central to somatoform disorders.

The gut is one of the most vulnerable organ systems in the body with respect to psychosocial problems causing symptoms. Although several different systems interact with each other, the brain-gut interactions have been studied the most widely. The central and enteric nervous systems seem to function in interdependent processes that are only beginning to be understood. The resultant GI pathophysiology is not detectable with traditional tests (blood, urine, or stool), or imaging techniques, and the perception of sensations is totally subjective. Therefore, the diagnosis of a functional GI disorder relies heavily on history and physical examination, rather than on excluding a medical or surgical illness. The resulting behaviors and the way in which these conditions are managed by clinicians can have an influence-either positive or negative-on an adolescent’s outcomes and quality of life. The similarities between this model, applied to functional GI symptoms, and our present understanding of dysmenorrhea, applied to functional gynecologic symptoms, are striking.

Targeted history to demonstrate attention to detail and identify medical/surgical conditions

Agreeing on the diagnostic process

A first step in the process of exchanging information (mistakenly labeled as “taking” a history) in somatoform disorders is to have all parties (clinician, adolescent, and parent) agree that physical symptoms have physical causes, but that these are due to pathologic or functional processes. Pathologic processes (eg, inflammation, infection, cancer) cause cellular disruption, tissue damage, or anatomic distortions that can be detected by a variety of tests, imaging procedures, or direct visualization with endoscopy. Other pathologic conditions (eg, epilepsy, cardiac conduction defects, lactose intolerance) are detected through procedures, such as EEG, ECG, or breath hydrogen measurement. Pathologic processes require medication, surgery or both, but also may benefit from supportive treatments that are prescribed with functional disorders. Thus, a daily routine, including a healthy diet and good sleep hygiene, physical activity, social supports, and skills to deal with stress, can be helpful. Functional processes can result in symptoms that are just as debilitating as pathologic ones, but are related to disruption of normal physiologic function to a degree that might not be detected by “testing.” Thus, the history and physical examination become essential elements in diagnosis. The example of a muscle spasm in the calf (“charley horse”) can help patients and parents understand what is meant by a functional disorder. This example is useful in the case of parietotemporal headaches or colicky abdominal pain, in which muscle contraction is the cause of the pain, although the resulting degree of distress and social dysfunction may be extreme. Mothers are especially likely to relate to this, because calf muscle spasms are common during pregnancy. The clinician can point out that muscles function by contracting and relaxing. If a muscle contracts and stays that way (spasm), the result is painful and tender to the touch, but any blood test, imaging, or even a biopsy of the muscle would be “normal.” Generally, functional disorders are diagnosed by history and physical examination; testing is performed to exclude conditions that might represent a threat to health or that may require different treatments.

Detailed history focused on the presenting symptoms

When somatoform disorders are being considered, some practitioners focus on psychosocial issues: wanting to avoid “reinforcing that something is wrong,” but to “go where the money is.” Experience suggests that it is better to focus meticulously on “chief complaints.” This does not reinforce illness, but gives a message that the symptoms are being taken seriously and prepares the patient for talking about symptoms, rather than testing for symptoms. The timing, location, radiation, quality, severity, prcipitants, and relievers of pain, as well as any associated symptoms, should be explored. With respect to functional disorders (eg, those that suggest a neurologic disorder, even if the symptoms are not in keeping with recognized neuroanatomy or physiology), the story of the symptoms should be examined in detail.

Although the history should focus on the details of symptoms, medical and psychosocial issues should be examined together; the assessment lays the groundwork for treatment. Thus, when an adolescent reports that her body “hurts all over,” inquiry about “What does that hurt stop you from doing?” puts the symptoms in the context of psychosocial issues. Even if a patient has a serious medical or surgical condition, it is important to know something about how an adolescent patient might cope with such a condition. Hippocrates is credited with the adage “I would rather know what kind of person has a disease, than what kind of disease a person has.” This is less likely with a “vertical” assessment process, in which medical conditions are addressed first, followed by an exploration of psychosocial factors only after there is a lack of medical evidence to account for symptoms. With a “horizontal” assessment, medical symptoms and psychosocial factors are addressed side by side; the latter are considered as a context in which to understand medical diagnoses or as a possible primary cause for symptoms. This approach also will reveal strengths and vulnerabilities that the adolescent and family have, and increase the likelihood of making a positive somatoform diagnosis, rather than one by exclusion.

History between visits essential to establish patterns

A daily journal of symptoms that is kept by the adolescent can help to establish patterns of what makes symptoms worse or better. An emphasis on the latter is useful in the treatment phase, because somatizing patients often report that “nothing makes it better.” If a parent completes a symptom journal for an adolescent, this is evidence that the suffering is extending to family members. If one asks an adolescent to keep such as journal, it is important to review the log during each visit. Otherwise, the patient may assume that there is not a real interest in the symptoms. Significant progress is being made when the adolescent is able to say, “I do not want to talk about what is in the journal anymore, I want to talk about the trouble that I am having with my parents.”

Physical examination focused on symptoms

Regardless of how unlikely it may seem that any abnormalities will be detected based on the history, a physical examination to determine the cause of functional symptoms should occur on the initial visit, as well as on subsequent visits. Patients who have neurologic symptoms should have a neurologic exam, using as many techniques that involve the “laying on of hands” as possible, including indirect ophthalmoscopy, deep tendon reflex testing, cranial nerve evaluation, and evaluation of cerebellar function. On follow-up visits, this can be done quickly; the interval history can be obtained and feedback regarding findings can be given during the examination. Physical examination for adolescents who have suspected somatoform disorders (1) reinforces the diagnosis of a somatoform condition for the physician; (2) identifi\es any changes that might occur over time, acknowledging that a positive diagnosis of a somatoform disorder is never 100% certain; and (3) demonstrates to the adolescent and parents that the illness will be monitored closely, even though this may not include diagnostic testing.

Laboratory and imaging studies

Laboratory and imaging studies should be selected based on the history and physical examination. Somatizing adolescents or their parents may ask for specific tests to be performed (eg, MRI for a headache, upper GI for abdominal pain). Such requests need to be interpreted with care; they may be generated by (mis)information that was obtained from television, the Internet, friends, or family members. Rather than outright rejection of a test as “inappropriate,” one can respond, “We could get that test, but it only would tell us about anatomy. Based on the history, I suspect that the cause of your pain is due to muscle spasms that will not show up on any test. ” If the symptoms and physical examination cause diagnostic uncertainty, the least invasive test that provides necessary information should be obtained. For example, an ultrasound of the abdomen can provide a great deal of detail. When such a test is reported as “normal,” it can be helpful to review the details of the study-in visual (the actual study) and written forms (report)- with the adolescent and parents. Similar to the detailed history and physical examination, this transmits the fact that the diagnostic process is being conducted carefully to identify any pathologic conditions.

Before any diagnostic procedures are performed, it is worthwhile to prepare the adolescent and parents for the expected results, including a positive framing on “negative” studies. One could say, “Based on your history and physical examination, I feel confident that your headaches are due to muscle spasm. The muscles that are most tender are those on the side of your head that attach to your jaw. As I showed you in the anatomy book, they are called the temporalis and masseter muscles. But, you and your parents are still worried that you might have a brain tumor. We can get a CT scan to provide reassurance that there is no tumor. You already know some of things that cause your headaches to get worse, but there may be others that we have not figured out yet. Even before the CT scan comes back normal, we can work on some things that should help reduce your pain and suffering. For one thing, you are not sleeping very well and we know that sleeping problems can cause these muscles to tighten. You also seem to have a lot of worries, which also can cause involuntary contraction of the scalp muscles that attach to the jaw.”

Applied physiology in diagnosis and the development of intervention strategies

As Barsky and Borus [33] pointed out, without an explanatory model for the symptoms, negative findings provide little reassurance to the patient and family. But, as pointed out by Campo and Fritz [9], after a somatoform disorder is the operating diagnosis, the clinician should present the diagnostic impression clearly, frankly, and directly; however, this should be done in a manner that builds a foundation for intervention. Three physiologic explanations can be used to provide an understanding of the likely cause of symptoms, alone or in combination.

Conditioned responses

Conditioned responses are well-recognized patterns that are based on normal physiology, in which a repeated stimulus causes a repeated response. The result is that the response can occur in the absence of the original conditioning stimulus, especially if it is linked with another stimulus. With operant conditioning, symptoms are self- perpetuating. Thus, symptoms that may have been initiated by a virus or other agent, “take on a life of their own.” Most adolescents and parents are familiar with the concepts of conditioned response in the context of training desired animal behaviors. Using this paradigm, symptoms are viewed as undesired conditioned responses, and operant deconditioning can be included as an element of treatment. To avoid the impression that this is something that is being done to the adolescent, one should include the adolescent in the development of the deconditioning strategies that are used for symptom reduction.

Multiple triggers and precipitants

Because mind-body disconnections often lead to polarized viewpoints about symptom causation, patients often interpret any psychologic interpretation as “you think it is all in my head.” To avoid this dichotomization, it may be helpful to discuss with the adolescent how the body has a limited number of ways to respond to various triggers (ie, the muscles of the GI tract can contract or relax; bowel wall spasm or distention each can cause pain); however, many things can trigger a “final common pathway.” Bowel wall spasm causes the same pain, whether it is related to irritable bowel syndrome or to lymphoma. Factors that are mediated through the central nervous system-and therefore, are made worse by anxiety or depression-should be included in the list of triggers that are discussed. This is more realistic and accurate than there being a single “cause” for symptoms, and prepares the adolescent for working on psychologic issues, in addition to incorporating other therapies (eg, diet [including fiber], physical activity, bowel habits, antispasmodic medications, relaxation techniques). One can avoid the dichotomization by asking, “If working on psychological issues can help your symptoms improve by 10%, wouldn’t that be worth it? Now, I believe that your symptoms can improve a lot more than that, but there is no single thing that will provide full relief. It’s a package deal.”

Reflexes

Because adolescents who have somatoform disorders often are sensitive to implications that their symptoms are voluntary, purposeful, or intentional (possibly because of the DSM-IV diagnostic algorithm), it often helps to emphasize that several automatic, involuntary, subcortical “reflexes” are at work and cause symptoms. Function in the autonomie nervous system is based on the balance of sympathetic and parasympathetic tone. Insufficient or excessive activity or imbalance between the two arms can result in symptoms that are related to this dysfunction. The vagus nerve, which carries autonomie efferents from the brain to the heart, lungs, stomach, and intestines, has numerous outputs that can result in symptoms. Most adolescents are familiar with feeling “butterflies” in their stomach when nervous, and all parents are familiar with the gastrocolic reflex of infants.

The explanation for the symptoms that was provided to the 12- year-old who had conversion reaction in the case scenarios was, “The EEG was normal during the movements that looked like a seizure. Therefore, we know that the muscles were not twitching because of any messages coming directly from the brain, but they were twitching when they were not supposed to and you definitely did not want them to. Somewhere along the pathway between the nerves and the muscles, the messages to fire got mixed up. The same thing happens with the muscles that make your vocal cords move. When they are supposed to relax, they remain contracted part-way. That is why you had noisy breathing that sounded like asthma. The pulmonary function test shows the pattern of what happens if someone tries to breathe in when the vocal cords are not relaxed completely. Fortunately, the muscle twitching and the vocal cord dysfunction are not caused by anything permanent, and should get better over time. But, we do not have to just wait until your symptoms get better; there are some things that we can help you with to get those muscles contracting and relaxing the way you want them to, when you want them to. Some of my patients who have symptoms like these worry about them happening around friends or in school. So, we also need to work on helping you deal with worries.”

Prescribe face-saving interventions

The biopsychosocial approach that has been mapped out so far is highly interactive, and is a therapeutic partnership between the clinician and the adolescent. Underlying mood disturbance, anxiety, stress, or unresolved conflict need to be addressed. Because the presentation is somatic, the treatment must include some kind of somatic intervention, usually in combination with a variety of cognitive-behavioral interventions, such as described by McCann and LeRoux elsewhere in this issue. Family therapy also can be helpful [34], especially if the symptoms are disruptive to family functioning. Mental health treatment may be accepted more readily if it is described as a part of the treatment plan that is included in all such cases, and that the purpose of mental health intervention is to prevent secondary problems that might perpetuate symptoms. Framing the therapist as a professional who will help the clinician manage the overall care also can be helpful. It should be made clear that the primary care or specialty provider will continue to monitor the adolescent’s symptoms in partnership with the mental health therapist. Depending on the nature of the symptoms, the somatic interventions that are prescribed may be attention to daily structure of eating and sleep; physical, occupational, or speech therapy; or various complementary and alternative medicine (CAM) therapies (eg, biofeedback, yoga, massage, acupuncture). It can be useful to include the family in this phase of symptom management, because the family (especially grandparents) may have beneficial folk remedies that could be suggested. If physical, occupational, or speech therapy is prescribed, or if any CAM therapies are pursued, it is useful for the clinician to describe the situation about the adolescent to the therapists to avoid team splitting. Return to school is important because not attending school may cause the adolescent to fall behind academically. It may \be useful to have the patient return to school only after a prescribed period of tutoring to ensure that the patient is caught up with class work. Tutoring should not be open-ended, but should be based on the tutor’s assessment of the time that is needed. Some schools allow in- school tutoring, which provides a graduated re-entry into school; the adolescent is in the school building, but does not have the pressure of being in the classroom. The socialization that can occur in such circumstances can encourage the full return to school. Returning to school half-days initially also can smooth the re- entry process for adolescents who have missed a great deal of school because of somatic symptoms. The plan for school return should be previewed with the school nurse and guidance counselor to ensure that it is feasible and that someone will be able to monitor progress. Because of the dynamics of overprotectiveness that can arise in these situations, a parent may impede return to school. When such collusion is suspected, it may help to contact the other parent directly to engage his or her help in carrying out the plan.

Summary

Somatoform disorders are presented in the first article in this issue of Adolescent Medicine Clinics because the physical symptoms that cause the adolescent to present for diagnosis and treatment reflect the interaction of the psyche and the soma in ways that are poorly understood. Because of dualistic conceptualizations that are encouraged by technology such as MRI, CT scans and other technologically advanced tools, patients who have these conditions often suffer. As noted by Cassell [35], “suffering is experienced by persons, not merely by bodies, and has its source in challenges that threaten the intactness of the person as a complex social and psychological entity.” Clinicians who care for adolescents who have somatic complaints also suffer when they are unable to provide relief of an adolescent’s suffering. Cassell [36] noted that “physicians are less skilled at what were once thought to be the basic skills of doctors-discovering the history of an illness though questioning and physical examination, and working toward healing the whole person.” The biopsychosocial approach offers a means of working toward healing the whole person, and the focus of this article is on practical solutions to difficult challenges that are presented by adolescents and their families.

References

[1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition. Washington, DC: American Psychiatric Association; 2000.

[2] Spratt EG, DeMaso D. Somatoform disorder: somatization. Available at: http://www.emedicine. com/ped/topic3015.htm. Accessed October 15, 2005.

[3] Mayou R, Kirmayer LJ, Simon G, et al. Somatoform disorders: time for a new approach in DSM-V. Am J Psychiatry 2005; 162:847-55.

[4] Wolraich ML, Felice ME, Drotar D. The classification of child and adolescent mental diagnosis in primary care. In: Diagnostic and statistical manual for primary care (DSM-PC) child and adolescent versions. Elk Grove Village (IL): American Academy of Pediatrics; 1996.

[5] Morrison J. DSM-IV made easy: the clinician’s guide to diagnosis. New York: Guilford Press; 1995.

[6] Gold MA, Friedman SB. Conversion reactions in adolescents. Pediatr Ann 1995;24:296-306.

[7] Silber TJ, Pao M. Somatization disorders in children and adolescents. Pediatr Rev 2003;24(8): 255-64.

[8] Fabrega H. The concept of somatization as a cultural and historical product of Western medicine. Psychosom Med 1990;52:653- 72.

[9] Campo J, Fritz S. Somatization in children and adolescents. J Am Acad Child Adolesc Psychiatry 1994;33:1223-35.

[10] Garralda ME. A selective review of child psychiatric syndromes with a somatic presentation. Br J Psychiatry 1992;161:759- 73.

[11] Alfven G. Preliminary findings on increased muscle tension and tenderness, and recurrent abdominal pain in children. A clinical study. Acta Paediatr 1993;82:400-3.

[12] Garber J, Walker LS, Zeman J. Somatization symptoms in a community sample of children and adolescents: further validation of the children’s somatization inventory. Psychol Assess 1991;3:588- 95.

[13] Oster J. Recurrent abdominal pain, headache, and limb pains in children and adolescents. Pediatrics 1972;50:429-36.

[14] Campo JV, McWilliams L, Comer D, et al. Somatization in pediatric primary care: association with psychopathology, functional impairment, and use of services. J Am Acad Child Adolesc Psychiatry 1999;38:1093-101.

[15] Campo JV, DiLorenzo C, Chiappetta L, et al. Adult outcomes of pediatric recurrent abdominal pain: do they “just grow out of it?” Pediatrics 2001;108:el-7.

[16] Hotopf M, Carr S, Mayou R, et al. Why do children have chronic abdominal pain, and what happens to them when they grow up? Population-based cohort study. BMJ 1998;316:1196-200.

[17] Walker LS, Quite JW, Duke M, et al. Recurrent abdominal pain: a potential precursor of irritable bowel syndrome in adolescents and young adults. J Pediatr 1998;132:1010-5.

[18] Engel GL. The need for a new medical model: a challenge for biomedicine. Science 1977; 196: 129-36.

[19] Frankel RM, Quill RE, McDaniel SH. The future of the biopsychosocial approach. In: Frankel RM, Quill TE, McDaniel SH, editors. The biopsychosocial approach: past, present, future. Rochester (NY): The University of Rochester Press; 2003. p. 4-5, 259.

[20] Engel GL. The application of the biopsypsychosocial model. In: Frankel RM, Quill TE, McDaniel SH, editors. The biopsychosocial approach: past, present, future. Rochester (NY): The University of Rochester Press; 2003. p. 6.

[21] Frankel RM, Quill RE, McDaniel SH. Introduction to the biopsychosocial approach. In: Frankel RM, Quill TE, McDaniel SH, editors. The biopsychosocial approach: past, present, future. Rochester (NY):

By Natalie Neysa Alund, The Dominion Post, Morgantown, W.Va.

Mar. 15–A preliminary hearing for murder suspect Michelle L. Michael is set for 3 p.m. March 20 in Monongalia County Magistrate Court in front of Magistrate Jennifer Wilson, said a court assistant. Michael’s bond on the first-degree murder charge was set at $350,000 in Mon County Circuit Court on Tuesday, said Peri DeChristopher, assistant prosecuting attorney. Michael was in custody at the North Central Regional Jail on Tuesday evening. “If she is able to post, she can be on home confinement,” DeChristopher said. Michael, 34, was charged with firstdegree murder and first-degree arson in the death of her husband, James Andrew Michael, in Magistrate Court on Friday. Bond was set at $100,000 in Magistrate Court for that charge. Access to deadly drug Although the drug that killed James Andrew Michaels is kept locked up, hospital medical professionals have access to it, said WVU Hospitals Spokesman Bill Case. Police said James Michael, 33, was killed with a “nondepolarizing neuromuscular blocking drug” — a drug that causes temporary paralysis, according to the National Institutes of Health. “It is used when people who are taking care of a patient need to insert a breathing tube,” Case said Tuesday. “Because that has to happen in a hurry often, the drug is kept in all of the intensive care units and in all of the operating rooms.” The drug is stored in a locked cabinet or a locked medical storage room, Case said. Physicians and other providers who administer the drug can get it at any time. That includes nurse practitioners. Michelle Michael, also known as Shelly, is a University Health Associates nurse practitioner assigned to work in the Pediatric Intensive Care Unit at Ruby Memorial Hospital, Case said. Police said Michael was found dead Nov. 29, 2005, after an arson fire at his home at 545 Killarney Drive. Based on the autopsy performed by the state medical examiner’s office, they say he died from a lethal dose of the drug, not from carbon monoxide poisoning from the fire. Case said Tuesday that Michelle Michael is still employed, but is on leave. He has said he cannot comment on whether any of the drug that killed James Michael was missing around the time of his death. “I can’t answer that because it would get into the specifics of the investigation of the case,” he said. The criminal complaint notes that the drug was present in Michael’s blood and caused his death. Morgantown Police Chief Phil Scott said Tuesday that police are not releasing copies of the autopsy, toxicology report, or police report. “It (the case) has not been adjudicated, and they are part of the investigation still,” Scott said. Morgantown Police Sgt. H.W. Sperringer said MPD is not releasing if James Michael was dead before the fire broke out or how much of the drug was in his blood. He also would not say if police have any other suspects, because the investigation is ongoing and the case is awaiting the preliminary hearing. Sperringer did say that police are waiting lab results from the U.S. Bureau of Alcohol, Tobacco, Firearms and Explosives to learn if an accelerant was used to start the fire, which damaged two upstairs bedrooms of the home. Before Friday, Morgantown Police would not comment on how Michelle Michael came to be a suspect in her husband’s death. But according to the criminal complaint, Michael had access to the drugs, which are not available to the public. It says Michelle Michael went to work during the early morning hours of the fire, left work and returned to her residence before the fire was discovered, then returned to work.

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Copyright (c) 2006, The Dominion Post, Morgantown, W.Va.

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Summary

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The US healthcare industry includes about 3,000 managed healthcare companies with combined annual revenue of about $350 billion. Large participants include Aetna, UnitedHealth, and Humana, and non-profit organizations such as Kaiser Permanente and state Blue Cross/Blue Shield organizations. The industry has become concentrated, with the 50 largest organizations holding more than 60 percent of the market.

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Demand is driven by the rising costs of providing medical care. The profitability of individual companies depends on efficient operations and the ability to negotiate favorable contracts with healthcare providers. Large companies and organizations have advantages in negotiating contracts with healthcare providers. Small companies can compete successfully only by providing special coverage plans, or in small markets. The industry is highly automated, with annual revenue per employee close to $1 million.

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By Jon Frank, The Virginian-Pilot, Norfolk, Va.

Mar. 14–VIRGINIA BEACH — The master bedroom where Elise Makdessi and Quincy Brown were killed 10 years ago was a blood-stained mess when police arrived on the evening of May 14, 1996.

Two bodies with multiple wounds had produced bloo d patterns everywhere.

Blood speckled the walls, stained the bed and floor, and covered clothing worn by the victims and the chief suspect in the slayings: Elise’s husband, Eddie Makdessi.

On Monday, that bloody scene became a crash course in forensics for jurors who will decide whether Makdessi is guilty of two counts of first-degree murder.

One of the nation’s top crime scene experts — Ross Gardner of Atlanta — testified Monday that based on the blood evidence, the slayings could not have happened in the manner described by Makdessi in his statements to police.

Gardner presented a PowerPoint analysis of the blood-stain evidence at the crime scene.

Using computer software, Gardner’s three-dimensional analysis re-created two of the crime’s participants — Brown and Eddie Makdessi — showing where they likely were located when Brown was shot three times in the upper body .

Gardner also described how he thinks Elise Makdessi, an air traffic controller at Oceana Naval Air Station, was stabbed with a knife as she lay spread-eagle on the bed, her arms and legs tied to the four-poster bed.

Based on the blood spatters in the room, Gardner testified, the slayings could not have happened in the manner described by Makdessi in his statements to police.

Gardner acknowledged that after nine years of analysis, there are still things about the bedroom he cannot explain. “There is a complexity there,” he said. “I am looking, but I can’t find what I need to know.”

Gardner’s three hours of testimony concluded the prosecution’s case against Makdessi. The defense will begin its case today.

Gardner wrote several books on crime scene analysis and lectures worldwide on the subject. He was the commonwealth’s 47th witness in the trial, which began one week ago.

Prosecutors claim that Makdessi killed Brown and his wife partly out of jealous rage and partly to collect $700,000 in life insurance benefits.

Makdessi claims that he was assaulted and knocked unconscious by Brown after returning with his wife from a restaurant. He claims that when he came to, he saw Brown raping and stabbing his wife. He claims he shot Brown, then tried to save his wife. He claims he shot Brown a second and third time as Brown lunged at him, then Makdessi called 911.

Brown died at the scene. Elise Makdessi was pronounced dead at the hospital.

When police initially failed to charge Makdessi, an insurance company paid him $500,000 for temporary coverage arranged by the couple in the weeks before Elise Makdessi’s death.

Kevin Heaney of the New York Life Insurance Co. testified Monday that Makdessi called him frequently before receiving the check, wanting to know, “Where do I stand? Am I going to get paid?”

Makdessi also received $200,000 from the Navy.

After getting the money, Makdessi left the country for six years. He was arrested when he returned to the United States in 2003, and he has been in jail awaiting trial ever since.

Last week, a crime scene analyst with the Virginia Beach Police Department testified that he made a mistake when he first looked at the crime scene almost a decade ago.

“I was wrong,” said Harry Holmes. His initial evaluation of the blood-spatter evidence seemed to confirm part of Makdessi’s version of how the incident occurred.

Gardner testified Monday that the bedroom was a “confusing, very complex crime scene” that continues to leave many questions unanswered.

For instance, he said, he cannot tell which victim was killed first, nor can he explain why Eddie Makdessi’s DNA does not appear on the knife used to kill Elise Makdessi, while Brown’s DNA does.

Gardner said he can definitely say Brown was not shot in the manner described by Makdessi.

Gardner said blood-spatter evidence on the back wall and on Makdessi’s clothing proves that Brown was shot the first time while kneeling in the bedroom. He said Brown then was shot twice while falling back onto the floor. Additional blood spatter, and a bullet found imbedded in the carpet immediately below Brown’s body, proves this, Gardner testified.

The last shot was fired with Makdessi standing directly over Brown, Gardner said.

Also, Gardner said, there is no evidence that Brown ever held the knife that killed Elise Makdessi, but there are multiple stains on Eddie Makdessi’s clothing made by contact with the knife.

Gardner said the earlier crime scene analysis was wrong because it did not take into account how multiple gunshots create extra blood-

spatter patterns.

Reach Jon Frank at (757) 222-5122 or [email protected].

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Copyright (c) 2006, The Virginian-Pilot, Norfolk, Va.

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

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By Natalie Neysa Alund, The Dominion Post, Morgantown, W.Va.

Mar. 14–Police say Suncrest resident James Andrew Michael didn’t die from fire — he died from a lethal dose of drugs. His wife, Michelle L. Michael, 34, was charged with first-degree murder and first-degree arson in connection with his death Friday. James Michael, 33, was found dead the morning of Nov. 29, 2005, after a fire engulfed his home at 545 Killarney Drive. The fire was ruled an arson. M i c h a e l ‘ s autopsy, conducted by the state medical examiner’s office, determined that he did not die from carbon monoxide poisoning caused by the fire, according to the criminal complaint. The complaint says that a toxicology indicates that a lethal dose of a “nondepolarizing neuromuscular blocking drug” was present in Michael’s blood, which caused his death. Nondepolarizing neuromuscular blocking drugs are primarily used in hospitals and are not available to the public, the complaint says. The drugs, which cause temporary paralysis, are generally used before inserting tracheal tubes, according to the National Institutes of Health Web site. Michelle Michael, also known as Shelly, is a nurse practitioner in the Neonatal Intensive Care Unit at Ruby Memorial Hospital and has access to those drugs, the criminal complaint says. WVU Hospitals spokesman Bill Case said Monday evening he did not have sufficient information about which WVUH employees have access to the drugs because those who know were gone for the day. Before Friday, Morgantown Police would not comment on how Michelle Michael came to be a suspect in her husband’s death. But according to the criminal complaint, James Michael was with his wife on the night before he died and on the morning of his death. It also says Michelle Michael went to work during the early morning hours of the fire and then left her place of work and returned to her residence before the fire was discovered. She then returned to work. Michelle Michael was later interviewed by detectives in reference to her activities on the day her husband died. Her statements were inconsistent and some were proven to be false, the complaint says. Michelle Michael remained incarcerated Monday at North Central Regional Jail. Background On Nov. 29, James Michael was found dead in an upstairs bedroom at his two-story brick house in the Suncrest section of Morgantown. He was the only person home at the time of the fire. Officials were unable to identify James Michael’s body for several days after the blaze. A positive ID was made through dental records, police said. The fire was ruled an arson in February. While battling the blaze, firefighters were made aware that James Michael had not shown up for work that morning as he usually did. His car then was found in the garage. Investigators from the Morgantown Fire Department and the U.S. Bureau of Alcohol, Tobacco, Firearms and Explosives said the fire originated in a bedroom of the house, but would not say which one. James Michael was the president and CEO of Mountaineer Home Medical, a Maple Drive home-respiratory therapy company. He also was the head coach of the Evansdale Youth Football team. James Michael left behind two children from a previous marriage. Michelle Michael also has two from a previous marriage. Morgantown Police Sgt. H.W. Sperringer said the children were put in the care of family members after Michelle Michael’s arrest.

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Copyright (c) 2006, The Dominion Post, Morgantown, W.Va.

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

By RACHEL ELLIS

A LEADING scientist will claim this week that he has proof that patients who undergo major organ transplants can inherit the personalities of their donors.

Gary Schwartz, a professor of psychology at the University of Arizona, says he has details of 70 cases where this controversial phenomenon has occurred.

And he will argue that it affects at least ten per cent of people who have a heart, lung, kidney or liver transplant. The theory that personality and character traits can be transferred via an organ transplant has existed for some time, but most scientists have ridiculed the notion.

Professor Schwartz now claims to have evidence that in the most extreme cases patients adopt a donor’s taste in food, take up the same interests and pastimes as a donor, and even develop talents that a donor possessed. In one case, outlined opposite, a woman who had been health-conscious and calm began craving fast food and became aggressive, just like the biker whose heart and lungs she received.

In another, a seven-year-old girl had nightmares about being killed after being given the heart of a girl who had been murdered.

Professor Schwartz will present his findings at a holistic living conference in London next weekend, titled Icons of the Field. Critics put such events down to chance, the trauma of the surgery or the side-effects of the drugs that transplant patients have to take.

But last night Professor Schwartz, who is also a professor of medicine, neurology, psychiatry and surgery and has published more than 400 scientific papers, said that all transplant patients should be warned that there is a chance they will inherit the personality of a donor.

‘It is a big ethical question, but I believe transplant patients should be told there is a possibility that they will take on a donor’s characteristics,’ he said.

‘Then they can have a choice. They can decide what is important to them: being active and being with their family, but with the chance that they might take on some traits of the donor that they might not like. Our research shows that about ten per cent of patients will inherit some of a donor’s characteristics. However, it may be higher because most patients are afraid to share their experiences.

‘I don’t want to frighten people, but to make it more acceptable for them to share what is happening to them.

If this is a real phenomenon, we shouldn’t ignore it and it requires further scientific study.’ Professor Schwartz’s claims are based on the theory that all major organs develop a certain amount of memory. When they are transplanted, this memory can be transferred-from one person to another.

He explained: ‘When the organ is placed in the recipient, the information and energy stored in the organ is passed on to the recipient.

‘The theory applies to any organ that has cells that are interconnected.

They could be kidneys, liver and even muscles. The stories we have uncovered are very compelling and are completely consistent with this systematic memory hypothesis.’ Since starting his research in the Eighties, Professor Schwartz has attracted widespread criticism from the medical establishment.

In one startling experiment, he claimed to prove that consciousness lives on after we die. He studied a man called Montague Keen, who vowed to communicate with his wife from beyond the grave. After Mr Keen’s death from a heart attack in January 2004, some scientists, including Professor Schwartz, claimed there was strong evidence that Mr Keen had succeeded in proving there was an afterlife.

In the year to March 31, 2005, almost 3,000 major organ transplants were carried out in the UK, including 1,783 kidney swaps, 656 liver transplants and 290 heart replacements. Most of the organs were taken from 752 people who died, but more than 1,000 kidneys were donated by living people, often relatives or friends of the recipients.

In the UK, more than 13 million people 22 per cent of the population are on the NHS Organ Donor Register, and about 6,600 patients are awaiting transplants. Last year more than 400 died while on the waiting list.

NEW YORK (Reuters Health) – After folic acid fortification
of enriched grain products was fully implemented in 1998,
deaths due to strokes dropped rapidly in the US and Canada,
according to a report in the American Heart Association’s
journal Circulation.

The main reason for folic acid fortification was to reduce
the number of babies born with neural tube defects such as
spina bifida. The present findings suggest, however, that there
may have been an unintended benefit.

There is “accumulating, controversial evidence” that
homocysteine — an amino acid in the blood — is a risk factor
for stroke and heart disease, Dr. Quanhe Yang, from the Centers
for Disease Control and Prevention in Atlanta, said in a
statement. Folate decreases homocysteine levels, which may help
explain the drop in stroke deaths.

Yang’s team compared stroke mortality trends between 1990
and 2002 in the US and Canada with those in England and Wales,
where folate fortification is not required.

Stroke mortality was already falling in the US and Canada
from 1990 to 1997, but in 1998 a precipitous drop began, the
report indicates. In the US, the annual decrease in mortality
during the earlier period was 0.3 percent, whereas starting in
1998 the reduction was 2.9 percent. Similar results were seen
in Canada.

By contrast, stroke mortality rates did not decline
significantly in England and Wales between 1990 and 2002, the
report indicates.

“If folic acid fortification is responsible for even a
fraction of the accelerated improvement we observed, this
public health benefit is an important bonus to the reduction in
neural tube defect rates previously demonstrated,” Yang and
colleagues conclude.

SOURCE: Circulation, March 14, 2006.

By Mike Power

ISLA TIGRE, Panama (Reuters) – When Kuna Indian medicine man Mandiuliguina Flores speaks, everyone listens. For his dark-skinned indigenous audience, the albino shaman’s milky white skin gives him special powers.

In a quirk of history and genetics, Panama’s Kuna tribe has one of the world’s highest occurrences of albinos, revered as an elite group that the Kuna call “the children of the moon.”

Kuna mythology puts albinos — who have pale skin and white or ginger hair due to pigment deficiency — at the heart of creation, teaching that God sent his albino son to Earth to teach humans how to live.

Even today, the Kuna see albinos as highly intelligent and some even claim they have supernatural powers.

“I can heal any snake bite,” said healer Flores outside his thatched hut on tiny Isla Tigre island, his pale-yellow eyes flitting around in their sockets, a side-effect of his albinism, and his ginger hair peeping out from his pork-pie hat.

“I attend to women in childbirth. I can remove stuck fish bones from your throat with this pill, and I can cure headaches by touching your head,” he said.

“He can tell your future, too,” whispered one bystander.

The Kuna, known for their colorful and intricate woven fabrics and indigenous dress, live on a string of remote islands running 200 miles along Panama’s Caribbean coast toward Colombia.

They moved here from the rain forests of eastern Panama in the mid-1800s to avoid mosquitoes, snakes, diseases and territorial rivalry. They farm on the mainland and sleep on the islands, an autonomous territory known as Kuna Yala.

Charles Woolf, an anthropologist at Arizona State University, says the incidence of albinism here is higher than any comparable population on the planet.

A BLESSING, NOT A CURSE

In the United States, among white people of European descent, albinism overall occurs at a rate of 1 in 30,000-40,000. On some islands in Kuna Yala, the rate stands at 1 in 165.

Anthropologists attribute the high frequency to cultural protection of albinos and the slaughter wrought by Spanish conquistadors in the 16th century.

The Spaniards devastated the Kuna with attacks or diseases, reducing the islands’ founding gene pool to only 5,000 people from a population that once hit 750,000.

While Kuna warriors fought off the Spanish and carried out revenge attacks, albinos would stay indoors to avoid sunlight.

They survived where their compatriots were slaughtered by Spanish muskets.

Albino skin is sensitive to sunlight and burns easily, and the genetic disorder could easily be seen as a curse in the blisteringly hot tropics.

But to be born albino in Kuna Yala is to be born into a revered group whose importance is enshrined in Kuna cosmology.

In a self-fulfilling prophecy, many albinos in this culture become community leaders, medicine men, shamans, politicians or entrepreneurs.

“With advancing civilization and the availability of economic opportunities for albinos out of the sunshine that were not available previously, they have done well in some cases, with some becoming high achievers,” said Woolf.

The head of the Kuna General Congress of Culture, IkwaYokkiler Ferrer is albino. He commands widespread respect in Kuna communities for his work preserving their culture and traditions.

BRINGERS OF LIGHT

Weegi Baller, a 12-year-old albino on Rio Sidra, is one of seven albinos on this tiny, cramped island of more than 1,000 people. His sister Elederis, 13, and is also albino.

Weegi helps his mother with chores around the house as his skin is too fair to venture outdoors. But once, during an eclipse, he showed his powers, says his mother.

Her young son climbed onto the roof of the hut with a bow and arrow and fired it at the moon which was covering the sun. “The sun suddenly came out,” she said, beaming proudly.

Saila Aurelio Meza Smith, the chief of Isla Tigre, where the Kuna violently overthrew Panamanian forces in a 1925 rebellion, says albinos’ powers can be supernatural.

“I saw an albino grab an angry snake by the neck. It did him no harm. I saw the same albino smash a wasp’s nest open, but he was not stung. The same albino once dived from a high tree into a shallow river. He swam out, laughing. That is the power of an albino,” he said.

This respect wasn’t always apparent, however. Anthropologists say in the past some parents even killed newborn albino babies.

“Marriage discrimination against albinos and infanticide of albinos were common during the early part of the 20th century,” said Woolf.

Nowadays, though, it seems revered albinos have only themselves to fear.

Medicine man Flores says the powers of a few moon children are waning. “Some of them go to dances and are involved in drugs and chase women, so they have lost some of their powers,” he said.

By Matt James, The Fresno Bee, Calif.

Mar. 12–Other Stories * The other victims Which local sports are you most interested in right now? Is it the Bulldogs and WAC women’s basketball, Bulldogs baseball or softball, prep basketball regionals, Fresno Falcons and ECHL playoffs, or something else? Kathleen Freeman said: Were are the local baseball reports online for March 9, 10, and 11? [Join the talk!] MERCED — From the chaos, the broken bones, the frantic teenagers and the burning cars, a police officer saved Gerald Hayden. The officer left town long ago, but he still remembers the 15-year-old boy saying his back was broken, and he remembers the screams when he picked him up. For the next month, Gerald thought about sports a lot while he was in the hospital, as his body shriveled from 137 pounds to 112, as doctors tried to save his organs and get him healthy enough for back surgery. He wondered whether he would ever play water polo or tennis again, or whether he would ever run. No one knew. Gerald Hayden is 25 now. He has been paralyzed from the waist down for more than a decade, since the crash that left two boys paralyzed and a homecoming queen dead. He is in Italy, where today he will ski the downhill at the 2006 Turin Winter Paralympics. In the coming week, he will compete in four alpine skiing events — downhill, super-G, slalom and giant slalom — in Sestriere, the same location where Bode Miller skied the same events last month in the able-skier Games, though as Gerald says, “You probably won’t see us on NBC.” And like Miller, Gerald probably won’t win a medal. He hasn’t even been competing for two years. Some of the Paralympic skiers have been doing it for two decades. They fly from continent to continent on a World Cup circuit. They have sponsors and Web sites. They are randomly drug-tested. Gerald has raced just one international event, the World Cup Finals two weeks ago in Artesina, Italy, where in his first race, the slalom, he bounced out of a rut, wiped out and went sliding down the course on his side. Laughing, he says, “Not a great way to start my World Cup career.” ———— The last day Gerald Hayden walked started out so well. Like most Paralympians, he has a story. It is a sad one, like most of their how-did-you-get-here stories, which is why they don’t like to tell them. No point complaining about turbulence to the guy sitting next to you on a plane. The day was Sept. 22, 1995, a football Friday for Golden Valley High, the new school on the south side of Merced. The city had outgrown Merced High and so the previous year, three classes — freshmen, sophomores and juniors — became the first to attend Golden Valley. Without seniors, they didn’t have many athletic victories that first year. The second year, though, the Cougars’ football team started 2-0. Mayor Richard Bernasconi announced a “Mayor’s Cup” that would be kept by the winner of the cross-town football game. Golden Valley beat Merced that Friday night, 53-14, and there was a dance afterward. Word spread of a bonfire party south of town. No one wanted the night to end. Two of Gerald’s friends were catching a ride with a junior, which sounded a lot cooler to Gerald than having his mom pick him up after a dance. In all, four sophomore boys, all 15, all too young for driver’s licenses, got into a Honda Passport with 16-year-old Matthew Hunwardsen. Brian Lee took the passenger seat. Kristopher Wyman sat in the back left. Jonathan Meuser jumped in next to him. Gerald sat on the right. They drove down Childs Avenue, over Highway 99, past the fields of junk cars, Barger Veterinary Clinic and RBJ Transport. They drove by the Merced Flea Market, turned left onto Highway 59 and drove out of the south end of Merced toward El Nido, a little cluster of houses that breaks up the alfalfa fields. Gerald just wanted to go home. It was late. He was sitting in the back, dozing off, his head resting against the window. He and Jonathan had played in a junior varsity water polo match that day. They were supposed to play another the next day. It was nearly midnight by then, and they still hadn’t found the bonfire everyone had been talking about. They turned around and drove back toward Merced. About that time, three girls were leaving for the bonfire, heading south down Highway 59 in Tina Church’s Toyota. Tina was driving. Joy Akers sat in the passenger’s seat. Shaunna Soares was in the back. They were seniors, all on the softball team, and Joy played volleyball. They had been best friends for years, grown up in each other’s houses, spent so much time together it was all but impossible for their parents not to think of the other two as daughters, too. ———— Jeff Catchings had arrested a woman that night. He was a Merced police officer, part of the gang violence suppression unit. He was just 27. Since the day he became a cop, he had dreamed of being a special agent, of throwing himself into drawn-out, complicated investigations, of going undercover, busting bad guys in a big city. The woman he arrested was the mother of a gang member, for whom she had thrown a party that night. There were warrants out for her, and Catchings wanted to make a point that parents should be responsible for their kids’ bad behavior, not encouraging it, and so he cuffed her, put her in the front seat and drove south down Highway 59 toward the county jail. The John Latorraca Correctional Center was a couple of miles west of 59, a right turn on Sandy Mush Road halfway to El Nido. In daylight, you could see the radio tower first, driving past fence-lined pastures with windmills and mud holes and water troughs where the cows liked to gather. In front of the jail was a chain-link fence with a green covering that made the place look like the most carefully guarded batting cage in the world. But Catchings and the woman hadn’t quite gotten to Sandy Mush when they saw the car wreck that Merced residents would read about, that would haunt the families of those eight teenagers for years.

———— Matthew Hunwardsen had tried to pass two vehicles at once. The second was a tomato truck. But the headlights of an oncoming car, Tina Church’s car, were too close, too big, and he swerved. Tina swerved, too. The two cars slammed into each other on the shoulder of the highway, where the green grass blades still poke through the gravel. “In 16 years,” Catchings said, “it was the worst head-on I’ve seen. It’s amazing any of them lived.” Smoke poured out from under the hood of the girls’ car as he ran to it. Students in other cars had gotten out and were yelling. They’re trapped inside. Catchings smashed a window, cut Joy Akers’ seat belt and pulled her out. Then he and two high school boys got Shaunna Soares out. There was nothing he could do for Tina Church. The SUV had spun against her door, and she was pinned in. There was never an explosion, but the fire moved fast, burned the tires and swallowed the front seat. Another officer and an off-duty firefighter arrived, and they helped pull the five boys from the SUV as the fire grew hotter. They placed the two girls and the five boys on the ground side by side, one after another, bleeding and burned and some unconscious. Two boys in the back wearing seat belts were the only ones conscious. The impact had folded their bodies forward at the waist. By then, nearly 20 Golden Valley students had stopped on their way to or from the bonfire. They watched the cars burn with their school’s first homecoming queen, Tina Church, still inside. “I want to say she died on impact,” Catchings says, “but there’s no way to know.” At the scene, officers had thought Matthew Hunwardsen was drunk because he was stammering around mumbling nonsense. But it turned out to be a head injury. When it was finally finished and the ambulances had driven away, Catchings walked back to his unmarked squad car. The doors were unlocked. The woman in handcuffs hadn’t moved. In the 10 1/2 years since that Friday night, Catchings did become a special agent, moved to Los Angeles, hated Los Angeles, and is now an agent with the Bureau of Narcotic Enforcement in Sacramento. He doesn’t go undercover because he looks too much like a cop. He still thinks about the boys sometimes, even though he doesn’t remember their names. Neither Gerald nor Kristopher Wyman would walk again. My back is broken, Gerald told him that night. “It’s something I hope he doesn’t regret,” the officer says. “If we didn’t take him, he was going to burn.” ———— They don’t hold Paralympic skiing events on the bunny slopes. At the World Cup Finals two weeks ago in Artesina, Italy, another skier shot off course, went over a ledge and fell into a ravine. The downhill was so fast, a Japanese racer fractured a vertebra and an Australian dislocated a hip before they canceled it, with Gerald at the top of the mountain waiting his turn. His ascent has been a quick one. He didn’t start training seriously until the fall of 2004, after moving to Winter Park, Colo., where he still lives, but was ranked in the top 50 in the world by the end of the season. A year later, he was in the top 35 in every event, and still needed three podium finishes at the Meridian Cup a month ago in Winter Park to make the Turin team. The coaches selected 20 male skiers. Gerald was No. 18. The next week, he took fourth in the slalom at the U.S. Nationals, qualified for the World Cup Finals and was on a plane out of Fresno, bound for San Francisco, Chicago and, finally, Munich, Germany. His grandmother had given Gerald’s parents $1,000 to travel to Turin, but they slipped it to him to pay for the World Cup trip. He doesn’t have any sponsors and doesn’t get funding from the U.S. national team because, well, he’s not on the U.S. national team yet. “I’ve exceeded my expectations,” he said last week. “I just want to ski as well as I can. If all I do is come in 20th, I’ll be satisfied with that. That’ll still mean I’m 20th in the world. “Two years ago, I’d have never guessed I’d be in Sestriere today.” ———— After the surgery, the doctor took a deep breath and released it slowly. Gerald’s father was not supposed to see this, but he did, and so before the doctor walked into the waiting room, led them to a conference room and told them the news, Stuart Hayden knew his son would not walk again. The 15-year-old boy had gone into the back surgery with hope and woke up to such despair. They could not repair the damage. He would be able to move certain leg muscles, but not enough to walk or stand without crutches. Gerald was so angry. At anyone. No one. Everyone. He wallowed in everything he would never be able to do. For years, his parents tried not to help him too much, tried not to pity him. He didn’t want their help anyway. He was in the hospital for so long he grew 3 inches before they let him go home. He needed a rotating bed to keep from getting bed sores. Hard to believe his greatest sports achievement was yet to come. ———— Skiing had been a part of Gerald’s life since he was 11, until he switched to snowboarding, like the rest of his friends. Before long, he strapped on his snowboard and climbed onto the trampoline in the backyard because he wanted to try a flip. His mom is the only one who flipped that day. After he was paralyzed, after the back brace finally came off, he tried monoskiing. It felt like he was attached to a toboggan. He fell, a lot. The monoski looked like a bucket bolted to an extra-wide ski, and when he fell, the ski wedged up in the air, meaning he and the seat did the stopping, scraping along the snow. It hurt, but mostly it was exciting. He tried it first in 1996, on a trip he and his parents took to the Tahoe Adaptive Ski School. He had to learn to roll his hips instead of his ankles, and finally his muscles learned, and the skill suddenly clicked, the way it did when he learned to ski, or snowboard. After five years at the University of California at Davis getting an economics degree, he went to a racing camp and decided to move to Colorado and give racing a try. ———— After the crash, the city ached. The teenagers’ families suffered. Even now, they are still recovering from what happened, when lives careened in new directions, when fates were decided by who had called shotgun and who had to ride in the middle. When a girl died. They’ve all asked “Why?” so many times the past decade it seems pointless now. Why does a boy in the middle of the back seat, not wearing a seat belt, sustain injuries he can recover from, and the two boys sitting next to him, wearing seat belts, never get to walk again? Why do so many good kids have to suffer? Why did Tina Church have to die? Gerald Hayden stopped asking for the most part. He was so mad for so long. “The hardest adjustment is becoming comfortable in your own skin,” he says. “The self-perception has to change. You’re not an abled person who has been hurt. You’re just a person who uses a wheelchair.” This week, Gerald Hayden will ski on a mountain in Italy. He will wear the same jackets, the same shoes, the same gloves and scarves as the Olympians. He will race on the same mountain, eat the same free food in the village. He attended the Opening Ceremony in Turin on Friday and there will be a closing one next Sunday. “We go to a coffee shop and they’re excited to have us there,” he said. “We’re celebrities, but they don’t know who we are.” And in his case, it won’t really matter whether he wins a medal. “I’m so happy for him,” says Louisa Soares, Shaunna’s mother. “People are dealt different situations in life,” Jonathan Meuser says. “He just took what life gave him and made the best of it.” The Paralympian thinks back to his life before the wreck. It seems so long ago. “We’re out there ripping it up on the slopes,” he says. “You know, sometimes we get mad at these able-bodied skiers because they get in our way. We’re better at it than they are. That feels good.” The reporter can be reached at [email protected] or (559) 441-6217. Read his blogat www.fresnobeehive.com.

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Copyright (c) 2006, The Fresno Bee, Calif.

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

By Valdes, Edna K; Feldman, Sheldon M; Krassilnik, Nina

Mammary carcinoid is an uncommon neoplasm. It accounts for approximately 5 per cent of all breast carcinomas. It is well-known that neuroendocrine elements can be demonstrated in ductal and lobular carcinoma. However, it is still controversial whether mammary carcinoid tumors should be considered a distinct clinical entity or be treated as a variant of conventional breast carcinoma. Differentiating these lesions from benign lesions such as epithelial hyperplasia and papillomas can be challenging at times. We present a case of neuroendocrine tumor of the breast.

THE PATIENT IS A 41-year-old female with a history of right breast ductal carcinoma in situ for which she underwent lumpectomy and postoperative radiation therapy approximately 3 years earlier. She was doing well on tamoxifen. A screening mammogram revealed new indeterminate calcifications in the lateral aspect of the right breast posterior to the previous lumpectomy site. Sonography of the right breast identified five separate solid nodules with irregular margins as follows: 1.7 cm in the 9:00 position 5 cm from the nipple with an adjacent 7 mm nodule; 1.2 cm nodule in the 9:30 location 6 cm from the nipple; and two adjacent solid nodules measuring 1.6 cm and 1.3 cm, respectively, in the 9:30 location 4 cm from the nipple. Sonographic-guided needle biopsy of four of these nodules as well as a core biopsy of one of these nodules revealed ductal carcinoma with neuroendocrine features (Fig. 1). The tumor was estrogen receptor positive, progesterone receptor negative, and Her-2 negative.

On physical examination, no abnormality was noted other than echymotic region secondary to the needle biopsies. Metastatic evaluation did not demonstrate any distant disease. She underwent right mastectomy, right axillary sentinel node biopsy, right deep inferior epigastric perforator flap reconstruction, and left mastopexy. Pathology revealed a 1.5-cm multifocal carcinoid (carcinoma with neuroendocrine differentiation) of the breast with an intraductal component (Figs. 2 and 3). The sentinel lymph nodes were negative.

The patient recently completed four cycles of adriamycin and cytoxan.

Discussion

Mammary carcinoid is an uncommon neoplasm.1, 2 It accounts for approximately 5 per cent of all breast carcinomas.2, 3 In 1947, Vogler5 found argyrophilic “clear” cells in the human breast ducts and considered them to be of endocrine nature. In 1963, Feyrter and Hartmann4 described two breast carcinomas with carcinoid growth pattern and thus suggested a degree of (neuro) endocrine differentiation. However it was not until 1977, when Cubilla and Woodruff6 stated that the granules in the tumor cells were of the neurosecretory type and named these tumors “carcinoids.” In 1982, Azzapardi7 presented 14 cases of carcinoid tumors in which he showed that argyrophilic breast tumors form a spectrum with wide range of morphological and histochemical appearances and a variable prognosis.

Since Cubilla and Woodruff6 first described primary breast carcinoids, many researchers have attempted to further define these tumors by microscopy and immunohistochemical staining methods. To date there is still no universal definition of a breast carcinoid tumor. Diagnosis based on mammographic or sonographic appearance of these tumors is not possible.7

It is well-known that neuroendocrine elements can be demonstrated in ductal and lobular carcinoma. However, it is still controversial whether mammary carcinoid tumors should be considered a distinct clinical entity or be treated as a variant of conventional breast carcinoma.1 Endocrine breast carcinomas usually contain estrogen receptors, sometimes at very high levels. A surprisingly high number of male breast carcinomas (20%) show evidence of endocrine differentiation compared with 5 per cent in women.4

The following categories encompass the majority of mammary endocrine tumors: low-grade insular duct carcinoma (type A), which occurs most frequently; cellular mucinous carcinoma (type B), which allegedly have better prognosis4, 8; lobular carcinoma, alveolar type (type F); small cell undifferentiated carcinoma (type G), which is the most distinctive and the least common type.

FIG. 1. Ultrasound-guided fine-needle aspiration specimen showing malignant cells (Wright-Giemsa, original magnification 400).

FIG. 2. Surgical pathology showing carcinoma with neuroendocrine differentiation (hematoxilin-eosin, original magnification 400).

Most endocrine tumors of the breast, except small cell carcinomas, are well differentiated and consist of densely cellular, solid nests and trabeculae of cells separated by delicate fibrovascular stroma. The tumor cells occasionally form rosette- like structures and display peripheral nuclear palisading reminiscent of carcinoid tumors.9 Because of the mild cytologic atypia of carcinoid cells, differentiating these lesions from benign lesions such as epithelial hyperplasia and papillomas can be challenging on fine-needle aspiration specimen.4 Two histopathological features are used to identify these tumors: argyrophilia and ultrastructural “neurosecretory” granules.3 Features that can help in differentiation of these lesions include peripheral palisading of the nuclei, pseudorosette formation, accumulation of intracellular mucin, and demonstration of endocrine features by silver precipitation or immunohistochemical methods.4

FIG. 3. Neuroendocrine differentiation of the tumor cells is confirmed by staining for synaptophysin (immunoperoxidase, original magnification 400).

The principal differential diagnosis of mammary carcinoid include lobular carcinoma, mammary non-Hodgkin’s lymphoma, and carcinoid tumor metastatic to the breast. The cytological features of metastatic carcinoid are similar to that of breast carcinoid. Therefore, to differentiate these two entities, medical history and clinical investigation to rule out carcinoid tumor elsewhere is of utmost importance.2

Although no carcinoid syndrome has been reported, an increased production of parathyroid hormone, norepinephrine, adrenocorticotrophic hormone, calcitonin, human chorionic gonadotropin, chromogranin, bombesin, gastrin, B-endorphins, serotonin, and substance P have been reported in argyrophil breast tumors.2, 3, 10 Nodal or distant metastases have been reported in about 18 per cent of all the cases and only when the tumor was 2.5 cm or larger and with ten or more mitoses/10 HPF.3 Metastases have been reported to bone, liver, lungs, and brain.10 There is some data in the literature supporting the use of anthracyclines in the treatment of neuroendocrine differentiated breast carcinoma. Because this tumor is felt to be less aggressive, surgical resection of metastatic disease can lead to a lasting disease-free survival.11

The overall prognosis of mammary carcinoma with carcinoid features is generally considered to be comparable to that of conventional breast carcinomas2 and seems to correlate well with their size and degree of anaplasia.12 However, the small cell subtype is reportedly a very aggressive tumor with poor prognosis for which no clear management has been agreed upon. Stage, tumor size, and lymph node status are the prognostic factors. In most series, patients were treated with modified radical mastectomy, various chemotherapeutic regimens and adjuvant radiation therapy to the chest wall and draining lymph nodes, with mode and total dose as in primary breast cancer. The commonly used chemotherapeutic agents are VP16 and cisplatin. Neoadjuvant chemotherapy has also resulted in decreased tumor size. However, no long-term follow-up studies are available.13, 14

Conclusion

The concept of endocrine differentiation of breast cancers is well-established.4 Although mammary carcinoids often demonstrate an innocent histologic and cytologic appearance, they probably carry a similar prognosis to that of conventional breast carcinomas2 and seem to correlate well with their size and degree of anaplasia,12 whereas the small cell subtype is reportedly a very aggressive tumor with poor prognosis for which no clear management has been agreed upon.13, 14 Diagnosis cannot be established based on mammographic or sonographic appearance of these tumors.7 Therefore, the treatment approach should be decided upon accordingly.2, 15 Although very rare, carcinoid tumor has been reported to metastasize to the breast. Therefore, the possibility of metastasis to the breast from a primary in the lung or even in the gastrointestinal tract should always be kept in mind and ruled out.16

REFERENCES

1. wee A, Nilsson B, Chong SM, Raju GC. Bilateral carcinoid tumor of the breast. Report of a case with diagnosis by fine needle aspiration cytology. Acta Cytol 1992;36:55-9.

2. Ni K, Bibbo M. Fine needle aspiration of mammary carcinoma with features of a carcinoid tumor. A case report with immunohistochemical and ultrastructural studies. Acta Cytol 1994; 38:73-8.

3. Giacchi R, Sebastiani M, Lungarotti F. The so-called “carcinoid” tumors of the breast. Ital J Surg Sci 1986;16:249-53.

4. Maluf HM, Koerner FC. Carcinomas of the breast with endocrine differentiation: a review. Virchows Arch 1994;425: 449-57.

5. Nesland JM, Memoli VA, Holm R, et al. Breast carcinomas with neuroendocrine differentiation. Ultrastruct Pathol 1985;8: \225-40.

6. Kaneko H, Sumida T, Sekiya M, et al. A breast carcinoid tumor with special reference to ultrastructural study. Acta Pathol Jpn 1982;32:327-32.

7. Hartgrink HH, Lagaay MB, Spaander PJ, et al. A series of carcinoid tumors of the breast. Eur J Surg Oncol 1995;21:609-12.

8. Fisher ER, Palekar AS, Collaborators NSABP. Solid and mucinous varieties of so-called mammary carcinoid tumors. Am J Clin Pathol 1979;72:909-16.

9. Sapino A, Righi L, Cassoni P, et al. Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol 2000;17:127-37.

10. Dubilier LD, Stoeckinger JM. Carcinoid tumor of the breast. J Ky Med Assoc 1982;80:147-9.

11. Berruti A, Saini A, Leonardo E, et al. Management of neuroendocrine differentiated breast carcinoma. Breast 2004;13: 527- 9.

12. Forouhar FA. Morphologic study of carcinoid-like tumors and their relation to true carcinoids, using tumors of the breast as a model. Tumori 1983;69:171-6.

13. Sridhar P, Matey P, Aluwihare N. Primary carcinoma of breast with small-cell differentiation. Breast 2004;13:149-51.

14. Stein ME, Gershuny A, Abdach L, Quigley MM. Primary small- cell carcinoma of the breast. Clin Oncol (R Coll Radiol) 17:202-2.

15. Van Laarhoven HAJ, Gratama S, Wereldsma JCJ. Neuro-endocrine carcinoid tumours of the breast: a variant of carcinoma with neuroendocrine differentiation. J Surg Oncol 1991;46: 125-32.

16. Pereda E, Ibanez T, Ereno C, et al. Well differentiated neuroendocrine carcinoma of the breast. Arch Anat Cytol Path 1995;43:164-6.

EDNA K. VALUES, M.D., SHELDON M. FELDMAN, M.D., F.A.C.S., NINA KRASSILNIK, M.D.

From the Louis Venet Comprehensive Breast Service, Beth Israel Medical Center, New York, New York

Address correspondence and reprint requests to Edna K. Valdes, M.D., Phillips Ambulatory Care Center, 10 East Union Square, Suite 4E, New York, NY 10003.

Copyright The Southeastern Surgical Congress Feb 2006

By Self, Michael; Dunn, Ernest; Cox, John; Brinker, Karl

Improvements in immunosuppression have increased patient and graft survival in transplant recipients. As a result, there is greater risk of neoplastic processes such as breast cancer. Treatment in this population is complicated by the necessary immunosuppression, vascular accesses, and transplant grafts. General surgeons may expect to encounter more of these complex patients in the community setting. We sought to evaluate the surgical treatment of breast cancer in patients with renal transplants. Hospital and private physician records were queried to identify patients who developed breast cancer after a renal or pancreatic/renal transplantation. These charts were reviewed for demographics, type of breast cancer and treatment, location of dialysis access, and complications. From June 1, 1994, to May 31, 2004, 14 patients were identified. Eight patients had functioning transplants. All patients underwent operative interventions. Ten patients underwent adjuvant treatment. Three had functioning transplants and chose not to risk the graft with cessation of immunotherapy. However, no patient with functioning transplants who underwent chemotherapy developed organ failure. Breast cancer after transplantation poses a unique dilemma. The threat of transplanted organ failure is a major concern to these patients and often supersedes adjuvant therapies.

As OF 2001, THERE WERE more than 7 million American adults suffering from a decline in their renal function.1 In that same year, 15,331 underwent a kidney transplant for end-stage renal disease.2 This is greatly increased from the 9,655 transplants performed in 1988. Improvements in immunosuppressive therapy continue to further the life span of these recipients. Logically, the incidence of induced and naturally occurring neoplasms will escalate as this population of patients grows. This is true for cancers such as those of the breast, as nearly 40 per cent of transplant patients are female.3

Treatment of breast cancer in the transplant population is complicated by immunosuppression, dialysis access, and transplant grafts. General surgeons can expect to encounter more of these complex patients in the community setting. However, there is limited information regarding the surgical treatment of this intricate disease process. We sought to evaluate the unique dilemma of the treatment of breast cancer in patients with renal transplants.

Patients and Methods

This study was a retrospective review of data collected on all patients who underwent a kidney or kidney/pancreas transplant at Methodist Health System, a community-based hospital in Dallas, Texas. Hospital and private physician records were queried to identify those patients with a newly diagnosed breast cancer during the period from June 1, 1994, to June 30, 2004. These charts were reviewed for demographics, type of breast cancer, medical and surgical treatment, method of dialysis and location of access, type of transplant immunosuppression, and complications.

Results

Methodist Health System began its transplant program in 1981. From its inception to June 2004, 1,944 kidney and 129 kidney/ pancreas transplants were performed. During the 10-year study period, there were 741 transplants performed with 14 patients developing breast cancer. The characteristics of this group are shown in Table 1. The average age was 54.2 years. The mean time from transplant to the diagnosis of breast cancer was 8.29 years (0.8 to 16.3 years). None of the 14 patients had breast cancer prior to the study or their transplant. The patients were followed, on average, 3.35 years (0.5 to 8.7 years) after the diagnosis.

TABLE 1. Patient Characteristics

At the time of diagnosis of their breast cancer, eight kidney transplant patients had functioning transplants. Both of the combined kidney/pancreas transplant patients had continued function of their pancreatic graft. However, one patient lost the renal component due to chronic rejection. Of the remaining patients, all were undergoing hemodialysis for chronic organ failure.

Two patients had ductal carcinoma in situ. Invasive disease was discovered in 12 individuals: five patients presented with stage I disease; five had stage II; two individuals had stage IV disease.

All patients underwent some form of operative intervention. Mostly, modified radical mastectomy (MRM) with levels I and II nodal dissection was performed. Two individuals within the MRM group initially had lumpectomies for presumed in situ disease. This was followed by a completion mastectomy and node dissection after discovering invasive carcinoma within the initial specimen. Sentinel node biopsy was not offered due to either prior axillary dissection for vascular access or surgeon preference. Additionally, many of the patients presented prior to the use of sentinel node biopsy technique. No individuals were noted to have major wound complications.

The functioning of access grafts after nodal surgery was a concern. Two patients had functioning grafts on the ipsilateral side of the node dissection. One of these individuals developed access dysfunction in the form of decreased flow. This was amenable to percutaneous dilatation. Ipsilateral graft placement was not performed after nodal surgery. No patient in the study group developed upper extremity lymphedema.

Adjuvant therapy was presented to the patients on a case-by-case basis. Five of the six who opted for breast conservation (i.e., lumpectomy) underwent radiation therapy alone. The remaining patients varied in their course of therapy. One patient with stage IV dis ease had chemotherapy alone. Four individuals had combined chemoradiation. Two were for locally advanced cancers, one for metastatic disease, and one for recurrent disease. None of the five patients who underwent chemotherapy developed transplant failure or renal insufficiency after treatment; however, one patient had preexisting graft failure at the time of treatment and eventually died from metastatic carcinoma.

The remaining four patients underwent no adjuvant treatment at all. One had a prior history of Hodgkin disease for which she had prior radiation therapy. Her breast cancer was found at stage I and she opted for a MRM. Another was a male patient with stage I papillary carcinoma treated with a simple mastectomy. One patient had a stage II cancer and underwent lumpectomy and axillary node dissection. This was followed by a completion mastectomy due to inadequate margins. One patient had a history of lupus and was not felt to be a candidate for radiation therapy. She was found, after lumpectomy for presumed in situ disease, to have a stage I cancer. She underwent a MRM and was treated with adjuvant tamoxifen.

Of the seven patients with invasive cancers who did not receive chemotherapy, four are listed above. Three patients with localized disease underwent adjuvant radiation therapy and were offered adjuvant chemotherapy but chose not to undergo treatment. These patients voiced concern over cessation or reduction of immunosuppression and the possibility of subsequent transplant dysfunction. None of these patients developed a recurrence during the follow-up period. Regarding hormonal therapy, tamoxifen was given to eight patients and letrozole to one.

Overall, there were two deaths. One patient died from sepsis- independent of the breast cancer treatment-which led to pulmonary failure. The other death occurred secondary to metastatic carcinoma. She represented the single recurrence within the group during the study period. Additionally, no patients experienced transplant insufficiency or failure.

Discussion

The diagnosis of breast cancer in a transplant patient confounds an already complex clinical picture. Many questions are raised, with little clinical data to guide management. Do transplant patients have a greater risk of breast cancer? To what degree does immunosuppression increase patients’ risk of breast cancer? What is the optimal management of immunosuppression once a diagnosis of breast cancer is made? How should systemic adjuvant therapy be incorporated in this population and what is the consequence of therapy on graft function? What is the approach to management of the axillae with respect to the need for vascular access in hemodialysis patients?

The risk of breast cancer in transplant patients is debated among authors. In a single institution study, Agraharkar et al. found that the relative risk of breast cancer in this patient population was approximately 0.7 when compared with that of the general population.4 His findings were consistent with other studies, including those from the Cincinnati Transplant Tumor Registry.5 Kasiske, in a similar article, agreed that the relative risk was not significant (0.82 in women, 1.88 in men).6 However, he went on to compare the rates of cancer post-transplant to that of non- transplant patients. This study demonstrated a nearly threefold increased rate of breast cancer during the first year in transplanted females when compared with the general public (343/ 100,000 vs 134/100,000). The incidence then decreased in years 2, 262/100,000, and year 3, 144/100,000. The male transplant population incidence mirrored that of the female with 3-year increases per 100,000 patient years from the baseline \of 1.5 to 6.8, 15.5, and 6.0, respectively. Although the risk may not be significantly increased, there is certainly a propensity toward more breast cancers as the total number of surviving transplant patients grows. In the current study, we discovered 14 breast cancers in 741 total transplants for an incidence of 1.9 per cent. However, our current 36-month patient survival is 94 per cent, thus giving the likelihood of higher prevalence in the future.

There is an established link between immunosuppressive therapies and the development of certain malignancies.7,8 These have largely been related to skin cancers and are primarily due to the effects of immunosuppression on the DNA strands and DNA repair mechanisms. Additionally, viral infections such as Epstein-Barr have been implicated in the proliferation of post-transplant lymphomas.9 These links have not been proved to be the case with breast cancers.10 Some studies suggest that the suppression of immune surveillance may contribute.11 In contrast, other authors suggest that immunosuppression may have a protective effect against breast cancers.12 Stewart contended that retrovirus-associated breast cancers were promoted by immune mechanisms and, therefore, immunosuppression during the premalignant phase reduced the transformation to cancer. He then reviewed 25,000 immunosuppressed women over 11 years and found 86 cases of de novo breast cancers. This contrasted with the expected 113 cases. In turn, the relative risk decreased to 0.49 in the first post-transplant year and then increased to 0.84 in ensuing years. However, these results could be the outcome of a strict screening program that is part of the transplant process and, therefore, excludes high-risk patients from transplantation.13 Our institution has a policy of performing screening mammograms on all female patients and a requisite 3-year waiting period after successful treatment for good prognosis, localized breast cancer. This is reflected by the relatively low number of breast cancers in our transplant population and an average diagnosis time of 8.29 years after transplant.

Management of immunosuppression, once a diagnosis of cancer has been made, is also an area of concern as there is little data available to guide decisions. Decreased or cessation of immunosuppression has been reported to be associated with remissions of the lymphoproliferative processes and Kaposi sarcoma; however, data involving therapeutic benefit of reducing immunosuppression in patients with solid tumors is anecdotal. Within our series, the management of immunosuppression was tailored to each patient’s circumstances. In all patients who had systemic chemotherapy, immunosuppression was altered or decreased to try to limit hematosuppression and drug toxicities. Some patients resisted these recommendations, wishing to preserve the transplant organ function over all other goals. These patients chose not to consider any therapy for their breast cancer that would require any adjustment of their immunosuppression. Largely, immunosuppression was not an issue in choosing appropriate management for our patients with breast cancer. Some authors do not recommend ceasing immunosuppression during the treatment of solid tumors.14 Some practitioners would rather decrease or temporarily suspend the immunosuppression.15

There are relatively few studies outlining the safety or efficacy of chemotherapeutic regimens in transplant populations. As described in the aforementioned studies, cessation of immunotherapy was initially thought to result in regression of neoplasms. This strategy has been suggested in treatment of transplant patients with malignant lymphoproliferative disease. In our study, the use of chemotherapy in three of the four patients with functioning grafts did not result in rejection or dysfunction possibly due to the fact that immunosuppression was continued during the treatment period. No recurrences were noted in the follow-up period of these patients. Interestingly, this group had very similar outcomes to the two patients who refused chemotherapy over concerns of a reduction in immunosuppression. However, this study’s limited group size precludes statistically significant conclusions on this matter. It is suggested that immunosuppressed patients be treated as non- immunosuppressed patients in cases of tumors such as those of the breast. Further studies have suggested that specific therapy-this includes chemotherapy, surgery, or radiation-be used in the treatment of solid organ cancers.16

It appears that, in our restricted study, functioning dialysis access grafts need not be replaced after nodal surgery. The relevant patients in our study had minor complications that cannot be directly attributed to the levels I and II axillary node dissection. Therefore, it appears that surgeons should continue to approach dialysis accesses as in those patients without axillary surgery. The role of sentinel node biopsy also requires further evaluation in this patient population as it was not used throughout our study period. The major concern in this procedure was the accuracy due to postaccess alterations in the axillae. This could be from either collaterals formation or inflammatory response in the axillae.

In conclusion, this unique problem creates a significant dilemma. There is a relatively small amount of information from which to gain counsel, and the majority of work in this area has come from the renal aspect. Zeier and Morath, in respective articles, define the prevalence and pathogenesis of post-transplant malignancies.17,18 However, discussion of the surgical management is mostly overlooked. In evaluating the results of our study, it appears that surgical approaches to breast cancer in the transplant population need not be altered. These patients provide a challenge in counseling of their treatment options. This population often places a high value on the maintenance of the transplant’s function, even to the point of altering standard recommendations for the treatment of their malignancy as the threat of graft loss often supercedes adjuvant therapy. The best approach is a combined effort among the disciplines of surgery, nephrology, and oncology. We recommend that surgeons continue to approach the primary cancer as one would in the normal population patient. Some consideration should be given to the approach of sentinel node evaluation. There is certainly a need for further study of the management of breast cancer in this population.

REFERENCES

1. National Kidney Foundation K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.

2. United States Renal Data System. USRDS 2003 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS, 2003. Available at www.usrds.org.

3. United States Renal Data System. USRDS 2003 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS, 2003. Available at www.usrds.org.

4. Agraharkar ML, Cinclair RD, Kuo YF, et al. Risk of malignancy with long-term immunosuppression in renal transplant patients. Kidney Int 2004;66:383-9.

5. Penn I. Posttransplant malignancies. Transplant Proc 1999; 31:1260-2.

6. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004; 4:905-13.

7. Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppresion and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant. 2004;4:87-3.

8. Chapman JR, Webster AC. Cancer after renal transplantation: the next challenge. Am J Transplant 2004;4:841-2.

9. Holmes RD, Sokol RJ. Epstein-Barr virus and posttransplant lymphoproliferative disease. Pediatr Transplant 2002;6: 456-64.

10. Campbell A, Moazami N, Ditkoff BA, et al. Short-term outcome of chronic immunosuppression on the development of breast lesions in premenopausal heart and lung transplant patients. J Surg Res 1998;78:27-30.

11. Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppresion and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4:87-3.

12. Stewart T, Tsai SC, Grayson H, et al. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 1995;346:796-8.

13. Weiss NS. Risk of breast cancer after renal or cardiac transplantation. Lancet 1995;346:1422.

14. Ondrus D, Pribylincova V, Breza J, et al. The incidence of tumors in renal transplant recipients with long-term immunosuppressive therapy. Int Urol Nephrol 1999;31:417-22.

15. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993; 12:8328-36.

16. Zeier M, Hartschuh W, Wiesel M, et al. Malignancy after renal transplantation. Am J Kidney Dis 2002;39:E5.

17. Morath C, Mueller M, Goldschmidt H, et al. Malignancy in renal transplantation. J Am Soc Nephrol 2004;15:1582-8.

18. Zeier M, Hartschuh W, Wiesel M, et al. Malignancy after renal transplantation. Am J Kidney Dis 2002;39:E5.

MICHAEL SELF, M.D., ERNEST DUNN, M.D.,* JOHN COX, D.O.,[dagger] KARL BRINKER, ..[double dagger]

From the Departments of *Surgery, [dagger]Oncology, and [double dagger]Nephrology, Methodist Hospitals of Dallas, Dallas, Texas

Presented at the North Texas Chapter of the American College of Surgeons Annual Meeting, Dallas, Texas, February 26, 2005.

Address correspondence and reprint requests to Ernest Dunn, M.D., P.O. Box 655999, Dallas, TX 75265.

Copyright The Southeastern Surgical Congress Feb 2006

By Duffy, Michael J

Background: Although multiple serum-based tumor markers have been described for breast cancer, such as CA 15-3, BR 27.29 (CA27.29), carcinoembryonic antigen (CEA), tissue polypeptide antigen, tissue polypeptide specific antigen, and HER-2 (the extracellular domain), the most widely used are CA 15-3 and CEA.

Methods: The literature relevant to serum tumor markers in breast cancer was reviewed. Particular attention was given to systematic reviews, prospective randomized trials, and guidelines issued by expert panels.

Results: Because of a lack of sensitivity for early disease and lack of specificity, none of the available markers is of value for the detection of early breast cancer. High preoperative concentrations of CA 15-3 are, however, associated with adverse patient outcome. Although serial determinations of tumor markers after primary treatment for breast cancer can preclinically detect recurrent/metastatic disease with lead times of ~2-9 months, the clinical value of this lead time remains to be determined. Serum markers, however, are the only validated approach for monitoring treatment in patients with advanced disease that cannot be evaluated by use of conventional criteria.

Conclusions: CA 15-3 is one of the first circulating prognostic factors for breast cancer. Preoperative concentrations thus might be combined with existing prognostic factors for predicting outcome in patients with newly diagnosed breast cancer. At present, the most important clinical application of CA 15-3 is in monitoring therapy in patients with advanced breast cancer that is not assessable by existing clinical or radiologic procedures.

2006 American Association for Clinical Chemistry

For many malignancies, serum tumor markers play an important role in patient management (1-5) (Table 1). In breast cancer, however, the role of serum markers is less well established. The most widely used serum markers in breast cancer are CA 15-3 and carcinoembryonic antigen (CEA).1 Less widely used markers include BR 27.29 (also known as CA27.29), tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS) and the shed form of HER-2 [Table 2; for a review, see Refs. (6-8)]. The potential uses of serum markers in breast cancer include aiding early diagnosis, determining prognosis, prospectively predicting response or resistance to specific therapies, surveillance after primary surgery, and monitoring therapy in patients with advanced disease. The aim of this review is to examine the role of serum tumor markers in the detection and management of patients with breast cancer. As CA 15-3 is the most widely used serum marker in breast cancer, most of the review will focus on it.

Aiding Early Diagnosis

Lack of sensitivity for early-stage disease combined with a lack of specificity precludes the use of all existing serum markers for the early diagnosis of breast cancer. For example, CA 15-3 concentrations are increased in ~10% of patients with stage I disease, 20% with stage II disease, 40% with stage III disease, and 75% with stage IV disease (9). According to an American Society of Clinical Oncology (ASCO) Expert Panel, a CA 15-3 concentration 5- to 10-fold above the upper limit of the reference interval could alert a physician to the presence of metastatic disease (9). However, a low concentration does not exclude metastasis (9).

As well as lacking sensitivity for early disease, CA 15-3 also lacks specificity for breast cancer. Increased concentrations of the marker can be found in a small proportion of apparently healthy individuals (~5%); in patients with certain benign diseases, especially liver disease; and in patients with other types of advanced adenocarcinomas (6-9). Consequently, for the foreseeable future, mammography and histopathology will remain the primary modalities for detecting early breast cancer.

Table 1. Malignancies in which serum tumor markers play an important role in patient management.

Determining Prognosis

Available prognostic factors for breast cancer include pathology criteria such as tumor size, tumor grade, and lymph node status (10), as well as newer biological factors such as hormone receptors, HER-2, urokinase plasminogen activator, and plasminogen activator inhibitor 1 (11, 12). All of these factors require tumor tissue, thus necessitating either biopsy or surgery. Clearly, it would be desirable to have a circulating prognostic marker for breast cancer, particularly if it provided independent prognostic information.

At least 10 published studies involving >4000 patients have addressed the relationship between preoperative concentrations of CA 15-3 and patient outcome (Table 3) (13-23). Although a range of cutoff points were used (25-40 kilounits/L), all of the identified studies apart from one concluded that high concentrations of the marker at initial presentation predicted adverse patient outcome. Indeed, in some studies, the prognostic impact of CA 15-3 was independent of tumor size and axillary nodal status (15, 22, 23). Significantly, in 2 reports (22, 23), CA 15-3 was found to be prognostic in lymph node-negative breast cancer patients, the subgroup in which new prognostic factors are most urgently required. In another study, however, CA 15-3 was not prognostic in patients free of axillary nodal metastases (24). A pooled analysis of all data relating preoperative concentrations of CA 15-3 with patient outcome should now be carried out.

Although most studies relating CA 15-3 to prognosis have used preoperative values, concentrations during follow-up can also provide prognostic information. Thus, Tampellini et al. (25) reported that patients with CA 15-3 values 30 days had a better prognosis than those with a shorter lead time. In that study (26), both the time interval between diagnosis and first abnormal CA 15-3 concentration (cutoff, 47 kilounits/L) were also of prognostic value.

Table 2. List of most widely used serum tumor markers in breast cancer.

These findings suggest that determination of CA 15-3 can provide real-time prognostic information in patients with breast cancer. Indeed, preoperative concentrations could be combined with existing prognostic factors for selecting patients for adjuvant therapy. For example, in lymph node-negative patients, preoperative concentrations of CA 15-3 might be combined with tumor size, tumor grade, estrogen receptor status, and HER-2 status for selecting who should or should not receive adjuvant chemotherapy.

Serum concentrations of the shed form of HER-2 have also been widely investigated for potential prognostic value in breast cancer. After performing a systematic review of the literature, Carney et al. (27) identified 20 publications involving >4000 patients that related serum HER-2 concentration to outcome. These studies showed that high HER-2 concentrations in patients with either early or metastatic breast cancer predicted adverse outcome as demonstrated by decreased time to disease progression, decreased disease-free survival, and decreased overall survival. It was not clear, however, whether the prognostic information provided by HER-2 was independent of the traditional factors.

Table 3. Published studies describing a prognostic value for preoperative concentrations of CA 15-3 in breast cancer.

Although less widely investigated as a prognostic factor than either CA 15-3 or HER-2, high preoperative concentrations of CEA are also associated with poor prognosis in breast cancer (16, 19, 21, 24). Furthermore, in one large study (n = 1046), patients with a decrease of >33% between pre- and postoperative concentrations were found to have a worse outcome than those with a lesser decrease (21). In multivariate analysis, this decrease in CEA predicted outcome independent of tumor size, lymph node status, and progesterone receptors.

Predicting Response to Therapy

As with prognostic factors, the available therapy-predictive markers in breast cancer, such as estrogen receptor, progesterone receptor, and HER-2 (28), all require tumor tissue for analysis. Preliminary findings, however, suggest that high serum HER-2 concentrations are associated with both poor response to endocrine therapy and cyclophosphamide-methotrexate-5-fluorouracil-based chemotherapy but can predict an improved response to a combination of trastuzumab (Herceptin) and chemotherapy [for a review, see Ref. (27)]. These preliminary findings should now be confirmed in a large prospective trial.

CA 15-3 and other MUC-1-related markers may also have a role in predicting response to therapy. Ren et al. (29) recently reported that overexpression of MUC-1 (the antigen detected in CA 15-3 and BR 27.29 assays) in a mouse model system conferred resistance to cis- platinum. This resistance appeared to result from the ability of MUC- 1 to inhibit apoptosis. Clearly, studies should now be carried out to determine whether either tumor tissue or serum concentrations of MUC-1-related markers predict response/resistance in patients undergoing treatment with platinum-based therapies.

Surveillance after Primary Treatment

Follow-up of patients after primary treatment for breast cancer with clinical examination, radiology, and biochemical testing isnow standard practice in many centers. This practice is based on the assumption that the early detection of recurrent or metastatic disease enhances the chances of cure or survival. The evidence currently available, however, does not support this widely held assumption.

Two large multicenter randomized prospective trials (each with >1000 patients) compared outcome in patients followed up with clinical visits and mammography vs those who were followed up with an intensive regime that included radiology and traditional laboratory testing (30, 31). Both studies concluded that use of an intensive follow-up program failed to improve outcome. Similarly, after pooling of the data from the above 2 studies, no significant difference in either disease-free interval or overall survival emerged between patients with intensive vs nonintensive surveillance (32).

In addition to these 2 large prospective trials, a systematic review of studies comparing control vs intensive follow-up regimes for newly diagnosed breast cancer patients has also been carried out (33). Of 4418 reports identified, 38 were considered eligible for analysis. Although the data were not sufficiently homogeneous to integrate statistically, the authors concluded that patient survival and quality of life were not affected by the intensity of follow-up or location of care. The authors also concluded that there was insufficient evidence to draw broad conclusions with respect to best practice for breast cancer follow-up care regarding morbidity reduction, cost-effectiveness, and patient involvement in care.

Clearly, the available data do not support the use of an intensive follow-up program using standard biochemical testing and radiology after primary treatment for breast cancer. However, as pointed out by Emens and Davidson (34), the value of surveillance depends on both the sensitivity and specificity of the available diagnostic tests as well as the efficacy of therapy available for recurrent/ metastatic disease.

Diagnostic tests and treatments are continually evolving. Several of the published studies comparing minimal vs intensive follow-up may therefore have limitations with respect to the modern management of patients with breast cancer. These limitations include the following:

* Use of older and less sensitive biochemical tests rather than the newer tumor markers such as CA 15-3. For example, in a large randomized trial that enrolled 4105 patients, routine biochemical tests such as alkaline phosphatase, aspartate transaminase, γ- glutamyltransferase, bilirubin, calcium, and creatinine were shown to be of limited value in detecting metastasis after treatment for operable breast cancer (35).

* Use of older radiologic procedures rather than newer procedures such as computed tomography, magnetic resonance imaging, and positron emission tomography scanning.

* Most of the reports comparing outcome in control and intensively followed-up patients predate the availability of new treatments for recurrent/metastatic breast cancer, such as the taxanes, the new generation of aromatase inhibitors, and trastuzumab (36).

In recent years, several reports have shown that serial concentrations of tumor markers increase before radiologic or clinical evidence of disease relapse [for reviews, see Refs. (6- 9)]. In a review of the literature, an ASCO Expert Panel identified 12 studies that used serial CA 15-3 measurements to monitor patients for recurrence after breast cancer surgery. In 7 of these trials, data were available in sufficient detail to allow pooling of results. Summation of the data showed that 67% of 352 patients had increased CA 15-3 either before or at the time of recurrence (9). In 1320 patients without evidence of recurrence at the time of study, 92% had CA 15-3 concentrations within reference values. The mean lead time from marker increase to clinical diagnosis of recurrence varied from 2 to 9 months.

Although serial CA 15-3 concentrations can preclinically detect recurrent/metastatic disease, it is unclear whether the introduction of early treatment based on this lead time improves disease-free survival, overall survival, or quality of life for patients. In an attempt to address these issues, several small-scale studies have been carried out. In one of the first of these, Jager (37) randomized patients with increasing concentrations of tumor markers (CA 15-3 or CEA) but without evidence of metastatic disease to receive (n = 21) or not receive (n = 26) medroxyprogesterone acetate. For the untreated patients, the median time interval between increase in marker concentration and detectable metastasis was 4 months, but for the treated patients it was >36 months.

In a second study, Nicolini and coworkers (38, 39) compared outcome in 36 asymptomatic patients who received salvage treatment based on tumor marker increases (CA 15-3, CEA, or TPA) vs 32 patients who were given treatment only after radiologic confirmation of metastasis. Survival from both the time of mastectomy and salvage treatment was significantly improved in the group with tumor marker- guided treatment than in those treated conservatively.

In a third study, Kovner et al. (40) randomized asymptomatic patients with increasing mammary cancer antigen concentrations to receive (n = 23) or not receive tamoxifen (n = 26). After a median follow-up of 11 months, 7 of 29 (24%) in the control group had relapsed, whereas none of the 23 patients randomized to receive treatment developed a recurrence (P = 0.012).

Although these 3 studies contained small numbers of patients, they all suggested that early treatment based exclusively on increasing marker concentrations improved prognosis. These findings, however, are not sufficiently strong to recommend a change in clinical practice, i.e., to recommend that asymptomatic patients with increasing marker concentrations should start new therapy. Many expert panels (including ASCO, European Society of Medical Oncology, and European Society of Mastology) therefore recommend that tumor markers should not be used in the routine surveillance of patients after primary treatment for breast cancer (9, 41-43). Other organizations, such as the European Group on Tumor Markers (EGTM) as well as the National Academy of Clinical Biochemistry (NACB), however, recommend the use of tumor markers during surveillance (44, 45).

Monitoring Response to Therapy in Advanced Disease

Traditionally, International Union against Cancer (UICC) criteria have been used for assessing response to therapy in patients with advanced breast cancer (41). UICC criteria include physical examination, measurement of lesions, radiology, and isotope scanning (46). Multiple studies (47-49) and 3 multicenter trials (50-52), however, have shown that changes in serial concentrations of tumor markers, particularly CA 15-3, correlate with response. In 2 of these multicenter trials, the alterations in tumor marker concentrations were shown to correlate well with UICC criteria (50, 51). Indeed, the use of markers to monitor therapy has several advantages over conventional criteria, including increased sensitivity, more objective measurement, and more convenience for patients (6, 7).

On the basis of data from 11 low-level evidence studies (9), an ASCO Panel concluded that 66% of patients with chemotherapy-induced disease regression exhibited decreases in marker concentrations, 73% of those with stable disease had no significant change in marker concentrations, and 80% with progressive disease displayed increasing concentrations (9). In most of these studies, a change in CA 15-3 concentration >25% was regarded as a significant alteration.

The same ASCO Panel also reviewed the literature on the use of CEA in monitoring response to treatment (9). Eighteen low-level evidence studies were reviewed. Of these, 6 reported results only in patients with high concentrations of CEA. Overall, 82% of the patients were found to have decreasing concentrations with disease response, whereas 74% had increasing concentrations with progressive disease. Of the 12 studies reporting results for patients with advanced disease irrespective of whether CEA was increased, 61% of patients showed a decrease in CEA concentrations with tumor response and 65% showed an increase with tumor progression.

Although the available data show relatively good correlations between alterations in serial tumor marker concentrations and response to therapy in advanced breast cancer, the ASCO Panel concluded that neither CA 15-3 nor CEA should be routinely used for this purpose (9, 41). However, the guidelines also stated “that in exceptional circumstances such as the presence of osseous metastasis, which are difficult to evaluate clinically, the marker level may be able to support the clinical estimate of disease status. However, the marker cannot in any situation stand alone to define response to treatment” (41). The ASCO Panel did not address the use of breast cancer serum markers other than CA 15-3 and CEA.

Although the ASCO Panel was unable to recommend routine use of tumor markers for monitoring treatment in advanced breast cancer, according to Cheung et al. (7), measurement of tumor markers is the only validated method for determining response in patients with disease not assessable by UICC criteria. Overall, 10%-40% of patients with breast cancer have nonassessable disease, i.e., those with irradiated lesions, pleural effusion, ascites, lytic bone disease, and sclerotic bone disease (7).

In contrast to the ASCO Panel, both the NACB and EGTM Panels recommended use of CA 15-3 for monitoring therapy in patients with advanced breast cancer (44, 45). According to the EGTM Panel, markers should be measured before every chemotherapy course and at 3- month intervals for patients receiving hormone therapy (44). This Panel defined a clinically significant increase in marker concentration as an increase of at least 25% overthe previous value. This increased concentration should be confirmed with a second sample taken within 1 month. The Panel also stated that a confirmed decrease in marker concentration of >50% was consistent with tumor regression (44).

Although CA 15-3 and CEA are the most widely used markers in monitoring chemotherapy in patients with advanced breast cancer, emerging data suggest that serum HER-2 may be of use in patients undergoing treatment with trastuzumab-based therapy. Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain of HER-2 and is now widely used in combination with chemotherapy for the treatment of patients with HER-2- overexpressing advanced breast cancer (53).

In a recent retrospective study, Eesteva et al. (54) compared serum HER-2 and CA 15-3 for monitoring trastuzumab-based therapy in 99 patients with advanced breast cancer. Concordance between clinical status and HER-2 concentrations was 0.793 compared with 0.627 for CA 15-3. When both markers were combined, the concordance with clinical status increased to 0.83. Although progression-free survival did not differ significantly between patients with increased vs normal baseline HER-2 concentrations, it did differ according to whether the patient’s HER-2 concentration at 2 to 4 weeks after start of therapy was >77% or 77% of baseline, the median progression-free survival was 217 days, whereas for those with concentrations

In another preliminary report, Kostler et al. (55) showed that in patients responding to trastuzumab-based therapy, serum HER-2 concentrations decreased significantly as early as from day 8 of treatment. In contrast, no significant changes were observed in patients with progressive disease. Using multiple logistic regression analysis, they found that change in HER-2 concentrations were the only factor that predicted the likelihood of response after 8 days of treatment. Furthermore, measurement of serial concentrations of HER-2 predicted risk of disease progression as early as day 15 of treatment.

These preliminary findings suggest that serum HER-2 may be an early indicator of response and progressionfree survival in patients with advanced breast cancer undergoing trastuzumab-based treatment. These early findings, however, require validation in a large prospective trial before serum HER-2 can be recommended for monitoring of trastuzumab-based treatment in patients with advanced breast cancer.

Caveats in the Use of Tumor Markers for Surveillance and Monitoring of Therapy in Patients with Breast Cancer

Despite recommendations from the ASCO Panel (9, 41), serum tumor markers such as CA 15-3 are widely used, particularly in Europe, for both postoperative surveillance and monitoring therapy in patients with advanced breast cancer. When serum tumor markers are used in these settings, several points should be borne in mind, including the following:

* None of the available markers is increased in all patients with breast cancer even in the presence of advanced disease. For those patients with advanced disease who do not have increased CA 15-3 concentrations, other markers, such as CEA, TPA, TPS, or the shed form of HER-2, may be considered for monitoring purposes.

* The available markers are most sensitive for detecting distant metastases and are of little value in diagnosing locoregional recurrences (56-59).

* The magnitude of change between successive marker concentrations that constitutes a critical change is not clear. According to Soletormos et al. (60), this so-called critical difference should be based on both the analytical imprecision of the assay (CV^sub a^) and the normal intraindividual biological variation (CV^sub I^). Assuming CV^sub a^ values of 11.2% for CA 15- 3, 9.5% for CEA, and 11% for TPA, successive concentrations must differ by 30%, 31%, and 72%, respectively, for P values to be significant at a 0.05 level (60).

* Paradoxical patterns of tumor marker concentrations after initiation of chemotherapy may occur. For example, transient alterations in marker concentrations can occur after the commencement of chemotherapy (62-63). The spurious increases or spikes are probably attributable to therapy-mediated apoptosis or necrosis of tumor cells. Hayes et al. (62) reported a spike for either CA 15-3 or CEA in 7 of 16 patients undergoing chemotherapy. For CA 15-3, the peak of the spike above the initial value was 125% (range, 30%-230%), and its duration was 67 days (range, 31-101 days). All patients in whom a spike was observed ultimately showed either disease regression or had stable disease. In another study, spikes in CA 15-3 and CEA returned to pretreatment values by 60 days (63). As well as chemotherapy, treatment with granulocyte colony- stimulating factor can also cause increases in CA 15-3 concentrations (64).

* Certain benign diseases may give rise to increased marker concentrations. Thus, chronic active hepatitis, liver cirrhosis, sarcoidosis (65), hypothyroidism (66), and megablastic anemia (67) have all been reported to increase CA 15-3 concentrations.

Conclusion

The main disadvantages of existing serum markers for breast cancer are a lack of sensitivity for low-volume disease and a lack of specificity. Consequently, the available markers are of no value in either screening or diagnosing early breast cancer. Although of little use for early diagnosis, however, CA 15-3 may be the first independent circulating prognostic marker described for breast cancer. Preoperative CA 15-3 concentrations may thus be combined with established prognostic factors for use in deciding which lymph node-negative breast cancer patients should receive adjuvant chemotherapy. Currently, one of the most widely used applications of tumor markers in breast cancer is in the follow-up of patients with diagnosed disease. In the absence of data from a large randomized trial, however, the clinical value of this practice is unclear. Finally, markers are potentially useful in monitoring therapy in advanced disease, particularly in patients who cannot be assessed by standard modalities.

The author’s work mentioned above was supported by both the Irish Cancer Society and a Program Grant from the Health Research Board of Ireland.

1 Nonstandard abbreviations: CEA, carcinoembryonic antigen; TPA, tissue polypeptide antigen; TPS, tissue polypeptide-specific antigen; ASCO, American Society of Clinical Oncology; EGTM, European Group on Tumor Markers; and UICC, International Union against Cancer.

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Department of Nuclear Medicine, St. Vincent’s University Hospital; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin; and Dublin Molecular Medicine Institute, Dublin, Ireland.

Address for correspondence: Department of Nuclear Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Fax 353- 1-2696018; e-mail [email protected].

Received September 8, 2005; accepted December 13, 2005.

Previously published online at DOI: 10.1373/clinchem.2005.059832

Copyright American Association for Clinical Chemistry Mar 2006

By Carrie Mason-Draffen, Newsday, Melville, N.Y.

Mar. 10–A former employee of a Port Washington medical-equipment distributor has filed a $30-million lawsuit against the company, alleging its chief executive and lawyer sexually harassed her.

Pascale Legagneur, 27, a Garden City resident who worked at Drive Medical Design and Manufacturing as an executive assistant to general counsel Richard S. Kolodny, said she was forced to distribute pornographic e-mails.

After she complained, chief executive Harvey P. Diamond fired her, the lawsuit says.

She filed suit against the company in U.S. District Court in Central Islip on Feb. 6. Last spring, while still at the company, she filed a complaint with the U.S. Equal Employment Opportunity Commission. But the agency’s New York office was unable to determine whether any violations occurred. Legagneur received a standard letter giving her the right to sue in court. The lawsuit names the company and four executives.

“We wouldn’t have pursued it beyond the EEOC if it didn’t raise important issues about the matter in which women are treated at that company,” her attorney, Christopher Brennan of Ziegler, Ziegler & Associates in Manhattan, said recently.

The company’s attorney, Paul Siegel of Jackson Lewis’ Melville office, said the commission didn’t find any violations and that he plans to fight the lawsuit.

“The company will vigorously defend its rights,” said Siegel, who also represents the four executives.

Legagneur said the harassment began shortly after she started working for Drive in July 2004 as Kolodny’s assistant. The job, which paid $42,000 a year, included reviewing his e-mail and sending responses.

In September of that year, Kolodny sent Legagneur an e-mail with a subject line announcing that “August Is Breast Appreciation Month,” according to the lawsuit. The e-mail included images of bare-breasted, bosomy women.

A couple of months later, she opened an e-mail that a major Drive customer sent to Kolodny. The subject line said “Sunsets — Your Vote Counts,” but the e-mail turned out to contain a pornographic picture, the complaint said.

She complained to Kolodny. But after looking at the e-mail, he laughed and ordered her to forward it to the chief executive and to executive vice president Jeffrey Schwartz, also a defendant. She said Kolodny told her to include the message “Check this out,” the complaint said.

Diamond, Schwartz and defendant Douglas C. Francis, also an executive vice president, sent Kolodny X-rated e-mails, which the defendant was required to open, the complaint said.

In June, Diamond fired her. The lawsuit seeks $30 million in compensatory and punitive damages.

—–

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Q: Yoga and Pilates are such popular forms of exercise, but I prefer swimming. I don’t read much about it as a good overall form of exercise. Wouldn’t swimming also provide “core training” and strengthening of the abs? When swimming, aren’t you doing some of the stretching and lengthening Pilates does? Is swimming as beneficial as yoga or Pilates for the over-40 group for maintaining strength and flexibility?

A: Comparing exercises is hard to do, but every one, when done correctly, activates and works, to some extent, the core muscles.

The reader is right, though; swimming traditionally gets cut out of the core hoopla. I asked help from Mary Meyer, a Seattle personal trainer who specializes in swimming and triathlon training (www.marymeyerlifefitness.com).

Meyer acknowledges that swimming isn’t generally considered in the same league as Pilates and yoga when it comes to core work, but that is largely, in her mind, because you don’t have an instructor standing over you and harping about activating those muscles while you’re swimming. She also acknowledges that swimmers typically carry a bit more body weight for the sake of buoyancy and insulation, but looks can be deceiving.

“I have a hard time when a client comes in and says I want the six-pack or the eight-pack or whatever,” she says. “I tell them then maybe swimming isn’t the way to go.”

Swimming works true core muscles _ the functional ones behind the abs facade. The sport builds strength and flexibility, focusing mostly on the upper body. In fact, the power of the body from the hips or upper thigh to the shoulders is the most important factor in effective swimming, she says.

Swimming is also one of the few activities in which you can safely hyperextend your legs (such as when you kick down on the crawl stroke and butterfly). Meyer suggests varying strokes to increase the benefits.

While swimming is good for any age, it’s especially good for the 40-and-older group, she says, “considering it is a non-weight-bearing, low-impact sport that uses most of the muscles in the body.”

But it must be done correctly. For best results, be sure you rotate, power through and finish each stroke rather than swimming flat and cutting your stroke short. Establish as efficient an aquatic line as possible, swimming with head, shoulders, hips and feet in the same line on/to the surface of the water, and holding a straight line from side to side like a spear.

Good swimmers don’t overload their arms and hands. The arm-stroke pattern is effectively a catch and throw, with about 70 percent of the propulsion coming off the throw when combined with a hip-driven core rotation. This is similar to throwing and hitting baseballs.

The kick also stabilizes the lower torso front and back. It initiates from the diaphragm, as though the legs join there instead of at the hips.

Central to form and endurance is proper breathing, which is also essential in yoga and Pilates. Breathing in the water isn’t as natural as on land, and many beginning, even intermediate swimmers do not do it efficiently enough to reap the most benefits from the movement. Rhythm, concentration and flow make the difference. Once you are comfortable with swimming technique and breathing, swimming can be less taxing on lungs than running, because arms, with their smaller muscles, don’t require as much oxygen as legs do. (You can, however, build a lower-body workout by using kickboards and fins.)

___

FIT BIT

Pilates offers pluses, but …

Is Pilates also a good calorie-burning workout? A recent study by the nonprofit American Council on Exercise says: sort of.

The study concluded that the cardiovascular benefits of Pilates appear to be limited. Even though participants think they’re working hard _ and from a muscular standpoint, they are _ they are not achieving significant aerobic or calorie-burning benefits.

“Pilates has a long list of benefits including improved body mechanics, balance, coordination, strength and flexibility,” said Dr. Cedric Bryant, chief exercise physiologist for the council. “While the ACE study shows that a Pilates session burns a relatively small amount of calories, it is still a valuable addition to any exercise routine.

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Richard Seven is a Pacific Northwest magazine writer at The Seattle Times. Send questions on workouts, equipment or nutrition to him at: Pacific Northwest magazine, The Seattle Times, P.O. Box 70, Seattle, WA 98111, or e-mail rseven(at)seattletimes.com. Past columns can be found at http://www.seattletimes.com/onfitness/)

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(c) 2006, The Seattle Times.

Visit The Seattle Times Extra on the World Wide Web at http://www.seattletimes.com/

Distributed by Knight Ridder/Tribune Information Services.

_____

PHOTO (from KRT Photo Service, 202-383-6099): onfitness

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected]. 1027847

By The Buffalo News, N.Y.

Mar. 9–Cardinal Health, a $75 billion Ohio company that is 16th the Fortune 500 list, announced Wednesday that it has agreed to buy Niagara Falls-based ParMed Pharmaceuticals for $40.1 million.

“We’re one of the largest distributors of pharmaceuticals in the U.S.,” said Jim Mazzola, spokesman for Cardinal Health, which has its headquarters in Dublin, outside Columbus.

ParMed, which had been owned by Alpharma Inc. of Fort Lee, N.J., has a main office in Niagara Falls and staff in West Seneca and Jamestown for a total of about 120 workers. The company’s primary customers are independent pharmacies, not chain stores.

Alpharma said ParMed has annual revenues of about $53 million.

ParMed’s focus of selling medicine in smaller quantities compliments Cardinal Health’s distribution to bigger hospital and drug store chains. “It’s still reaching a very important set of customers,” said Mazzola.

Cardinal Health’s “full line distribution business,” of interest to large clients, includes managing inventory and deliveries, sometimes multiple times a day. “CVS is one of our largest customers,” said Mazzola.

While he did not expect staffing changes at ParMed, Mazzola said the combined needs of the clients of both companies should allow Cardinal Health to get better prices for shipping and the drugs it buys.

“Our intent is to have the business operate as it has been today,” said Mazzola of ParMed. “We’re excited just to bring it on board and have it operate.”

—–

To see more of The Buffalo News, N.Y., or to subscribe to the newspaper, go to http://www.buffalonews.com.

Copyright (c) 2006, The Buffalo News, N.Y.

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

CAH, ALO,

15,000-year-old remains suggest a shift away from coarser foods

HealthDay News — A nearly complete 13,000- to 15,000-year-old skeleton of a woman has the oldest recorded case of impacted wisdom teeth ever documented, say scientists at the Field Museum in Chicago.

The teeth may also point to a key shift in human nutrition.

For years, it was believed that Magdalenian Girl, excavated in France in 1911, was a girl because her wisdom teeth had not erupted. Wisdom teeth usually come in between 18 and 22 years of age.

However, new high-quality digital X-rays revealed that the skeleton had impacted wisdom teeth that had failed to erupt at the normal time. Therefore, Field Museum scientists concluded that Magdalenian Girl was actually a 25- to 35-year-old woman.

The finding is significant because impacted teeth are believed to be the result of dietary changes historically associated with later developments in human cultures. Impacted teeth typically did not occur during the Stone Age due to a coarse diet that required more chewing and higher bite forces. This likely stimulated the growth of the jawbone, creating more room for wisdom teeth to erupt, the scientists explained.

“Finding impacted wisdom teeth 15,000 years ago indicates that the human diet might have already changed, some would say ‘deteriorated,’ earlier than previously thought,” Robert D. Martin, Field Museum provost and primatologist, said in a prepared statement.

Magdalenian Girl will be placed on permanent display as part of Evolving Planet, a new Field Museum exhibit depicting the story of life on Earth. The exhibit opens March 10.

More information

The U.S. National Library of Medicine has more about impacted teeth.

By Telly Nathalia

JAKARTA — An Indonesia-Japan venture said on Thursday it has created what it believes is a more effective bird flu vaccine for poultry and hopes to quickly boost production to help nations fight the deadly H5N1 flu strain.

PT. IPB Shigeta said it is using a new production technique called reverse genetics in which an inactivated, genetically modified form of the H5N1 virus is grown in special chicken eggs.

The inactivated virus is then harvested for production of the vaccine.

“This is the first in the world. It is non-lethal and safe to be produced,” said Kamaluddin Zarkasie, director of the venture, told reporters.

Since 2004, Japanese drugmaker Shigeta Animal Pharmaceuticals Inc. and Indonesia’s government-backed Bogor Institute of Agriculture (IPB) have worked together to create the vaccine, called bird CLOSE 5.1.

Bird flu has killed 96 people since 2003 and led to the deaths through infection or culling of more than 200 million poultry in many countries.

Several nations, including China, Vietnam and France, are vaccinating poultry but birds can still be virus carriers without showing symptoms.

The joint venture, in a statement, said most current bird flu vaccines for poultry use the H5N2 strain as the seed virus but that meant they were not completely effective because of the genetic differences between H5N1 and the less pathogenic

H5N2.

“The vaccine will be highly effective against currently circulating highly pathogenic avian influenza H5N1 viruses because of the closeness of the antigenic match between the vaccine strain and the epidemic viruses,” the statement said.

There are several sub-strains of H5N1 that have been detected.

Toyama-based Shigeta, which has an 80 percent stake in the venture, said private and government companies around Asia have already requested 517 million doses of the vaccine.

The venture has built a plant in the West Java city of Bogor and plans two bigger factories in the same area.

Zarkasie said the vaccine would hit the market next month.

Shigeta forecast 2006 vaccine sales could reach 8.5 billion yen ($72.6 million).

The venture might also build vaccine factories in Romania and Nigeria, Zarkasie said.

In Indonesia, H5N1 has affected birds in about two-thirds of the country’s provinces and killed 20 people.

Scientists fear the virus could mutate and spread easily from person to person, triggering a pandemic that could kill millions and cripple economies.

Pressure is growing on vaccine makers to create a treatment that will immunize humans and reverse genetics is one of the production methods being tested.

($1 = 117 yen)

By Anne Harding

NEW YORK — Three out of four Americans aged 50 to 70 aren’t getting regular colon cancer screening, according to a survey sponsored by the maker of a new screening test for the disease.

Colon cancer is currently the second leading cancer killer in the United States, with 60,000 Americans expected to die from the disease this year.

The American Cancer Society recommends that everyone get a colonoscopy to test for colon cancer at age 50. But 26 percent of the 1,200 people surveyed said their doctor had never discussed colon cancer screening with them, and 24 percent said they didn’t get screened because they had no symptoms of the disease. Twenty-eight percent said they didn’t want to have a colonoscopy.

Dr. David Stein, director of education for the Colon Cancer Foundation and the chief of the division of colorectal surgery at Drexel University College of Medicine in Philadelphia, points out that this test isn’t something most people are comfortable chatting about around the water cooler, despite efforts by Katie Couric and others to raise awareness of the need for colon cancer screening. “The stigma of a colonoscopy is pretty significant,” he told Reuters Health.

However, if a person with no family history of the disease has a colonoscopy at 50, the doctor performing the test is able to review the entire colon, and no problems are found, he or she doesn’t need to have the test again for 10 years, Stein added. “At 50 you can go get it done and you’re good ’til 60,” he said.

The survey, conducted by Harris Interactive, was sponsored by EXACT Sciences Corp., a Marlborough, Massachusetts-based company that makes a new non-invasive test that screens for colon cancer by looking for cancer-related DNA in the stool.

Stool DNA tests, which can be done at home, have a roughly 60 percent rate of detection, and rarely yield false-positive results. “When it does detect something, it’s pretty accurate,” Stein said.

Such non-invasive tests are better than nothing for people who refuse to have colonoscopies, according to Stein, who notes that the American Cancer Society advises people who refuse colonoscopies to have some other type of colon cancer screening test.

The worst thing about a colonoscopy is not the test itself, which is usually performed with some sort of anesthesia, it’s the preparation beforehand, Stein noted, in which a person takes laxatives and, in some cases, enemas to clear the bowel. Virtual colonoscopy, in which a CAT scan or MRI is used to scan the bowel, still requires the colon-clearing prep, Stein said, while its effectiveness remains controversial and insurance does not cover it.

Despite the prep’s unpleasantness, Stein adds, it’s a small price to pay for a test that can be lifesaving. “In the big picture it’s a no-brainer.”

By Shea, J L

Key words: CHINESE WOMEN, CHINA, SYMPTOMS, MENOPAUSAL STATUS, AGE, ATTITUDES

ABSTRACT

Objectives The China Study of Midlife Women (CSMW) aimed to determine in mid-life Chinese women, first, the frequency of various symptoms often included in studies of menopause or the climacteric, second, attitudes toward menopause and aging, and, third, the relationship between symptoms and menopausal status, chronological age and attitudes.

Methods A questionnaire was administered via face-to-face interview to a general population sample of 399 Chinese women living in two communities in northern China.

Results The Chinese women displayed a low to moderate frequency of reporting 21 symptoms across vasomotor, vaginal, sleep-related, cognitive, emotional and somatic categories. Their attitudes toward menopause and aging tended to be more positive, neutral or ambivalent, as opposed to negative. There was a small, statistically significant association between six symptoms and menopausal status, four symptoms and chronological age, and 11 symptoms and negative attitudes toward menopause and aging.

Conclusions Across the measures utilized in this study, Chinese women’s symptom reporting is more strongly associated with their attitudes towards menopause and aging than their menopausal status or chronological age. More research is needed on cross-cultural, cross-ethnic and individual variation in women’s interpretations of statements often included in mid-life attitudinal scales.

INTRODUCTION

Scholars have long debated which symptoms are related to the menopause transition1, with some linking a broad range of physical and psychological symptoms and others a narrow set of physical symptoms. Several studies conducted in western countries have found that women’s attitudes toward menopause and aging may contribute as much or more to the production of various symptoms as either menopause or aging themselves do2-5. Studies of mid-life women in some non-Western societies have suggested that a more positive orientation toward menopause and aging in those societies helps to account for their relatively low symptom level6-10.

To explore these questions, this article draws on material from the China Study of Midlife Women (CSMW), a project the author conducted in mainland China over several years in the 1990s11,12. In relation to this sample, the analysis examines:

(1) The frequency of various symptoms commonly discussed in the research literature on menopause or the climacteric;

(2) Whether any of these symptoms demonstrate an association with menopausal status and/ or chronological age;

(3) The frequency of various attitudes toward menopause and aging; and

(4) The relationship between various symptoms and women’s attitudes toward menopause and aging.

METHODS

This research was conducted in a rural village and an urban neighborhood in the municipality of Beijing in 1994. These communities were designated by the Chinese government as respectively rural (nongcun) and urban (chengshi) based on their relative population densities, proximity to agricultural production and other factors. Each of these two sites was a middle-income community accessible for study due to positive grassroots rapport established over many years. Project approval was secured from the Institutional Review Boards of Harvard University and Peking Union Medical College Hospital, the Central Ministry of Public Health in China, and local leaders in the surveyed communities. Based on residency lists secured from the local urban and rural residency committees, a total sample was taken of mid-life women between the ages of 40 and 65 years in the village and a block of the neighborhood. At the time of the study, permission to do survey research was extremely difficult for foreign-led research projects such as this to attain, and, as a result, random samples of numerous communities were not possible. Informed consent was requested from each woman, and the participation rate was over 90%. A total of 420 women participated. In this analysis, data from 399 of these women are analyzed. The remaining 21 cases were set aside due to missing data or artificially induced menopause. None of the 399 women examined in this analysis had undergone surgical menopause.

Table 1 Sample characteristics of the Chinese women in the study, age 40-65 years

The sample was divided fairly evenly between the urban and rural sites and between women aged 40-49 and 50-65 years (Table 1). Based on standard definitions13,115 women were premenopausal, 98 perimenopausal, and 186 postmenopausal. Although more educated than the national average for women of their age, a broad range of educational levels was represented, with almost one-quarter having 3 years or less of schooling. A wide variety of occupations, from factory and service jobs to educational, managerial and technical work, was represented at both field sites, but the rural sample was distinguished by having a considerable proportion of women who were currently doing collective agricultural labor or raising pigs or chickens at home.

The questionnaire included a checklist asking women whether they had experienced various symptoms over the previous 2 weeks. Presentation of this checklist was not in any way linked with menopause or aging. The 21 checklist symptoms analyzed here (Table 2) were chosen for their association with biomedically oriented menopausal indexes13 and/or cross-cultural research projects on female mid-life9. The Chinese translations were developed through months of participant observation in Beijing, reading Chinese clinical and self-help literature, checking with local researchers, and pilot testing on local women14.

Table 2 Frequency of symptoms in previous 2 weeks in 399 mid- life Chinese women between the ages of 40 and 65 years

This part of the questionnaire addressing respondents’ attitudes toward menopause and aging was presented after and at a distance from the symptom checklist. Some items were derived from other menopause questionnaires1, and some from Chinese self-help books or everyday conversations with Chinese residents. Comprising 19 statements on the end of menstruation and 20 statements on the transition from middle to old age, they were introduced as ‘something that some people say’ (shuofa huo chuanshuo). Women were asked to give their opinion on each statement by answering ‘agree’, ‘disagree’, ‘it depends’, or ‘unsure’.

As many women were accustomed to stating their age by the lunar calendar and most were unfamiliar with formal definitions of menopausal status, questions allowing the researcher to calculate these in standard biomedical terms were included. Women were designated as premenopausal if they had menstruated during the past 3 months with regular periods over the past 12 months. Perimenopausal status was defined as menstruating during the past 12 months but not during the previous 3 months, or during the past 3 months but with increased irregularity. Postmenopausal status was defined as not menstruating within the previous 12 months. Women who had had a hysterectomy or oophorectomy, or who had undergone chemotherapy or radiation, were excluded from analysis.

The questionnaire was administered to each respondent in a face- to-face interview in women’s homes or an offset corner of a public space. Interviews were conducted in Mandarin Chinese by a team of eight local Chinese professional women following extensive training14.

Responses were coded numerically and entered into a database. Attitudinal items required special attention. After entry in raw form, attitudinal responses were coded on a scale of 1 to 4, with 4 representing the negative pole, and 1, the positive. Depending on the question, either agree or disagree was coded 4, with its opposite coded 1. ‘It depends’ was coded 3 as an ambivalent answer, and ‘unsure’ was coded 2 as a neutral response. These codes were multiplied by response frequency and added and then divided by four to create a negativity score for each item. A score close to 1.00 indicates a very positive attitude, near 4.00 a very negative one, and near 2.5 ambivalence or neutrality.

After coding, regression analysis was conducted to see if there was any relationship between checklist symptoms and either menopausal status, chronological age, the Menopause Attitudes score, or the Aging Attitudes score. Different techniques were used depending on the combination of continuous and categorical variables. Standard regression analysis was conducted when both outcome and predictor were continuous variables. Logistic regression was used when there was a dichotomous outcome and a continuous predictor. ANOVA-derived regression was used when both the dependent and independent variables were categorical.

RESULTS

Symptom frequency

Around one-half of the sample reported memory problems, feeling irritable and backache. Less than 10% reported night sweats, cold sweats and vaginal pain during sex (although three-quarters reported being sexually active12). A very low rate was found for all the vasomotor and vaginal symptoms, which were reported much less frequently than most sleep-related, cognitive, emotional, and somatic symptoms. The rate for hot flushes was slightly over 10% and, for vaginal dryness, under 15%. Difficulties sleeping were reported by about one-third. Within the cognitive and emotional categ\ories, around half of the sample reported memory problems and feeling irritable, but there were lower rates for difficulty concentrating, melancholy symptoms, and anxiety. Conceptually linked with the mid-life: transition in Japan and found in over one-half of mid-life Japanese women9, stiff shoulders was reported by less than 15% of the Chinese sample. (In interpreting the overall symptom frequencies given in Table 2, one needs to remember that over one- quarter of the sample was premenopausal and having regular menstrual periods (28.8%). Frequencies of six symptoms, including hot flushes, feeling tired, night sweats, insomnia, memory problems and anxiety, were significantly higher among periand postmenopausal women than in the overall sample including premenopausal women.)

Relationship of symptoms to menopausal status and age

Regression analysis showed that most of the 21 symptoms were not associated with menopausal status or chronological age (Table 3). However, night sweats, insomnia, memory problems, and anxiety were associated with both menopausal status and age, while hot flushes and feeling tired were related to menopausal status only. Although these were statistically significant relationships (p

Frequency of attitudes

On all 19 items on the Menopausal Attitudes Scale, the Chinese women gave more positive, neutral or ambivalent responses than negative ones. Reflecting this, their overall score on the Menopausal Attitudes Scale was 2.67. Six items exhibited a somewhat higher relative frequency of negative responses than typical for the rest of the scale; these items linked the end of menstruation with rapid aging, susceptibility to illness, senescence, feeling irritable and losing one’s temper. Comparing across menopausal status, there were relatively minor differences in the distribution of attitudes. The statement about the end of menstruation harming women’s health exhibited the largest difference, with premenopausal women giving the least positive response distribution. Across all items, the postmenopausal women had the most positive distribution of attitudes toward menopause (2.57) and the perimenopausal women the least (2.92), with the premenopausal women hovering in between (2.64).

With a score of 2.29 on the Aging Attitudes Scale, the Chinese women’s attitudes toward midlife aging were also mostly positive, neutral or ambivalent. Only one item out of 20 had a negative- leaning distribution; it was comprised of a well-known Chinese aphorism that, upon entering the mid-life transition, one lacks the energy and strength to do the things that one is interested in doing. In addition, six items with a positive distribution had more negative responses than typical. Three link middle age with rapid aging, susceptibility to illness, and regret over not realizing one’s aspirations. The others relate to losing one’s temper easily in the mid-life transition, being afraid of becoming a burden in old age, and younger generations not listening to their elders. The largest difference across age groups was displayed for a statement about women not noticing that they are aging if their lives are full of interesting activities, with women in their forties the least positive. Overall, there was a small difference by age in attitudes toward mid-life aging. Women in their fifties had the most positive attitudes toward aging (2.29) and women in their sixties the least positive (2.71), with the forty-somethings in between (2.45).

Table 3 Symptoms, menopausal status and age among 399 mid-life Chinese women between the ages of 40 and 65 years

On both scales, a large proportion of respondents replied either ‘it depends’ or ‘unsure’ instead of agreeing or disagreeing. In the interviews, many said that they did not know enough to state an opinion or that one could not generalize on these matters because every person or situation was different. Overall, the Chinese women’s score on the Menopause Attitudes Scale (2.67) was slightly less positive than on the Aging Attitudes Scale (2.29). This difference appears to be largely a function of menopause being seen as less salient in life than generic aging11, making for more unsure and ambivalent answers. In addition, the mixture of statements in the Aging Attitudes Scale may be more conducive to positive responses.

Relationship of symptoms to attitudes

Regression analysis showed some statistically significant associations (p

Table 4 Symptoms and attitudes among 399 mid-life Chinese women between the ages of 40 and 65 years

DISCUSSION

Frequencies of symptoms

Placing these symptom frequencies in crosscultural context, the hot flush rate among these Chinese women is considerably lower than the findings of many studies conducted in western countries; the rates of many other symptoms, however, are comparable4,15. A recent metaanalysis conducted by the National Institutes of Health summarized the sample frequencies for selected symptoms across numerous studies of mid-life women. They found a wide range of results, with anywhere from 14 to 80% for hot flushes, 4-39% for vaginal dryness, 16-60% for sleep disturbance, and 8-38% for mood symptoms16. This Chinese sample’s rate for hot flushes falls below the NIH range, but its rates are mid-range for vaginal dryness, sleep disturbance and most mood symptoms, except for irritability, which exceeds the NIH range. It is difficult to interpret these comparative results because of the tremendous methodological variation across studies comprising the NIH metaanalysis. Those studies differed in terms of the time frame specified for symptom recollection (e.g. previous 2 weeks/month/year, during menopause, ever before), the precise age span of the sample (e.g. age 45-55, 40- 60, 40-65 years), the stage(s) of the menopausal transition being examined, and whether surgically menopausal women were included. In this case, over one-quarter of the Chinese women were premenopausal and no surgically menopausal women were included, whereas, in the NIH meta-analysis, some studies did not have any premenopausal women and some included surgically menopausal women.

In this light, it must also be remembered that the 10.5% Chinese hot flush figure reported above is indexed to the previous 2 weeks. By contrast, the lifetime hot flush rate for the Chinese women in this present study was 32.4%, which is placed low-middle in the NIH range. This rate is similar to the lifetime rate found by Xu and colleagues17 in their 1990 community study of over 5000 mainland Chinese women also aged 40-65 years (36.8%). With respect to popular generalizations about Asian women, it is interesting to note that this Chinese rate is somewhat higher than the lifetime rate found among Japanese women (19.6%) by Lock18. Even when we limit the Chinese sample to the 45-55-year age range used in Lock’s Japan study, a higher relative Chinese lifetime hot flush rate remains (40.4%). This indicates that, while the short-term rate is similar for each sample (China 13.5%, Japan 12.3%), a different dynamic may operate over longer time frames.

Frequencies of attitudes

Overall, it was quite common for the Chinese women to express uncertainty concerning their attitudes toward menopause and women’s mid-life aging, probably due to little societal emphasis on the topic at the time of the study. Most either gave positive answers or said they didn’t know or ‘it depends’. The tendency among the Chinese women for attitudes toward menopause and aging to be positive, neutral or ambivalent is consistent with several other studies conducted in western and non-western countries9,19,20. Precise cross-cultural comparison of the results is difficult, however, because different studies have been based around varying attitudinal measures. Cross-cultural comparison of such attitudes is particularly challenging due to issues of translation, both in questionnaire design and in women’s interpretations of items.

The results on subgroup variation in Chinese women’s attitudes run in opposite directions with regard to Neugarten’s2 experiential hypothesis. The results of the present study support the notion that women’s views of menopause are more positive when personal experience is gained, but run counter to the idea that experience with generic aging mitigates negativity. These results underscore the importance of distinguishing menopause from aging in attitudinal measures; while overlap exists, there are important distinctions in women’s orientations toeach concept, a nuance often missed in the research literature.

Relationships between symptoms, menopausal status and age

In the recent NIH report16, the relationship between various symptoms and menopausal status was also examined. The NIH consensus was that most studies examined found that only hot flushes, night sweats, vaginal dryness and perhaps trouble sleeping are related to the menopausal transition. The finding of an association in the Chinese sample of menopausal status with hot flushes, night sweats and insomnia is consistent with the NIH analysis. The Chinese findings linking memory problems, anxiety and feeling tired with menopausal status, however, are not. This difference may be in part related to the fact that the NIH findings are a crossstudy generalization, de-emphasizing variation across populations.

As menopausal status and age naturally co-vary (Table 1), it is not surprising that there was considerable overlap in their symptom associations in the Chinese study. That said, there was a somewhat stronger relationship between the examined symptoms and menopausal status, as opposed to age. At the same time, however, none of the associations was large, perhaps because of the wide variety of factors that contribute to the production and expression of symptoms like these21.

Relationships between symptoms and attitudes

The Chinese results support the findings in other populations that women with negative attitudes toward menopause and aging tend to have higher levels of symptom reporting2-5,22,23. Furthermore, the Chinese study showed that negative attitudes accounted for almost twice as many symptoms as menopausal status and age did.

In some other studies, an association has been found between both menopausal status and women’s attitudes, at least for hot flushes4. In the Chinese study, hot flushes, night sweats, insomnia and anxiety were associated only with menopausal status and/or age and not with women’s attitudes. Lack of association between these symptoms and Chinese women’s attitudes may be related to how there was no strong conceptual association between these symptoms and female mid-life in China at the time. Instead, irritability was more strongly linked with notions of mid-life transition in China11,14. In this light, it is significant that irritability was associated only with women’s attitudes and not with menopausal status or age.

Limitations

This study is limited in several ways. First, as a cross- sectional study, it is uncertain whether relationships found here reflect a causal connection or just a correlation. Other factors co- varying with menopause and/or age may be the real mechanisms producing the experience and/or expression of these symptoms. Also, the direction of relationships is indeterminate. An association could mean that attitudes contribute to symptom production, but it could also mean that symptom experience shapes attitudes, or both.

Second, one of the attitudinal items on both scales – namely, the health-care statement – was interpreted by the Chinese respondents in two different ways, with a bearing on scoring. Observation revealed that most women took the statement as intended – that is, menopause is normal and natural, so women do not need extraordinary health-care measures. Some women, however, displayed a different interpretation. They retorted that older women have a right to health care and should not have to rely on taking care of themselves. These women did not necessarily see menopause as a time of sickness, but they felt that mid-life women deserved special treatment as much as anyone else. As a result, scoring this minority’s disagreement with this item as ‘negative’ is problematic. Similar issues with varied interpretation of attitudinal items may help to account for puzzling cross-ethnic results found with regard to Asian-American women in the US-based SWAN study24,25.

Third, these results cannot be assumed to be representative of all Chinese women. The sample size was modest, and the women studied were living in the capital region of the People’s Republic of China, an area considerably more developed economically than many other parts of China. In addition, sweeping social change has transformed China over the past decade since this study was conducted, and this cohort of women, born between 1928 and 1954, is quite different from later generations traversing mid-life. For example, mid-life women in China today tend to have had more lifetime exposure to formal educational opportunities, biomedical ideas and practices, and western media, diet and lifestyle.

Fourth, menopausal status was designated according to self- reported menstrual history, and hormonal assays were not taken in this study. It is unclear whether and how these women’s self- reports related to physiological changes in hormonal profile.

IMPLICATIONS AND DIRECTIONS FOR FUTURE RESEARCH

This study found that the mid-life Chinese women studied tended to have a lower prevalence of hot flushes, but a similar rate of reporting of many other symptoms, as compared to mid-life women in North America and many other western countries. The proclivity found among these Chinese women to eschew negative attitudes toward menopause and aging is consistent with several other studies conducted in both western and non-western countries, as is the link they demonstrated between negative attitudes and symptom reporting. Further research should investigate whether the low to moderate rate of symptom reporting and the relatively positive attitudes toward menopause and aging found in this study extend to current generations of mid-life women in the Beijing area and other regions of China. In addition, such research needs to examine whether there is a widespread tendency for negative attitudes toward menopause and aging among Chinese women to have a stronger association to symptom reporting than either menopausal status or chronological age do. In a broader context, more research is needed in a wide variety of settings world-wide to elucidate cross-cultural, ethnic and individual differences in women’s interpretations of various items commonly used in attitudinal scales on menopause and aging. Furthermore, additional information is needed on the degree to which various women differentiate their views of menopause from their views of aging. Such ethnographic knowledge is vital for understanding the local and individual meanings that may contribute to women’s experiences of mid-life and the production, expression and interpretation of symptoms therein.

ACKNOWLEDGEMENTS

Throughout the research, feedback was provided by James L. Watson, Arthur Kleinman, Rubie S. Watson, Michael Phillips and Xu Ling. Any errors are the author’s own.

Conflict of interest Nil.

Source of funding Financial support was provided by the Mellon Foundation, FLAS, CSCC, NSF, Chiang Chingkuo Foundation, NIMH, Cora DuBois Trust, Freeman Foundation, Lintilhac Foundation, Parimitas, and University of Vermont Dean’s Fund.

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18. Lock M. Contested meanings of the menopause. Lancet 1991;337:1270-2

19. Kaufert P, Gilbert P. Women, menopause, and medicalization. Cult Med Psych 1986;10:7-21

20. Woods NF, Mitchell ES. Symptom experiences of midlife women: observations from the Seattle Midlife Women’s Health Study. Maturitas 1996; 25:1-10

21. Martinez-Hernaez A. What’s Behind the Symptom? On Psychiatric Observation and Anthropological Understanding. Amsterdam: Harwood Academic, 2000

22. Avis, NE, Crawford, SL, McKinlay SM. Psychosocial, behavioral, and health factors related to menopause symptomatology. Women’s Health 1997;3:103-20

23. Perz JM. Psychological and social concomitants of the female menopause\: a longitudinal study. Maturitas 1997;27:82

24. Sommer B, Avis N, Meyer P, et al. Attitudes toward menopause and aging across ethnic/ racial groups. Psychosom Med 1999;61:868- 75

25. Avis N, Stellato R, Crawford S, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52:345-56

26. StataCorp, Stata Reference, A-F, College Station, Texas: Stata Press, 1997

J. L. Shea

Department of Anthropology, University of Vermont, Burlington, Vermont, USA

Correspondence: Professor J. L. Shea, Department of Anthropology, 515 Williams Hall, University of Vermont, Burlington, Vermont 05405, USA

Received 8-07-05

Revised 14-11-05

Accepted 18-11-05

ORIGINAL ARTICLE

2006 International Menopause Society

DOI: 10.1080/13697130500499914

Copyright CRC Press Feb 2006

By MacLennan, Alastair H; Sturdee, David W

So-called ‘bioidentical or bioequivalent hormones’ are increasingly being sold direct to women on the internet or through laboratories and compounding chemists, who encourage patients to obtain prescriptions for these unregistered and unproven concoctions from their doctor. Gullible doctors are often writing prescriptions dictated by outside agencies that have purportedly assessed the woman’s hormonal needs through salivary hormone testing. Women are being falsely informed on multiple internet sites or through media advertisements in various ways that ‘Bioidentical hormone therapy has all of the good effects of HRT with none of the severe side- effects that have caused so many women looking for menopause relief to steer away from traditionally administered HRT.’ Most sites start with fear tactics and may falsely represent the true risks of pharmaceutical HRT and then state or infer that their pharmacy- mixed hormones have similar or greater benefits, with no risk or no mention of risk. Quite correctly, they say that hormone therapies are best tailored to the individual and her needs, but the pseudo science is that they claim that a woman’s clinical need can be calculated from her saliva.

In truth, there is no scientific evidence to back claims for ‘bioidentical hormones’ that they have any advantage over conventional therapies, but there is evidence that they may sometimes be dangerous1. So-called ‘bioidentical’ hormones are claimed to be synthesized from many of the same sources as traditional HRT, e.g. yams. The hormone made by the ‘bioidentical’ manufacturer is often claimed to be ‘natural’ and, in advertisements, it is inferred that the identical estradiol, produced by the regulated pharmaceutical industry from the same yam source, is somehow different and not natural. Great play is often made of pharmaceutical estrogens produced from non-vegetable sources, e.g. equine estrogens, but there is little mention that these estrogens are mostly converted in the human into human estrogens. It should be clearly stated that there are no published peer-reviewed data to show that a single or multiple salivary hormone assays can accurately reflect the hormonal status or needs of a woman and, in particular, there has been no validation that they can be used to titrate hormone regimens to give an appropriate hormonal response. It is not been shown that hormonal blood levels are useful in adjusting hormonal therapies, and salivary levels also have not been correlated with clinical response. Most experienced clinicians realize that hormone regimens are best tailored by the clinical response and not by biochemistry reports.

The ‘bioidentical’ hormonal mixtures are compounded in buccal troches or transdermal creams and may contain estrogens (estrone, estradiol and estriol), progesterone, testosterone, dehydroepiandrosterone (DHEA), thyroxine, growth hormone and melatonin. Purveyors of these hormones use loopholes in some countries’ therapeutic goods regulations, where these hormones are either considered as complementary medicines (which are often poorly regulated) or where there are regulations that allow the importation of drugs that are not available in that country but are needed for a specific patient. In reality, the hormones are imported by compounding pharmacists before any patients are identified and, through various forms of advertising, women and doctors are attracted. Financial incentives are sometimes offered to doctors to prescribe the mixtures and to use laboratories, which claim without validation that they can effectively measure salivary hormones and thereby recommend the precise mixtures of hormones to be compounded to give the desired clinical effect.

The ‘bioidentica’ salesmen play on recent media hype about registered menopausal hormone therapies and the illusion that their hormones are somehow more ‘natural’ and therefore somehow safer than those synthesized by a pharmaceutical company. In reality, unlike the strict requirements for registered pharmaceutical products, the bioidentical products can be synthesized and imported without regulatory quality control evidence of purity, dosage, contamination, bioavailability, etc. They are compounded with other hormones and ingredients in local pharmacies without safety data concerning these combinations and doses and without adequate pharmacy audits of the compounding process. They are sold without evidence of the pharmacokinetics, clinical effect, sideeffects and drug interactions of these particular hormonal regimens. Some of the individual hormones used such as DHEA have not been approved by therapeutic regulatory authorities and have no quality data to justify their clinical use. In 2001, the FDA analyzed a variety of 29 product samples from 12 compounding pharmacies and found that 34% of them failed one or more standard quality tests2.

Wren and colleagues have conducted one of very few pharmacokinetic studies of bioidentical hormones delivered in a buccal troche and assessed both plasma and salivary levels, with the conclusion that salivary levels were highly variable and their accuracy and value were uncertain for therapeutic monitoring of hormonal therapy3. Wren and his colleagues also conducted a double- blind, randomized, controlled trial of transdermal progesterone cream, finding no clinical beneficial effect. Of greater concern, these authors found that this progesterone regimen had no measurable effect on the endometrium and thus would not suppress estrogen- induced endometrial proliferation4. There have been anecdotal reports of endometrial cancers following the use of bioidentical hormonal regimens containing ‘natural’ estrogens and progesterone. Thus, there is great concern that progesterone given by buccal or transdermal routes, in conjunction with estrogen, is not proven to suppress the risk of endometrial cancer induced by estrogen therapy. If the estrogens used in ‘bioidentical’ mixtures are the same and can reach bioequivalent serum levels, they are likely to have the same benefits as registered estrogens. However, they will also have the same risks. If the opposing progesterone used does not have a protective endometrial effect, it will have greater risks than conventional combined HRT.

The cost of the unproven ‘bioidentical hormones’ is usually several times greater than traditional menopausal hormone therapies and the patient often has to pay dearly for the salivary tests. Both the patient and her doctor may receive results of these assays from ‘hormone consultants’, whose qualifications are unknown, who have not seen the patient, and who give unvalidated interpretations of the results that they reflect abnormal adrenal, ovarian and/or thyroid function. In examples of these reports that we have seen, the ‘hormonal consultant’ advocates the precise hormonal mixtures and doses that the patient should obtain and the doctor should prescribe. This has huge medicolegal implications for the prescriber who takes the responsibility for the quality, risks and evidence for the use of this unregistered complementary and alternative therapy. In a recent Climacteric Editorial, Breen outlined the ethical responsibilities for those advocating and prescribing complementary medicines . The prescriber must inform the patient when a therapy is unproven, the patient must be fully informed of any risks associated with such therapy, access to proven therapies should not be denied, a second medical opinion should be offered if there are potential risks to an unproven and unconventional therapy, and doctors should not gain financially from the sale of these products.

Medical negligence could be claimed:

* If you were unaware of the published risks of the hormones in your prescription;

* If you have not fully informed your patient of these risks;

* If you were unaware of known drug interactions for these products;

* If you were unsure of the appropriate hormonal mixtures and doses you prescribed;

* If there is no supporting peer-reviewed academic data for your therapeutic regimen;

* If you had given the impression to the patient that ‘bioidentical hormones’ were safe.

There is some doubt that medical indemnity agencies will indemnify doctors if they prescribe unproven complementary products, especially if they have escaped any scrutiny by the relevant national therapeutic regulatory agency. In Australia, the Australasian Menopause Society wrote to the medical indemnity agencies in Australia and could not obtain any clear assurance that their members would be covered for the prescription of such products. The four agencies that replied had many caveats about the adequacy of evidence for the product and the extent that the patient was informed about its proven risks and benefits, and would not guarantee cover. Therefore, the prescriber may be at personal financial risk if litigation ensued because an adverse event, e.g. thromboembolism, was claimed to have been precipitated by ‘bioidentical’ therapy. In some countries, a doctor must be fully indemnified to be registered to practice medicine. So, they may also risk their medical registration. One wonders why prescribers of bioidentical hormones take such risks!

In Australia and the USA, there has been a recent proliferation of compounding chemists who have taken advantage ofpostmenopausal women’s need for and anxiety about conventional HRT and the loopholes in current legislation in these countries. These compounding pharmacies are now manufacturing ‘bioidentical’ hormonal mixtures and delivery systems in such proportions that they have effectively become a large, inadequately regulated pharmaceutical industry. It is time for the international drug regulatory authorities to regulate this industry, which is based on false promise, pseudo science and pecuniary interest without responsibility for the interests and health of the consumer.

References

1. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004;11:356-67

2. Beasley D. Use of “bioidentical” female hormones questioned. Reuters Health Information, Oct 31, 2005

3. Wren BG, Day RO, McLachlan AJ, Williams KM. Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric 2003;6:104-11

4. Wren BG, Champion SM, Willets K, et al. Transdermal progesterone and its effects on vasomotor symptoms, blood lipid levels, bone metabolic markers, mood, and quality of life for postmenopausal women. Menopause 2003;10:13-8

5. Breen KJ. Ethical issues in the use of complementary medicines. Climacteric 2003;6:268-72

Copyright CRC Press Feb 2006

By SEAN POULTER

A NEW brain disease in sheep might infect humans, Government experts have warned.

The condition is similar to mad cow disease and classic scrapie, a brain-wasting disease which has been known to exist in sheep for more than 100 years.

The discovery has triggered concerns that the public could be at risk from eating lamb, while Government experts are to consider slaughtering flocks of sheep where the disease is detected.

Last night the consumer group Which? demanded the Government tell the public whether there is a health concern.

They are calling for ‘urgent’ laboratory tests on both mice and monkeys to understand whether the disease can be transmitted to humans.

The Food Standards Agency also accepts there is a risk the disease could be passed to humans and is to discuss the issue at a board meeting next week.

The ‘mad sheep disease’ has been found in flocks raised in Britain and Europe, including France, Germany, Norway and Portugal.

In the last few days, two farms in central France have been quarantined after the disease was found in sheep sent for slaughter.

As many as 82,000 British sheep could be infected with the disease from a national sheep flock of 14million.

Which? chief policy adviser Sue Davies said: ‘We need urgent answers to the many uncertainties surrounding this finding so that there is a better understanding of whether there are any human health implications and, if so, whether existing control measures are adequate.’ There is no evidence that scrapie could pass to humans. However, the new atypical scrapie has different characteristics suggesting human transmission is possible.

The Government’s expert committee investigating human and animal brain diseases, SEAC, has issued a report flagging up its concerns.

Scientific tests to date suggest that brain tissue from infected sheep can pass on the disease to other sheep.

Consequently, other sheep tissue could also be a risk.

The SEAC report warns: ‘As atypical scrapie is experimentally transmissible, the possibility that it may be transmissible to humans must be considered.’

SEAC said that at the moment it is in the dark as to how the disease is spread between animals. However, it it said ‘the possibility that it has spread through feed cannot be excluded.’ SEAC concluded: ‘There is no evidence of a risk to human health, but a theoretical risk cannot be excluded.

‘Comparative transmission studies with humanised mice and other species including primates are urgently needed to inform on the potential risk to human health.’ The Food Standards Agency has signalled that it takes the warnings seriously.

A spokesman said: ‘The FSA has always been open about the uncertainty surrounding the possible risk of BSE and other brain diseases in sheep.

‘Much more work is needed before we can form a clearer picture of what, if any, risk there might be to people.

‘Whilst FSA advice remains that we are not advising people to stop eating sheep and goats, this issue will be discussed thoroughly by our board and kept under review as evidence emerges.’ The FSA is to look at measures necessary to reduce any risk to the public. This could involve slaughtering any flocks where cases are found.

[email protected]

By Karla Gale

NEW YORK (Reuters Health) – Increases in psychosocial
stress seem to increase a woman’s odd of having, or developing,
a vaginal infection termed bacterial vaginosis (BV),
researchers report.

“Bacterial vaginosis is a common condition that is not well
understood in terms of how women get it and what degree of harm
it causes, or even how you can prevent whatever harm it may be
causing,” Dr. Mark A. Klebanoff told Reuters Health.

There is evidence, added the researcher from the National
Institute of Child Health and Human Development in Bethesda,
Maryland, that BV increases the risks of HIV infection,
post-operative infection, and premature delivery among women
who are pregnant.

However, it is hard to eradicate and often recurs.

To gain a better understanding of the disease, Klebanoff
and his associates recruited 3614 women, between the ages of 15
to 44, who were not pregnant or on long-term antibiotic therapy
and had a normal immune system.

According to the team’s report in the American Journal of
Obstetrics and Gynecology, the subjects underwent pelvic
examinations quarterly for 1 year. The investigators found that
the likelihood of having BV was associated with age, race,
income, frequency of douching, frequency of vaginal
intercourse, number of recent sex partners, and the use of
hormonal contraceptives.

The investigators evaluated the subjects’ psychosocial
stress over the preceding 30 days at each examination using.

They also found that stress was linked to BV, with each
1-point increase on the Perceived Stress Scale (range 1.00 to
5.00) associated with a 1.15-fold greater risk of being
positive for BV.

“The magnitude of the effect is relatively small, but one
that is large enough to be meaningful,” co-researcher Dr. Tonja
R. Nansel, also with the NICHHD, told Reuters Health.

Stress may have immune-altering effects that affect the
risk of vaginosis, Klebanoff said, adding that “there is
plausible speculation that chronic stress is associated with
some local immune defects,” but further documentation will be
required.

He noted that the study is ongoing and the researchers are
still collecting a wide range of data, including hygiene
habits, sex behaviors, as well smoking, alcohol and drug use,
“to get a better handle on what factors are associated with BV,
and to see which ones might be amenable to treatment.”

SOURCE: American Journal of Obstetrics and Gynecology,
February 2006.