Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

A recombinant Listeria monocytogenes vaccine expressing a model tumour antigen protects mice against lethal tumour cell challenge and causes regression of established tumours.

Listeria monocytogenes is an intracellular organism that has the unusual ability to live in the cytoplasm of the cell. It is thus a good vector for targeting protein antigens to the cellular arm of the immune response. Here we use a model system, consisting of colon and renal carcinomas that express the influenza virus nucleoprotein and a recombinant L. monocytogenes that secrets this antigen, to test the potential of this organism as a cancer immunotherapeutic agent. We show that this recombinant organism can not only protect mice against lethal challenge with tumour cells that express the antigen, but can also cause regression of established macroscopic tumours in an antigen-specific T-cell-dependent manner.

In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression.

Downregulation of major histocompatibility complex (MHC) class I expression is an important mechanism by which tumors evade classical T cell-dependent immune responses. Therefore, a system was designed to evaluate parameters for active immunization against MHC class I- tumors. Mice were capable of rejecting a MHC class I- tumor challenge after immunization with an irradiated granulocyte/macrophage colony-stimulating factor (GM-CSF) transduced MHC class I- tumor vaccine. This response was critically dependent on CD4+ T cells and natural killer (NK) cells, but minimally on CD8+ T cells. A strong protective response against MHC class I+ variants of the tumor could be elicited when mice were immunized with irradiated MHC class I+ GM-CSF-secreting tumor cells. This response required CD4+ and CD8+ T cells, and in addition, elimination of NK cells resulted in outgrowth of tumors that had lost expression of at least one MHC class I gene. Finally, class I MHC expression on the vaccinating cells inhibited the response generated against a MHC class I- tumor challenge. These results demonstrate that the host is capable of being immunized against a tumor that has lost MHC class I expression and reveal conditions under which distinct effector cells play a role in the systemic antitumor immune response.

CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease.

C3H/HeJBir mice are a new substrain that spontaneously develop colitis early in life. This study was done to determine the T cell reactivity of C3H/HeJBir mice to candidate antigens that might be involved in their disease. C3H/HeJBir CD4+ T cells were strongly reactive to antigens of the enteric bacterial flora, but not to epithelial or food antigens. The stimulatory material in the enteric bacteria was trypsin sensitive and restricted by class II major histocompatibility complex molecules, but did not have the properties of a superantigen. The precursor frequency of interleuken (IL)-2-producing, bacterial-reactive CD4+ T cells in colitic mice was 1 out of 2,000 compared to 1 out of 20,000-25,000 in noncolitic control mice. These T cells produced predominately IL-2 and interferon gamma, consistent with a T helper type 1 cell response and were present at 3-4 wk, the age of onset of the colitis. Adoptive transfer of bacterial-antigen-activated CD4+ T cells from colitic C3H/HeJBir but not from control C3H/HeJ mice into C3H/HeSnJ scid/scid recipients induced colitis. These data represent a direct demonstration that T cells reactive with conventional antigens of the enteric bacterial flora can mediate chronic inflammatory bowel disease.

Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4.

The generation of antigen-specific antitumor immunity is the ultimate goal in cancer immunotherapy. When cells from a spontaneously arising murine renal cell tumor were engineered to secrete large doses of interleukin-4 (IL-4) locally, they were rejected in a predominantly T cell-independent manner. However, animals that rejected the IL-4-transfected tumors developed T cell-dependent systemic immunity to the parental tumor. This systemic immunity was tumor-specific and primarily mediated by CD8+ T cells. Established parental tumors could be cured by the systemic immune response generated by injection of the genetically engineered tumors. These results provide a rationale for the use of lymphokine gene-transfected tumor cells as a modality for cancer therapy.

Prospective endoscopic evaluation for gastrointestinal graft-versus-host disease: determination of the best diagnostic approach.

The best endoscopic diagnostic strategy for gastrointestinal (GI) graft-versus-host disease (GVHD) is unknown. Over a 48-month period, all patients with unexplained diarrhea at risk for acute gastrointestinal GVHD were prospectively identified. Acute GVHD was defined as symptoms and histologic evidence of GVHD occurring within 100 days of transplant or donor lymphocyte infusion (DLI). Colonoscopy was performed with multiple biopsies of the ileum, right colon and rectosigmoid colon. Next, upper endoscopy with duodenal and random gastric biopsies of both antrum and body were performed. All biopsies were evaluated for GVHD by an experienced GI pathologist. Over the study period, 24 patients (mean age 37 years; 62.5% male) were evaluated. The median time from transplantation or DLI was 30.5 days. The biopsy site with the highest yield was the distal colon (82%). A combination of upper endoscopy with sigmoidoscopy and colonoscopy with ileal biopsies were equivalent ( approximately 94%). In patients with diarrhea at risk for GVHD, biopsies of the distal colon had the highest diagnostic yield suggesting the importance of sigmoidoscopy and biopsy. Colonoscopy and ileoscopy or flexible sigmoidoscopy plus upper endoscopy had the highest diagnostic yields.

Controlled release, biodegradable cytokine depots: a new approach in cancer vaccine design.

Experimental studies using murine tumor models have demonstrated that potent systemic immunity can be generated using tumor vaccines engineered by gene transfer to secrete certain cytokines. The underlying physiological principle behind these strategies involves the sustained release of high doses of cytokine at the site of the tumor. In some cases, this paracrine approach appears to enhance tumor antigen presentation and avoids systemic cytokine toxicity. The widespread clinical use of autologous cytokine gene transduced tumor vaccines may be limited by the technical difficulty and labor intensity of individualized gene transfer. We have therefore explored an alternate approach to generating sustained release of cytokines local to the tumor cells. High doses of granulocyte-macrophage colony-stimulating factor encapsulated in cell-sized gelatin-chondroitin sulfate microspheres were mixed with irradiated tumor cells prior to s.c. injection. This vaccination scheme resulted in systemic anti-tumor immune responses comparable to granulocyte-macrophage colony-stimulating factor gene transduced tumor vaccines.

Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

Graft-versus-host-like colitis associated with malignant thymoma.

A case of a patient with a malignant thymoma who developed an unusual form of colitis is reported. The patient was a previously healthy 20-year-old man who was referred to the Johns Hopkins Medical Institution for biopsy and resection of a mediastinal mass, which proved to be a malignant thymoma. During this hospitalization and subsequently, the patient developed severe chronic diarrhea, the etiology of which remained uncertain after routine work-up, including cultures. Colonoscopic biopsies revealed only minimal inflammation but numerous, prominent apoptotic lesions within crypt epithelium, suggestive of an autoimmune or graft-versus-host-like colitis. The patient, who was immunocompetent and human immunodeficiency virus (HIV) negative, had no known risk factors for graft-versus-host-disease (e.g., no blood transfusions, no transplantation history before diarrheal episodes). Stool cultures for pathogenic bacteria and viruses were negative. The diarrhea and histologic findings eventually improved with steroid therapy yet returned on recurrence of the thymoma. This unusual form of colitis has not been previously reported to be associated with thymoma and is interesting in light of the role the thymus plays in immune regulation.

Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at the Johns Hopkins Hospital.

Collagenous colitis is a relatively rare disorder presenting mainly in middle-aged women as watery diarrhea. Endoscopic and radiographic studies of the colon are usually normal, and diagnosis must be made by biopsy. The characteristic biopsy findings are a combination of increased mucosal inflammation (collagenous colitis) as well as subepithelial collagenous thickening. The mucosal inflammatory changes include increased lamina propria plasma cells, prominent intraepithelial lymphocytes, and in some cases, numerous eosinophils. The collagenous thickening has qualitative as well as quantitative differences from normal, and may be highlighted by Masson trichrome stains. Simply quantitating the thickness of a subepithelial collagen layer is neither adequate nor necessary for the diagnosis of collagenous colitis. Major problems in diagnosing collagenous colitis arise from focusing solely on the subepithelial region without attention to inflammatory changes. For example, tangential sectioning of normal colon results in an artifactually thickened basement membrane, and such cases have been wrongly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus subepithelial collagenization, rather than focusing on any single feature in isolation.

Lymphocytic ("microscopic") colitis: a comparative histopathologic study with particular reference to collagenous colitis.

Lymphocytic colitis, previously termed "microscopic colitis", is a clinicopathologic syndrome of watery diarrhea, grossly normal colonoscopy, and mucosal inflammatory changes. Since lymphocytic colitis is a new, incompletely characterized entity, a histopathologic study was performed to compare lymphocytic colitis (n = 16), collagenous colitis (n = 17), idiopathic inflammatory bowel disease (n = 16), acute colitis (n = 16), and histologically normal colon (n = 12). The study was a blinded semiquantitative analysis of histologic features in the surface epithelium, lamina propria, and crypts. The most distinctive feature of lymphocytic colitis was increased intraepithelial lymphocytes, particularly in the surface epithelium (P = .0001 v idiopathic inflammatory bowel disease, acute colitis, and normal colon). Other prominent features of lymphocytic colitis included surface epithelial damage (P less than .005 v idiopathic inflammatory bowel disease and normal colon), increased lamina propria chronic inflammation (P less than .01 v normal), and minimal crypt distortion or active cryptitis. There were striking similarities between lymphocytic colitis and collagenous colitis, but subepithelial collagen thickening was seen only in collagenous colitis. Idiopathic inflammatory bowel disease showed prominent crypt distortion and greater active inflammation, in addition to minimal intraepithelial lymphocytes. Acute colitis occasionally demonstrated prominent surface epithelial damage, but was otherwise dissimilar from lymphocytic colitis. We reached the following conclusions: (1) the entity "microscopic colitis" shows characteristic histopathology including prominent lymphocytic infiltration of epithelium, and thus, a more appropriate designation is lymphocytic colitis; (2) although lymphocytic colitis closely resembles collagenous colitis, each entity is distinct on biopsy; and (3) lymphocytic colitis is readily distinguishable from idiopathic inflammatory bowel disease, acute forms of colitis, and normal colorectum.

A prospective trial of telepathology for intraoperative consultation (frozen sections).

Telepathology is a maturing technology that, for a variety of reasons, has not been widely deployed. In addition, clinical validation is relatively modest compared with accepted telemedicine applications such as teleradiology. A prototype telepathology system (Tele-Path(sm)) featuring high-resolution images selected from a remote microscope site has been developed at the University of Alabama at Birmingham (UAB). To validate the diagnostic efficacy of the system, a prospective study was undertaken of parallel diagnoses by conventional microscopy and telepathology with a remotely operated microscope. Slides from 99 intraoperative consultations from 29 tissue/ organ sites in the University of Alabama Hospitals by 9 academic pathologists were used in the study. Each microscopic and telepathology diagnosis was compared with the final diagnosis rendered by a referee pathologist. Diagnoses were classified as correct, false positive, or false negative or classification error. Of the 99 frozen sections evaluated, 3 cases were deferred. Of the remaining 96 cases, 2 received incorrect diagnoses in both the microscopic and telepathology arms of the study. Three errors occurred only in the telepathology arm. There was 1 false-positive diagnosis, 1 false-negative diagnosis, and 1 classification error. Statistical analysis indicated no significant difference between telepathology and conventional microscopy. Qualitative data indicated that the pathologists were generally satisfied with the performance of the system. Telepathology using this system paradigm is sufficiently accurate for real time utilization in a complex surgical environment. Telepathology therefore may be an effective model to support the surgical services of hospitals lacking full-time pathology coverage, resulting in full-time access to anatomic pathology services.

Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study.

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the "no-majority" group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388.

Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation.

Morphologic assessment of dysplasia in Barrett esophagus, despite limitations, remains the basis of treatment. We rigorously tested modified 1988 criteria, assessing intraobserver and interobserver reproducibility. Participants submitted slides of Barrett mucosa negative (BE) and indefinite (IND) for dysplasia, with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and with carcinoma. Two hundred fifty slides were divided into 2 groups. The first 125 slides were reviewed, without knowledge of the prior diagnoses, on 2 occasions by 12 gastrointestinal pathologists without prior discussion of criteria. Results were analyzed by kappa statistics, which correct for agreement by chance. A consensus meeting was then held, establishing, by group review of the index 125 slides, the criteria outlined herein. The second 125-slide set was then reviewed twice by each of the same 12 pathologists, and follow-up kappa statistics were calculated. When statistical analysis was performed using 2 broad diagnostic categories (BE, IND, and LG v HG and carcinoma), intraobserver agreement was near perfect both before and after the consensus meeting (mean kappa = 0.82 and 0.80). Interobserver agreement was substantial (kappa = 0.66) and improved after the consensus meeting (kappa = 0.70; P =.02). When statistical analysis was performed using 4 clinically relevant separations (BE; IND and LGD; HGD; carcinoma), mean intraobserver kappa improved from 0.64 to 0.68 (both substantial) after the consensus meeting, and mean interobserver kappa improved from 0.43 to 0.46 (both moderate agreement). When statistical analysis was performed using 4 diagnostic categories that required distinction between LGD and IND (BE; IND; LGD; HGD and carcinoma), the pre-consensus meeting mean intraobserver kappa was 0.60 (substantial agreement), improving to 0.65 after the meeting (P <.05). Interobserver agreement was poorer, with premeeting and postmeeting mean values unchanged (kappa = 0.43 at both times). Interobserver agreement was substantial for HGD/carcinoma (kappa = 0.65), moderate to substantial for BE (kappa = 0.58), fair for LGD (kappa = 0.32), and slight for IND (kappa = 0.15). The intraobserver reproducibility for the diagnosis of dysplasia in BE was substantial. Interobserver reproducibility was substantial at the ends of the spectrum (BE and HG/carcinoma) but slight for IND. Both intraobserver and interobserver variation improved overall after the application of a modified grading system developed at a consensus conference but not in separation of BE, IND, and LGD. The criteria used by the group are presented. HUM PATHOL 32:368-978.

Special histologic stains are rarely beneficial for the evaluation of HIV-related gastrointestinal infections.

During a 28-month period, endoscopic mucosal biopsy specimens from all HIV-infected patients were submitted for routine histologic evaluation. Immunoperoxidase staining for cytomegalovirus and herpesvirus antigens (esophagus), mycobacterial and fungal staining, and Gram staining of mucosal biopsy specimens were done. Special fungal and acid-fast stains were selectively performed in patients with absolute CD4 cell counts of less than 200 cells per microliter (200 x 10(6)/L) and/or with diarrhea and or wasting syndrome. Treatment was based on the endoscopic and histologic findings, and long-term follow-up was performed. The 121 symptomatic HIV-infected patients underwent 221 upper and/or lower endoscopies with 285 biopsy sites. The sensitivity and specificity of H&E staining for the diagnosis of gastrointestinal cytomegalovirus were 97% and 100%, respectively. The results of fungal and mycobacterial stains neither altered therapy nor identified previously undiagnosed infections in any patient. Long-term follow-up revealed no patient in whom an infection was missed on routine H&E, which affected outcome. Routine H&E staining is accurate for the diagnosis of gastrointestinal opportunistic infections in HIV-infected patients. Special histologic stains for fungal, mycobacterial, and viral infections did not increase the diagnostic yield or alter medical therapy but doubled the costs.

Inferential language in high-function children with autism.

Despite average verbal intelligence, high-function children with autism have social comprehension deficits that are expressed by how they use and understand language. In this paper, we explored the general hypothesis that high-function children with autism make some, but not all, of the pragmatic inferences necessary for successful communication, even when they have the ability to perform noninferential language tasks. We contrasted the ability of 8 high-function children with autism (each with Verbal IQ > 70) and typically developing children to use and understand: pragmatic inferences about given or presupposed knowledge in mental state words; pragmatic inferences about new or implied knowledge in mental state words; bridging inferences essential for coherence; elaborative inferences involved in enriching a communication by means of figurative language; and the intentional inferences involved in speech acts. High-function children with autism could define words and identify multiple meanings for ambiguous words. In understanding words for mental states, they made inferences from mental state verbs to given or presupposed knowledge. However, they failed to infer what mental state verbs implied in context; to make inferences about social scripts; to understand metaphor; and to produce speech acts, all of which are inferences that are the basis of successful social communication because they elaborate meaning or convey intentions.

Intelligence patterns among children with high-functioning autism, phenylketonuria, and childhood head injury.

High-functioning children with autistic-spectrum disorder show the typical pattern of lower Comprehension relative to their own scores on Block Design. This profile is shared, almost exactly, by age- and IQ-matched children with poorer control PKU. Quite distinct profiles are shown by children with better control PKU, who show no difference between Block Design and Comprehension, and by children with head injury involving frontal lobe contusion, who show slightly better Comprehension that Block Design. The data bear on several questions: the relation between Comprehension deficits and language functions measured by Vocabulary; the limits of the advantages conveyed by higher IQ to autistic individuals; whether impaired Comprehension in autism indexes persisting symptoms and/or impairments on theory of mind tasks; the possibility that dopamine deficiency is common to autism and poorer control PKU; and the need for future research aimed at understanding the relations among neurodevelopmental disorders.

Carcinoid tumor of the hepatic duct presenting as a Klatskin tumor in an adolescent and review of world literature.

This is a case presentation of a 14-year-old boy with the radiological diagnosis of cholangiocarcinoma occluding the hepatic duct bifurcation. His only symptom at presentation was jaundice and further workup confirmed a mass at the porta hepatis. Surgical treatment resulted in a resection of the hepatic bifurcation tumor with a final pathological diagnosis of a carcinoid tumor of the hepatic duct bifurcation. To our knowledge, this is only the second case presented of a resected carcinoid tumor in adolescence. In this communiqué we present the above case and review of the world literature of biliary neuroendocrine tumors.

Prevalence of polycystic ovary syndrome in women seeking treatment from community electrologists. Alabama Professional Electrology Association Study Group.

OBJECTIVE: To determine the prevalence of the polycystic ovary syndrome (PCOS) among women seeking electrology, clients presenting to nine electrology centers completed a questionnaire. STUDY DESIGN: Women with potential risk factors were referred to the University of Alabama at Birmingham. They underwent a detailed history and physical examination, including hirsutism scoring by a modified Ferriman-Gallwey (F-G) method. Serum was assayed for total testosterone, sex hormone binding globulin and dehydroepiandrosterone sulfate. RESULTS: Three hundred fifteen (40%) of 779 patients had potential risk factors for hyperandrogenism and were referred. Eighty-two (26%) completed their evaluation. Six were excluded secondary to prepubertal or menopausal status. Of the remaining 76 patients, 20% had F-G scores of 7 or 8, 13% had scores of 9 or 10, and 21% had scores > 10. Forty-nine (64%) patients reported irregular menstrual cycles. Sixty-four patients were not receiving hormonal therapy: 25 reported regular menstrual cycles, and 39 reported irregular cycles. Seventeen (68%) of the 25 had at least one abnormal androgen value, while 33 (85%) of the 39 women had at least one abnormal value (nonsignificant difference). Overall, PCOS was evident in 39 of the 76 women, or 12% of the 315 patients who were referred for further evaluation. CONCLUSION: Thirty-nine of the 315 referred patients (12%) fulfilled the diagnostic criteria for PCOS. However, they were not receiving medical care for this condition. In addition, this percentage is a conservative estimate in that 74% of the referred patients did not pursue a medical evaluation. Therefore, efforts to educate both electrologists and their clients of the possibility of underlying endocrine disorders and subsequent metabolic morbidity should be undertaken.