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Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

Objective: To perform a head to head comparison of these two nomograms by an external validation combined with an identification of probability cut-offs when to indicate NS., Methods: The full models of the nomograms of Ohori et al. and Steuber et al. were used to calculate the risk of ECE based on PSA and side specific information on clinical stage, biopsy Gleason score, % positive cores, and % cancer in cores. A dataset of 968 prostate half lobes was used retrospectively for analysis. All patients underwent laparoscopic robot-assisted or open radical prostatectomy for localized prostate cancer., Results: The predictive accuracy of the Ohori nomogram was at 0.80 and for the Steuber Nomogram at 0.78 (comparison P > 0.05). In the calibration plot, the Ohori nomogram showed less departures from ideal predictions than the Steuber nomogram. The best probability cut-off to allow NS for the Ohori nomogram seemed to be ≤ 10%, permitting NS in 59.7% of all cases and being associated with a false negative rate of 10%. The best cut-off for the Steuber nomogram seemed to be ≤ 8%, permitting NS in 44% and associated with a false negative rate 12.5%., Conclusions: The Ohori et al. and the Steuber et al. nomograms allow highly accurate and comparable predictions of the risk of side specific ECE., Level of Evidence: 4., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Unlabelled: A prospective study was lead in order to analyze the accuracy of an X-ray device settled in the operating room for margin assessment, when performing breast-conserving surgery., Patients and Methods: One hundred and seventy patients were included. All lesions were visible on the preoperative mammograms. An intraoperative X-ray of the lumpectomy specimen was systematically performed for margins assessment. Final histological data were collected and the accuracy of intraoperative specimen radiography (IOSR) for margin assessment was analyzed., Results: IOSR allowed an evaluation of margins status in 155 cases (91.2%). After final histological examination, the positive margins rate would have been 6.5% if margin assessment had relied only on IOSR., Conclusion: Margin assessment with a two-dimensional X-ray device would have allowed the achievement of negative margins in 93.5% of the cases. Moreover, this procedure allows important time-saving and could have a substantial economical impact., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Elderly patients with metastatic breast cancer have a prognosis and outcome that may be dependent on a host of factors., Patients and Methods: We retrospectively analyzed 401 female breast cancer patients who developed metastatic disease after the age of 70 years in order to define potential prognostic factors for specific survival at the time of first recurrence., Results: With a median follow-up of 60 months from the time of recurrence, the median specific survival was 21.0 months (95% CI 17.0-23.0). In multivariate analysis we demonstrated that negative hormonal receptor status (p = 0.002), presence of positive lymph nodes at initial cancer diagnosis (hazard ratio, HR = 1.37; 95% CI 1.07-1.75; p = 0.01), site of metastasis (p < 10(-4)) and metastasis-free interval (HR = 0.99; 95% CI 0.95-0.99; p = 0.008) constituted unfavorable independent prognostic factors able to predict specific survival from the time of metastatic occurrence. Age at initial diagnosis, Scarff-Bloom Richardson grade and adjuvant treatments were significant only in univariate analysis., Conclusion: These survival prognostic factors associated with the use of a specific geriatric questionnaire to assess frailty may assist physicians in evaluating the patient's survival potential and choose a tailored treatment to this cancer population.

Purpose: To analyze dose-volume histogram parameters and pathologic response after preoperative high-dose-rate brachytherapy (HDRB) for high-risk early stage cervical cancers (ESCCs)., Methods and Materials: From June 2007 to December 2011, 32 patients with a histologically proven invasive cervical cancer with high risk of local recurrence (size >2cm, adenocarcinoma type, perineural and/or lymphovascular invasion) underwent a preoperative HDRB, which delivered a total dose of 39Gy in nine fractions over 5 days. All the patients underwent hysterectomy after HDRB., Results: With a median clinical target volume of 50cc (minimum-maximum, 42-74), the median V100 was 49cc (minimum-maximum, 42-50). Median D90 was 45Gy (equivalent dose at 2Gy per fraction, 56Gyαβ10). Median D2cc was 34Gy, 31Gy, 28Gy, and 38Gyαβ3 for bladder, rectum, sigmoid, and vagina, respectively. Twenty-eight patients (88.5%) achieved a complete histologic response after surgery, whereas for the 4 remaining patients, residual tumor cells (3 patients) and gross residual disease (1 patient) were observed in the pathologic specimen. With a median followup of 24 months (minimum-maximum, 5-48), no local recurrence was observed; 1 patient died of intercurrent cause. Early toxicity occurred within the 30 days after HDRB (Common Terminology Criteria for Adverse Events v3.0) was G1 diarrhea for 15 patients (47%) and G1 urinary frequency or urgency for 13 patients (40.6%). No G2-G3 toxicities were noticed., Conclusions: Preoperative HDRB for high-risk ESCCs represents a well-tolerated procedure, which leads to a high rate of postoperative pathologic response. Dose-volume histogram parameters were at least equivalent to those obtained with a low-dose-rate procedure. Long-term results will help to analyze the place of preoperative brachytherapy in the management of high-risk ESCCs., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Sunitinib is a standard of care for metastatic renal cell carcinoma (mRCC). Hypothyroidism is frequently observed under sunitinib therapy. This study was conducted to prospectively determine the correlation between thyroid function and progression-free survival (PFS) in this population., Patients and Methods: One hundred and eleven mRCC patients treated with sunitinib were evaluated for serum thyroid-stimulating hormone (TSH) and T4 levels before treatment and every 6 weeks during treatment. Survival was analysed according to a landmark method with a cut-off of 6 months, excluding early progressive or early-censored patients., Results: Out of the 102 patients with normal baseline thyroid function, 53% developed thyroid dysfunction, including 95% hypothyroidisms out of which 90.9% received L-thyroxine replacement. Median time to TSH alteration was 5.4 months. Median PFS was 11.7 months for the entire population. Median PFS was not different between the groups with abnormal or normal thyroid function after 6 months of treatment (18.9 and 15.9 months, respectively, log-rank P = 0.94, hazard ratio = 1.02, 95% confidence interval = 0.54-1.93). There was no difference even after adjustment for Memorial Sloan-Kettering Cancer Centre classification and therapy line., Conclusions: Abnormal thyroid function with hormonal substitution did not increase survival in our population, independent of initial prognosis and previous treatments. Larger comparative studies are deserved to validate these conclusions.

Background/aim: We describe the incidence of Guillain-Barré syndrome (GBS) in a large United States cohort., Methods: Between 2000 and 2009, we identified visits with an ICD-9 code for GBS (357.0) from all persons with continuous enrollment for at least 1 year. The primary case definition was restricted to emergency department and inpatient visits. We calculated age-standardized rates and used multivariate Poisson regression to assess variation in rates by sex, age, season and year of diagnosis. We tabulated descriptive characteristics and the positive predictive value (PPV) for a subset of the visits with available medical record review., Results: 1,619 visits with the GBS ICD-9 code were identified from 50,290,898 person-years of observation. After considering the PPV (55%) for record-reviewed visits, the age-standardized incidence rate was approximately 1.72/100,000 person-years. The rate was 40% higher for males and increased by 50% for every 10-year increase in age. The rate was 15% higher in winter and spring compared with summer. Rates were higher in more recent years., Conclusions: GBS rates are higher in males and increase considerably with age. The potential reasons for differences in rates by season and the increased rates in more recent years should be further investigated., (Copyright © 2012 S. Karger AG, Basel.)

Introduction: Conventional grey scale ultrasound has only limited sensitivity and specificity in the detection of prostate cancer. Real time elastography is a promising modality to overcome this problem. The goal of the current study was an evaluation of real time elastography for the correct detection of prostate cancer lesions in prostatectomy specimens., Patients and Methods: Between 11/2008 and 05/2009, 28 patients diagnosed with prostate cancer and scheduled for radical prostatectomy underwent real time elastography before radical prostatectomy. Elastography was performed using a Hitachi(®) EUB 7500 ultrasound machine with a V53W rectal probe at 7,5MHz by one operator. During the exam, each prostate was partitioned into 12 sectors (anterior, posterior, left, right, base, middle gland, apex). Suspect zones were identified and filed depending on their localization. The prostatectomy specimens were processed according to the Stanford protocol in 3-5mm step sections. The preoperative and postoperative results regarding tumor localization were compared., Results: In total, 88 cancer lesions could be identified in the prostatectomy specimen, where 125 sectors were positive for a total of 336 sectors evaluated. Based on elastography 134 suspicious sectors were identified. For real time elastography, the sensitivity and specificity for correct cancer identification were 73.4 and 79.0 %, respectively. The negative and positive predictive value was 83.4 and 67.4 %, respectively. Accuracy for correct identification of the tumor lesion was 76.5 %., Conclusion: In this study, real time elastography showed high accuracy in the identification of prostate cancer lesions in the prostate. Routine use of elastography could improve the diagnosis of prostate cancer, as well as the therapeutic management., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Introduction: Focal therapy of prostate cancer is gaining more and more interest. One of the drawbacks of focal therapy of prostate cancer is the problem of correct identification of prostate cancer lesions. The aim of the study was to evaluate the ability of real-time elastography to correctly identify the prostate cancer index lesion., Materials and Methods: In 32 patients, real-time elastography was performed the day before prostatectomy. During the examination, the location of the main lesion suspicious for prostate cancer was prospectively recorded. Moreover, the results of the randomized multicore biopsies were also used to predict the location of the index lesion. The preoperative elastography results, the biopsy results, and a combined use of elastography and biopsy results were then compared with the pathological results to calculate the diagnostic values for correct index lesion identification., Results: When using real-time elastography alone to identify the prostate cancer index lesion, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 58.8, 43.3, 54.1, 48.1, and 51.6%, respectively. Data from randomized biopsies alone achieved 67.8, 48.4, 56.8, 60.0, and 58.1%, respectively. The combination of elastography and biopsy data increased the values to, respectively, 84.9, 48.4, 61.9, 75.0, and 66.1%., Conclusion: In this study, real-time elastography alone did not allow to identify the prostate cancer index lesion with satisfactory reliability. The combination of real-time elastography and data from randomized 12 core biopsies allows promising ability to correctly identify the prostate cancer index lesion.

Objective: Exposure to thimerosal, a mercury-containing preservative that is used in vaccines and immunoglobulin preparations, has been hypothesized to be associated with increased risk of autism spectrum disorder (ASD). This study was designed to examine relationships between prenatal and infant ethylmercury exposure from thimerosal-containing vaccines and/or immunoglobulin preparations and ASD and 2 ASD subcategories: autistic disorder (AD) and ASD with regression., Methods: A case-control study was conducted in 3 managed care organizations (MCOs) of 256 children with ASD and 752 controls matched by birth year, gender, and MCO. ASD diagnoses were validated through standardized in-person evaluations. Exposure to thimerosal in vaccines and immunoglobulin preparations was determined from electronic immunization registries, medical charts, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We used conditional logistic regression to assess associations between ASD, AD, and ASD with regression and exposure to ethylmercury during prenatal, birth-to-1 month, birth-to-7-month, and birth-to-20-month periods., Results: There were no findings of increased risk for any of the 3 ASD outcomes. The adjusted odds ratios (95% confidence intervals) for ASD associated with a 2-SD increase in ethylmercury exposure were 1.12 (0.83-1.51) for prenatal exposure, 0.88 (0.62-1.26) for exposure from birth to 1 month, 0.60 (0.36-0.99) for exposure from birth to 7 months, and 0.60 (0.32-0.97) for exposure from birth to 20 months., Conclusions: In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs.

Objective: We report our experiences regarding the peri- and postoperative complications as well as pathological and functional results of robot-assisted radical prostatectomy during the implementation phase and the learning curve of the technique., Material: All clinical, paraclinical, as well as peri- and postoperative events of the first 102 patients were filed. Postoperative complications were classified according to the Clavien classification. Regarding functional results, continence was defined as the use of 0 pads or one pad for security reasons. Erectile function was classified into absence of spontaneous erections, erections insufficient for sexual intercourse and erections sufficient for sexual intercourse., Results: Median procedure time was 240min, blood-loss 400mL and transfusion rate 2%. Overall, 7.8% of all patients had perioperative complications, 13.7% had minor and 4.9% had mayor post operative complications. The overall positive surgical margin rate was 16.0%. At 12month, 87% of all patients were continent and 21.1% had spontaneous erections and 47.4% had sexual intercourse., Conclusion: Patients treated during the implementation phase of robot-assisted radical prostatectomy show rates of peri- and postoperative complications, as well as pathological and functional results comparable to the results of centers of excellence published in the literature., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background: Medullary thyroid cancer (MTC) is characterized by early regional lymph node metastasis, the presence of which represents a critical obstacle to cure. At present no molecular markers have been successfully integrated into the clinical care of sporadic MTC. The present study was designed to evaluate TP53INP1 expression in MTC and to assess its ability to guide the surgeon to the optimal extent of surgery performed with curative intent., Methods: Thirty-eight patients with sporadic MTC were evaluated. TP53INP1 immunoexpression was studied on embedded paraffin material and on cytological smears., Results: TP53INP1 was expressed in normal C cells, in C-cell hyperplasia, and in 57.9% of MTC. It was possible to identify two groups of MTC according to the proportion of TP53INP1 expressing tumor cells: group 1 from 0% to <50% and group 2 from 50% to 100% of positive cells. Patients with a decreased expression of TP53INP1 (group 1) had a lower rate of nodal metastasis (18.8% versus 63.4% in group 2; P = 0.009), with only minimal lymph node involvement per N1 patient (2.7% of positive lymph nodes versus 22.9%; P < 0.001) and better outcomes (100% of biochemical cure versus 55.5%; P < 0.001). Patients with distant metastases were only observed in group 2. Cytological samples exhibit similar results to their embedded counterparts., Conclusions: TP53INP1 immunoexpression appears to be a clinical predictor of lymph node metastasis in MTC. The evaluation of TP53INP1 expression may guide the extent of lymph node dissection in the clinically node-negative neck. These findings require prospective validation.

Background: Cystic pancreatic endocrine tumors (PETs) are rare neoplasms with a preoperative diagnostic challenge. The aim of this study was to evaluate the preoperative diagnostic strategy for these tumors and to assess the clinical and pathologic characteristics., Methods: Six cases of cystic PET were retrospectively enrolled. Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) was performed in 4 cases. All cytomorphologic data from conventional smears, ThinPrep preparations, and cell block preparations were reported in detail., Results: There were 3 male and 3 female patients with a mean age of 52.3 years. Tumor size ranged from 10 mm to 60 mm (mean, 29.8 mm). EUS-FNAB contributed to an accurate diagnosis in all cases. Cytologically, loosely cohesive aggregates and single cells were predominant. Cells were small and typically plasmacytoid, with occasional cytoplasmic vacuolization. Nuclei were round or oval, uniform, with finely and evenly distributed chromatin. Immunocytochemistry confirmed the endocrine differentiation. Histologic findings were typical for endocrine proliferation. All tumors were well differentiated., Conclusions: Cystic PET is an unusual finding that presents diagnostic challenges for both endoscopists and cytologists. EUS-FNAB with the Thinprep preparation technique and cell block material were found to be helpful in improving diagnostic accuracy. Immunocytochemical staining with endocrine markers confirmed the diagnosis., (2009 American Cancer Society.)

Multicystic peritoneal mesothelioma is a rare lesion occurring mainly in women in a reproductive age. Its pathogenesis is unclear. We report three cases of multicystic peritoneal mesothelioma in patients that were 28, 38 and 47 years of age (one male, two females). A history of abdominal surgery was reported in two cases. Explorative laparotomy was presumptive of a pseudomyxoma peritoni in two cases, and hyperthermic intraperitoneal chemotherapy was performed. Histological examination demonstrated multicystic lesions with mesothelial cells lining confirmed by immunohistochemical analysis. Unusual findings such as hyperplasia, hobnail features, cytoplasmic vacuolisation and papillary pattern were occasionally noted. The clinical presentation, pathogenesis and pathologic features including differential diagnosis of multicystic peritoneal mesothelioma are discussed.

Background: Erlotinib is an orally active small-molecule tyrosine kinase inhibitor targeted against human epidermal growth factor receptor 1/epidermal growth factor receptor (ErbB1), known to be overexpressed in a variety of cancers, including prostate cancer., Patients and Methods: This was a phase II monocentric study of 30 patients with advanced or metastatic prostate cancer, 29 had castration-resistant prostate cancer and 23 had received prior chemotherapy. Patients received erlotinib: 150 mg/day, increased to 200 mg at week 4, and continued until progression or unacceptable toxicity. Efficacy was defined as a decrease or stabilization of prostate-specific antigen (PSA) without clinical progression. Clinical benefit was evaluated by Karnofsky performance status and pain intensity, and response was an improvement in one of these parameters without worsening in the other., Results: Median age was 69 years (range 51-77 years), and median PSA 102 ng/ml (range 3-1213 ng/ml). Dose escalation to 200 mg was possible in 16 (55%) patients. Moderate toxicity was observed. No patient had a decrease in PSA, 14% had stabilization, less than the >or=20% expected. PSA-doubling time, evaluated before and after erlotinib, was increased for 10 patients (P = 0.0058). Clinical benefit was achieved in 40% of patients., Conclusion: Erlotinib demonstrated an improvement in clinical benefit. Future directions should include evaluating its use in less advanced prostate cancer.

Background: The measles-mumps-rubella vaccine has been associated with immune thrombocytopenia purpura in 2 small studies., Methods: By using the Vaccine Safety Datalink, we identified measles-mumps-rubella-vaccinated children aged 1 to 18. A case of immune thrombocytopenia purpura was defined as a patient with a platelet count of < or = 50,000/microL with clinical bleeding and normal red and white blood cell indices. The immune thrombocytopenia purpura incidence rates during exposed (42 days after vaccination) and unexposed time periods were determined. A retrospective cohort of vaccinated children was used to determine incident rate ratios for children aged 1 to 18 years, 12 to 23 months, and 12 to 15 months., Results: A total of 1,036,689 children received 1,107,814 measles-mumps-rubella vaccinations; there were 259 confirmed patients with immune thrombocytopenia purpura. Because only 5 exposed cases occurred after age 2, analyses were limited to children aged 12 to 23 months. Exposed patients aged 12 to 23 months had lower median platelet counts than those who were unexposed and had similar median duration of illness (11 vs 10 days). The incident rate ratio was highest for children aged 12 to 15 months at 7.10. The incident rate ratio for boys aged 12 to 15 months was 14.59, and the incident rate ratio for girls in the same age group was 3.22. Seventy-six percent of immune thrombocytopenia purpura cases in children aged 12 to 23 months were attributable to measles-mumps-rubella vaccination. This vaccine causes 1 case of immune thrombocytopenia purpura per every 40,000 doses., Conclusion: Measles-mumps-rubella vaccine that is given in the second year of life is associated with an increased risk of immune thrombocytopenia purpura.

Background: Whole-cell pertussis (wP) and measles vaccines are effective in preventing disease but have also been suspected of increasing the risk of encephalopathy or encephalitis. Although many countries now use acellular pertussis vaccines, wP vaccine is still widely used in the developing world. It is therefore important to evaluate whether wP vaccine increases the risk of neurologic disorders., Methods: A retrospective case-control study was performed at 4 health maintenance organizations. Records from January 1, 1981, through December 31, 1995, were examined to identify children aged 0 to 6 years old hospitalized with encephalopathy or related conditions. The cause of the encephalopathy was categorized as known, unknown or suspected but unconfirmed. Up to 3 controls were matched to each case. Conditional logistic regression was used to analyze the relative risk of encephalopathy after vaccination with diphtheria-tetanus-pertussis (DTP) or measles-mumps-rubella (MMR) vaccines in the 90 days before disease onset as defined by chart review compared with an equivalent period among controls indexed by matching on case onset date., Results: Four-hundred fifty-two cases were identified. Cases were no more likely than controls to have received either vaccine during the 90 days before disease onset. When encephalopathies of known etiology were excluded, the odds ratio for case children having received DTP within 7 days before onset of disease was 1.22 (95% confidence interval [CI] = 0.45-3.31, P = 0.693) compared with control children. For MMR in the 90 days before onset of encephalopathy, the odds ratio was 1.23 (95% confidence interval = 0.51-2.98, P = 0.647)., Conclusions: In this study of more than 2 million children, DTP and MMR vaccines were not associated with an increased risk of encephalopathy after vaccination.

Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.

Immunocytochemistry (ICC) of thyroid peroxidase (TPO) using the monoclonal antibody MoAb47 has been used as malignancy marker on thyroid fine needle aspiration. However, little is known about the fate of TPO in thyroid carcinoma. We performed a qualitative PCR (Q-PCR) analysis to measure the expression of variants of tpo mRNA in 13 normal tissue samples, 30 benign tumors (BT), 21 follicular carcinomas (FC), 20 classical papillary carcinomas (PCc), 12 follicular variants of papillary carcinomas (PCfv) and nine oncocytic carcinomas (OC). We also studied mutations involving the ras, Braf, ret or pax8 genes. Results of Q-PCR were closely correlated with those of ICC (P < 0.0001; R = 0.59) and showed that overall tpo expression was lower in all carcinomas than in normal and BT (P < 0.05). The ratio tpo2 or tpo3 to tpo1 was inversed in follicular tumors. Genetic mutations were observed in 90% of PCc, 61.9% of FC, 41.7% of PCfv, 0% of OC and 10% in BT. pax8-ppar gamma1 rearrangement was correlated with qualitative changes in tpo mRNA (P < 0.01). These results confirmed the decrease of TPO expression in 97% of thyroid carcinomas regardless of histological type and the overexpression of shorter splice variants in follicular tumors. Both reduction in quantity of TPO and impairment of its maturation process could account for the atypical immunohistochemical reaction of MoAb47 with TPO.

Background: Medullary thyroid carcinoma (MTC) is a rare disease, with variable tendency to lymphatic spread. The aim of this retrospective study was to identify distinctive features of large MTC with and without nodal metastases., Methods: Between 1993 and 2003, 28 consecutive patients underwent total thyroidectomy and neck node dissection for sporadic MTC larger than 10 mm in diameter., Results: All tumours were confirmed to be malignant with a locally invasive pattern of growth. Lymph node metastases were present in 16 patients (N1) and absent in 12 (N0). There were no statistically significant differences between patients with N0 and N1 tumours concerning age (mean 52.1 versus 53.4 years), male:female ratio (0.7 versus 1.0), basal preoperative calcitonin concentration (mean 3238 versus 3076 pg/ml) and tumour size (23.3 versus 23.9 mm). There were differences in the incidence of tumour invasion (P < 0.001), vascular embolism (P = 0.011) and peritumoral thyroiditis (P = 0.039). Measurement of basal and stimulated calcitonin levels after surgery confirmed biochemical cure in all patients with N0 tumours and half of those with N1 disease (P = 0.006)., Conclusion: There were no preoperative factors that predicted node status for MTC larger than 1 cm in this series. Total thyroidectomy and nodal dissection remains the optimal treatment.

Like children exposed to Chernobyl fallout, the workers who cleaned up after the accident, also known as liquidators, have exhibited an increased incidence of thyroid cancer. A high prevalence of ret/PTC3 rearrangement has been found in pediatric post-Chernobyl thyroid tumors, but this feature has not been investigated in liquidator thyroid tumors. In this study we analyzed the prevalence of ret/PTC1 and ret/PTC3 in thyroid tumors from 21 liquidators, 31 nonirradiated adult Ukrainian patients, and 34 nonirradiated adult French patients. ret rearrangements in carcinomas were found in 83.3% of liquidators, 64.7% of Ukrainian patients, and 42.9% of French patients. The prevalence of ret/PTC1 was statistically similar in the three groups. The prevalence of ret/PTC3 was significantly higher in liquidators than in French patients (P = 0.03) but it was also high in nonirradiated Ukrainian patients who exhibited values intermediate between liquidators and French patients. In adenomas the prevalence of rearrangement was significantly higher in all Ukrainians than in French patients (P = 0.004). Like children exposed to Chernobyl fallout, liquidators showed a high prevalence of ret/PTC3. This finding suggests that irradiation had the same effect regardless of age. However, given the high rate of ret/PTC3 in nonirradiated adult Ukrainians, the possibility of genetic susceptibility or low-level exposure to radiation in that group cannot be excluded.

Data on five allergic conditions were abstracted from the medical records of 180 cases of childhood acute lymphoblastic leukaemia (ALL) and 718 matched controls. Odds Ratios (OR) and 95% Confidence Intervals (CI) were estimated for composite variables and for individual allergies using conditional logistic regression modelling. Allergies were divided into late and early diagnoses (those made within the year before the matched case's ALL diagnosis and those made earlier, respectively). Among the early diagnoses, atopy or hives was significantly associated with ALL (OR=2.20; 95% CI: 1.16-4.16). Significant associations were found for late diagnoses of atopy or hives (OR=3.78; 95% CI: 1.00-14.29) and of asthma (OR=3.10; 95% CI: 1.39-6.95). None of the other allergic conditions were associated with ALL. These results are contrary to those of prior studies of childhood ALL and allergy.

We report a case of signet ring cell carcinoma of the pancreas. This rare variant of ductal adenocarcinoma is composed exclusively of signet ring neoplastic cells in a mucinous stroma. Altogether, clinical, radiological and immunohistochemical data supported the pancreatic origin of the tumor.

Objective: To assess the level of increased risk, if any, of hospitalizations for aseptic meningitis after Jeryl-Lynn mumps strain measles-mumps-rubella (MMR) vaccine in the Vaccine Safety Datalink population., Study Design: A possible increased risk of aseptic meningitis 8 to 14 days after receipt of MMR was observed in a preliminary screening analysis of automated data from the Vaccine Safety Datalink (VSD) project Year 2 analysis. To further evaluate this association a retrospective 10-year matched case-control study was undertaken in the four health maintenance organizations (HMOs) in the VSD project. Cases ascertained from a broad scan of the automated data were validated against a standard case definition. Two controls matched on age, sex, HMO and HMO membership were assigned per case., Results: The VSD project involves the cooperative collection of automated vaccination and medical outcome data from four large HMOs that currently have 500,000 children younger than 7 years of age under surveillance. Review of automated screening results from the first 2 years of data revealed a possible increased risk of aseptic meningitis 0 to 14 days after MMR with a relative risk of 3.61 (95% confidence interval, 1.0 to 13.1) although the total number of cases was small. Although the automated data had suggested a possible association of aseptic meningitis with MMR containing the Jeryl-Lynn strain of mumps, review of validated hospitalized cases during the observation period did not reveal evidence of an increased risk of aseptic meningitis after MMR containing the Jeryl-Lynn strain of mumps (odds ratio < 1.0 for all analyses)., Conclusion: Although it is recognized that hospitalized cases represent a minority of the total cases of aseptic meningitis, it is reassuring that in this evaluation no increased risk of aseptic meningitis after MMR vaccine was found.

Direct revascularisation of the foot permits the healing of distal trophic lesions. This is not always possible with a by-pass on a single isolated popliteal segment. When multi-segmental occlusive arterial lesions were found in femoral, popliteal and distal arteries sequential by-pass grafting was used to improve distal runoff. During a 5 year period (1988-1992), 53 sequential by-passes were performed in 52 patients with severe ischemia manifested by rest pain (17) or trophic lesions (36). Autogenous saphenous vein was used in 36 (10 reversed, 26 in-situ), homologous saphenous in 3 and composite (PTFE+saphenous) in 14. Proximal anastomosis was performed on 29 common femoral, 20 superficial femoral and 4 popliteal arteries. Intermediary anastomosis was performed on 6 above-knee and 31 below-knee popliteal arteries and on 16 distal arteries. All distal anastomoses were performed on distal arteries (13 cases on malleolar arteries). The mean follow-up was 18 months. Thirteen patients died during this period (mean 8.5 months after the surgery). Primary and secondary patency were respectively 66 and 79% over one year and 51 and 76% over two years. Limb salvage was obtained in 89% over one year and 86% over 2 years. Sequential by-pass is a useful alternative for limb salvage. This approach offers several hemodynamic advantages and may be the best procedure in patients with poor distal runoff.

Doctor ratings of clerkship performance are often discounted as not accurately reflecting clinical competence. Such ratings are influenced by the following uncontrolled variables: case difficulty; differing rater focus and standards; lack of agreement on what constitutes acceptable performance; and collective patient care responsibility masks individual contributions. Standardized direct measures of clinical competence were developed to control these factors and allow direct comparisons of student performance. Students saw 18 patients representing frequently occurring and important patient problems. Student actions and decisions were recorded and subsequent responses to questions revealed knowledge of pathophysiology, basis for actions, use and interpretation of laboratory investigations, and management. Actions and responses were graded using a pre-set key. The examination covered 73% of designated clinical competencies. Examinations scores corresponded with independent measures of clinical competence. Reliability studies indicated that new cases can be substituted in subsequent years with confidence that scores will maintain similar meaning. Costs are +6.95 per student per case, which is modest considering the quality and quantity of information acquired. Methods described are practical for evaluation of clerks and residents and for licensing and specialty certification examinations.

The accuracy and reproducibility of the standardized patient's presentation of a clinical problem was evaluated in 15 cases used in the evaluation of fourth year medical students in two universities. There were differences in the quality of standardized patient presentation between institutions and among the cases presented.