[Breast cancer in Finistère, France: epidemiological description and tendencies over a 10-year period (2000-2009) according to pathology data]. / Épidémiologie des cancers du sein dans le Finistère entre 2000 et 2009 à partir d'une base de données anatomopathologiques.

UNLABELLED: The aim of this study was the description of breast carcinoma over a 10-year period according to pathology data. METHOD: Descriptive epidemiological study based on data collection of pathological code ADICAP (injury, organ, and applied technical), histological, hormonal, node and administrative data. From January 1st 2000 to December 31st 2009, 6186 women living in Finistère have had a diagnosis of invasive breast carcinoma. The incidence rate involved from 125 per 100,000 women to 136 in 2009. Average age to the first diagnosis was 61.4 ± 13.6; class of age with the more important incidence rate was for the 50-74 years old. The different histological subtypes varied over the period (P<0.0001). Tumour's size was notified for more than 75% in the whole period of the study. The average size evolved significantly over the period (P<0.0001 from 23.5mm [± 18.4] in 2000 to 21.02 [± 16.2] in 2009, particularly after 2003 [P<0.0002]). The grade status (SBR, MSBR and Elston Ellis) showed a trend to the gravity decrease over the period (respectively P=0.03 [r(2)=-0,04]; P<0.0001 [r(2)=-0.10]; P<0.0001 [r(2)=-0.08]). CONCLUSION: Our results confirm the interest of pathology database for the description of invasive breast cancer.

Comparison of different commercial kits for HER2 testing in breast cancer: looking for the accurate cutoff for amplification.

INTRODUCTION: Accurate determination of human epidermal growth factor receptor 2 (HER2) status is essential for optimal patient management with trastuzumab (Herceptin). However, standard guidelines do not specify a particular commercial kit, antibody or probe for testing, and discrepancies arise from variability between kits. The aim of this study was to compare the accuracy of four commercially available fluorescence/chromogenic in situ hybridisation (FISH/CISH) kits and validate one for the resolution of borderline immunohistochemistry (IHC) cases. The interpretation pitfalls, optimal threshold values, assay duration and complexity of each kit were also considered. METHODS: The Food and Drug Administration (FDA)-approved dual-probe FISH assay PathVysion was chosen as the 'gold standard' against which pharmDx (dual-probe) and INFORM (mono-probe) FDA-approved FISH kits and the SPoT-Light CISH kit were compared. Tumours were also evaluated by IHC with the FDA-approved HercepTest kit and a validated in-house IHC protocol. Fifty-five patients with invasive breast carcinoma were selected as a representative proportion of HER2 IHC 2+ cases. RESULTS: HER2 amplification was observed in 31% of tumours by PathVysion compared with 33% with pharmDx. The number of amplified tumours detected by INFORM and CISH varied with the threshold applied. Agreement was excellent between PathVysion and pharmDx (100%), good with SPoT-Light (89%; cutoff at least five signals per nucleus) and moderate with INFORM (76%; cutoff more than four signals per nucleus). Agreement with INFORM improved to 98% with a cutoff of at least six signals per nucleus. CONCLUSION: With an appropriate cutoff, the INFORM kit was comparable to dual-probe FISH kits for evaluating HER2 status. We validate and recommend CISH as an appropriate assay for HER2 scoring that is easy to interpret and requires equipment readily found in, or that can be adapted to, all pathology laboratories. For borderline IHC cases, dual-probe FISH analysis remains the most useful protocol to apply.

Evolution of CFTR protein distribution in lung tissue from normal and CF human fetuses.

In order to determine whether or not CFTR protein distribution differs between the airways of fetuses with Cystic Fibrosis (CF) from the airways of normal fetuses we studied the distribution pattern of the CFTR protein in lung. Cases of normal and CF human fetuses as well as cases of normal neonates were examinated. Our aim was to establish whether CFTR expression during pregnancy could be correlated with the maturation of the airways, and to compare normal and CF samples. We hypothesized that any difference between normal and CF fetal lung in CFTR protein expression could be related to a functional change appearing in early development even if no morphological differences could be detected at the light microscopic level. The distribution of CFTR protein progressively increased from 10 weeks of gestation (WG) to mid-gestation, but thereafter decreased until term. The CFTR protein was first detected in the cytoplasm of undifferentiated epithelial cells. Before mid-gestation, the immunostaining was strongly positive in bronchi, in sub-mucosal glands, and in lung parenchyma. Then, it became localized to the apical zone of the epithelial cells. This pattern correlated with differentiation during the second half of gestation. The main difference observed between normal and CF fetuses was a 3-week delay in detectability of the CFTR protein expression in the latter until 15 weeks of gestation. These results support the hypothesis of an early functional change. Abnormal fetal lung CFTR protein regulation could give rise to a predisposition to the post-natal inflammatory changes of the airways that characterize CF disease.

[Treatment of squamous cell carcinoma of the pancreas with gemcitabine]. / Traitement d'un carcinome épidermoïde primitif du pancréas par gemcitabine.

Primary squamous cell carcinoma of the pancreas is a rare tumor. We report a case of a 49 years old patient with a metastatic squamous cell carcinoma of the pancreas. Histological diagnosis was established by echoguided biopsy of the liver. Due to that, we cannot be sure that this tumor was not adenosquamous with a metastatic component from only the squamous part of the lesion. Two types of chemotherapy have been performed. The first one was radiochemotherapy with an association of 5FU and cisplatinum. Gemcitabin was the second one. An objective response was obtained with gemcitabin and the patient's health improved. To our knowledge, this has never had been reported beforehand. However the prognosis of this cancer remains poor. Overall survival was 8 months.

Diagnosis and outcome of complete hydatidiform mole coexisting with a live twin fetus.

OBJECTIVE: The aim of this study was to highlight the outcome of complete hydatidiform mole (CHM) coexisting with a live co-twin. METHODS: We investigated four cases of such pregnancy by ultrasound, pathological, cytogenetic, and molecular techniques. Information on clinical follow-up and outcome was also available. RESULTS: All four pregnancies were spontaneous: two ended with the delivery of a live-born baby, while the other two were terminated because of signs of serious maternal pathology or intrauterine fetal death. The criteria for carrying on with the pregnancy are reviewed. The immediate outcome depends on the maternal criteria of serious pathology and on the likelihood of intrauterine fetal death. The risk of persistent trophoblastic disease (PTD) is the same as in the case of a singleton complete mole and also seems to be correlated with the zygosity mechanism identified by molecular analysis. CONCLUSION: Hydatiform mole with a live co-twin fetus is a rare obstetric occurrence. In the case of a normal fetal karyotype, it is justifiable to await developments in the absence of maternal complications. However, treatment criteria still need improvement and diligent maternal follow-up is always warranted in the postpartum period.

Factors associated with liver steatosis and fibrosis in chronic hepatitis C patients.

UNLABELLED: Liver steatosis is a common finding in patients infected with hepatitis C virus (HCV). Host and viral factors have been associated with steatosis, but their relative contributions have not been clearly addressed. It has been suggested that steatosis plays a role in the progression of liver fibrosis. AIMS: To assess: a) factors associated with steatosis in patients infected with hepatitis C virus; b) their impact on liver fibrosis. PATIENTS AND METHODS: Three hundred and fourteen untreated patients were included. Lifetime alcohol consumption was estimated. Liver fibrosis, inflammation and necrosis were assessed using the METAVIR score. Body mass index (BMI) was determined. The scoring system for steatosis was as follows: 0, no steatosis; 1, less than 10%; 2, 10% to 30%; 3, 30% to 70%; 4, more than 70% of hepatocytes affected. RESULTS: In univariate analysis, steatosis was associated with elevated BMI (P=0.001), excessive alcohol intake (P=0.005), genotype 3 (P<0.001) and moderate to severe histological activity (P=0.01). Multivariate analysis showed that steatosis correlated with two independent factors: genotype 3a (OR=60.7; 95% CI: 7.6-483.4) (P<0.001) and BMI (OR=4.86; 95% CI: 1.8-13.15) (P=0.002). In univariate analysis, severe fibrosis (F2-F3-F4) was associated with older age (P<10(-5)), male gender (P=0.001), disease duration (P<0.006), BMI (P<10(-4)), alcohol intake (P<10(-6)), severity of histological activity (P<10(-5)) and steatosis (P<10(-6)). In multivariate analysis, three independent factors were associated with severe fibrosis: disease duration > 10 years (OR=3.17; 95% CI: 0.65-15.4) (P=0.015), presence of steatosis (OR=3.17; 95% CI: 1-9.99) (P<0.049) and genotype 3a (OR=5.56; 95% CI: 1.4-22.1) (P=0.015). CONCLUSION: In patients with chronic hepatitis C, steatosis is significantly associated with genotype 3 infection and high BMI. Steatosis is an independent risk factor associated with severe fibrosis. These results have major implications for the management of patients with chronic hepatitis C.

Morphological and immunohistochemical pattern of tubo-ovarian dysplasia and serous tubal intraepithelial carcinoma.

OBJECTIVE: Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous "ovarian dysplasia" and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls. STUDY DESIGN: Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO). RESULTS: Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p<0.0001, for ovaries and 6.54 vs 1.58, p<0.0001 for tubes). Increased γH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs. CONCLUSION: The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.

Mixture of hyaluronic acid, chondroitin 6 sulphate and dermatan sulphate used to completely regenerate bone in rat critical size defect model.

Skeletal bone losses are mainly filled with autologous graft or artificial materials. Osteoblasts are essential to maintain bone homeostasis and bone repair through a matrix synthesis. We have previously demonstrated that adherence and regenerative matrix composition are fundamental to bone healing, even in critical situations. In this work the critical size defect technique was used to evaluate the systemic activity on bone regeneration of a novel mixture of extracellular polysaccharides. A 5mm diameter hole was made in each parietal bone of male Wistar rats. The right parietal bone hole was filled with a mixture of hyaluronic acid, chondroitin 6 sulphate, and dermatan sulphate mixed with 2.5% NaCl solution, while the left hole was left free of material and untreated and considered as control. Twenty-one days after surgery, the holes and surrounding tissues were examined visually, using X-rays, and by histological staining. Using the matrix substitute, bone healing was almost complete after 21 days in the treated hole and always complete in the control side due to some systemic effect. Neovascularization was also observed along with organized trabecular bone on both sides. No abnormal bone growth or connective tissue abnormalities were noted. At the end of the experiment, 95.1% (± 3.2) bone healing (n=20) was observed on the treated side; conversely, healing bone and histological structure were better on the control side.

Is There a Relationship between Ovarian Epithelial Dysplasia and Infertility?

Aim. Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies performed in patients at genetic risk of ovarian cancer. Similar histopathological abnormalities have been revealed after ovulation stimulation. Since infertility is also a risk factor for ovarian neoplasia, the aim of this study was to study the relationship between infertility and ovarian dysplasia. Methods. We blindly reviewed 127 histopathological slides of adnexectomies or ovarian cystectomies according to three groups-an exposed group to ovulation induction (n = 30), an infertile group without stimulation (n = 35), and a spontaneously fertile control group (n = 62)-in order to design an eleven histopathological criteria scoring system. Results. The ovarian dysplasia score was significantly higher in exposed group whereas dysplasia score was low in infertile and control groups (resp., 8.21 in exposed group, 3.69 for infertile patients, and 3.62 for the controls). In the subgroup with refractory infertility there was a trend towards a more severe dysplasia score (8.53 in ovulation induction group and 5.1 in infertile group). Conclusion. These results raise questions as to the responsibility of drugs used to induce ovulation and/or infertility itself in the genesis of ovarian epithelial dysplasia.

Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer.

PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) -positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer. PATIENTS AND METHODS Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point. Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71). CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.