Deep Learning for Detecting BRCA Mutations in High-Grade Ovarian Cancer Based on an Innovative Tumor Segmentation Method From Whole Slide Images.

BRCA1 and BRCA2 genes play a crucial role in repairing DNA double-strand breaks through homologous recombination. Their mutations represent a significant proportion of homologous recombination deficiency and are a reliable effective predictor of sensitivity of high-grade ovarian cancer (HGOC) to poly(ADP-ribose) polymerase inhibitors. However, their testing by next-generation sequencing is costly and time-consuming and can be affected by various preanalytical factors. In this study, we present a deep learning classifier for BRCA mutational status prediction from hematoxylin-eosin-safran-stained whole slide images (WSI) of HGOC. We constituted the OvarIA cohort composed of 867 patients with HGOC with known BRCA somatic mutational status from 2 different pathology departments. We first developed a tumor segmentation model according to dynamic sampling and then trained a visual representation encoder with momentum contrastive learning on the predicted tumor tiles. We finally trained a BRCA classifier on more than a million tumor tiles in multiple instance learning with an attention-based mechanism. The tumor segmentation model trained on 8 WSI obtained a dice score of 0.915 and an intersection-over-union score of 0.847 on a test set of 50 WSI, while the BRCA classifier achieved the state-of-the-art area under the receiver operating characteristic curve of 0.739 in 5-fold cross-validation and 0.681 on the testing set. An additional multiscale approach indicates that the relevant information for predicting BRCA mutations is located more in the tumor context than in the cell morphology. Our results suggest that BRCA somatic mutations have a discernible phenotypic effect that could be detected by deep learning and could be used as a prescreening tool in the future.

Immune alveolitis in interstitial lung disease: an attractive cytological profile in immunocompromised patients.

BACKGROUND: Bronchoalveolar lavage (BAL) is a major diagnostic tool in interstitial lung disease (ILD). Its use remains largely quantitative, usually focused on cell differential ratio. However, cellular morphological features provide additional valuable information. The significance of the "immune alveolitis" cytological profile, characterized by lymphocytic alveolitis with activated lymphocytes and macrophages in epithelioid transformation or foamy macrophages desquamating in cohesive clusters with lymphocytes, remains unknown in ILD. Our objective was to describe patients' characteristics and diagnoses associated with an immune alveolitis profile in undiagnosed ILD. METHODS: We performed a monocentric retrospective observational study. Eligible patients were adults undergoing diagnostic exploration for ILD and whose BAL fluid displayed an immune alveolitis profile. For each patient, we collected clinical, radiological and biological findings as well as the final etiology of ILD. RESULTS: Between January 2012 and December 2018, 249 patients were included. Mean age was 57 ± 16 years, 140 patients (56%) were men, and 65% of patients were immunocompromised. The main etiological diagnosis was Pneumocystis pneumonia (PCP) (24%), followed by drug-induced lung disease (DILD) (20%), viral pneumonia (14%) and hypersensitivity pneumonitis (HP) (10%). All PCP were diagnosed in immunocompromised patients while HP was found in only 8% of this subgroup. DILD and viral pneumonia were also commonly diagnosed in immunocompromised patients (94% and 80%, respectively). CONCLUSION: Our study highlights the additional value of BAL qualitative description in ILD. We suggest incorporating the immune alveolitis profile for the diagnosis and management of ILD, especially in immunocompromised patients, since it guides towards specific diagnoses.

Complete post-mortem data in a fatal case of COVID-19: clinical, radiological and pathological correlations.

A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse crazy-paving lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.

The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).

BACKGROUND: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). METHODS: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). RESULTS: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). CONCLUSIONS: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. TRIAL REGISTRATION: Not applicable.

[PD-L1 testing in non-small cell lung carcinoma: Guidelines from the PATTERN group of thoracic pathologists]. / Tests immunohistochimiques PD-L1 dans les cancers du poumon non à petites cellules : recommandations par le groupe PATTERN de pathologistes thoraciques.

Lung cancer is the leading cause of cancer death in France with low response rates to conventional chemotherapy. Nevertheless, new therapies have emerged recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck & Co), or PD-L1 ICI, such as atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, Astra-Zeneca), and avelumab (BAVENCIO®, EMD Serono). The prescription of pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients requires the demonstration of PD-L1 expression by tumor cells by immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is now considered as a companion diagnostic tool for this drug. Numerous standardized PD-L1 assays performed on dedicated platforms have been validated in clinical trials, each antibody being associated to one specific PD1 or PD-L1 inhibitor. However, not all pathologists have access to the dedicated platforms and the high cost of these assays is still a limitation to their implementation; in addition, the small size of the NSCLC tumor samples does not allow to perform at the same time multiple assays for multiple drugs. The use of laboratory-developed tests seems feasible but their validation must guarantee the same sensitivities and specificities as standardized tests. In this context, the French group of thoracic pathologists PATTERN has teamed up with thoracic oncologists to provide recommendations on the indication, the critical technical steps and the interpretation of the PD-L1 IHC test to help pathologists to implement quickly and in the best conditions this new theranostic test.

Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma.

Mesenchymal stem cell (MSC) immunosuppressive functions make them attractive candidates for anti-inflammatory therapy in allergic asthma. However, the mechanisms by which they ensure therapeutic effects remain to be elucidated. In an acute mouse model of house dust mite (Der f)-induced asthma, one i.v. MSC injection was sufficient to normalize and stabilize lung function in Der f-sensitized mice as compared to control mice. MSC injection decreased in vivo airway responsiveness and decreased ex vivo carbachol-induced bronchial contraction, maintaining bronchial expression of the inhibitory type 2 muscarinic receptor. To evaluate in vivo MSC survival, MSCs were labeled with PKH26 fluorescent marker prior to i.v. injection, and 1 to 10 days later total lungs were digested to obtain single-cell suspensions. 91.5 ± 2.3% and 86.6 ± 6.3% of the recovered PKH26(+) lung cells expressed specific macrophage markers in control and Der f mice, respectively, suggesting that macrophages had phagocyted in vivo the injected MSCs. Interestingly, only PKH26(+) macrophages expressed M2 phenotype, while the innate PKH26(-) macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26(+) MSCs expressed 10- to 100-fold more COX-2 than before injection, suggesting in vivo MSC phenotype modification. Together, the results of this study indicate that MSCs attenuate asthma by being phagocyted by lung macrophages, which in turn acquire a M2 suppressive phenotype. Stem Cells 2016;34:1836-1845.

Food allergy enhances allergic asthma in mice.

BACKGROUND: Atopic march refers to the typical transition from a food allergy in early childhood to allergic asthma in older children and adults. However the precise interplay of events involving gut, skin and pulmonary inflammation in this process is not completely understood. OBJECTIVES: To develop a mouse model of mixed food and respiratory allergy mimicking the atopic march and better understand the impact of food allergies on asthma. METHODS: Food allergy to ovalbumin (OVA) was induced through intra-peritoneal sensitization and intra-gastric challenge, and/or a respiratory allergy to house dust mite (HDM) was obtained through percutaneous sensitization and intra-nasal challenges with dermatophagoides farinae (Der f) extract. Digestive, respiratory and systemic parameters were analyzed. RESULTS: OVA-mediated gut allergy was associated with an increase in jejunum permeability, and a worsening of Der f-induced asthma with stronger airway hyperresponsiveness and pulmonary cell infiltration, notably eosinophils. There was overproduction of the pro-eosinophil chemokine RANTES in broncho-alveolar lavages associated with an enhanced Th2 cytokine secretion and increased total and Der f-specific IgE when the two allergies were present. Both AHR and lung inflammation increased after a second pulmonary challenge. CONCLUSION: Gut sensitization to OVA amplifies Der f-induced asthma in mice.

[Pre-analytical stage for biomarker assessment in breast cancer: 2014 update of the GEFPICS' guidelines in France]. / Recommandations du GEFPICS concernant la phase pré-analytique pour l'évaluation de HER2 et des récepteurs hormonaux dans le cancer du sein : mise à jour 2014.

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.

[2014 update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France]. / Mise à jour 2014 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers du sein en France.

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.

Impact of PD-L1 Expression on the Overall Survival of Caucasian Patients with Advanced EGFR-Mutant NSCLC Treated with Frontline Osimertinib.

BACKGROUND: The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI. OBJECTIVE: We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment. METHODS: Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis. RESULTS: Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9). CONCLUSIONS: Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.

Margin width should not still enforce a systematic surgical re-excision in the conservative treatment of early breast infiltrative ductal carcinoma.

BACKGROUND: In cases where breast conservative surgery was performed for infiltrative ductal carcinoma (IDC), margin status is an independent prognostic factor for local ipsilateral relapse (LIR). There is no validated definition of a clear margin. We investigated factors associated with residual disease on re-excision specimen and the impact of margin status on the risk of LIR. METHODS: From January 1992 to December 2002, 454 patients were retrospectively included. Patients had undergone conservative surgery and radiotherapy for IDC. Two groups were defined: group 1, involved or close margin (<3 mm) and a re-excision; and group 2, involved or close margin without re-excision. The risk factors for residual disease in the re-excision specimen were analyzed in group 1, and the rate of 5-year LIR was analyzed in both groups. RESULTS: Among patients who experienced a surgical re-excision for involved or close margin, 21% (55 of 206) had residual tumor. The multivariate analysis showed that only a margin involved with intraductal carcinoma remained predictive for residual disease. According to the multivariate analysis, only hormone therapy (p < 10(-6)), diffuse involved margins (p = 0.003), and margins involved with intraductal component (p < 10(-6)) were predictive of LIR. Re-excision for a margin involved with intraductal carcinoma significantly improved local relapse-free survival (p < 0.001). CONCLUSIONS: In cases of IDC, re-excision for a close margin or a focally involved margin had no impact on local relapse-free survival. The decision to perform a surgical re-excision for an involved margin should not be systematic but should take multiple risk factors into consideration, such as patient age or margin diffuse involvement.

Mesothelioma In Situ Mimicking Well-differentiated Papillary Mesothelial Tumor.

We have previously hypothesized that well-differentiated papillary mesothelial tumor (WDPMT) consists of 2 morphologically identical lesions, one of which is true WDPMT, while the other is a form of mesothelioma in situ. Here, we report 8 examples of the latter phenomenon, 3 with pleural disease (2 men/1 woman, ages 66 to 78 y); and 5 with peritoneal disease (all women, ages 31 to 81 y). At presentation the pleural cases all had effusions but no evidence of pleural tumor on imaging. Four of the 5 peritoneal cases had ascites as the initial finding and all 4 had nodular lesions that by imaging and/or direct inspection were thought to represent a diffuse peritoneal malignancy. The fifth peritoneal case presented with an umbilical mass. Microscopically, the pleural and peritoneal lesions looked like diffuse WDPMT, but all had lost BAP1. Occasional microscopic foci of superficial invasion were present in 3/3 pleural cases, while single nodules of invasive mesothelioma and/or occasional foci of superficial microscopic invasion were found in all of the peritoneal cases. The pleural tumor patients developed what clinically appeared to be invasive mesothelioma at 45, 69, and 94 months. Four/five peritoneal tumor patients underwent cytoreductive surgery and heated intraperitoneal chemotherapy. Three with follow-up data are alive without recurrence at 6, 24, and 36 months; 1 patient refused treatment but is alive at 24 months. We conclude that mesothelioma in situ morphologically mimicking WDPMT is strongly associated with the synchronous or metachronous development of invasive mesothelioma, but that these lesions appear to progress very slowly.

Impact of first-line immunotherapy on survival and intracranial outcomes in a cohort of non-small cell lung cancer patients with brain metastases at diagnosis.

BACKGROUND: Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. METHODS: Our study assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). RESULTS: Between 01 and 2018 and 05-2021, 118 patients were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805). After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95 %CI: 0.23-0.89, and HR = 0.52, 95 %CI: 0.27-1.01, respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95 %CI: 0.25-0.84) and 59% (HR = 0.41, 95 %CI: 0.23-0.77) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 - 0.92), whereas whole-brain was not. CONCLUSIONS: Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.

Dissecting the Origin of Heterogeneity in Uterine and Ovarian Carcinosarcomas.

Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Identification of novel markers for the diagnosis of malignant pleural mesothelioma.

The diagnosis of malignant pleural mesothelioma is difficult, with the most common differential diagnoses being benign pleural diseases and metastatic adenocarcinomas (ADCA). To identify novel markers that would be able to improve diagnostic accuracy, we performed a genome-wide gene expression analysis on tumor cell lines established from pleural effusions (malignant pleural mesothelioma and lung ADCA). This analysis led to the identification of genes encoding novel and pertinent cellular and soluble markers, for which the expression was validated by real-time RT-PCR. Immunohistochemical staining of tumor biopsy specimens with anti-type III collagen antibodies showed positive labeling for mesothelioma cells but not for ADCA cells. Using enzyme-linked immunosorbent assay, we showed that the C-C motif chemokine 2 (CCL2) concentration was significantly higher in pleural effusions from patients with mesothelioma (n = 61) than in subjects with ADCA (n = 25) or with benign pleural effusions (n = 15): median (interquartile range) = 2.99 ng/ml (1.76 to 6.01) vs 0.99 ng/ml (0.51 to 1.83) and 1.47 ng/ml (0.80 to 1.56), respectively, P < 0.0001. Conversely, the galectin-3 concentration was lower in mesothelioma: 11.50 ng/ml (6.73 to 23.53) vs 24.74 ng/ml (20.42 to 70.35) and 17.64 ng/ml (14.81 to 24.68), respectively, P < 0.0001. The areas under the curve for CCL2 were 0.8030 and 0.7716 for the differentiation of mesothelioma from ADCA or benign pleural effusions, respectively. Similarly, the areas under the curve obtained for galectin-3 were 0.7980 and 0.6923, respectively. In conclusion, type III collagen, CCL2, and galectin-3 are promising new diagnostic markers for mesothelioma.

ß1, ß2, and ß3 adrenoceptors and Na+/H+ exchanger regulatory factor 1 expression in human bronchi and their modifications in cystic fibrosis.

To date, three ß-adrenoceptor (ß-AR) subtypes have been identified, but only ß(1)-ARs and ß(2)-ARs have been characterized in human lungs. Moreover, ß(2)-ARs physically interact with the cystic fibrosis transmembrane conductance regulator (CFTR) through the Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) protein. ß(3)-ARs, which stimulate CFTR activity in transfected cells, have not been identified in human lungs. This study aimed (1) to characterize the presence of ß-AR subtypes, especially ß(3)-AR, in human bronchi, and (2) to compare their expression as well as that of NHERF1 in non-cystic fibrosis (CF) versus advanced CF lung samples. In human non-CF bronchi, ß(1)-AR, ß(2)-AR, ß(3)-AR, and NHERF1 transcripts and proteins were expressed mainly in bronchial epithelial cells. Those results were strengthened by the native expression of ß(1)-AR, ß(2)-AR, and ß(3)-AR in a human epithelial cell line, 16HBE14o(-). All ß-AR subtypes stimulated CFTR activity. In CF bronchi, we demonstrated ß(1)-AR and ß(3)-AR overexpression, and NHERF1 and ß(2)-AR underexpression. The origin of this protein remodeling (involving the physical or functional absence of CFTR, infection, inflammation, or high adrenergic tone) deserves further investigation. These results evidence for the first time, to the best of our knowledge, the presence of ß(3)-ARs in human bronchi, and suggest their usefulness as a putative new pharmacologic target in lung diseases where fluid homeostasis is altered. Furthermore, NHERF1 may be a new therapeutic target in patients with CF, to facilitate the trafficking of mutated CFTR to plasma membrane.

Pure flat epithelial atypia (DIN 1a) on core needle biopsy: study of 60 biopsies with follow-up surgical excision.

Flat epithelial atypia (FEA) is recognized as a precursor of breast cancer and its management (surgical excision or intensive follow-up) remains unclear after diagnosis on core needle biopsy (CNB). The aim of this study was to determine the underestimation rate of pure FEA on CNB and clinical, radiological, and pathological factors of underestimation. 4,062 CNBs from 5 breast cancer centers, performed over a 5-year period, were evaluated. A CNB diagnosis of pure FEA was made in 60 cases (1.5%) (the presence of atypical ductal hyperplasia, lobular neoplasia, radial scars, phyllodes tumor, papillary lesions, ductal carcinoma in situ or invasive carcinoma at CNB were exclusion criteria), and subsequent surgical excision was systematically performed. The histological diagnosis was retrospectively reviewed using standardized criteria and the precise terminology of the World Health Organization by two pathologist physicians. At surgical excision, 6 (10%) ductal carcinoma in situ and 2 (3%) invasive carcinoma were diagnosed. The total underestimation rate was 13%. FEA was associated with atypical ductal hyperplasia in 10 (17%) cases and with lobular neoplasia in 2 (3%) at final pathology. Residual FEA was found in 14 (23%) cases. No clinical, radiological or pathological factors were significantly associated with underestimation. Our data highlight the importance of recognizing and diagnosing FEA in core needle biopsies. Thus, the presence of FEA on CNB, even in isolation, warrants follow-up excision.

FDG PET evaluation of early axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients.

PURPOSE: Regional axillary lymph node status has remained the single most independent variable to predict prognosis both in terms of disease recurrence and survival. This study aimed to prospectively assess sequential [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) findings as early predictors of axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients. METHODS: Images were acquired with a PET/CT scanner in 52 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third and sixth course of chemotherapy before surgery. Clinical examination and ultrasound (US) were used to assess the size of axillary nodes. Decrease in the standardized uptake value (SUV) with PET corrected or not for partial volume effects was compared to the pathological response. RESULTS: The sensitivity, specificity and accuracy of axillary node staging was higher with PET (75, 87 and 80%) than with US (50, 83 and 65%), and even more so when PET images were corrected for partial volume effects (86, 83 and 84%). While FDG uptake did not vary much in non-responders, as confirmed by histopathological analysis, it markedly decreased to baseline levels in responders (p < 10(-5)). Fifty per cent of baseline SUV was considered the best cutoff value to distinguish responders from non-responders. The sensitivity, specificity, negative predictive value and accuracy of FDG PET after one course of chemotherapy were, respectively, 96, 75, 95 and 84%. CONCLUSION: The pathological status of regional axillary lymph nodes in stage II and III breast cancer patients could be accurately predicted after one course of neoadjuvant chemotherapy based on FDG PET images.

Clinical and survival impact of FDG PET in patients with suspicion of recurrent cervical carcinoma.

PURPOSE: The aim of this retrospective study was to evaluate the contribution of (18)F-FDG PET to the clinical management and survival outcome of patients suspected of recurrent cervical carcinoma and in line with the hypothesis that early diagnosis of recurrent cervical cancer may improve overall survival. METHODS: A total of 40 patients underwent conventional imaging (CI) and FDG PET/CT for suspected cervical cancer. Clinical management decisions were recorded with CI and additional PET/CT. Discordances and concordances between CI and PET/CT results were compared to the final diagnosis as based on histopathology analysis or follow-up considered as the gold standard. RESULTS: The final diagnosis was established pathologically (n = 25) or by median clinical follow-up for 48 months after the PET (n = 15). The PET/CT was positive in 76% (20/26) of patients compared to 19% (6/26) with CI. Globally PET/CT modified the treatment plan in 55% (22/40) of patients and in 75% (18/24) when the CI was negative prior to PET/CT. These changes led to the use of previously unplanned therapeutic procedures in 37.5% (15/40). When FDG PET was positive for recurrence (> 3 foci), the median overall survival was 12 months (2-70) compared to patients with PET findings with < or = 1 focus for which the median survival was not attained (p = 0.007). A multivariate analysis of prognostic factors demonstrated that abnormal FDG uptake (> 3 foci) was the most significant factor (p < 0.03) for death from cervical cancer. CONCLUSION: FDG PET is a valuable tool in the case of suspected recurrence of cervical cancer on account of its impact on treatment planning and especially in predicting patient outcome.