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Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease in terms of morphological characteristics, protein expression profiles, genetic abnormalities, and potential for progression. Molecular heterogeneity has been extensively studied in DCIS. Yet morphological heterogeneity remains relatively undefined. This study investigated morphological intratumor heterogeneity in a series of 51 large DCIS. Nuclear atypia, DCIS architecture, necrosis, calcifications, stromal architecture, and stromal inflammation were assessed in one biopsy slide and three representative slides from each corresponding resection. For each histopathological feature, a histo-score was determined per slide and compared between the biopsy and the resection, as well as within a single resection. Statistical analysis comprised of Friedman tests, post hoc Wilcoxon tests with Bonferroni corrections, Mann-Whitney U tests, and chi-square tests. Despite substantial morphological heterogeneity in around 50% of DCIS, the histopathological assessment of the biopsy did not statistically significantly differ from the resection. Morphological heterogeneity was not significantly associated with patient age, DCIS size, or type of surgery, except for a weak association between heterogeneous stromal inflammation and smaller DCIS size. At the group level, the degree of heterogeneity did not significantly affect the representativity of a biopsy. At the individual patient level, however, the presence of necrosis, intraductal calcifications, myxoid stromal changes, and high-grade nuclear atypia was underestimated in a minority of DCIS patients. This study confirms the presence of morphological heterogeneity in DCIS for all six evaluated histopathological features. This should be kept in mind when taking biopsy-based treatment decisions for DCIS patients.

Contains fulltext : 245198.pdf (Publisher’s version ) (Closed access) High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

ObjectivesSince most patients with ductal carcinoma in situ (DCIS) of the breast are treated upon diagnosis, evidence on its natural progression to invasive carcinoma is limited. It is estimated that around half of the screen-detected DCIS lesions would have remained indolent if they had never been detected. Many patients with DCIS are therefore probably overtreated. Four ongoing randomized noninferiority trials explore active surveillance as a treatment option. Eligibility for these trials is mainly based on histopathologic features. Hence, the call for reproducible histopathologic assessment has never sounded louder.MethodsHere, the available classification systems for DCIS are discussed in depth.ResultsThis comprehensive review illustrates that histopathologic evaluation of DCIS is characterized by significant interobserver variability. Future digitalization of pathology, combined with development of deep learning algorithms or so-called artificial intelligence, may be an innovative solution to tackle this problem. However, implementation of digital pathology is not within reach for each laboratory worldwide. An alternative classification system could reduce the disagreement among histopathologists who use “conventional” light microscopy: the introduction of dichotomous histopathologic assessment is likely to increase interobserver concordance.ConclusionsReproducible histopathologic assessment is a prerequisite for robust risk stratification and adequate clinical decision-making. Two-tier histopathologic assessment might enhance the quality of care.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge. ispartof: MODERN PATHOLOGY vol:33 issue:3 pages:354-366 ispartof: location:United States status: published

Ductal carcinoma in situ (DCIS) of the breast is able to induce stromal changes, which likely reflect the crosstalk between DCIS and its microenvironment. These changes harbor prognostic information, although the interobserver variability of scoring stromal changes is moderate. A more robust evaluation of the DCIS-associated stroma is therefore needed. The aim of this study was to characterize P4HA2 expression, which is involved in collagen biosynthesis, in DCIS and to assess whether P4HA2 expression enables a more robust evaluation of the DCIS-associated stroma compared to histomorphology. This study included 410 patients with DCIS. Stromal changes were scored on hematoxylin/eosin-stained whole slides. P4HA2 expression in DCIS-associated stroma was assessed by whole slide immunohistochemistry. One hundred DCIS lesions were evaluated by seven pathologists to study the interobserver variability in the assessment of stromal changes and stromal P4HA2 expression. High P4HA2 expression in stromal fibroblasts was present in 14.1% of the patients. High P4HA2 expression was associated with the presence of periductal stromal changes (P = 0.004). The interobserver variability was similar for the assessment of stromal changes and the percentage of P4HA2-positive fibroblasts. Although we demonstrated a significant association between high P4HA2 expression in fibroblasts and the morphological presence of stromal changes, it seems unlikely that P4HA2 expression can be used as an alternative for the histopathological evaluation of the DCIS-associated stroma. ispartof: JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA vol:26 issue:4 pages:367-375 ispartof: location:United States status: published

OBJECTIF : Vu le manque de registre du cancer et de programme de dépistage à grande échelle du cancer du col utérin dans la plupart des pays africains, des modèles mathématiques sont à la base des données disponibles. Cette étude vise à cerner concrètement les particularités épidémiologiques et histopathologiques du cancer du col utérin. MÉTHODES : Parmi les cancers (n = 5801) diagnostiqués dans cinq laboratoires d’anatomie pathologique de Kinshasa durant 10 ans, les lames histologiques des cancers du col ont fait l’objet d’une relecture et d’une classification selon l’OMS 2014. RÉSULTATS : Les cancers du col utérin (n = 1280) ont représenté 22 % de l’ensemble des cancers et 40,4 % des cancers mammaires et gynécologiques. La tranche d’âge la plus touchée était celle de 49 à 58 ans. Le carcinome malpighien correspond à 73,2 %, l’adénocarcinome à 18,4 % et le carcinome adénosquameux à 8,4 % des cancers cervicaux. Les sous-types se distribuaient comme suit : le carcinome kératinisant 47,2 %, le non kératinisant 20,8 %, l’adénocarcinome usuel 9,6 % et le villoglandulaire 5,3 %. Dans le sous-type des carcinomes mucineux, seul le variant à cellules en bague à chaton (1,3 %) était représenté. Parmi les cancers du col utérin, 69 % étaient de grade histologique I, 20 % de grade II et 11 % de grade III. CONCLUSION : Cette étude des particularités épidémiologiques et histopathologiques du cancer du col utérin à Kinshasa fournit une base de données concrètes pour initier un registre du cancer et des campagnes de dépistage et de vaccination contre le HPV. [Epidemiologic and histopathologic characteristics of 1280 uterine cervical cancers in Kinshasa]. OBJECTIVE: Due to the lack of both cancer registry and large scale cervical screening in most african countries, only theoretical studies are available. The objective of our work was to provide epidemiological and histopathological characteristics of cervical cancer based on concrete observations. METHODS: This study was carried out on all cancers (n=5801) collected in the last 10 years from 5 pathology laboratories of Kinshasa; the histologic slides of the cervical cancers (n=1280) were reviewed by at least two pathologists and classified according to the 2014 OMS classification. RESULTS: The cervical cancers accounted for 22% of all cancers and 40,4% of breast and gynecological cancers. The cervical cancer was the most common among women aged 49-58. Squamous cell carcinomas were the most observed type (73,2%) followed by adenocarcinomas (18,4%) and adenosquamous carcinomas (8,4%). Keratinized (47,2%) and non keratinized squamous carcinoma (20,8%) were the most frequent subtypes among squamous carcinomas and the usual adenocarcinoma among adenocarcinomas (9,6%). In the mucinous adenocarcinoma subtype, only the signet ring cells (1,3%) variant was found. Among cervical cancers, 69% were grade I, 20% grade II and 11% grade III. CONCLUSION: Our study provides a concrete database of epidemiological and histopathological cervical cancer particularities in Kinshasa, useful to initiate a cancer register, as well as cervical screening and HPV vaccine campaigns.

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH +). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC) +). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases.Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH.Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC + /FISH +) and 16 discordant (ALK IHC + /FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR = 4.5; 95% CI = 1.2-15.9; p = 0.010.Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by low bone mass and spontaneous fractures, as well as extra-skeletal manifestations, such as dental abnormalities, blue sclera, hearing loss and joint hypermobility. Tendon ruptures have been reported in OI patients. Here, we characterized the biomechanical, structural and tissue material properties of bone and tendon in 5-week-old female osteogenesis imperfecta mice (oim), a validated model of severe type III OI, and compared these data with age- and sex-matched WT littermates. Oim tendons were less rigid and less resistant than those of WT mice. They also presented a significantly higher rate of pentosidine, without significant modification of enzymatic crosslinking. The oim bones were less resistant and avulsion fractures were evident at high tendinous stress areas. Alterations of trabecular and cortical bone microarchitectures were noticed in young female oim. Bone tissue material properties were also modified, with a less mature and more mineralized matrix in association with lower collagen maturity. Our data suggest that the tendon-to-bone unit is affected in young oim mice, which could explain tendon ruptures and bone fragility observed in OI patients.

BACKGROUND: Despite their emerging therapeutic relevance, there are many discrepancies in anatomical description and terminology of the articular nerves supplying the human knee capsule. This cadaveric study aimed to determine their origin, trajectory, relationship and landmarks for therapeutic purpose. METHODS: We dissected 21 lower limbs from 21 cadavers, to investigate the anatomical distribution of all the articular nerves supplying the knee joint capsule. We identified constant genicular nerves according to their anatomical landmarks at their entering point to knee capsule and inserted Kirschner wires through the nerves in underlying bone at those target points. Measurements were taken, and both antero-posterior and lateral radiographs were obtained. RESULTS: The nerve to vastus medialis, saphenous nerve, anterior branch of obturator nerve and a branch from sciatic nerve provide substantial innervation to the medial knee capsule and retinaculum. The sciatic nerve and the nerve to the vastus lateralis supply sensory innervation to the supero-lateral aspect of the knee joint while the fibular nerve supplies its infero-lateral quadrant. Tibial nerve and posterior branch of obturator nerve supply posterior aspect of knee capsule. According to our findings, five constant genicular nerves with accurate landmarks could be targeted for therapeutic purpose. CONCLUSION: The pattern of distribution of sensitive nerves supplying the knee joint capsule allows accurate and safe targeting of five constant genicular nerves for therapeutic purpose. This study provides robust anatomical foundations for genicular nerve blockade and radiofrequency ablation.

The long delay between asbestos exposure and the development of mesothelioma will likely result in an increased incidence of mesothelioma in our industrialized societies. Radiation therapy is another factor known to induce these tumors. We describe a rare case of foamy looking mesothelioma in a 63-year-old patient with a long oncology history of a supposed peritoneal carcinomatosis. The pathologist was faced with a diagnostic pitfall as this peritoneal clear cell tumor expressed transcription factor binding to immunoglobulin heavy constant mu enhancer 3 (TFE3) at the nuclear level. Fortunately, the pathologist performed an extensive panel of immunomarkers, leading to a final diagnosis of epithelioid mesothelioma. Thus, we describe the first case of mesothelioma expressing TFE3. Note that there was no rearrangement of TFE3 in fluorescence in situ hybridization.

BACKGROUND: Even though the clinical features of Graves' orbitopathy (GO) are well known, its exact pathogenesis remains controversial. The imbalance of redox homeostasis in the connective tissue could play a crucial role leading to an inflammatory state and edema of soft orbital tissues, thus contributing to orbital hypoxia and increase in hypoxia-inducible factor (HIF)-1α. This oxidative stress appears to target the orbital cells such as fibroblasts and also adipocytes. This study aims to explore which pathways can lead to the aforementioned oxidative stress in GO adipose cells and therefore offers new plausible therapeutic targets. METHODS: Orbital fat samples were obtained from patients with GO (Western blot [WB]: n = 8, immunohistochemistry [IHC]: n = 8) and from control patients (WB: n = 5, IHC: n = 3-5). They were processed for WB analysis and IHC of the antioxidants (catalase, superoxide dismutase 1) and for HIF-1α. The expression of caveolin-1 (Cav-1) and deiodinase 3 (DIO3), known to be regulated by HIF-1α, was also analyzed by WB and IHC, as well as the targets of Cav-1: glucose transporter type 4 (Glut-4), NADPH oxidase (NOX)-2, and endothelial nitric oxide synthase (eNOS). Triiodothyronine (T3) expression was also analyzed by IHC. RESULTS: In GO adipocytes, the expression of catalase was reduced, whereas that of HIF-1α was strongly increased. A decreased local T3 supply was associated with DIO3 upregulation. The low expression of Cav-1 in GO adipocytes was associated not only with low expression of Glut-4 but also with an increased expression of NOX-2 and active eNOS phosphorylated on serine 1177. CONCLUSIONS: Cav-1 and DIO3, both sensitive to hypoxia and to the increase of HIF-1α, play a pivotal role in the oxidative stress in GO adipocytes. DIO3 regulates the cellular supply of T3, which is essential for the cell homeostasis. Cav-1 determines the cellular glucose supply through Glut-4 and regulates the activity of NOX-2 generating superoxide anions and that of eNOS generating nitric oxide (NO).

Dual-color silver-enhanced in situ hybridization (SISH) is a well-established method for determining the HER2 gene amplification status in invasive breast cancers with equivocal “2+” HER2 protein expression. Dual-color SISH applies 2 different probes on a single tissue slide: a probe for the HER2 gene and a centromere 17 (CEP17) probe. [...]

Summary Background There is a renewed interest for prepectoral reconstruction. We aimed to describe the feasibility and the early complications associated with immediate one-stage direct-to-implant (DTI) reconstruction using prepectoral anatomical polyurethane (PU) foam-coated implants alone, for women with breast cancer or mutation carriers undergoing risk-reducing surgery. Methods We performed a single-center, retrospective review of 50 patients (mean age of 49 years), who underwent skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) and immediate prepectoral PU implant-based reconstruction. All procedures were performed by the same senior operator, from July 2018 to March 2020. Results A total of 64 mastectomies (25 SSMs and 39 NSMs) with one-stage prepectoral PU foam-coated implant reconstruction were performed. Out of 50 patients, 6 required surgical revision within 30 days, because of hematoma (2), wound dehiscence (2) infection (1), and full thickness nipple-areolar complex (NAC) necrosis (1). Four patients developed a cutaneous rash with spontaneous resolution. Statistical analysis showed a significant influence of hypothyroidism and previous radiotherapy on the risk of complications. The association with prior radiotherapy (pRT) was not significant using binary logistic regression. When excluding oncological reasons and patient's wish for NAC excision, our decision to perform an NSM was influenced by breast cup size, preoperative measurements, and breast weight. Conclusions Early experience with immediate prepectoral DTI reconstruction with PU-covered implants alone suggests that it is a reliable procedure. Prior breast irradiation does not increase postoperative complication rates in our series. NAC preservation was decided according to preoperative lower breast measurements.

Introduction The descending genicular artery (DGA) has recently been mentioned as accompanying some nerves in the medial aspect of the knee joint. This could be clinically relevant as the arteries could serve as landmarks for accurate nerve capture during ultrasound-guided nerve blockade or ablation. The aim of this cadaveric study was to investigate the anatomical distribution of the DGA, assess the nerves running alongside its branches, and discuss the implications for regional anesthesia and knee pain interventions. Methods We dissected the femoral artery all along its course to identify the origin of the DGA, from which we carefully dissected all branches, in twenty-seven fresh-frozen human specimens. Simultaneously, we systematically dissected the nerves supplying the medial aspect of the knee from proximally to distally and identified those running alongside the branches of the DGA. The surrounding anatomical landmarks were identified and measurements were recorded. Results The DGA was found in all specimens, arising from the femoral artery 130.5 ± 17.5 mm (mean ± SD) proximally to the knee joint line. Seven distribution patterns of the DGA were observed. We found three consistent branches from the DGA running alongside their corresponding nerves at the level of the medial aspect of the knee: the artery of the superior-medial genicular nerve, the artery of the infrapatellar branch of the saphenous nerve, and the saphenous branch of the DGA. Conclusion The consistent arteries and surrounding landmarks found in this study could help to improve the capture of the targeted nerves during ultrasound-guided interventions. This article is protected by copyright. All rights reserved.

Insulinoma-associated protein-1 (INSM1), a transcription factor encoded by the insulinoma associated-1 gene, is a second-generation biomarker of neuroendocrine differentiation. Its sensitivity and specificity in comparison with chromogranin-A and synaptophysin have been extensively validated in several organs, but evidence regarding its expression in mammary neoplasms is limited. In this study, INSM1 immunohistochemistry was validated in a cohort of 22 mammary neoplasms, enriched with special type breast carcinomas with known neuroendocrine differentiation as determined by immunohistochemistry for synaptophysin and chromogranin-A. Subsequently, INSM1 expression was evaluated in a consecutive series of 66 invasive breast cancer biopsies. In the validation cohort, 14 tumors were synaptophysin-positive, of which all but one showed INSM1 immunoreactivity. Eight tumors were synaptophysin-negative, of which 3 showed focal nuclear INSM1 expression. Six tumors were chromogranin-A-positive, of which one was INSM1-negative. When compared with synaptophysin, INSM1 seems more sensitive but less specific than chromogranin-A. In the biopsy cohort, only one invasive carcinoma of no special type showed substantial INSM1 immunoreactivity (ie, 25% of the tumor cells). Three more cases showed 1% nuclear INSM1 staining. We conclude that neuroendocrine differentiation in invasive breast carcinoma of no special type is a rare finding. Immunohistochemical biomarkers, comprising INSM1 as well as the first-generation biomarkers chromogranin-A and synaptophysin, are useful to distinguish neuroendocrine differentiation in breast neoplasms. The identification of neuroendocrine differentiation can be helpful to establish the diagnosis of special type breast carcinomas such as solid papillary carcinoma.

Periductal stromal tumors (PSTs) of the breast are considered as a rare subtype of phyllodes tumors. These rare fibroepithelial lesions display a biphasic morphology, characterized by a cellular stroma surrounding benign ducts. Unlike phyllodes tumors, they do not present with a leaflike architecture, rendering a biopsy diagnosis of a PST very challenging. In this report, we compare the histopathological features of a PST with those of a borderline phyllodes tumor. We discuss the differences and similarities between both entities, and we highlight the potential pitfalls of the respective biopsies. Both cases illustrate that PSTs and phyllodes tumors are part of the same spectrum. This biological spectrum implies that “hybrid” lesions do exist, which can be hard to classify.

Background Genicular nerve blockade is a possible treatment for patients with knee osteoarthritis. Pain relief and improvement in functioning is expected. This procedure could be of major interest for patients in low-income countries where total knee arthroplasty is not available for the population. This study aims at assessing the immediate benefits on pain, gait, and stairs kinematics after a genicular nerve blockade in patients suffering from knee osteoarthritis in Cameroun. Methods A prospective study was carried out on 26 subjects in Cameroun. A genicular nerve blockade was performed on 14 women with painful knee osteoarthritis grade 2–4. Lower limb joint angles were recorded with inertial sensors before and 1 h after injection. Patient-reported outcomes of pain and perceived difficulty were collected, as well as 10 m and 6 min walking tests. A reliability analysis of inertial sensors was performed on a sample of 12 healthy subjects by calculating the intraclass correlation coefficient and the standard error of measurement. Results Pain and perceived difficulty decreased significantly (p Conclusions This study quantified improvement of gait and stair climbing immediately after a genicular nerve blockade in patients suffering from knee OA in Cameroon. This is the first study objectifying this effect, through wearable sensors. Trial registration Pan African Clinical Trial Registry, PACTR202004822698484. Registered 28 March 2020 - Retrospectively registered.

Introduction The chronic complications of bone free-flap revascularization surgery are mainly characterized by skin fistulization of the osteosynthesis material, which sometimes leads to reactivation of the osteoradionecrotic phenomenon. The objective of the study is to evaluate the benefit of mandibular basilar edge preservation in bone reconstructive surgery in irradiated areas performed for the treatment of advanced mandibular osteoradionecrosis. Materials and methods A retrospective monocentric study conducted between 2003 and 2018 including all patients undergoing revascularization surgery for the treatment of advanced osteoradionecrotic lesion with respect to the basilar margin was conducted. Results Eight patients (7 males and 1 female, aged 50 to 63 years) who had a marginal mandibulectomy with reconstruction by bone free flap or composite free flap were included. The stability of the reconstruction (junction native mandible/bone free flap) was achieved on average by using 1.75 [range 0–4] mini plates (Medartis® Modus 2.0, Medartis AG, Basel, Switzerland). During the follow-up (30 ± 13 months) no chronic complication related to a dissociation of the osteosynthesis material or a reactivation of the osteoradionecrotic phenomenon were identified. Conclusions Despite the limited number of patients, it seems that the increase in the friction surface between the free flap and the native mandibular bone, linked to the preservation of the basilar edge, improves the primary stability of the reconstruction. This reduction in mechanical stress on osteosynthesis materials limits its use and reduces the rate of chronic complications of bone flap revascularization surgery in irradiated areas.

In this study, we describe an intrathoracic microsurgical lymphatico-venous anastomosis as an alternative surgical technique for the treatment of refractory chylothorax in an infant. This procedure allowed us to restore enteral nutrition within days of surgery. At 3-year follow-up, there was no recurrence of pleural effusion.

Rationale & Objective Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. Study Design Multicenter retrospective cohort study. Setting & Participants 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. Predictor Positive immunostaining for podocyte antigens on archived kidney biopsy samples. Outcomes Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. Analytical Approach Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. Results 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R−/THSD7A−) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+ MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P = 0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+ MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. Limitations Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. Conclusions Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

Glutaraldehyde-treated pericardia for cardiovascular applications have poor long-term clinical results. The efficacy of a combined physical/chemical treatment to improve pericardium biocompatibility and vascular regeneration was assessed and compared with detergent treatment and two commercial bovine pericardia: PeriGuard (DGBP) and Edwards pericardium (nDGBP). The physical and chemical process was applied to bovine and human pericardia (DBP-DHP), and the detergent process was applied to bovine (DDBP). Native (NBP) and treated bovine tissues were assessed for decellularization (HE/DAPI/DNA/α-Gal and MHC-1 staining) and mechanical integrity ex vivo. Twenty Wistar rats received subcutaneous patches of each bovine tissue to assess immunogenic response up to 4 months (flow cytometry). Ten additional rats received four subcutaneous bovine-treated patches (one/condition) to evaluate the inflammatory reaction (CD3/CD68 immunostaining), calcification (von Kossa staining/calcium quantification), and integration assessment (Hematoxylin and eosin staining). Finally, 15 rodents received a patch on the aorta (DBP n = 5, DHP n = 5, and DGBP n = 5), and vascular biocompatibility and arterial wall regeneration were assessed after 4 months (CD3/CD68/CD31/ASMA and Miller staining). DBP reached the higher level of decellularization, no immunogenic response whereas maintaining mechanical properties. DBP induced the lowest level grade of inflammation after 2 months (P

The law of series is a phenomenon that pathologists frequently come across. It represents the observation that a rare diagnosis, once encountered, has the mysterious tendency of occurring again within a short time frame. [...]

In COPD, epithelial changes are prominent features in the airways, such as goblet cell hyperplasia and squamous metaplasia. In contrast, it remains unclear whether ciliated cells are reduced and which pathways dysregulate epithelial differentiation. We hypothesized that bronchial epithelial cell lineage specification is dysregulated in COPD because of an aberrant reprogramming through transforming growth factor (TGF)-β1. Surgical lung tissue from 81 COPD and 61 control (smokers and non-smokers) patients was assessed for bronchial epithelial cell phenotyping by immunohistochemistry, both in situ and in vitro in reconstituted air-liquid interface (ALI) cultures. The role of TGF-β1 was studied in vitro. COPD epithelium in large airways, when compared to controls, showed decreased β-tubulin IV + ciliated cells (4.4%, 2.5–8.8% versus 8.5%, 6.3–11.8% of surface staining, median and IQR, p = 0.0009) and increased MUC5AC + goblet cells (34.8%, 24.4–41.9% versus 10.3%, 5.1–17.6%, p in vitro, at least in part through TGF-β1.

Mandibular osteoradionecrosis (ORN) is one of the most serious complications of radiotherapy of the head and neck, and is characterised by hypoxia, hypovascularisation, and hypocellularity. Periosteal free flaps have intrinsic osteogenic, and extrinsic neoangiogenic, properties that are related to the periosteum. Our objective was to present our experience with the use of periosteal free flaps in the treatment of ORN (Notani class I or II) that are refractory to conservative management or have a large area of bone (≥2 cm) exposed. We organised a single-centre, retrospective study between 2003 and 2013 and describe the management of 11 patients (4 women and 7 men) who were being treated for refractory mandibular ORN. Thirteen periosteal free flaps were used: inner femoral condylar periosteum (n = 4), iliac crest (n = 1), external brachial with humeral periosteum (n = 1), and forearm with radial periosteum (n = 7). During follow-up we found three acute complications (haematoma, partial necrosis, and total vascular necrosis) that required immediate construction of a second periosteal free flap. There were also two chronic complications (fistula and post-traumatic fracture). With only one progressive lesion identified, the ORN was stopped in 11/12 patients. Two examples of osteoconduction were identified on postoperative images at six months and two years. Because of its osteoconductive and neoangiogenic capacities, the periosteal free flap seems to offer a real biological dimension to the treatment of ORN, and its efficiency favours its early revascularisation.

Liver transplantation is the treatment for end-stage liver diseases and well-selected malignancies. The allograft shortage may be alleviated with living donation. The initial UCLouvain experience of adult living-donor liver transplantation (LDLT) is presented. A retrospective analysis of 64 adult-to-adult LDLTs performed at our institution between 1998 and 2016 was conducted. The median age of 29 (45.3%) females and 35 (54.7%) males was 50.2 years (interquartile range, IQR 32.9-57.5). Twenty-two (34.4%) recipients had no portal hypertension. Three (4.7%) patients had a benign and 33 (51.6%) a malignant tumor [19 (29.7%) hepatocellular cancer, 11 (17.2%) secondary cancer and one (1.6%) each hemangioendothelioma, hepatoblastoma and embryonal liver sarcoma]. Median donor and recipient follow-ups were 93 months (IQR 41-159) and 39 months (22-91), respectively. Right and left hemi-livers were implanted in 39 (60.9%) and 25 (39.1%) cases, respectively. Median weights of right- and left-liver were 810 g (IQR 730-940) and 454 g (IQR 394-534), respectively. Graft-to-recipient weight ratios (GRWRs) were 1.17% (right, IQR 0.98%-1.4%) and 0.77% (left, 0.59%-0.95%). One- and five-year patient survivals were 85% and 71% (right) vs. 84% and 58% (left), respectively. One- and five-year graft survivals were 74% and 61% (right) vs. 76% and 53% (left), respectively. The patient and graft survival of right and left grafts and of very small (

Because of disabling sequelae of open fasciotomy in anterior compartment syndrome (ACS) of the leg, we wanted to describe and validate a cadaveric model of ACS. We hypothesized that, first, anterior compartment syndrome (ACS) could be reproduced in cadaveric leg and, second, fasciotomy without complete skin incision could lower the intramuscular pressure (IMP) in an equivalent range to complete dermatofasciotomy. Lower limb ACS was reproduced by progressive injection of physiologic serum in the anterior compartment of 23 fresh frozen cadaveric legs with monitoring of IMP, in order to reach a maximal stabilised IMP higher than 30mmHg. Subcutaneous minimally invasive fasciotomy was performed on 14 legs through 5 transversal mini-incisions of the skin (2cm) along the axis from the tibial tuberosity to the posterior aspect of the lateral malleolus. Standard open fasciotomy of the anterior compartment was performed on the remaining 9 legs as control. IMP was measured after the skin incisions and after every fasciotomy through skin incisions in the first group and after skin and fascia incisions in the control group. A maximal IMP of 43±2mmHg was obtained by injection of 177±9ml physiologic serum into the anterior compartment of the leg. In the control open fasciotomy group, the skin incision alone did not lower IMP significantly, whereas fasciotomy lowered IMP to 10±1mmHg, which is statistically different from maximal IMP (p

With the advent of screening mammography, the incidence of ductal carcinoma in situ (DCIS) has increased. DCIS accounts for around 20% of breast cancers diagnosed at present. The histiocytoid variant of clear cell DCIS is a rare subtype of DCIS, characterized by epithelial cells with a clear and foamy cytoplasm. Histiocytoid DCIS serves as a potential diagnostic pitfall, since it can be easily mistaken for intraductal collections of foamy macrophages. In this article, we report a particular case of biphasic DCIS, characterized by an extensive histiocytoid-type clear cell component and a conventional “non-clear” cell component. Both components presented with HER2 protein overexpression. We discuss the diagnostic challenge and differential diagnosis of clear cell DCIS, as well as the role of HER2 overexpression in DCIS pathogenesis.

Background The optimal perfusate partial pressure of oxygen (PO2) during hypothermic machine perfusion (HMP) is unknown. The aims of the study were to determine the functional, metabolic, structural, and flow dynamic effects of low and high perfusate PO2 during continuous HMP in a pig kidney ischemia-reperfusion autotransplant model. Methods The left kidneys of a ±40 kg pigs were exposed to 30 minutes of warm ischemia and randomized to receive 22-hour HMP with either low perfusate PO2 (30% oxygen, low oxygenated HMP [HMPO2]) (n = 8) or high perfusate PO2 (90% oxygen, HMPO2high) (n = 8), before autotransplantation. Kidneys stored in 22-hour standard HMP (n = 6) and 22-hour static cold storage (n = 6) conditions served as controls. The follow-up after autotransplantation was 13 days. Results High PO2 resulted in a 3- and 10-fold increase in perfusate PO2 compared with low HMPO2 and standard HMP, respectively. Both HMPO2 groups were associated with superior graft recovery compared with the control groups. Oxygenation was associated with a more rapid and sustained decrease in renal resistance. While there was no difference in functional outcomes between both HMPO2 groups, there were clear metabolic differences with an inverse correlation between oxygen provision and the concentration of major central metabolites in the perfusion fluid but no differences were observed by oxidative stress and metabolic evaluation on preimplantation biopsies. Conclusions While this animal study does not demonstrate any advantages for early graft function for high perfusate PO2, compared with low perfusate PO2, perfusate metabolic profile analysis suggests that aerobic mechanism is better supported under high perfusate PO2 conditions.

PURPOSE: In the mandible, the condylar neck vascularization is commonly described as mainly periosteal; while the endosteal contribution is still debated, with very limited anatomical studies. Previous works have shown the contribution of nutrient vessels through accessory foramina and their contribution in the blood supply of other parts of the mandible. Our aim was to study the condylar neck's blood supply from nutrient foramina. METHODS: Six latex-injected heads were dissected and two hundred mandibular condyles were observed on dry mandibles searching for accessory bone foramina. RESULTS: Latex-injected dissections showed a direct condylar medular arterial supply through foramina. On dry mandibles, these foramina were most frequently observed in the pterygoid fovea in 91% of cases. However, two other accessory foramina areas were identified on the lateral and medial sides of the mandibular condylar process, confirming the vascular contribution of transverse facial and maxillary arteries. CONCLUSIONS: The maxillary artery indeed provided both endosteal and periosteal blood supply to the condylar neck, with three different branches: an intramedullary ascending artery (arising from the inferior alveolar artery), a direct nutrient branch and some pterygoid osteomuscular branches.

In Hashimoto’s thyroiditis (HT), oxidative stress (OS) is driven by Th1 cytokines’ response interfering with the normal function of thyrocytes. OS results from an imbalance between an excessive production of reactive oxygen species (ROS) and a lowering of antioxidant production. Moreover, OS has been shown to inhibit Sirtuin 1 (SIRT1), which is able to prevent hypoxia-inducible factor (HIF)-1α stabilization. The aims of this study were to determine the involvement of NADPH-oxidases (NOX), SIRT1, and HIF-1α in HT pathophysiology as well as the status of antioxidant proteins such as peroxiredoxin 1 (PRDX1), catalase, and superoxide dismutase 1 (SOD1). The protein expressions of NOX2, NOX4, antioxidant enzymes, SIRT1, and HIF-1α, as well as glucose transporter-1 (GLUT-1) and vascular endothelial growth factor A (VEGF-A), were analyzed by Western blot in primary cultures of human thyrocytes that were or were not incubated with Th1 cytokines. The same proteins were also analyzed by immunohistochemistry in thyroid samples from control and HT patients. In human thyrocytes incubated with Th1 cytokines, NOX4 expression was increased whereas antioxidants, such as PRDX1, catalase, and SOD1, were reduced. Th1 cytokines also induced a significant decrease of SIRT1 protein expression associated with an upregulation of HIF-1α, GLUT-1, and VEGF-A proteins. With the exception of PRDX1 and SOD1, similar results were obtained in HT thyroids. OS due to an increase of ROS produced by NOX4 and a loss of antioxidant defenses (PRDX1, catalase, SOD1) correlates to a reduction of SIRT1 and an upregulation of HIF 1α, GLUT-1, and VEGF-A. Our study placed SIRT1 as a key regulator of OS and we, therefore, believe it could be considered as a potential therapeutic target in HT.

Cases of CMV proctitis are frequently reported in immunocompromised patients. However, some cases of CMV proctitis are linked to a CMV primary infection and to unprotected anal intercourse in immunocompetent patients. The most common symptom is bloody diarrhea (hemorrhagic colitis). The endoscopic exam can present in distincts forms. The diagnostic is based on a set of clinical, biological, endoscopic and histological arguments. The prognosis of the disease is favorable. The treatment is supportive. A research on other sexually transmitted diseases must be conducted.Des cas de rectite à cytomégalovirus (CMV) sont fréquemment rapportés chez des patients immunodéprimés. Cependant, certains cas de rectite à CMV sont associés à une primo-infection à CMV et des rapports anaux non protégés chez une personne immunocompétente. La diarrhée hémorragique est le symptôme le plus fréquent. La présentation endoscopique est variée. Le diagnostic repose sur un faisceau d’arguments cliniques, biologiques, endoscopiques et histologiques. Le pronostic de l’affection est favorable. Le traitement est simplement supportif. Une recherche d’autres maladies sexuellement transmissibles doit être réalisée.

AIMS: Robust prognostic markers for ductal carcinoma in situ (DCIS) of the breast require high reproducibility and thus low interobserver variability. The aim of this study was to compare interobserver variability among 13 pathologists, in order to enable the identification of robust histopathological characteristics. METHODS AND RESULTS: One representative haematoxylin and eosin-stained slide was selected for 153 DCIS cases. All pathologists independently assessed nuclear grade, intraductal calcifications, necrosis, solid growth, stromal changes, stromal inflammation, and apocrine differentiation. All characteristics were assessed categorically. Krippendorff's alpha was calculated to assess overall interobserver concordance. Cohen's kappa was calculated for every observer duo to further explore interobserver variability. The highest concordance was observed for necrosis, calcifications, and stromal inflammation. Assessment of solid growth, nuclear grade and stromal changes resulted in lower concordance. Poor concordance was observed for apocrine differentiation. Kappa values for each observer duo identified the 'ideal' cut-off for dichotomisation of multicategory variables. For instance, concordance was higher for 'non-high versus high' nuclear grade than for 'low versus non-low' nuclear grade. 'Absent/mild' versus 'moderate/extensive' stromal inflammation resulted in substantially higher concordance than other dichotomous cut-offs. CONCLUSIONS: Dichotomous assessment of the histopathological features of DCIS resulted in moderate to substantial agreement among pathologists. Future studies on prognostic markers in DCIS should take into account this degree of interobserver variability to define cut-offs for categorically assessed histopathological features, as reproducibility is paramount for robust prognostic markers in daily clinical practice. A new prognostic index for DCIS might be considered, based on two-tier grading of histopathological features. Future research should explore the prognostic potential of such two-tier assessment. ispartof: HISTOPATHOLOGY vol:73 issue:6 pages:923-932 ispartof: location:England status: published

Objectives: Given the crucial role of pathology reporting in the management of breast cancers, we aimed to investigate the quality and variability of breast cancer pathology reporting in Belgium. Materials and methods: Detailed information on non-molecular and molecular parameters was retrieved from the pathology protocols available at the Belgian Cancer Registry for 10,007 breast cancers diagnosed in Belgium in 2008. Results: Substantial underreporting was shown for several clinically relevant non-molecular parameters, such as lymphovascular invasion. High-volume laboratories performed only slightly better than others, and analyses at the individual laboratory level showed clear inter-laboratory variability in reporting for all volume categories. Information on ER/PR and HER2 IHC was mentioned in respectively 91.7% and 90.8% of evaluative cases. HER2 ISH data were available for 78.5% of the cases judged to be 2+ for HER2 IHC. For cases with different specimens analysed, discordance between these specimens was highest for HER2, followed by PR. For HER2, results obtained from different laboratories were even less concordant. In addition, inter-laboratory differences were noted in the used ER/PR scoring systems, the proportion of ER-/PR+ cases, and the relation between histological grade and ER/PR positivity. Data on Ki67 were only available for 43.8% of the investigated cases, and showed inconsistent use of cut-off values. Conclusion: Breast pathology reporting in Belgium in 2008 was suboptimal and showed considerable inter-laboratory variability. Synoptic reporting has been proposed as a facilitator towards increased reporting quality and harmonization, but the lack of aligned informatics remains a major hurdle in its concrete implementation. (C) 2014 Elsevier Ltd. All rights reserved.

BACKGROUND: In the field of vascularized composite tissue allotransplantation, the surgical design of facial subunit grafts is an evolving concept. The purpose of the present article is to study the possibility of dividing the historical nose and lip face transplant into several morphologic and functional subunit grafts, depending on their respective supply. METHODS: This study was conducted in 20 adult cadavers. The facial artery and its branches were dissected bilaterally in 16 fresh and four embalmed heads. Nasolabial perfusion was assessed by selective injection of methylene blue and eosin (n = 2) or India ink (n = 2) in the superior labial and distal facial arteries. Dynamic perfusion through the distal facial artery was illustrated by fluoroscopy (n = 3). Three nose-upper lip grafts were harvested and injected with barium sulfate for microangiography computed tomographic analysis. Finally, three isolated nasal and bilabial grafts were procured and their vascular patency assessed by fluoroscopy. RESULTS: The distal facial artery can perfuse the entire nose, septum, and upper lip, without any contribution of the superior labial artery. A dense anastomotic network indeed exists between the respective distal rami of both vessels. Furthermore, the exclusion of the superior labial artery from the harvested nasal subunit allowed safe bilabial subunit procurement, from the same specimen. CONCLUSIONS: The authors' results demonstrate the feasibility of harvesting nasal and labial subunits, in an isolated or a combined manner. These results can find applications in subunit autologous replantation, allotransplantation, allogenic face partial retransplantation, and the emerging field of vascularized composite tissue engineering.

OBJECTIVE: Salvage surgery in recurrent SCCHN is associated with poor outcomes. This study aimed to better identify suitable surgical candidates and those at high risk of new recurrence. MATERIALS AND METHODS: Single-center retrospective analysis of 109 patients undergoing salvage surgery for recurrent SCCHN. Univariate and multivariate analyses were used to identify prognostic factors affecting disease-free survival (DFS). RESULTS: The following factors showed a significant impact on DFS: Disease-free interval >6months [HR 0.53; p=0.04], age>70years [HR 0.26; p=0.03], primary chemoradiotherapy [HR 2.39; p

Summary Background: Congenital melanocytic nevi are present at birth or may appear in the first weeks of life. Small and medium-size lesions are relatively common, affecting approximately 1% of newborns; large or giant melanocytic nevi occur in 1/20,000e1/500,000 births. The main concern raised by these lesions is their potential risk of degeneration which is strongly size-dependent and estimated in the literature between 0% and 40% over a lifetime. Although multiple treatment modalities have been described, to date there is no consensus regarding their optimal management. Patients and methods: Four neonates (three females and one male) presenting giant congenital nevi with a mean age 12 days (7e24 days) were referred to our Plastic Surgery department for treatment from 2012 to 2013. All patients underwent an alternative dermabrasion procedure with the innovative use of hydrosurgery. All procedures were performed under general anaesthesia by the same senior operator (Dr. B.Bayet). Results: The mean operating time was significantly reduced compared to conventional techniques. No complications were observed in the postoperative course. Good final results were obtained in three patients after a mean follow-up of respectively 11, 8 and 4 months. The first operated neonate showed a complete recurrence of pigmentation of the treated areas after 6 months. Conclusions: The need for early treatment in giant congenital nevi is admitted by all. Hydrosurgery is easy to use and allows to achieve a selective and symmetric resection with an obvious cleavage plane and clean-cut borders. Furthermore, this procedure has convinced us with its speed of use, ensuring significant time saving, and therefore less morbidity for the neonate. Aesthetic results as well as recurrence rate may be comparable to conventional techniques. However, regular follow-up to detect any malignancy is necessary.

Northern elephant seals (NES) (Mirounga angustirostris) from the Año Nuevo State Reserve (CA, USA) were longitudinally sampled during the post-weaning fast in order to study the mobilisation and redistribution of various classes of persistent organic pollutants (POPs), such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) between blubber and blood. Inner and outer blubber layers were analysed separately. Organohalogenated compounds were detected in all blubber samples in the decreasing order of their concentrations: p,p'-DDE>PCBs?HCB>PBDEs. The concentrations of all studied compounds were homogeneously distributed in the blubber layer at early fast, since the concentrations of POPs were statistically not different in the inner and outer layers. With the progression of the fast, the concentrations of PBDEs, PCBs and p,p'-DDE increased more sharply in inner blubber than in outer blubber. As a result, their levels became significantly higher in inner blubber as compared to outer blubber at late fast. The rise of pollutant concentrations in blubber might result from a less efficient mobilisation than triglycerides and/or a reuptake by adipocytes of some of the pollutants released into the circulation. The mobilisation of pollutants from blubber was higher at late fast. An increase of pollutant concentrations was observed in serum between early and late fast. Lower halogenated congeners (i.e. tetra-CBs) were present in higher proportions in serum, whereas the higher halogenated congeners (i.e. hepta-CBs) were mainly found in the inner and outer blubber layers. The transfer ratios of both PBDEs and PCBs from inner blubber to serum decreased with the number of chlorine and bromine atoms. In addition, the distribution of both types of compounds between serum and blubber was strongly influenced by their lipophilic character (log Kow values), with more lipophilic compounds being less efficiently released from blubber to serum.

Purpose Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. Methods From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. Results Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. Conclusion This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment.

In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction.Surgical lung tissue and primary broncho-epithelial cultures (in air–liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1.The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release.In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming.

BACKGROUND: To assess the performance of a predictive model of non-response to neoadjuvant chemotherapy (NAC) in patients with breast cancer based on texture, kinetic, and BI-RADS parameters measured from dynamic MRI. METHODS: Sixty-nine patients with invasive ductal carcinoma of the breast who underwent pre-treatment MRI were studied. Morphological parameters and biological markers were measured. Pathological complete response was defined as the absence of invasive and in situ cancer in breast and nodes. Pathological non-responders, partial and complete responders were identified. Dynamic imaging was performed at 1.5 T with a 3D axial T1W GRE fat-suppressed sequence. Visual texture, kinetic and BI-RADS parameters were measured in each lesion. ROC analysis and leave-one-out cross-validation were used to assess the performance of individual parameters, then the performance of multi-parametric models in predicting non-response to NAC. RESULTS: A model based on four pre-NAC parameters (inverse difference moment, GLN, LRHGE, wash-in) and k-means clustering as statistical classifier identified non-responders with 84 % sensitivity. BI-RADS mass/non-mass enhancement, biological markers and histological grade did not contribute significantly to the prediction. CONCLUSION: Pre-NAC texture and kinetic parameters help predicting non-benefit to NAC. Further testing including larger groups of patients with different tumor subtypes is needed to improve the generalization properties and validate the performance of the predictive model.

BACKGROUND: To enhance the reproducibility of aortic valve-sparing reimplantation and annuloplasty, we analyzed the topographic relationship between the ventriculoaortic junction (VAJ), basal ring (BR), and sinotubular junction (STJ). The root base thickness is also quantified. METHOD: Fifty-eight fresh human aortic valves were analyzed. The root was dissected to the limit where the aortic wall terminates into the cardiac structures (VAJ). Root height was measured externally from the STJ to the VAJ and internally from the STJ to the BR defined as the plane passing through the cusps nadir. The root base thickness was measured at the BR and orthogonal to the internal wall; except at the right coronary sinus, where it was measured between the BR internally and the VAJ externally. Measurements were taken at the middle of the 3 sinuses and commissures. RESULTS: The VAJ is at the same level as the BR from the noncoronary sinus (-0.1 ± 0.9 mm) to the left coronary sinus (0.5 ± 1.3 mm); it is above the BR from the left/right commissure (4.6 ± 1.4 mm) to the right/non commissure (2.5 ± 1.6 mm). The external root height was highest at the non/left commissure (21.5 ± 2.6 mm) followed by the right/non commissure (19.2 ± 2.3 mm) then the left/right commissure (15.7 ± 2.2 mm) (P < .05). The mean root base thickness was 3.2 mm, ranging from 1 ± 0 mm at the left/non commissure to 6.2 ± 1.2 mm at the right coronary sinus (P < .001). CONCLUSIONS: The VAJ is not planar; it is above the level of the BR from the left/right to the right/non commissure. As a consequence, the external height of the non/left commissure is greater than the other 2 commissures. These findings should be taken into consideration when performing aortic valve-sparing reimplantation or external annuloplasty.

The aims of this study were first to clearly define two different entities: locoregional recurrences and limited metastatic disease and secondly to evaluate the place of extensive surgery in these two types of recurrence.Material and Methods. Twenty-four patients were followed from June 2004 until May 2014. All patients underwent surgery but for 1 patient this surgery was stopped because the tumour was unresectable.Results. The median interval between surgery for the primary tumour and the locoregional recurrence or metastatic evolution was 129 months. Eight patients had pure nodal recurrences, 4 had nodal and muscular recurrences, 5 had muscular + skin recurrences, and 8 had metastatic evolution. Currently, all patients are still alive but 2 have liver metastases. Disease free survival was measured at 2 years and extrapolated at 5 years and was 92% at these two time points. No difference was observed for young or older women; limited metastatic evolution and locoregional recurrence exhibited the same disease free survival.Conclusion. Extensive surgery has a place in locoregional and limited metastatic breast cancer recurrences but this option must absolutely be integrated in the multidisciplinary strategy of therapeutic options and needs to be planned with a curative intent.

Congenital limb anomalies occur in Europe with a prevalence of 3.81/1,000 births and can have a major impact on patients and their families. The present study concerned a female fetus aborted at 23 weeks of gestation because she was affected by non-syndromic bilateral absence of the zeugopod (leg) and autopod (foot). Autopsy of the aborted fetus, X-ray imaging, MRI, and histochemical analysis showed that the distal extremity of both femurs was continued by a cartilage-like mass, without joint cavitation. Karyotype was normal. Moreover, no damaging variant was detected by exome sequencing. The limb characteristics of the fetus, which to our knowledge have not yet been reported in humans, suggest a developmental arrest similar to anomalies described in chicks following surgical experiments on the apical ectodermal ridge of the lower limbs.

Background: Some studies suggest that the clinical parameter "amenorrhea" is insufficient to define the menopausal status of women treated with chemotherapy or tamoxifen. In this study, we investigated and compared the ovarian function defined either by clinical or biological parameters in pre-menopausal breast cancer patients treated with tamoxifen administered as adjuvant therapy. Materials and Methods: Between 1999 and 2003, 138 premenopausal patients consecutively treated for early breast cancer were included. Sixty-eight received tamoxifen in monotherapy as the only adjuvant systemic treatment (Group I) and 70 were treated with tamoxifen after adjuvant chemotherapy (Group II). All patients had a confirmed premenopausal status based on clinical parameters and hormonal values at study entry. They were followed prospectively every 3 months for 3 years: menses data, physical examination and blood tests (LH, FSH, 17-beta-estradiol). Vaginal ultrasonography was carried out every 6 months. After 3 years, prospective evaluation was completed and monitoring of ovarian function was performed as usual in our institution (1x/year). All data were retrospectively evaluated in 2011. Results: Three patients were excluded from the study in group I and 2 were excluded in group II. Patients were divided into 4 subgroups according to clinical data, i.e. menses patterns. These patterns were assessed by questionnaires. a: Regular menses (>10 cycles/year) b: Oligomenorrhea (5 to 9 cycles/year) c: Severe oligomenorrhea (1 to 4 cycles/year) d: Complete amenorrhea Estrogen levels did not appear to have any impact on disease-free survival rates after 3 or 8 years. FSH values were also documented and analyzed. They exhibited the same profile as estradiol values. Conclusions: Amenorrhea is an insufficient parameter to define menopausal status in patients receiving tamoxifen. Low estradiol levels must be coupled with other biological parameters to characterize endocrine status. These data are very important for the choice of endocrine therapy. © 2013 Berliere et al.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Background: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. Methods: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). Results: A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HRGG3 vs GG1 5.6 (2.1-15.3); P < 0.001] and OS [HRGG3 vs GG1 7.2, 95% CI (1.6-32.2); P = 0.01]. Conclusions: GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status

To compare deep circumflex iliac (DCI) and deep inferior epigastric (DIE) pedicles as potential recipient vessels for a whole ovarian microvascular transplantation.Anatomical study.Laboratory of anatomy, university center.Ten fresh human female cadavers.Anatomical dissections, vascular injections, histologic analysis.Morphological analysis of the gonadic, DCI, and DIE pedicles; diameter of the vessels at regular intervals along their entire length. Comparisons of the caliber values between receiving (DCI and DIE) and gonadic pedicles aiming to determine the optimal size match.We highlight a tortuous appearance of the gonadic artery. This morphology contrasted with the venous system that included two or three straight veins, one of them being wider than the others. The gonadic vessels converge into a wider artery and vein at 5 cm from the ovary. An optimal size match existed between gonadic and DCI arteries and veins sections, in 13 of 14 gonadic pedicles.A safe microsurgical whole ovarian transplantation is feasible if the gonadic pedicle is harvested with a minimal length of 5 cm from the ovary. The DCI pedicle seems to have the best size match with the ovarian vessels to perform a reliable end-to-end microvascular anastomosis.

Goiter is associated with increased oxidative stress (OS). We studied the effects of an anti-inflammatory agent, 15 deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) and an antioxidant, N-acetylcysteine (NAC), on OS, thyroid function, and goiter expansion in a model of goiter induced by propylthiouracil (PTU) or perchlorate. OS was assessed by the immunodetection of 4-hydroxynonenal, thyroid function by measuring thyroxin (T4) and thyrotropin (TSH) plasma levels and detecting T4-rich thyroglobulin (Tg-I), and goiter expansion by weighing the thyroids and measuring cell proliferation (PCNA and cyclin D1 immunodetection). In both PTU and perchlorate-induced goiters, OS, TSH plasma levels, thyroid weight, and cell proliferation were strongly enhanced, whereas Tg-I expression was negative. All these parameters were reversed by NAC and 15dPGJ2 in PTU-goiters. In perchlorate-goiters, TSH plasma levels remained elevated and Tg-I-negative after NAC or 15dPGJ2 treatment. OS was reduced by NAC, but not by 15dPGJ2. In addition, NAC reduced PCNA and cyclin D1 immunostainings, as well as thyroid weight, whereas 15dPGJ2 influenced neither thyroid weight nor cell proliferation. In conclusion, NAC and 15dPGJ2 overcome PTU- but not perchlorate-induced effects. The retrieval of hormonal synthesis may result from direct chemical interactions between PTU and NAC/15dPGJ2. Although 15dPGJ2 has no effect in perchlorate-goiters, the reduction of OS by NAC is associated with altered goiter development, making OS a required condition for the growth of the thyroid gland.

Reactive oxygen species (ROS) are crucial for thyroid hormonogenesis, and their production is kept under tight control. Oxidative stress (OS) is toxic for thyrocytes in an inflammatory context. In vitro, Th1 pro-inflammatory cytokines have already been shown to decrease thyroid-specific protein expression. In the present study, OS level and its impact on thyroid function were analyzed in vitro in Th1 cytokine (interleukin [IL]-1alpha/interferon [IFN] gamma)-incubated thyrocytes (rat and human), as well as in vivo in thyroids from nonobese diabetic mice, a model of spontaneous autoimmune thyroiditis. N-acetylcysteine (NAC) and prostaglandin, 15 deoxy-(Delta12,14)-prostaglandinJ2 (15dPGJ2), were used for their antioxidant and anti-inflammatory properties, respectively. ROS production and OS were increased in IL-1alpha/IFNgamma-incubated thyrocytes and in destructive thyroiditis. In vitro, NAC not only reduced ROS production below control levels, but further decreased the expression of thyroid-specific proteins in addition to IL-1alpha/IFNgamma-inhibitory effects. Thus, besides ROS, other intracellular intermediaries likely mediate Th1 cytokine effects. In vivo, NAC and 15dPGJ2 reduced OS and the immune infiltration, thereby leading to a restoration of thyroid morphology. It is therefore likely that NAC and 15dPGJ2 mainly exert their protective effects by acting on infiltrating inflammatory cells rather than directly on thyrocytes.