Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis

To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment

Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma:A Large Multi-Institutional International Study

The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen's Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654-0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667-0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions

Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences

Immune infiltration in invasive lobular breast cancer

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels and composition of tumor infiltrating lymphocytes (TIL) and their association with clinico-pathological, and outcome variables in ILC, and to compare it with IDC. Methods: We considered two patient series with TIL data: a multi-centric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and TCGA patients. All ILC/IDC comparisons were done in ER-positive/HER2-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared to IDC (fold change =0.79; 95%CI: 0.70-0.88, P<.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariable analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although it did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intra-tumoral but not total CD8+ were statistically significantly lower in ILC compared to IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusion: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations

Molecular, cellular and tissue mechanisms of endometrial extracellular matrix breakdown leading to abnormal bleeding

Irregular dysfunctional bleeding of human endometrium is associated to and most likely induced by an untimely focal expression and activation of several MMPs, in particular MMP-1, -2, -3 and -9. Moreover, a decreased expression of TIMP-1 contributes to the degradation of the extracellular matrix in the areas where MMPs are expressed. The herogeneously decreased expression of ER alpha and PRA and B is probably involved in a focal loss of repression of the expression of MMPs, which are induced in the stromal cells by interleukin-1 alpha and/or by other as yet unidentified cytokines. Inflammatory cells, in particular neutrophils with their abundant content of proMMP-8 and -9, are recruited at the same sites and release these zymogens, which, once activated, increase the proteolysis of the extracellular matrix. The menstrual-like degradation of the endometrial extracellular matrix and of the basement membranes underlying the vessels and the surface epithelium will induce a bleeding episode, which probably becomes clinically noticeable when (or because) many superficial areas of the endometrium simultaneously undergo the lytic process.(SBIM 3)--UCL, 200

The potential oncogenic effect of tamoxifen on the endometrium.

We report the case of an in-situ endometrial adenocarcinoma with severe atypical hyperplasia which developed while the patient was on tamoxifen only 1 year after endometrial resection for benign pathology. A 55-year-old woman received tamoxifen as adjuvant therapy for breast cancer treated in 1994. At that time, a benign endometrial polyp was also removed before initiating tamoxifen treatment. In 1997, endometrial resection was performed for benign pathology (atrophic cystic endometrium). In 1998, an endometrial adenocarcinoma was diagnosed. This case illustrates that endometrial resection does not protect women taking tamoxifen against subsequent development of severe atypical lesions

Cytopathological features of solitary fibrous tumor of the pleura: a study of 5 cases.

Solitary fibrous tumor is a rare lesion of serosal membranes. In a pleural location, it may be confused clinically with a localized mesothelioma or a peripheral lung tumor. A transthoracic needle aspiration can be done to obtain material for a diagnosis in these easily accessible tumors. In the literature, there are only sporadic reports of cytology of solitary fibrous tumor in pleural fluid or in material obtained by percutaneous fine-needle aspiration. We had the opportunity to study five such cases by cytology and biopsy and in four cases we could study the resected specimen as well. We want to emphasize the possibilities of approaching diagnosis by cytologic material. A more precise diagnosis can be made if immunohistochemistry can be applied on a cell block or a concomitant biopsy specimen. We shall discuss the differential diagnosis of these tumors on cytologic material and/or biopsy and the usefulness of the CD34 antibody

Place de la cytoponction à l'aiguille fine dans la mise au point des nodules thyroïdiens

Alors que le nodule thyroïdien est une affection très fréquente, le cancer thyroïdien reste rare. Une difficulté est liée à l’impossibilité de définir avec certitude le degré de malignité. A ce jour, aucun examen paraclinique ne permet de répondre à cette question, mais la cytoponction à l’aiguille fine pourrait contribuer à améliorer le diagnosti