New insights and evidence on “Food Intolerances”: non-celiac gluten sensitivity and nickel allergic contact mucositis

The clinical examination of patients often comes across the observation of the existence of a close relationship between the ingestion of certain foods and the appearance of various symptoms. Until now, the occurrence of these events has been loosely defined as food intolerance. Today these conditions should more properly be called Adverse Food Reactions (AFRs) which can consist of the presentation of a wide variety of symptoms which are commonly identified as Irritable Bowel Disease (IBS) syndrome. In addition, systemic manifestations such as neurological, dermatological, joint and respiratory disorders may also occur in affected patients. Although the etiology and pathogenesis of some of them are already known, others, such as non-celiac gluten sensitivity and adverse reactions to nickel-containing foods, are not yet fully defined. The study was aimed at evaluating the relationship between the ingestion of some foods and the appearance of some symptoms, clinical improvement and detectable immunohistochemical alterations after a specific exclusion diet. One hundred and six consecutive patients suffering from meteorism, dyspepsia and nausea following the ingestion of foods containing gluten or nickel were subjected to the GSRS questionnaire, modified according to the "Salerno expert criteria". All patients underwent detection of IgA antibodies to tissue transglutaminase, oral mucosal patch test with gluten and nickel (OMPT), and EGDS including biopsies. Our data show that GSRS and OMPT, the use of APERIO CS2 software and the endothelial marker CD34 could be suggested as useful tools in the diagnostic procedure of these new pathologies. Larger, multi-center clinical trials could be helpful in defining these emerging clinical problems

Atypical cellular neurothekeoma (ACN) of the elderly: case report and brief review of the literature

Atypical cellular neurothekeoma (ACN) is an aggressive and rare variant of cellular neurothekeoma. Only few cases have been reported in the literature and the biological behavior seems to be uncertain. We describe the case of an ACN presenting on the scalp of an elderly man, emphasizing the cytologic features of malignancy. In addition, we provide a brief overview of the literature and discuss the differential diagnosis with other entities, and the possible diagnostic pitfalls

Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology

Introduction: Compared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). Methods: In this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples. Results and discussion: A total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy

Anti-aminoacyl-tRNA synthetase-related myositis and dermatomyositis: clues for differential diagnosis on muscle biopsy

Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX-deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two

CD73 expression and pathologic response to neoadjuvant chemotherapy in triple negative breast cancer

The immune system plays a key role in tumor surveillance and escape. Recently, CD73 has been proposed as a prognostic biomarker associated with disease-free survival and overall survival in triple negative breast cancer (TNBC). In this study, we investigated the role of both CD73 expression and stromal tumor–infiltrating lymphocytes (TILs) in predicting the pathologic response of TNBC to neoadjuvant chemotherapy (NACT).We retrospectively analyzed CD73 immunohistochemical expression and stromal TILs on 61 consecutive biopsies from patients who received standard NACT. Twenty-three patients (38%) achieved pathologic complete response (pCR). TILs were present in the majority of biopsies (93%) with percentages ranging from 2 to 80%. High TILs (≥ 50%) were found in 30% of cases, and in this group, pCR was achieved in 76.5% of cases. Levels of TILs were associated with a better pathologic response only at univariate analysis (p = 0.037). The median value of CD73 expression on tumor cells was 40%. In 32 (52.5%) basal biopsies, CD73 expression was below or equal to median value (“low CD73”). A pCR was obtained in 53% of cases with “low CD73” and in 21% with high CD73, and this was statistically different both at univariate (p = 0.011) and multivariate (p = 0.014) analysis. Our results suggest that CD73 expression better predicts the response to NACT than TILs in TNBC. Characterization of both TILs and microenvironment could be a promising approach to personalize treatment

Evaluating PD-L1 in head & neck squamous cell carcinoma: concordance between 22C3 PharmaDx and SP263 assays on whole sections from a multicenter study

Aims: The introduction of immunotherapy in head and neck squamous cell carcinoma (HNSCC) raises the need for harmonization between different types of antibodies and immunohistochemistry platforms for evaluating the expression of (Programmed death-ligand 1) PD-L1 with Combined Positive Score (CPS) in this tumor. We compare the expression of PD-L1, using the CPS and two widely used antibody (22C3 pharma Dx and SP263 assay) in a cohort of HNSCC. Methods and results: We analyzed forty-three whole sections of HNSCC with two different anti-PD-L1 antibodies, 22C3 pharma Dx and SP263 assay. Results, expressed as CPS, were evaluated by ten trained pathologists and statistical analyses, including interobserver agreement, were performed. We found a very similar distribution for PD-L1 expression between 22C3 pharmaDx assay and SP263 assay in our cohort and a strong significant correlation between the two assays for all specimens (Spearman r= 0.945; p<0.0001). The interobserver reliability among pathologists for the continuous scores of CPS with ICC and the correlation between the two assays was both good. Moreover, the agreement rate between assays was high at all cut-offs and was best for the most relevant cut-off of CPS ≥1, while the kappa values were always in the range of almost perfect. Conclusions: Two different assays (22C3 pharmaDx assay and SP263 assay) for PD-L1 in HNSCC showed high agreement. This data suggests the interchangeability of these two antibodies in the selection of patients with HNSCC for immunotherapy

beta-Amyloid Monomers Are Neuroprotective

The 42-aa-long beta-amyloid protein-A beta(1-42)-is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein)-overexpressing mice (Lesne et al., 2006), and neuronal cultures treated with synthetic A beta peptides (Lambert et al., 1998) indicate that self-association of A beta(1-42) monomers into soluble oligomers is required for neurotoxicity. The function of monomeric A beta(1-42) is unknown. The evidence that A beta(1-42) is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic A beta(1-42) monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration associated with AD. The neuroprotective action of A beta(1-42) monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of A beta(1-42) carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of A beta(1-42) may also cause neurodegeneration by depriving neurons of the protective activity of A beta(1-42) monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing A beta burden

Advancing the PD-L1 CPS test in metastatic TNBC: Insights from pathologists and findings from a nationwide survey

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of = 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC