Caveolin-1 in Kidney Chronic Antibody-Mediated Rejection: An Integrated Immunohistochemical and Transcriptomic Analysis Based on the Banff Human Organ Transplant (B-HOT) Gene Panel.

Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate marker of c-ABMR. Caveolin-1 expression was analyzed in a selected series of 22 c-ABMR samples and 11 controls. Caveolin-1 immunohistochemistry proved positive in peritubular and glomerular capillaries of c-ABMR specimens, irrespective of C4d status whereas all controls were negative. Multiplex gene expression profiling in c-ABMR cases confirmed Caveolin-1 overexpression and identified additional genes (n = 220) and pathways, including MHC Class II antigen presentation and Type II interferon signaling. No differences in terms of gene expression (including Caveolin-1 gene) were observed according to C4d status. Conversely, immune cell signatures showed a NK-cell prevalence in C4d-negative samples compared with a B-cell predominance in C4d-positive cases, a finding confirmed by immunohistochemical assessment. Finally, differentially expressed genes were observed between c-ABMR and controls in pathways associated with Caveolin-1 functions (angiogenesis, cell metabolism and cell-ECM interaction). Based on our findings, Caveolin-1 resulted as a key player in c-ABMR, supporting its role as a marker of this condition irrespective of C4d status.

Placenta histopathology in SARS-CoV-2 infection: analysis of a consecutive series and comparison with control cohorts.

Infection by SARS-CoV-2 has been shown to involve a wide range of organs and tissues, leading to a kaleidoscope of clinical conditions. Within this spectrum, an involvement of the fetal-maternal unit could be expected, but, so far, the histopathological evaluation of placentas delivered by women with SARS-CoV-2 infection did not show distinct hallmarks. A consecutive series of 11 placentas, delivered by 10 women with COVID-19 admitted to our Obstetrics and Gynecology clinic have been investigated and compared to a control cohort of 58 pre-COVID-19 placentas and 28 placentas delivered by women who had a previous cesarean section. Four out of eleven placentas showed changes consistent with chronic villitis/villitis of unknown etiology (VUE), while in one case, chronic histiocytic intervillositis was diagnosed. Thrombo-hemorrhagic alterations were observed in a subset of cases. Compared to the control cohort, chronic villitis/VUE (p < 0.001), chronic deciduitis (p = 0.023), microvascular thrombosis (p = 0.003), presence of infarction areas (p = 0.047) and of accelerated villous maturation (p = 0.005) showed higher frequencies in placentas delivered by women with COVID-19. Chronic villitis/VUE (p = 0.003) and accelerated villous maturation (p = 0.019) remained statistically significant by restricting the analysis to placentas delivered after a previous cesarean section. The observed differences in terms of pathological findings could be consistent with SARS-CoV-2 pathogenesis, but just a subset of alterations remained statistically significant after adjusting for a previous cesarean section. A careful consideration of potential confounders is warranted in future studies exploring the relationship between COVID-19 and pregnancy.

DNA Methylation Profiling Discriminates between Malignant Pleural Mesothelioma and Neoplastic or Reactive Histologic Mimics.

The diagnosis of malignant pleural mesothelioma (MPM) is challenging because of its potential overlap with other neoplasms or even with reactive conditions. DNA methylation analysis is effective in diagnosing tumors. In the present study, this approach was tested for use in MPM diagnosis. The DNA methylation patterns of a discovery cohort and an independent-validation cohort of MPMs were compared to those of 202 cases representing malignant and benign diagnostic mimics (angiosarcoma, desmoid-type fibromatosis, epithelioid sarcoma, leiomyosarcoma, lung adenocarcinoma, lung squamous cell carcinoma, melanoma, nodular fasciitis, reactive mesothelial hyperplasia, sclerosing fibrous pleuritis, solitary fibrous tumor, and synovial sarcoma). By both unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis, MPM samples in the discovery cohort exhibited a DNA methylation profile different from those of other neoplastic and reactive mimics. These results were confirmed in the independent validation cohort and by in silico analysis of the MPM-The Cancer Genome Atlas data set. Copy number variation profiles were also inferred to identify molecular hallmarks of MPM, including CDKN2A and NF2 deletions. Methylation profiling was effective in the diagnosis of MPM, although caution is advised in samples with low tumor cell content.

Gut Microbiota and Gynecological Cancers: A Summary of Pathogenetic Mechanisms and Future Directions.

Over the past 20 years, important relationships between the microbiota and human health have emerged. A link between alterations of microbiota composition (dysbiosis) and cancer development has been recently demonstrated. In particular, the composition and the oncogenic role of intestinal bacterial flora has been extensively investigated in preclinical and clinical studies focusing on gastrointestinal tumors. Overall, the development of gastrointestinal tumors is favored by dysbiosis as it leads to depletion of antitumor substances (e.g., short-chain fatty acids) produced by healthy microbiota. Moreover, dysbiosis leads to alterations of the gut barrier, promotes a chronic inflammatory status through activation of toll-like receptors, and causes metabolic and hormonal dysregulations. However, the effects of these imbalances are not limited to the gastrointestinal tract and they can influence gynecological tumor carcinogenesis as well. The purpose of this Review is to provide a synthetic update about the mechanisms of interaction between gut microbiota and the female reproductive tract favoring the development of neoplasms. Furthermore, novel therapeutic approaches based on the modulation of microbiota and their role in gynecological oncology are discussed.

Impact of COVID-19 lockdown measures on oncological surgical activity: Analysis of the surgical pathology caseload of a tertiary referral hospital in Northwestern Italy.

BACKGROUND AND OBJECTIVES: Italy was severely affected by the severe acute respiratory syndrome coronavirus 2 pandemic. Our Institution, Piedmont's largest tertiary referral center, was designated as a non-COVID-19 hospital and activities were reorganized to prioritize critical services like oncological care. The aim of this study was to investigate the efficacy in preserving the oncological surgical practice at our Institution during the most critical months of the COVID-19 epidemic by analyzing the surgical pathology activity. METHODS: The number of oncological surgical resections submitted to histopathological examination from 9th March 2020 to 8th May 2020 were collected as well staging/grading data and compared with the previous three pre-COVID-19 years (2017-2019). RESULTS: Overall, no decrease was observed for most tumor sites (5/9) while breast resections showed the largest drop (109 vs. 160; -31.9%), although a full recovery was already noticed during the second half of the period. Conversely, the selected control benchmarks showed a sharp decrease (-80.4%). Distribution of pathological TNM stages (or tumor grades for central nervous system tumors) showed no significant differences during the lockdown compared with previous years (p > .05). CONCLUSIONS: The present data suggest the possibility of preserving this cornerstone oncological activity during an evolving public health emergency thanks to a prompt workflow reorganization.

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review.

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target.

The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.