Rituximab Plus Chemotherapy Provides No Clinical Benefit in a Peripheral T-Cell Lymphoma Not Otherwise Specified with Aberrant Expression of CD20 and CD79a: A Case Report and Review of the Literature

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the most common entity of mature T-cell neoplasms. PTCL-NOS generally has an aggressive behavior and is often refractory to standard therapy. Only a few cases of PTCL with aberrant expression of B-cell antigens have been reported so far. This phenotypic aberrancy may lead to misdiagnosis as B-cell non-Hodgkin lymphomas and eventual inappropriate patient management, whereas in an accurately diagnosed PTCL, the presence of CD20 may appear as an appealing therapeutic target. In this setting, response to anti-CD20 monoclonal antibody in combination with chemotherapy has been poorly explored. We describe the case of a 59-year-old male diagnosed by a pathological and molecular approach as PTCL-NOS with aberrant co-expression of the B-cell antigens CD20 and CD79a, which proved non-responsive to the addition of rituximab to standard polychemotherapy. This case highlights that the presence of CD20 in PTCL may be misleading in the diagnosis and also act as a lure for the clinician to adopt a rituximab-based treatment, the effectiveness of which is undefined as the molecular mechanisms underlying B-cell marker expression in PTCL

Asbestos Fibers Enhance the TMEM16A Channel Activity in Xenopus Oocytes

Background: The interaction of asbestos fibers with target cell membranes is still poorly investigated. Here, we detected and characterized an enhancement of chloride conductance in Xenopus oocyte cell membranes induced by exposure to crocidolite (Croc) asbestos fibers. Methods: A two-microelectrode voltage clamp technique was used to test the effect of Croc fiber suspensions on outward chloride currents evoked by step membrane depolarization. Calcium imaging experiments were also performed to investigate the variation of ‘resting’ oocyte [Ca2+]i following asbestos exposure. Results: The increase in chloride current after asbestos treatment, was sensitive to [Ca2+]e, and to specific blockers of TMEM16A Ca2+-activated chloride channels, MONNA and Ani9. Furthermore, asbestos treatment elevated the ‘resting’ [Ca2+]i likelihood by increasing the cell membrane permeability to Ca2 in favor of a tonic activation of TMEME16A channels. Western blot analysis confirmed that TMEME16A protein was endogenously present in the oocyte cell membrane and absorbed by Croc. Conclusion: the TMEM16A channels endogenously expressed by Xenopus oocytes are targets for asbestos fibers and represent a powerful tool for asbestos–membrane interaction studies. Interestingly, TMEM16A channels are highly expressed in many types of tumors, including some asbestos-related cancers, suggesting them, for the first time, as a possible early target of crocidolite-mediated tumorigenic effects on target cell membranes

Placental Chorangiocarcinoma a Specific Histological Pattern of Uncertain Incidence and Clinical Impact: Systematic Review of the Literature

Chorangiocarcinoma is a very rare and misdiagnosed placental neoplasm. The unique morphologic features of the lesion distinguish it from other trophoblastic tumors and vascular abnormalities. We present a systematic review of the literature to provide clarity on chorangiocarcinoma entity and biology. A literature search was carried out in December 2022 using the keywords "Placental chorangiocarcinoma", "Chorangioma", "Placenta", and "Throphoblast proliferation". Articles published from 1988 to 2022 were obtained from Scopus, Google Scholar, and PUBMED. In our review, we examined maternal age, gestational age at the time of delivery, parity, type of pregnancy, placental weight, ultrasound features of the placenta, macroscopic examination and tumor size, microscopic examination, immunostaining, maternal beta-human chorionic gonadotropin, fetal and maternal outcome. Eight manuscripts were detected. They are all case reports. The macroscopic characteristics of the lesions were represented by the presence of a grey-yellow-white color well-demarcated round nodule. Microscopically, all the authors described typical aspects of malignancy as a high rate of mitosis, nuclear atypia and necrotic areas. In some cases, the presence of AE1/AE3 cytoplasmic positivity, p63 nuclear staining, and beta-human chorionic gonadotropin (BHCG) were reported. A good fetal outcome was reported in all cases of newborns with normal birth weight, except one with fetal growth restriction. Maternal outcome was good in all cases except one with maternal lung metastasis three months after delivery. The clinical course has probably underestimated the real incidence of the pathology. Only greater knowledge of its histology and its clinical course will allow us to evaluate the real prevalence of the disease

COVID-19 Pandemic: Huge Stress Test for Health System Could Be a Great Opportunity to Update the Workflow in a Modern Surgical Pathology

Simple Summary The COVID-19 pandemic has hit Northern Italy's regions hard in terms of deaths since February 2020. Containment measures have been applied to avoid contagion and reduce the patient infection rate. In this manuscript, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori in Milan, during the period of the first lockdown that occurred in Lombardy from March to May 2020, focusing on the variation in terms of exams between the pre-COVID-19 and COVID-19 periods and describing the measures applied to guarantee the safeguarding of workers. Moreover, we calculated if changes introduced within the workflow affected the average diagnosis time using Turn-Around-Time (TAT) metrics released by the Lombardy Region. We showed a sharp slowdown in exams during the first wave of COVID-19 and that the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department. Background: On December 2019, an outbreak of atypical pneumonia, known as COVID-19, was identified in Wuhan, China. This disease, characterized by the rapid human-to-human transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly in more than 200 countries. Northern Italy's regions have been hit hard in terms of deaths. Here, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori (INT) in Milan, the first Italian public cancer center, in the period of the lockdown that took place in Lombardy from March to May 2020. Method: The variation in terms of exams was calculated in two different timeframes: December 2019-February 2020 (pre-COVID-19) and March-May 2020 (COVID-19). During these periods, Turn-Around-Time (TAT) metrics released by the Lombardy Region were calculated to assess if changes applied to guarantee the safeguarding of workers affected the average diagnosis time. Results: In the COVID-19 period, there was a decrease for all the performed exams. The most considerable decrease was observed for PAP tests (-81.6%), followed by biopsies (-48.8%), second opinions (-41.7%), and surgical (-31.5%), molecular (-29.4%) and cytological (-18.1%) tests. Measures applied within the Pathology Department, such as digital pathology, remote working, rotations and changes in operating procedures, improved the diagnostic performance as required by the guidelines of the Lombardy Region in terms of TAT. At the same time, the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department. Conclusions: The sharp slowdown in cancer screening during the first wave of COVID-19 could seriously endanger cancer prevention in the near future

A new tool for investigation platelet activation in endometriosis patients

Objectives: Endometriosis (EM) is a gynecological disease characterized by chronic inflammation, due to the interaction of inflammatory cells with ectopic endometrium (1). Platelets (PLTs), recruited by procoagulant factors released from endometriotic stromal cells, secrete angiogenetic factors and induce overexpression of genes involved in pro-survival/ anti-apoptotic propensity, inflammationand extracellular matrix remodeling (2). We aimed to develop a tool to measure PLT activation (by small extracellular vesicles, s-EVs) in EM peritoneal fluids, as a potential predictive marker of EM severity. Materials & methods: S-EVs were isolated from EM peritoneal fluids and characterized with imaging (Atomic Force Microscopy; AFM) and protein expression analyses (Western blot, WB) (3). We explored gene expression in peritoneum and EM lesions using EndometDB (4). Results: We demonstrated the presence of s-EVs isolated from EM peritoneal fluids by liquid AFM, as showed by contact angle vs diameter scatterplot (Fig.1A-B), and by WB detecting the s-EV markers CD63, CD9, and TSG101 (Fig.1C). Using Endomet-DB, we highlighted the differentially expressed genes between control and EM peritoneum samples (Fig.1D). The protein expression of a panel of biomarkers of PTL in s-EVs was further confirmed by WB (Fig.1E). Conclusions: We propose applying s-EV research to EM investigation, generating a novel biochemical tool for PLT activation assessment and for the development of new diagnostics and therapies

Urinary proteomic profiles of prostate cancer with different risk of progression and correlation with histopathological features

Prostate cancer (PCa) is the most common tumor in men with extremely variable outcome, varying from latent or indolent form to very aggressive behavior. High grade tumors, expansions exceeding the prostatic capsule into the surrounding soft tissues and spreading through lymph vascular channels, represent the most consistent unfavorable prognostic factors. However, accuracy in the prediction of the disease progression is sometimes difficult. Along with new molecular diagnostic techniques and more accurate histopathological approaches, proteomic studies challenge to identify potential biomarkers predictive of PCa progression. In our study we analyzed the urinary proteomes of 42 patients affected by PCa through two-dimensional electrophoresis associated with mass spectrometry. Proteomic profiles were correlated to histopathological features including pTNM stage and tumor differentiation in order to provide new promising markers able to define more accurately the PCa aggressiveness and driving new therapeutic approaches

Poorly differentiated clusters (PDC) in colorectal cancer: Does their localization in tumor matter?

Poorly differentiated clusters (PDC) are aggregates of at least five neoplastic cells lacking evidence of glandular differentiation. By definition, they can be present at the invasive front (peripheral PDC or pPDC) and within the tumor stroma (central PDC or cPDC). In colorectal cancer (CRC), PDC are considered adverse prognosticators and seem to reflect epithelial mesenchymal transition (EMT). In this study, we have investigated the immuno-expression of two EMT-related proteins, E-cadherin and \u3b2-catenin, in PDC of primary CRCs and matched liver metastases. pPDC always showed nuclear \u3b2-catenin staining and diffusely reduced/absence of E-cadherin expression as opposed cPDC which showed nuclear \u3b2-catenin immunoreactivity and E-cadherin expression in about 50% of cases. In addition, the pattern of \u3b2-catenin and E-cadherin expression differed between PDC and the main tumor, and between primary CRC and liver metastasis (LM), in a percentage of cases. A discordant pattern of \u3b2-catenin and E-cadherin expression between pPDC and cPDC, between main tumor and cPDC, and between primary CRC and LM, confirms that EMT is a dynamic and reversible process in CRC. On the overall, this suggests that pPDC and cPDC are biologically different. We may advocate that PDC develop at the tumor center (cPDC) and then some of them migrate towards the tumor periphery while progressively completing EMT process (pPDC). Based on these results, PDC presence and counting may have different prognostic relevance if the assessment is done at the invasive front of the tumor or in the intratumor stroma

COVID-19, Pre-Eclampsia, and Complement System

Copyright © 2021 Agostinis, Mangogna, Balduit, Aghamajidi, Ricci, Kishore and Bulla. COVID-19 is characterized by virus-induced injury leading to multi-organ failure, together with inflammatory reaction, endothelial cell (EC) injury, and prothrombotic coagulopathy with thrombotic events. Complement system (C) via its cross-talk with the contact and coagulation systems contributes significantly to the severity and pathological consequences due to SARS-CoV-2 infection. These immunopathological mechanisms overlap in COVID-19 and pre-eclampsia (PE). Thus, mothers contracting SARS-CoV-2 infection during pregnancy are more vulnerable to developing PE. SARS-CoV-2 infection of ECs, via its receptor ACE2 and co-receptor TMPRSS2, can provoke endothelial dysfunction and disruption of vascular integrity, causing hyperinflammation and hypercoagulability. This is aggravated by bradykinin increase due to inhibition of ACE2 activity by the virus. C is important for the progression of normal pregnancy, and its dysregulation can impact in the form of PE-like syndrome as a consequence of SARS-CoV-2 infection. Thus, there is also an overlap between treatment regimens of COVID-19 and PE. C inhibitors, especially those targeting C3 or MASP-2, are exciting options for treating COVID-19 and consequent PE. In this review, we examine the role of C, contact and coagulation systems as well as endothelial hyperactivation with respect to SARS-CoV-2 infection during pregnancy and likely development of PE.Ferring COVID-19 Investigational Grant (GRAVISAR to RB); Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy (RC24/19 to GR and 09/21 to CA)

Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups

Lung neuroendocrine neoplasms (LNENs) classes, as proposed by the World Health Organization 2015, do not provide properly prognostic and therapeutic indications. In fact, high-throughput molecular analysis, based on next-generation sequencing, identified novel molecular subgroups, associated with different genomic signatures, that could pave the way for alternative therapeutic approaches. The present review, coupled with in silico molecular analysis, could show the current genomic alterations state in actual LNENS groups. Interestingly our manuscript suggests that the molecular novelties could improve the LNENs therapeutics efficacy. In more detail, we reported the differences of gene alterations and mutational rate between LNENS, confirming the central pathogenetic role given by a different mutational rate in chromatin remodeling genes and tumor suppressors TP53-RB1. In conclusion, our results underlined that a further molecular layer is needed to improve the efficacy of LNENs medical treatment.Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, TP53 and RB1 tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment

Pathological significance and prognostic value of Surfactant Protein D in cancer

Surfactant protein D (SP-D) is a pattern recognition molecule belonging to the Collectin (collagen-containing C-type lectin) family that has pulmonary as well as extra-pulmonary existence. In the lungs, it is a well-established opsonin that can agglutinate a range of microbes, and enhance their clearance via phagocytosis and super-oxidative burst. It can interfere with allergen-IgE interaction and suppress basophil and mast cell activation. However, it is now becoming evident that SP-D is likely to be an innate immune surveillance molecule against tumor development. SP-D has been shown to induce apoptosis in sensitized eosinophils derived from allergic patients and a leukemic cell line via p53 pathway. Recently, SP-D has been shown to suppress lung cancer progression via interference with the epidermal growth factor signaling. In addition, a truncated form of recombinant human SP-D has been reported to induce apoptosis in pancreatic adenocarcinoma via Fas-mediated pathway in a p53-independent manner. To further establish a correlation between SP-D presence/levels and normal and cancer tissues, we performed a bioinformatics analysis, using Oncomine dataset and the survival analysis platforms Kaplan-Meier plotter, to assess if SP-D can serve as a potential prognostic marker for human lung cancer, in addition to human gastric, breast and ovarian cancers. We also analyzed immunohistochemically the presence of SP-D in normal and tumor human tissues. We conclude that (1) in the lung, gastric and breast cancers, there is a lower expression of SP-D than normal tissues; (2) in ovarian cancer, there is a higher expression of SP-D than normal tissue; and (3) in lung cancer, the presence of SP-D could be associated with a favorable prognosis. On the contrary, at non-pulmonary sites such as gastric, breast and ovarian cancers, the presence of SP-D could be associated with unfavorable prognosis. Correlation between the levels of SP-D and overall survival requires further investigation. Our analysis involves a large number of dataset; therefore, any trend observed is reliable. Despite apparent complexity within the results, it is evident that cancer tissues that produce less levels of SP-D compared to their normal tissue counterparts, are probably less susceptible to SP-D-mediated immune surveillance mechanisms via infiltrating immune cells