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Deregulation such as overexpression of adhesion molecules influences cancer progression and survival. Metastasis of malignant cells from their primary tumor site to distant organs is the most common reason for cancer-related deaths. Junctional adhesion molecule-C (JAM-C), a member of the immunoglobulin-like JAM family, can homodimerize and aid cancer cell migration and metastasis. Here we show that this molecule is dynamically expressed on multiple myeloma (MM) cells in the bone marrow and co-localizes with blood vessels within the bone marrow of patients and mice. In addition, upregulation of JAM-C inversely correlates with the downregulation of the canonical plasma cell marker CD138 (syndecan-1), whose surface expression has recently been found to dynamically regulate a switch between MM growth in situ and MM dissemination. Moreover, targeting JAM-C in a syngeneic in vivo MM model ameliorates MM progression and improves outcome. Overall, our data demonstrate that JAM-C might serve not only as an additional novel diagnostic biomarker but also as a therapeutic target in MM disease.

Supplemental Digital Content is available in the text., Background. Uncontrolled donation after circulatory death (DCD) donors are an extraordinary resource to increase the number of lungs available for transplantation. However, the risk of the warm ischemia resulting from cardiac arrest to irreversibly damage the organs is considerable. Moreover, graft preservation issues and organizational problems often worsen the dangerous effects of warm ischemia. Ex vivo lung perfusion (EVLP) enables us to evaluate and recondition lungs whose functionality is doubtful, as well as to overcome the difficulties related to time and logistics. Methods. We report the case of uncontrolled DCD lungs successfully treated with an exceptionally prolonged EVLP. Because the donor’s blood count and liver biopsy showed signs of possible leukemia, EVLP was protracted up to 17 h while waiting for immunohistochemical analyses to rule out this diagnosis; eventually, the results came back negative, and the lungs were judged suitable for transplantation. Results. The recipient was a 32-y-old male individual with cystic fibrosis, colonized by Pandoraea pnomenusa. Bilateral transplantation required central extracorporeal membrane oxygenation. The patient was extubated after 36 h and was discharged 21 d after the operation. Despite early recolonization by Pandoraea pnomenusa and airway complications requiring pneumatic dilatation, he is alive and has a satisfactory respiratory function 15 mo after transplantation. Conclusions. Uncontrolled DCD represents a challenge due to both logistical issues and the complexity of graft evaluation before procurement. EVLP with cellular perfusate could be a valuable tool to overcome these limits. Nonetheless, caution should be exercised when interpreting the effects of this technique on airway healing.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank]0.001, P[trend]0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)].SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

Fibroblastic reticulum cell tumor (FRCT) is a rare dendritic neoplasm arising from fibroblastic reticulum cells (FBRCs) and exhibiting peculiar cytokeratin expression. FRCTs usually involve the lymph nodes, although they can also be encountered in the spleen and soft tissues. FRCTs are composed of mildly atypical spindle or ovoid cells, arranged in loose whorls, which express almost invariably low-weight cytokeratins, smooth muscle actin, and CD68. An admixed lymphoplasmacytic infiltrate is also frequently present in solid organ sites. The clinical picture may vary from very indolent to aggressive disease exhibiting features of malignancy, such as cytological pleomorphism, necrosis, or high mitotic rate and metastatic potential. FRCT is a challenging diagnosis, due to its rarity and deceptive cytokeratin expression. Hereafter, we revise the most recent literature regarding such condition and report the case of an extremely indolent splenic FRCT, with no features of malignancy.

Primary cutaneous γδ T-cell lymphomas (PCGDTLs) are a heterogeneous group of lymphomas representing about 1% of primary cutaneous T-cell lymphomas (CTCLs) and mostly regarded as clinically aggressive. Current WHO-EORTC classification recognizes different clinic-pathologic subsets of PCGDTL, but it suggests that cases showing a mycosis fungoides (MF)-like clinical presentation and histopathology should be classified as MF irrespective of phenotype for their indolent course. Herein, we describe a case of γδ-MF, featuring at onset a granulomatous pattern, with subsequent clinical worsening signaled by the development of an ulcero-necrotic lesion and systemic dissemination, leading to death in 5 months. Clinical progression was sustained by a shift to mature T-cell lymphoma composed of medium to large-sized blastoid T-cells featuring a T-cell receptor (TCR) silent immunophenotype.

Introduction: Little information about clinical presentation of mesenchymal tumors of the lower gastrointestinal (GI) tract due to their extreme heterogeneity is available for clinical management. Usually, small solitary asymptomatic polyps are accidently found during a screening colonoscopy performed for hematochezia, abdominal pain, constipation, diarrhea, and bowel obstruction. In this case series, we illustrate our experience with mesenchymal tumors of the lower GI tract, which are a group of unusual and quite challenging lesions. Case Presentation: We retrospectively collected mesenchymal tumors of the lower GI tract in our institution (Fondazione IRCSS Ca’ Granda – Ospedale Maggiore Policlinico di Milano) during the last 10 years. We reviewed the histological slides, and, when necessary, we performed immunohistochemical analyses to better characterize the tumors. A total of 99 cases were identified: 45 GISTs, 42 lipomas, 4 leiomyomas, 3 Kaposi sarcomas, 1 schwannoma, 1 ganglioneuroma, 1 hemangioma, 1 inflammatory fibroid polyp, and 1 challenging case of spindle cell melanoma. We focused on the most rare entities excluding therefore all GISTs and lipomas from re-evaluation. Conclusion: Mesenchymal tumors of the lower GI tract represent a highly heterogeneous group of lesions encompassing GISTs, lipomas, smooth muscle tumors (leiomyoma and leiomyosarcoma), GI schwannomas, inflammatory fibroid polyps, solitary fibrous tumors, and other unusual spindle cell tumors. Immunohistochemistry and, in selected cases, molecular biology remain a useful tool which, in addition to a meticulous study of the morphology, helps the pathologist in the tangled jungle of differential diagnosis.

Management of systemic mastocytosis is an emerging challenge which requires a multidisciplinary diagnostic approach and personalized treatment strategy. Midostaurin can rapidly reduce the disease burden, also in cladribine refractory cases.

Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up.We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients.Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality.Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality.

Healthcare workers experienced high degree of stress during COVID-19. Purpose of the present article is to compare mental health (depressive and Post-Traumatic-Stress-Disorders—PTSD—symptoms) and epigenetics aspects (degree of methylation of stress-related genes) in front-line healthcare professionals versus healthcare working in non-COVID-19 wards. Sixty-eight healthcare workers were included in the study: 39 were working in COVID-19 wards (cases) and 29 in non-COVID wards (controls). From all participants, demographic and clinical information were collected by an ad-hoc questionnaire. Depressive and PTSD symptoms were evaluated by the Patient Health Questionnaire-9 (PHQ-9) and the Impact of Event Scale—Revised (IES-R), respectively. Methylation analyses of 9 promoter/regulatory regions of genes known to be implicated in depression/PTSD (ADCYAP1, BDNF, CRHR1, DRD2, IGF2, LSD1/KDM1A, NR3C1, OXTR, SLC6A4) were performed on DNA from blood samples by the MassARRAY EpiTYPER platform, with MassCleave settings. Controls showed more frequent lifetime history of anxiety/depression with respect to cases (χ2 = 5.72, p = 0.03). On the contrary, cases versus controls presented higher PHQ-9 (t = 2.13, p = 0.04), PHQ-9 sleep item (t = 2.26, p = 0.03), IES-R total (t = 2.17, p = 0.03), IES-R intrusion (t = 2.46, p = 0.02), IES-R avoidance (t = 1.99, p = 0.05) mean total scores. Methylation levels at CRHR1, DRD2 and LSD1 genes was significantly higher in cases with respect to controls (p p = 0.03 and p = 0.03, respectively). Frontline health professionals experienced more negative effects on mental health during COVID-19 pandemic than non-frontline healthcare workers. Methylation levels were increased in genes regulating HPA axis (CRHR1) and dopamine neurotransmission (DRD2 and LSD1), thus supporting the involvement of these biological processes in depression/PTSD and indicating that methylation of these genes can be modulated by stress conditions, such as working as healthcare front-line during COVID-19 pandemic.

Highlights • Lung donation after cardiac death is a valuable option to fight organ shortage. • Grafts from an extended uncontrolled DCD donor were transplanted. • The recipient was a high-risk fragile patient with cystic fibrosis. • Ex-vivo lung perfusion has a pivotal role in graft function evaluation. • Good results were achieved despite several relative contraindications., Introduction Lung donation after circulatory death (DCD) has proved to be an effective strategy for expanding the donor pool, but is still considered challenging. We report a successful case of lung procurement from an extended-criteria uncontrolled DCD. Presentation of case We evaluated the lungs of an uncontrolled DCD from a hospital without extracorporeal membrane oxygenation (ECMO) program. The donor was a non-smoker 20-year old male with a history of cardiomyopathy, cardiocirculatory arrests, and Lennox-Gastaut syndrome. Cardiac arrest occurred in a swimming pool, and bronchoscopy showed signs of inhalation. We employed our usual normothermic in-situ open-ventilated lung approach. After retrieval, lungs were stored on ice, then evaluated with ex-vivo lung perfusion (EVLP) and judged suitable for transplantation. The recipient was a 26-year old female with cystic fibrosis on long-term oxygen therapy, on the waitlist for up to 21 months due to her anthropomorphic characteristics. She required central VA-ECMO support during bilateral lung transplantation. Primary graft dysfunction (PGD) within the first 72 h reached grade 3; post-operative peripheral VV-ECMO support was discontinued two days after surgery. The patient was discharged 28 days after surgery; she is alive two years after transplantation with no signs of rejection nor anastomotic complications. Discussion Despite the spreading use of lungs from controlled DCD, perplexities remain on uncontrolled DCD, namely: severe PDG, postoperative mortality, airway complications. Conclusion Our case report suggests that good results can be achieved with uncontrolled DCD despite the presence of relative contraindications: inhalation of water, prolonged ischemic times and recipient in poor conditions.

Interactions of malignant multiple myeloma (MM) plasma cells with the microenvironment control MM plasma-cell growth, survival, drug-resistance and dissemination. As microvascular density increases in the bone marrow in MM, we investigated whether bone marrow MM endothelial cells control disease progression via the junctional adhesion molecule-A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MM endothelial cells in 111 patients with newly diagnosed MM and in 201 with relapsed/refractory MM compared to the levels in patients with monoclonal gammopathy of undetermined significance and healthy controls. Elevated membrane expression of JAM-A on MM endothelial cells predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MM endothelial cells increased angiogenesis, whereas inhibition of this adhesion molecule impaired angiogenesis and MM growth in two-dimensional and three-dimensional in vitro cell cultures and chorioallantoic membrane assays. To corroborate these findings, we treated MM-bearing mice with a JAM-A-blocking monoclonal antibody and demonstrated impaired MM progression, corresponding to decreased MM-related vascularity. These findings support the concept that JAM-A is an important mediator of MM progression through facilitating MM-associated angiogenesis. Elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for the survival of both patients with newly diagnosed MM and those with relapsed/refractory MM. Blocking JAM-A restricts angiogenesis in vitro, in utero and in vivo and represents a suitable druggable molecule to halt neo-angiogenesis and MM progression.

Introduction: Breast cancer (BC) occurring during gestation or lactation is rare, yet highly challenging under both biological and clinical standpoints. This condition, referred to as pregnancy-associated (PA) BC (PABC), shows enrichment in mismatch repair (MMR) deficiency mutational signature, higher expression of immune-checkpoint genes, and less tumor-infiltrating lymphocytes (TILs) compared to non-PA BCs. Despite these insights, no comprehensive data on MMR protein status, immune checkpoints, and immune microenvironment are currently available for these tumors. The aim of this study was to characterize the MMR status and immunologic milieu of PABC. Methods: Among a multi-Institutional database comprising 142 PABCs, we conducted a comparative analysis of a cohort of PABC (n=29) and a control group of age-matched non-PA BCs (n=74). Distinct areas of each tumor and the corresponding normal breast tissue were incorporated into a tissue microarray (4-6 cores per case, mean 4.5). For all cases, both stromal and intratumoral TILs were quantified according to the International TILs Working Group recommendations. Representative slides were subjected to immunohistochemical (IHC) analysis of the MMR proteins (i.e. MLH1, MSH2, MSH6, and PMS2), programmed death-ligand 1 (PD-L1), CD4, and CD8. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and, when the protein was expressed only in a part of the tumor, MMR-heterogeneous (hMMR). PD-L1 expression was evaluated separately in the tumor cells, stromal TILs, and intratumoral TILs. Finally, the relative proportion of CD4+ and CD8+ cells was assessed in both stromal and intratumoral TILs. Results: The study group included 4 (14%) Luminal A, 10 (35%) Luminal B, 4 (14%) non-luminal HER2+, and 11 (37%) triple-negative (TN) PABCs. Taken together, both the dMMR and hMMR status were more common in PABCs than in non-PA BC (n=3/29, 19% vs. n=6/74, 8% and n=7/29, 24% vs. 14/74, 19%, respectively). Specifically, dMMR was seen in Luminal A (n=2, 50%) and in TN (n=1, 9%) PABCs. Conversely, in non-PA BCs, all Luminal A (n=15, 100%) were pMMR, while 5/45(11%) Luminal B and 1/13 (7%) TNBC were dMMR. Despite no differences were observed in intratumoral TILs, PABCs showed significantly higher levels of stromal TILs (p=0.01). Compared to the control group, PD-L1 expression in PABCs was significantly higher in the tumor cells and in stromal TILs (p Discussion: This study is the first to investigate the immune response alongside the MMR status by IHC in PABCs. Our findings broaden the understanding of the immunobiology underpinning PABC, suggesting that in these tumors i) MMR protein alterations occur at higher frequency than in non-PA BCs; ii) the tumor cells and tumor microenvironment may be capable to suppress the adaptive arm of immune system through the expression of PD-L1; and iii) lymphocytes located at the periphery rather than those inside of the tumor are likely to be implicated in the immune modulation. Conclusion: The MMR system and immune microenvironment may play a consistent role in the natural history of PABCs. An intimate knowledge of the multifaceted interplay between tumor and tumor immune microenvironment is likely to unveil clinically relevant mechanisms that may have a positive net health impact for women with BC during gestation or lactation. Citation Format: Nicola Fusco, Elena Guerini-Rocco, Barbara Buonomo, Roberto Croci, Caterina Fumagalli, Gianluca Lopez, Giorgio A Croci, Letterio Runza, Elham Sajjadi, Concetta Blundo, Luca Despini, Massimo Giroda, Viviana E Galimberti, Paolo Veronesi, Massimo Barberis, Stefano Ferrero, Giovanna Scarfone, Silvano Bosari, Giuseppe Viale, Fedro Peccatori. Integrated analysis of mismatch repair, PD-L1, and immune microenvironment status in pregnancy-associated breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-03.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

Umbilical endometriosis represents 30–40% of abdominal wall endometriosis and around 0.5–1.0% of all cases of endometriosis. The aim of this systematic review is to revisit the epidemiology, signs, and symptoms and to formulate a pathogenic theory based on literature data. We performed a systematic literature review using the PubMed and Embase databases from 1 January 1950 to 7 February 2021, according to the PRISMA guidelines. The review was registered at PROSPERO (CRD42021239670). Studies were selected if they reported original data on umbilical endometriosis nodule defined at histopathological examination and described as the presence of endometrial glands and/or stromal cells in the connective tissue. A total of 11 studies (10 retrospective and one prospective), and 14 case series were included in the present review. Overall, 232 umbilical endometriosis cases were reported, with the number per study ranging from 1 to 96. Umbilical endometriosis was observed in 76 (20.9%; 95% CI 17.1–25.4) of the women included in studies reporting information on the total number of cases of abdominal wall endometriosis. Umbilical endometriosis was considered a primary form in 68.4% (158/231, 95% CI 62.1–74.1) of cases. A history of endometriosis and previous abdominal surgery were reported in 37.9% (25/66, 95% CI 27.2–49.9) and 31.0% (72/232, 95% CI 25.4–37.3) of cases, respectively. Pain was described in 83% of the women (137/165, 95% CI 76.6–88.0), followed by catamenial symptoms in 83.5% (142/170, 95% CI, 77.2–88.4) and bleeding in 50.9% (89/175, 95% CI 43.5–58.2). In the 148 women followed for a period ranging from three to 92.5 months, seven (4.7%, 95% CI 2.3–9.4) recurrences were observed. The results of this analysis show that umbilical endometriosis represents about 20% of all the abdominal wall endometriotic lesions and that over two thirds of cases are primary umbilical endometriosis forms. Pain and catamenial symptoms are the most common complaints that suggest the diagnosis. Primary umbilical endometriosis may originate from implantation of regurgitated endometrial cells conveyed by the clockwise peritoneal circulation up to the right hemidiaphragm and funneled toward the umbilicus by the falciform and round liver ligaments.

A black-spotted duodenal mucosa was observed during endoscopy of a man with several comorbidities including hypertension and end-stage kidney disease. Histopathological examination revealed pigment-laden macrophages in the lamina propria of the duodenal villi, which was consistent with duodenal pseudomelanosis.

Low-risk myelodysplastic syndromes (LR-MDS) are a very heterogeneous disease, with extremely variable clinical features and outcome. Therapeutic strategies are still limited and mainly consist of erythropoiesis-stimulating agents (ESAs) and transfusion support. The contribution of molecular lesions and of autoimmune phenomena to pathogenesis and clinical course, including leukemic evolution, is a field of open investigation. We analyzed data from a cohort of 226 patients with LR-MDS followed at our center in the last 20 years, focusing on morphological, immunological (antiplatelets and anti-erythrocyte autoantibodies, anti-erythroblast antibodies), and molecular features. Hypoplastic bone marrow was found in 7% of the cases correlating with younger age, deeper cytopenia, lower dysplasia, and worse response to ESAs. A marker of autoimmunity was observed in 46% of the tested cases, who were younger, were less frequent dysplastic changes, and responded better to ESAs and steroids. Finally, 68% of the tested cases displayed at least one somatic mutation, most commonly SF3B1, TET2, ASXL1, and SRSF2, associated with older age, presence of neutropenia, and lower response to ESAs. Leukemic evolution (2.2%) was associated with presence of somatic mutations, and survival was favorably related to response to ESAs and transfusion independence. Overall, granular evaluation and re-evaluation are pivotal in LR-MDS patients to optimize clinical management.

Duodenal pseudomelanosis (also known as pseudomelanosis duodeni) is a rare endoscopic incidental finding defined by a pigmentation limited to the apex of the intestinal villi, which requires histological confirmation. While its exact pathogenesis is still poorly understood, it appears free from clinical consequences. This condition is believed to be associated with oral iron intake, antihypertensive drugs containing a sulfur moiety (i.e., hydralazine, furosemide), and several chronic diseases (i.e., hypertension, end-stage renal disease, diabetes). However, the exact prevalence of these treatments and comorbidities among patients with duodenal pseudomelanosis is not clearly defined. Several case reports and case series about duodenal pseudomelanosis have been published in recent years. In this review, we aimed to clearly define its endoscopic and microscopic presentation; its epidemiology, associated comorbidities, and drugs; the most useful special histochemical techniques used to classify the nature of the pigmentation; and the most relevant differential diagnoses. In addition, by considering our findings, we also formulated a number of hypotheses about its pathogenesis.

High-risk Myelodysplastic syndromes (MDS) represent therapeutical challenges and are usually managed with hypomethylating agents such as azacitidine. Given the lack of data in the literature concerning azacitidine effects on bone marrow, we retrospectively analyzed 57 high-risk MDS cases in order to identify any changes induced by azacitidine therapy or relevant correlations between therapy response and pre- or post-treatment features. Azacitidine treatment had no significant impact on bone marrow cellularity or morphological dysplastic features. On the contrary, although not statistically significant, we observed a slight decrease in CD34+ and CD117+ blasts and p53+ precursors after treatment. Moreover, pre-treatment IPSS-R cytogenetic score (p = 0.004), lymphocytic infiltrate (p = 0.017) and p53+ elements (p = 0.001) correlated with AML progression, pre-treatment lymphocytic infiltrate was also linked to better response to therapy (p = 0.004), suggesting an anti-tumoral role of bone marrow microenvironment. Post-treatment blast count impacted negatively on overall survival (p = 0.035) and risk of leukemic progression (p = 0.04), while both post-treatment lymphocytic infiltrate and p53+ elements showed significant correlation with treatment response (p = 0.004 and p = 0.003 respectively). Higher post-treatment p53+ elements correlated also with risk of leukemic progression (p = 0.013). Our results suggest the possible role of lymphocytic infiltrate and p53+ elements as predictive markers in MDS treated with azacitidine, disclosing new chapters in the understanding of MDS evolution and treatment.

BACKGROUND Phosphaturic mesenchymal tumors are rare neoplasms, frequently presenting with osteomalacia. These neoplasms usually grow at a slow rate and are associated with unspecific symptoms. CASE In this study, we present the case of a 70-year-old woman who had been suffering from musculoskeletal pain, hypophosphatemia, and spontaneous fractures. Positron emission tomography with Gallium showed increase uptake in a subpleural lesion. CONCLUSION The patient underwent surgical excision of the subpleural lesion with a non-intubated uniportal video-assisted thoracoscopic surgery approach.

Erythema multiforme (EM) is an immune-mediated reaction first described by von Hebra1 in 1860, presenting typically as acrofacial target lesions. The rash may be confined to the skin (EM minor), or it may involve ocular, oral, or genital mucosa with systemic symptoms (EM major). In most cases, only 1 outbreak of EM occurs in a lifetime; however, very rarely, repeated episodes of EM may occur, known as recurrent EM.2 Few cases of pediatric recurrent EM have been reported, with the etiology being identified in less than half of these cases.3 We report a pediatric case of recurrent EM resistant to conventional treatments in which a peculiar human leukocyte antigen (HLA) haplotype has been identified.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.

We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs’ GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.

Background Interactions between multiple myeloma plasma cells (MMPC) and the multiple myeloma (MM) niche control cell proliferation, drug resistance, and disease spreading through various adhesion molecules and chemokine receptors. Among these, junctional adhesion molecule-A (JAM-A) mediates MMPC-endothelial interactions and propagates neovascularization. Here we addressed whether JAM-A signaling mediates MMPC invasive behavior orchestrating intra- and extramedullary MM dissemination. Methods We investigated JAM-A expression with flow cytometry and immunohistochemistry in 60 MM patient bone marrow (BM) aspirates and biopsies at different disease stages with and without extramedullary disease (EMD) manifestation. We compared these results with RNA-Seq data from 647 newly diagnosed MM (NDMM) patients collected in the MMRF CoMMpass study. Using bioinformatics, we investigated JAM-A-related pathways with hierarchical cluster analysis. Subsequently, we functionally validated these JAM-A-related pathways regarding epithelial-mesenchymal transition (EMT), invasion, and MM dissemination in vitro. Results The median OS differed significantly in subjects with elevated membrane JAM-A expression levels, dividing the patients in the EMD JAM-Ahigh group with a median OS of 84.1 months, whereas median OS in JAM-Alow patients was not reached, irrespective of the EMD status (log-rank=4.19, P=.04). Immunohistochemistry analysis of BM biopsies confirmed these findings. RNA-Seq analysis corroborated the prognostic impact of JAM-A (log-rank=3.8, P=.051). High-risk patients with EMD and JAM-A expression displayed a unique gene-expression signature. Additionally, we constructed a novel expression cluster subgroup model, revealing complex molecular disease patterns and associations between clinical traits and expression markers. Strikingly, MM patients clustered by JAM-A expression levels and EMD manifestation revealed properties of epithelial-mesenchymal-transition and induced focal adhesion pathways. Notably, functional knockdown of JAM-A in MMPC in vitro not only reduced cell viability but also diminished MMPC adhesion molecules and CD138 surface expression. Furthermore, mTOR/PI3K in vitro inhibition with BEZ235 significantly downregulated surface expression in JAM-Ahigh MM cells. Interestingly, when we inhibited mTOR/PI3K in JAM-Alow MM cells, we observed JAM-A induction. Finally, ensuing functional shRNA knockdown of JAM-A halted MM invasion (P Conclusions Collectively, these data reveal JAM-A-mediated signaling critical for EMT transition and invasive behavior. Based on these findings we propose JAM-A as a promising biomarker and novel theragnostic target in MM patients.

Simple Summary Tyrosine kinase inhibitors (TKIs) are the treatment of choice for BCR-ABL1-positive chronic myeloid leukemia (CML). Dasatinib is a second generation TKI frequently associated with pleural effusion in up to 33% of patients. Here, we describe two cases of HHV8-negative large B cell effusion-based lymphoma (EBL) confined to the pleura, incidentally, diagnosed in patients presenting with dasatinib-related pleural effusion. One patient is alive and is in remission at 17 months from diagnosis, while unfortunately the other patient died of progressive disease and novel coronavirus disease 2019 (COVID-19)-related pneumonia 16 months from diagnosis. These cases of large B cell EBL in patients receiving dasatinib raise concern about a possible association and we strongly recommend cytological investigation in patients with persistent/relapsing pleural effusion under dasatinib to improve the knowledge about this entity. Abstract Tyrosine kinase inhibitors (TKIs) are the treatment of choice for BCR-ABL1-positive chronic myeloid leukemia (CML). Although TKIs have substantially improved prognosis of CML patients, their use is not free of adverse effects. Dasatinib is a second generation TKI frequently associated with pleural effusion in up to 33% of patients. This results in symptoms as dyspnea, cough and chest pain that may require therapy discontinuation. In the present report, we describe two exceptional cases of HHV8-negative large B-cell effusion-based lymphoma (EBL) confined to the pleura, incidentally, diagnosed in patients presenting with dasatinib-related pleural effusion. One patient (case 1) is alive and is in remission at 17 months from large B-cell EBL diagnosis while unfortunately the other patient (case 2) died of progressive disease and COVID-19 pneumonia 16 months from large B-cell EBL diagnosis. These cases raise concern about a possible association between large B-cell EBL and dasatinib, and the different clinical outcome of the two cases poses a challenge in treatment decision. For this reason, we strongly recommend cytological investigation in patients with persistent/relapsing pleural effusion under dasatinib, primarily to validate its possible association with lymphoma development and to improve the knowledge about this entity.

The definition of indolent lymphoma implies a lymphoid proliferation characterized, in the majority of the clinical scenarios, by a protracted, chronic course of disease, manageable over time, albeit not definitely curable. From the standpoint of the pathologist in charge of the diagnostic tissue workup, indolent grossly overlaps with so-called low grade, that is, composed of cells resembling the mature, non-blastic counterparts of the immune system, which are lymphocytes, centrocytes, plasma cells, and variants of these. This definition is formally not part of the WHO classification but still influences the diagnostic practice. A notable exception to the rule that links non-blastic morphology with indolent clinical behavior is mantle cell lymphoma, a proliferation of (mostly) small centrocytes, which presents an aggressive clinical behavior in a subset of patients. All these need to be kept in mind by both the hematologist and the pathologist when using the the “indolent” lymphoma.