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BACKGROUND Solitary fibrous tumour (SFT) is a unique mesenchymal neoplasm with classic features on histology and is characterised by the NAB2-STAT6 gene fusion. There are rare reports of SFTs with pancreatic involvement and only two cases in the literature reporting its features by preoperative fine needle aspiration (FNA). Herein, we characterise the cytomorphological features of four SFTs involving the pancreas by FNA to establish a preoperative diagnostic approach. METHODS The anatomic pathology archives of two academic medical centres were searched to identify patients with a pancreatic FNA cytology specimen and a confirmed diagnosis of SFT by surgical resection. The clinical history, pathological diagnosis, cytomorphological findings, and results of immunohistochemistry (IHC) were reviewed. RESULTS Four SFTs were identified from four patients with a median age of 59 years. The morphological features were variable but most frequently showed a bland spindled-to-epithelioid proliferation in fragments and single cells with small, oval, elongated, and hypochromatic nuclei in a haphazard arrangement with or without dense collagen. One tumour presented with a concurrent metastasis and showed a pure epithelioid component with necrosis and enlarged, hyperchromatic nuclei with conspicuous nucleoli and scattered mitoses. IHC was necessary for all diagnoses which were confirmed by surgical resection. CONCLUSIONS SFTs with pancreatic involvement are rare, and non-specific features and tumour heterogeneity can pose a diagnostic challenge on FNA; however, IHC can be used to make a definitive diagnosis. As a result, FNA is a simple, safe, cost-effective, and accurate approach that can be used to diagnose SFT in the pancreas.

Inhibitors of sodium/glucose co-transporter 2 (SGLT2) are currently in clinical use for type 2 diabetes (T2D) treatment due to their anti-hyperglycemic effect exerted by the inhibition of glucose reabsorption in the kidney. Inhibition of SGLT2 is associated with improvement of renal outcomes in chronic kidney disease associated with T2D. Our study aimed to describe the renal-specific phenotypic consequences of the SGLT2-loss of function "Jimbee" mutation within the Slc5a2 mouse gene in a non-diabetic/non-obese background. The Jimbee mice displayed reduced body weight, glucosuria, polyuria, polydipsia, and hyperphagia but were normoglycemic, with no signs of baseline insulin resistance or renal dysfunction. Histomorphological analysis of the kidneys revealed a normal architecture and morphology of the renal cortex, but shrinkage of the glomerular and tubular apparatus, including Bowman's space, glomerular tuft, mesangial matrix fraction, and proximal convoluted tubule (PCT). Immunofluorescent analysis of renal sections showed that SGLT2 was absent from the apical membrane of PCT of the Jimbee mice but remnant positive vesicles were detected within the cytosol or at the perinuclear interface. Renal localization and abundance of GLUT1, GLUT2, and SGLT1 were unchanged in the Jimbee genotype. Intriguingly, the mutation did not induce hepatic gluconeogenic gene expression in overnight fasted mice despite a high glucose excretion rate. The Jimbee phenotype is remarkably similar to humans with SLC5A2 mutations and provides a useful model for the study of SGLT2-loss of function effects on renal architecture and physiology, as well as for identifying possible novel roles for the kidneys in glucose homeostasis and metabolic reprogramming.

In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3. Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient’s tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).

Background: Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure, for which there are currently no effective therapies. We examined the pattern and phenotype of cellular proliferation at different timepoints in a mouse model characterized by a peri-anastomotic AVF stenosis. Methods: Standard immunohistochemical analyses for cellular proliferation and macrophage infiltration were performed at 2, 7 and 14 d on our validated mouse model of AVF stenosis to study the temporal profile, geographical location and cellular phenotype of proliferating and infiltrating cells in this model. Results: Adventitial proliferation and macrophage infiltration (into the adventitia) began at 2 d, peaked at 7 d and then declined over time. Surprisingly, there was minimal macrophage infiltration or proliferation in the neointimal region at either 7 or 14 d, although endothelial cell proliferation increased rapidly between 2 d and 7 d, and peaked at 14 d. Conclusions: Early and rapid macrophage infiltration and cellular proliferation within the adventitia could play an important role in the downstream pathways of both neointimal hyperplasia and inward or outward remodelling.

BK viremia (BKV) is a recognized and potentially serious problem in renal transplantation. The risk factors and the impact of BKV on renal allograft and patient survival are controversial. This study reports an 8-year, single-center experience on the prevalence, risk factors, and outcomes of BKV in kidney transplant recipients. This is a retrospective analysis of all patients who received a kidney transplant at the University of Kentucky and had BK viral titers available from 2009 to 2017. BKV was defined by a polymerase chain reaction viral load of ≥ 10,000 copies per mL. Demographic, clinical, and laboratory data generated during routine outpatient follow up and inpatients records were collected. Independent risk factors for BKV were determined using uni- and multivariate analysis. Graft and patient survival was compared using Kaplan-Meier analysis, and the severity of polyomavirus nephropathy on biopsy was scored using the Banff 2017 classification. We identified 122 BK positive (19%) and 527 BK negative (81%) patients. BKV developed after a median of 115 days (range, 80–249 days) following kidney transplantation. The 1-, 5-, and 10-year graft survival was 97%, 75%, and 33% in the BKV group and 96%, 85%, and 71% in the BK negative group, respectively. Likewise, the 1-, 5-, and 10-year patient survival was 98%, 84%, and 52% in the BKV group and 98%, 92%, and 84% in the BK negative group. Male sex, age at transplantation, maintenance steroids, and alemtuzumab induction were associated with developing BKV in the multivariate analysis. We concluded that BKV is not uncommon after renal transplantation. The determinants for BKV are male sex, older transplant recipients, and maintenance steroids. BKV adversely affected graft and patient survival. A unified approach for BKV and polyomavirus nephropathy treatment is needed.

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3‐tier morphologic classification scheme derived from in‐depth statistical analysis of a large multinational patient cohort. Here we report a multicenter “modern‐era” validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long‐term follow‐up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis., This multicenter study further validates the 3‐tier classification of polyomavirus nephropathy introduced by a 2018 Banff Working Group, underscoring its significance for diagnosis and prognosis as well as for clinicopathologic and comparability studies.

BACKGROUND The aim of this retrospective analysis was to investigate the effect of human leukocyte antigen (HLA) and calculated panel reactive antibody (cPRA) on BK virus activation as evidenced by BK viremia (BKV). PATIENTS AND METHODS At our institution, 649 kidney transplant patients were screened for BKV from 2009 to 2017. Patients were considered to have BKV if they had >10 000 copies/mL of BK DNA in their blood. Donor and recipient HLA and cPRA, demographic, clinical and laboratory data, as well as immunosuppressive medications were collected. RESULTS We identified 122 BK positive and 527 BK negative patients. Only 25% of the patients had cPRA of 20% or more, and 64% had more than three HLA-A, -B, and -DR mismatches. In both univariate and multivariate analyses, male gender, age, and maintenance of steroid therapy significantly increased the risk of BKV (P = 0.005, 0.005 and

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/β-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells.

The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of Rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion and suppressor activity of iTregs. Rapamycin, PI-103 and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to Rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogenic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation. This article is protected by copyright. All rights reserved.

Background: In adults, membranous nephropathy (MN) is a major cause of nephrotic syndrome. While a majority of cases of MN are idiopathic, secondary forms can be seen in the setting of autoimmune disease, neoplasia, infection, and after being exposed to certain therapeutic agents. Both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections could cause MN. However, the effect of coexisting HIV and HCV infection on the spectrum and progression of kidney disease as well as the effect of MN treatment on HIV and HCV infection are not well known. Methods: In this study, we describe a patient with hemophilia A and acquired HIV and HCV infections, a patient who developed severe nephrotic syndrome and for whom renal biopsy showed MN. Results: Patient responded well to adrenocorticotropic hormone gel without adversely affecting HIV or HCV infections. Conclusion: Adrenocorticotropic hormone gel might be useful in the management of complex cases of idiopathic MN.

Vascular calcification is present in arterial vessels used for dialysis vascular access creation prior to surgical creation. Calcification in the veins used to create a new vascular access has not previously been documented. The objective of this study was to describe the prevalence of venous calcification in samples collected at the time of vascular access creation. Sixty-seven vein samples were studied. A von Kossa stain was performed to quantify calcification. A semi-quantitative scoring system from 0 to 4+ was used to quantify the percentage positive area for calcification as a fraction of total area (0: 0; 1+: 1-10%; 2+: 11-25%; 3+: 26-50%; 4+: >50% positive). Twenty-two of 67 (33%) samples showed evidence of venous calcification. Histologic examination showed varying degrees of calcification within each cell layer. Among the subset of patients with calcification, 4/22 (18%), 19/22 (86%), 22/22 (100%), and 7/22 (32%) had calcification present within the endothelium, intima, media, and adventitia, respectively. The mean semi-quantitative scores of the 22 samples with calcification were 0.18 ± 0.08, 1.2 ± 0.14, 1.6 ± 0.13, and 0.36 ± 0.12 for the endothelium, intima, media, and adventitia, respectively. Our results demonstrate that vascular calcification is present within veins used to create new dialysis vascular access, and located predominately within the neointimal and medial layers.

Unacceptable HLA antigens are largely determined by testing sera with Luminex single antigen (LSA) beads. Table 1 shows the MFI values for the five DQB7 beads in three pre-transplant specimens performed on a patient with a cPRA of 99%. DQA1*05 and DQA1*06:01, but not DQB7, were listed as unacceptable antigens. A deceased donor with DQA1*01,03 and DQB5,7 became available and was virtual and flow cytometry crossmatch compatible. On post-op day 14, the patient presented with graft dysfunction. A biopsy contained evidence of antibody mediated rejection (AMR), which was supported by microarray. A donor specific antibody (DSA) screen revealed a greater than 10-fold increase in the previously negative DQB7 beads (DQA1*02:01/DQB1*03:01 and DQA1*03:01/DQB1*03:01) in addition to the previously positive DQA1*05:03, DQA1*05:05, and DQA1*06:01 beads and was consistent with a DSA to DQB7. C1q testing was positive for DQA1*05 only, which was not donor specific. The patient was aggressively treated for AMR but a repeat biopsy on post-op day 25 contained a thrombotic microangiopathy consistent with AMR. The allograft was removed on post-op day 75 due to non-function. Investigation into this case revealed a previous failed transplant with a DQB7 positive donor at another institution, which was unknown to our laboratory. Although the DQA1* typing was not available for the first donor, DR/DQB linkage analysis favors DQA1*05 consistent with the pre-transplant LSA and post-transplant C1q results. Based upon the clinical course, we hypothesize DQB7 specific memory B cells, formed in response to the first donor, facilitated accelerated AMR, which may have been avoided by listing DQB7 as an unacceptable antigen. In conclusion, the results of the LSA assay are only one component of the patient’s immunological profile. Decisions regarding the listing of unacceptable antigens must additionally take into consideration previous immunizing events, like a failed transplant, and this information must be provided to the histocompatibility laboratory for optimal patient care.

Context.—The increasing use of contrast-enhanced magnetic resonance imaging (MRI) of the breast as a valuable adjunct to mammography and ultrasound in the detection of breast lesions, in association with needle core biopsy taken from the suspicious areas, has major workload implications for histopathology laboratories wherever breast MRI is practiced. Objective.—To establish the number of histologic levels necessary for the evaluation of breast MRI-guided needle core biopsy specimens taken from suspicious areas on breast MRI examination. Design.—Retrospective histologic review of a series of breast MRI-guided core needle biopsies, initially examined routinely at 4 levels, in the Pathology Department at Mount Sinai School of Medicine in New York, New York. Results.—Accurate diagnostic classification was possible after examination of the first level in 95.4% of cases. For a small group of patients (4.4%), 4 levels were considered to provide additional useful information, although this information did not alter the diagnosis. In only a single case (0.2%) was it likely that routine examination of 4 levels could have led to an incidental finding of a very small intraductal papilloma (0.15 cm) present only at the second histologic level. However, this incidental finding would have not changed the patient outcome. Conclusions.—Needle core biopsies for MRI-detected abnormalities should be routinely examined at only 1 level. Further levels may be needed in occasional cases to identify more conclusively an associated pathologic abnormality and may be of particular value when assessing atypical intraductal proliferative epithelial lesions.

Fibrillary glomerulonephritis (FGN) is a rare disorder with poor renal prognosis. It is a heterogeneous disease associated with significant risk of end-stage renal disease (ESRD). Its etiology and pathogenesis have not been clearly identified. We report a case of a patient presenting with hypertensive crisis, nephrotic range proteinuria, and rapidly progressive glomerulonephritis (RPGN). The kidney biopsy demonstrates crescentic GN on light microscopy (LM) and strong pseudo-linear/globular glomerular basement membrane (GBM) staining for immunoglobulin G on immunofluorescence (IF), suggestive of anti-GBM disease. However, circulating anti-GBM antibodies were negative. Electron microscopy (EM) revealed fibrillary deposits in the GBM, confirming the diagnosis of FGN. Review of the literature revealed very few reported similar cases. It appears that severe hypertension and heavy proteinuria, while uncommon in anti-GBM disease, are consistent findings in RPGN form of FGN.

Thrombotic microangiopathy (TMA) is a severe disorder with poor outcomes. The cause is unknown for many patients, although TMA is associated with connective tissue disorders, including systemic lupus erythematosus (SLE). While uncommon, TMA is one of the most serious complications of SLE and in many cases may be resistant to therapy. We report a patient with SLE complicated by TMA that was refractory to standard therapy but responded well to eculizumab, with continued remission after 1 year of follow-up. Eculizumab might be useful in the management of resistant cases of TMA caused by SLE.

Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomosis (AV) is a major etiology of vascular access failure in AV fistulas (AVF) and AV grafts (AVG). Recently, our group has reported that severe VNH also occurs prior to vascular access placement. The objective of this study was to perform a comparison of the cellular phenotypes within the neointima from veins collected from subjects at the time of new vascular access creation and stenotic veins from subjects with failed AVGs and AVFs. Vein samples, collected at the time of new access surgery, and stenotic vein segments, collected at access revision, were evaluated for expression of α-smooth muscle actin (SMA), vimentin, and desmin within the neointima, and quantified using semiquantitative scoring. Within the neointima, the majority of cells from vein samples collected at the time of new access surgery were contractile smooth muscle cells, and veins from stenotic AVF and AVG were predominately myofibroblasts. Our results suggest the possibility of different mechanistic pathways in response to vascular injury that occurs prior to vascular access creation vs. after access creation, and that divergent therapeutic approaches may be needed for treating vascular injury in these two settings.

Vascular calcification is present in arterial vessels used for dialysis vascular access creation prior to surgical creation. Calcification in the veins used to create a new vascular access has not previously been documented. The objective of this study was to describe the prevalence of venous calcification in samples collected at the time of vascular access creation. Sixty-seven vein samples were studied. A von Kossa stain was performed to quantify calcification. A semi-quantitative scoring system from 0 to 4+ was used to quantify the percentage positive area for calcification as a fraction of total area (0: 0; 1+: 1-10%; 2+: 11-25%; 3+: 26-50%; 4+:50% positive). Twenty-two of 67 (33%) samples showed evidence of venous calcification. Histologic examination showed varying degrees of calcification within each cell layer. Among the subset of patients with calcification, 4/22 (18%), 19/22 (86%), 22/22 (100%), and 7/22 (32%) had calcification present within the endothelium, intima, media, and adventitia, respectively. The mean semi-quantitative scores of the 22 samples with calcification were 0.18 ± 0.08, 1.2 ± 0.14, 1.6 ± 0.13, and 0.36 ± 0.12 for the endothelium, intima, media, and adventitia, respectively. Our results demonstrate that vascular calcification is present within veins used to create new dialysis vascular access, and located predominately within the neointimal and medial layers.