Clinical Significance of the Cystic Phenotype in Alport Syndrome.

RATIONALE & OBJECTIVE: Alport syndrome (AS) is the most common genetic glomerular disease caused by mutations that affect type IV collagen. However, the clinical characteristics and significance of AS with kidney cysts are not well defined. This study investigated the prevalence and clinical significance of cystic kidney phenotype in AS. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: One hundred-eight patients with AS and a comparison cohort of 79 patients with IgA nephropathy (IgAN). Clinical, genetic, and imaging data were collected from medical records. EXPOSURE: Cystic kidney phenotype evaluated by ultrasonography and defined as the presence of≥3 cysts in each kidney; demographic characteristics and estimated glomerular filtration rate (eGFR) at disease onset. OUTCOME: Cystic kidney phenotype in the AS and IgAN cohorts; time to chronic kidney disease (CKD) stage 3b and longitudinal changes in eGFR in the AS cohort. ANALYTICAL APPROACH: Logistic regression analysis to test independent strengths of associations of clinical/demographic features with the binary outcome of cystic phenotype. Survival analysis for the outcome of reaching CKD stage 3b and linear mixed models for changes in eGFR over time in the AS cohort. RESULTS: We studied 108 patients with AS; 76 (70%) had a genetic diagnosis. Autosomal dominant AS was prevalent, accounting for 68% of patients with a genetic diagnosis. Cystic kidney phenotype was observed in 38% of patients with AS and was associated with normal-sized kidneys in all but 3 patients, who showed increased total kidney volume, mimicking autosomal dominant polycystic kidney disease. The prevalence of cystic kidney phenotype was significantly higher in patients with AS when compared with the group of patients with IgAN (42% vs 19%; P=0.002). Patients with the cystic kidney phenotype were older and had more marked reduction in eGFR than patients without cystic changes. Among patients with AS, the cystic phenotype was associated with older age and a faster decline eGFR. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: Cystic kidney phenotype is a common finding in AS. The cystic kidney phenotype is a common finding in AS, suggesting a possible role in cystogenesis for the genetic variants that cause this disease. PLAIN-LANGUAGE SUMMARY: Hematuria is the classic renal presentation of Alport syndrome (AS), a hereditary glomerulopathy caused by pathogenic variants of the COL4A3-5 genes. An atypical kidney cystic phenotype has been rarely reported in individuals with these variants. To determine the prevalence of kidney cysts, we performed abdominal ultrasonography in a large group of patients with AS and a comparison group of patients with another glomerular kidney disease, IgA nephropathy (IgAN). Multiple kidney cysts, usually with normal kidney volume, were found in 38% of patients with AS. A few patients' kidney volumes were large enough to mimic a different hereditary cystic kidney disease, autosomal dominant polycystic kidney disease. The overall prevalence of kidney cysts in AS was more than double that observed in the well-matched comparison group with IgAN. These findings emphasize the high prevalence of cystic kidney phenotype in AS, suggesting a likely association between the genetic variants that cause this disease and the development of kidney cysts.

Spontaneous synchronous bilateral hemothorax as the only finding in primary pleural angiosarcoma: a case report and a literature review.

Angiosarcoma is a rare malignancy of vascular origin, mostly originating from skin, soft tissues, and breast, but rarely also from the pleura. We present the case of a 55-year-old man who referred to our hospital for a spontaneous bilateral hemothorax. The CT angiography did not show any source of active bleeding; plus, no pleural or lung masses were observable. Cytological and microbiological analyses made on a sample of pleural fluid resulted negative. Despite numerous blood transfusions and thoracenteses, the patient deceased from hemorrhagic shock ten days later and the diagnosis of primary pleural epithelioid angiosarcoma was obtained only by autopsy. Additionally, we present a review of the literature about primary pleural angiosarcomas.

Acute heart failure due to COVID-19 related myocardial injury and de novo hypertensive cardiomyopathy: a challenging diagnosis.

We report a COVID-19 case with acute heart and kidney failure in a healthy young male. Echocardiography showed severe systolic and diastolic left ventricle dysfunction, with diffuse myocardial thickening. Cardiac MRI showed aspects of focal myocarditis, and hypertensive cardiomyopathy. Renal biopsy demonstrated limited acute tubular injury, and hypertensive kidney disease. Coronary angiography excluded critical stenoses. Unlike what we initially suspected, myocardial inflammation had a limited extent in our patient; severe hypertension causing cardiomyopathy and multi-organ damage, not diagnosed before, was primarily responsible for severe illness. Correct diagnosis and guidelines-directed treatment allowed a favorable course.

Combined renal proximal tubulopathy and crystal storing histiocytosis in a patient with κ light chain multiple myeloma.

Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the presence of a serum monoclonal spike (M-spike) of more than 3 g/dL or more than 10% clonal plasma cells in the bone marrow and at least one myeloma-defining event, such as hypercalcemia, anemia, bone lesions, or renal impairment. The kidney is a major target organ, and renal impairment is frequently the first manifestation of the disease. Renal damage occurs in up to 40% of patients and 10-20% will require dialysis. Monoclonal immunoglobulin light chains are the major causes of renal complications in multiple myeloma. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease, AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components, are constituted by light chain cast nephropathy, light chain proximal tubulopathy, and crystal-storing histiocytosis.We report the case of a 66-year-old woman who presented with albumin-predominant moderate proteinuria and renal failure. Serum and urine immunofixation electrophoresis showed monoclonal κ light chain in both. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving proximal tubular epithelial cells and crystal storing histiocytosis. Multiple myeloma with crystal storing histiocytosis was discovered in bone marrow biopsy. Thus, we present an unusual case of a myeloma patient presenting light chain proximal tubulopathy and crystal-storing histiocytosis both in the kidney and in the bone marrow.

An increase in MYC copy number has a progressive negative prognostic impact in patients with diffuse large B-cell and high-grade lymphoma, who may benefit from intensified treatment regimens.

MYC translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of MYC have also been detected in these patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of MYC increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for MYC, BCL2, and BCL6 rearrangements. We enumerated the number of MYC copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of MYC translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with MYC copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of MYC extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of MYC had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with MYC translocation. The survival of patients with >4 copies, translocation or amplification of MYC seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence in situ hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of MYC.

Neoplasms derived from plasmacytoid dendritic cells.

Plasmacytoid dendritic cell neoplasms manifest in two clinically and pathologically distinct forms. The first variant is represented by nodular aggregates of clonally expanded plasmacytoid dendritic cells found in lymph nodes, skin, and bone marrow ('Mature plasmacytoid dendritic cells proliferation associated with myeloid neoplasms'). This entity is rare, although likely underestimated in incidence, and affects predominantly males. Almost invariably, it is associated with a myeloid neoplasm such as chronic myelomonocytic leukemia or other myeloid proliferations with monocytic differentiation. The concurrent myeloid neoplasm dominates the clinical pictures and guides treatment. The prognosis is usually dismal, but reflects the evolution of the associated myeloid leukemia rather than progressive expansion of plasmacytoid dendritic cells. A second form of plasmacytoid dendritic cells tumor has been recently reported and described as 'blastic plasmacytoid dendritic cell neoplasm'. In this tumor, which is characterized by a distinctive cutaneous and bone marrow tropism, proliferating cells derive from immediate CD4(+)CD56(+) precursors of plasmacytoid dendritic cells. The diagnosis of this form can be easily accomplished by immunohistochemistry, using a panel of plasmacytoid dendritic cells markers. The clinical course of blastic plasmacytoid dendritic cell neoplasm is characterized by a rapid progression to systemic disease via hematogenous dissemination. The genomic landscape of this entity is currently under intense investigation. Recurrent somatic mutations have been uncovered in different genes, a finding that may open important perspectives for precision medicine also for this rare, but highly aggressive leukemia.

BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations.

The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.

Pathological Complete Response to Pembrolizumab plus Axitinib Combination following Serious Immune-Related Adverse Events in an Advanced Renal Cell Carcinoma Patient with a History of Rheumatoid Arthritis.

Immune checkpoint inhibitors (ICIs)-based combinations have improved survival outcomes of advanced renal cell carcinoma (RCC) patients and are currently recommended as first-line treatment options. Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) of unknown etiology characterized by a chronic inflammatory process involving joints and extra-articular organs. Patients with AD are usually excluded from large randomized clinical trials investigating immunotherapeutic drugs. Therefore, little is known about clinical outcomes of patients with a history of RA treated with ICIs in real-world practice. In the present study, we report the clinical outcome of an advanced RCC patient with a history of RA treated with pembrolizumab in combination with axitinib. The patient experienced serious immune-related adverse events (irAEs) and achieved pathological complete response following only one ICI administration. Our case report shows that ICI-based combinations can be administered efficaciously in advanced RCC patients with a history of AD. However, a close monitoring of these patients is required, given the risk of irAEs and clinical exacerbations of symptoms associated with the preexisting AD. Moreover, prospective clinical data are needed to assess the hypothesis of a correlation between the onset of irAEs and AD flares and responses and survival outcomes to ICIs.

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study.

The objective of this study was to evaluate the clinical features, prognostic factors, and efficacy of treatments in patients with blastic plasmacytoid dendritic cell neoplasm with a leukemic presentation at onset of the disease. In order to do this, a retrospective multicenter study was performed from 2005-2011 in 28 Italian hematology divisions in which 43 cases were collected. Forty-one patients received an induction therapy, consisting of an acute myeloid leukemia-type regimen in 26 patients (60%) and acute lymphoid leukemia/lymphoma-type regimen in 15 patients (35%). Six patients (14%) underwent allogeneic hematopoietic stem cell transplantation. Seventeen patients (41%) achieved a complete remission: seven after acute myeloid leukemia-type treatment and 10 after an acute lymphoid leukemia/lymphoma-type regimen, with a significant advantage for acute lymphoid leukemia/lymphoma-type chemotherapy (P=0.02). Relapse occurred in six of the 17 patients (35%) who achieved complete remission, more frequently after acute lymphoid leukemia/lymphoma-type chemotherapy. The median overall survival was 8.7 months (range, 0.2-32.9). The patients treated with an acute myeloid leukemia-type regimen had an overall survival of 7.1 months (range, 0.2-19.5), whereas that of the patients receiving acute lymphoid leukemia/lymphoma-type chemotherapy was 12.3 months (range, 1-32.9) (P=0.02). The median overall survival of the allogeneic hematopoietic stem cell transplant recipients was 22.7 months (range, 12-32.9), and these patients had a significant survival advantage compared to the non-transplanted patients (median 7.1 months, 0.2-21.3; P=0.03). In conclusion, blastic plasmacytoid dendritic cell neoplasm with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia. The rarity of this disease does not enable prospective clinical trials to identify the better therapeutic strategy, which, at present, is based on clinicians' experience.

Post-transplant lymphoproliferative disease of donor origin, following haematopoietic stem cell transplantation in a patient with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare condition that originates from dendritic cells. We report on the first case of Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) of donor origin in a BPDC patient post-allogeneic haematopoietic stem cell transplantation (HSCT). Flow cytometry study identified a cell population CD4+/CD56+/CD45RA+/CD123+/TCL1+ suggestive of BPDCN diagnosis, which was confirmed by a lymph node biopsy (cells positive for BCL11a, BDCA-2, CD2AP, CD123, TCL1 and S100). Cytogenetic analysis revealed a complex karyotype: (19 metaphase) 47,XX,t(1;6)(q21;q2?5),-13 + 2mar[11]/47, XX, +21 [3]/46,XX [5]. The patient was started on acute myeloid leukaemia (AML) induction schedule, and subsequently an allogeneic HSCT was performed. On day +36 post-HSCT, bone marrow biopsy/aspirate showed complete morphological remission, and chimerism study showed 100% donor chimera. However, on day +37, the patient was found to have enlarged cervical and supraclavicular lymphoadenopathy, splenomegaly and raised lactic dehydrogenase. EBV-DNA copies in blood were elevated, consistent with a lytic cycle. A lymph node biopsy showed EBV encoded RNA and large atypical B cells (CD45dim-, CD4+/CD56+, monoclonal for k-chain, CD19+/CD20+/CD21+/CD22+/CD38+/CD43+/CD79ß-/CD5-/CD10-), consistent with PTLD monomorphic type. Chimerism study showed that PTLD was of donor origin. This case together with the recent literature findings on BPDCN and PTLD are discussed.

[Staphylococcus-associated glomerulonephritis without IgA deposits: a case report].

Staphylococcus-associated glomerulonephritis (SAGN) represents a possible version of parainfectious glomerulonephritis and is a pathological entity that's now constantly increasing in developed countries. It is known how bacterial infections can be a possible trigger for various type of glomerulonephritis with clinical onset and evolution comparable to the ones observed in parainfectious glomerulonephritis. Furthermore, in clinical practice the identification and isolation of the pathogenic microorganism responsible for the development of parainfectious glomerulonephritis is not always possible. Therefore, in those cases in which SAGN is suspected, it is often necessary to recur to kidney biopsy in order to come to as much as possible correct diagnosis. Historically, according to scientific literature, the most distinctive anatomopathological feature of SAGN is represented by predominant or codominant mesangial IgA deposits, sometimes associated with C3 deposits. These findings make the differential diagnosis between SAGN and IgA nephropathy often necessary. However, many reports describe how SAGN can also be characterized by a varying spectrum of immunological deposits. In some cases, for example, IgA deposits can be absent and in some other cases it is described a net dominance of C3 deposits. In this case, it becomes extremely important to exclude a possible occurrence of C3 glomerulopathy (C3GN), considering how different are the therapeutic approach and the prognostic implications associated to it. However, the differential diagnosis between SAGN and C3GN can be very hard. Here's a case report about a patient who has been hospitalized into our Unit after developing a form of Staphylococcus Aureus associated glomerulonephritis which presented atypical anatomopathological features.

Case Report: 18F-PSMA PET/CT Scan in Castration Resistant Prostate Cancer With Aggressive Neuroendocrine Differentiation.

The development of a neuroendocrine phenotype as a mechanism of resistance to hormonal treatment is observed in up to 20% of advanced prostate cancer patients. High grade neuroendocrine prostate cancer (NEPC) is associated to poor prognosis and the therapeutic armamentarium is restricted to platinum-based chemotherapy. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) imaging has recently emerged as a potential new standard for the staging of prostate cancer and PSMA-based radioligand therapy (RLT) as a therapeutic option in advanced metastatic castration resistant prostate cancer (mCRPC). PSMA-based theranostic is not currently applied in the staging and treatment of NEPC since PSMA expression on neuroendocrine differentiated cells was shown to be lost. In this case series, we present 3 consecutive mCRPC patients with histologically proven high grade neuroendocrine differentiation who underwent PSMA-PET/CT and surprisingly showed high tracer uptake. This observation stimulates further research on the use of PSMA-based theranostic in the management of NEPC.

[Kidney involvement in Waldenström's disease - case report].

Waldenström's disease is a rare haematological neoplasm involving B lymphocytes, characterized by medullary infiltrated lymphoplasmacytic lymphoma and by the presence of a monoclonal M paraprotein. Although rarely, this condition may lead to heterogeneous renal involvement and cause severe renal failure. We report the clinical case of a patient with overt nephrotic syndrome in Waldenström's disease treated with a combination chemotherapy (rituximab, cyclophosphamide, dexamethasone) until complete renal and haematological remission.

An immunohistochemical study of the myenteric plexus in idiopathic achalasia.

BACKGROUND: Achalasia is a primary esophageal motor disorder characterized by degenerative changes of the myenteric plexus. The pathophysiologic abnormalities may be the final result of several intermeshing mechanisms, and more than one single factor may cause the motor abnormalities. AIMS: To report our experience in investigating the myenteric plexus of achalasia patients undergoing esophagomyotomy. PATIENTS AND METHODS: Tissue samples from 12 patients undergoing Heller myotomy for achalasia were evaluated and compared with esophageal tissue specimens from 7 controls. Enteric neurons and interstitial cells of Cajal (ICC) were assessed by immunohistochemical methods, and the presence of vasoactive intestinal polypeptide ergic fibers and of CD3 lymphocytes. The possible presence of herpesvirus was also assessed by immunohistochemistry, whereas that of papillomavirus was assessed by in-situ hybridization. RESULTS: Compared with controls, achalasia patients displayed a significant decrease of both enteric neurons and ICC. Immunoreactivity for vasoactive intestinal polypeptide was completely absent in each patient. CD3 staining disclosed myenteric plexitis in 5 (42%) patients; no control patient had plexitis. All patients were completely negative for the presence of both herpes simplex virus and human papillomavirus. CONCLUSIONS: The enteric nervous system of the lower esophageal sphincter area is impaired in patients with "idiopathic achalasia," and the abnormalities involve ICC and neurons in many patients. The triggering factors for these abnormalities are, however, still unknown.

Malignant transformation to schwannoma in a patient affected by type 1 neurofibromatosis as demonstrated by F-18-FDG-PET/CT.

Neurofibromatosis type I (NF1) is an autosomal dominant multisystem disorder. Patients with NF1 are at increased risk for developing both benign and malignant tumours. We report the case of a patient with histologically documented NF1, who underwent F18-FDG-PET/CT for staging purposes. The study revealed intense uptake at multiple masses located at the thighs (the largest presented SUV max of 6.8), popliteal regions, legs, left foot, left supraclavicular region, and at the thoracic wall between the 11th and 12th right ribs. The surgical biopsy of the largest popliteal lesion with higher uptake at F18-FDG-PET/CT documented the presence of a malignant schwannoma at histological examination. In conclusion, F18-FDG-PET/CT was probably able to help the discrimination between benign lesions related to known NF1 and the malignant transformed ones, and to assist clinical decision making.

Acute Kidney Injury due to Anticoagulant-Related Nephropathy : A Suggestion for Therapy.

The relationship between kidneys and anticoagulation is complex, especially after introduction of the direct oral anticoagulants (DOAC). It is recently growing evidence of an anticoagulant-related nephropathy (ARN), a form of acute kidney injury caused by excessive anticoagulation. The pathogenesis of kidney damage in this setting is multifactorial, and nowadays, there is no established treatment. We describe a case of ARN, admitted to our Nephrology Unit with a strong suspicion of ANCA-associated vasculitis due to gross haematuria and haemoptysis; the patient was being given dabigatran. Renal biopsy excluded ANCA-associated vasculitis and diagnosed a red blood cell cast nephropathy superimposed to an underlying IgA nephropathy. Several mechanisms are possibly responsible for kidney injury in ARN: tubular obstruction, cytotoxicity of heme-containing molecules and free iron, and activation of proinflammatory/profibrotic cytokines. Therefore, the patient was given a multilevel strategy of treatment. A combination of reversal of coagulopathy (i.e., withdrawal of dabigatran and infusion of its specific antidote) along with administration of fluids, sodium bicarbonate, steroids, and mannitol resulted in conservative management of AKI and fast recovery of renal function. This observation could suggest a prospective study aiming to find the best therapy of ARN.

Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis.

CONTEXT: Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis. OBJECTIVE: To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis. DESIGN, SETTING, AND PATIENTS: Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy. MAIN OUTCOME MEASURES: We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility. RESULTS: Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls. CONCLUSION: In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets.

Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.

Standard vs delayed ligature of the dorsal vascular complex during robot-assisted radical prostatectomy: results from a randomized controlled trial.

PURPOSE: Prospective randomized trial to compare standard vs delayed approach to dorsal vascular complex (s-DVC vs d-DVC) in robot-assisted radical prostatectomy (RARP). METHODS: Patients scheduled for RARP were randomized into a 1:1 ratio to receive either s-DVC or d-DVC by two experienced surgeons. In s-DVC arm an eight-shaped single stitch was given at the beginning of the procedure and the DVC was subsequently cut at time of apical dissection; in d-DVC arm the plexus was transected at the end of prostatectomy, prior to apex dissection and then sutured. Primary endpoint was difference in estimated blood loss (EBL) and a sample size of 226 cases was calculated; ad interim analysis was planned after 2/3 of recruitment. RESULTS: Endpoint was reached at ad interim analysis after 162 cases (81 s-DVC, 81 d-DVC) and recruitment was, therefore, interrupted. Baseline and tumor characteristics were overlapping. EBL was significantly higher in d-DVC arm (mean EBL 107 vs 65 ml, p = 0.003), but without differences in post-operative hemoglobin, transfusions and complications. Overall PSM rate was higher in d-DVC arm (21.0 vs 14.8%, p = 0.323), with statistical significance relatively to organ-confined disease (15.5 vs 3.6%, p = 0.031). Apical involvement was instead significantly higher in s-DVC arm (prevalence in PSM patients 66.7 vs 23.5%, p = 0.020). Post-operative PSA, continence and potency rates were similar between groups. CONCLUSIONS: Standard and delayed approaches to DVC are safe and lead to similar functional outcomes. A delayed approach exposes to a higher risk of PSM in organ-confined disease but with a lower risk of apical involvement.