Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy?

PURPOSE: We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. RESULTS: Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. CONCLUSIONS: The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

Assessing hepatic steatosis by magnetic resonance in potential living liver donors.

PURPOSE: To determine the accuracy of magnetic resonance imaging-proton density fat fraction (MRI-PDFF) measurements for detecting liver fat content in potential living liver donors and to compare these results using liver biopsy findings. METHODS: A total of 139 living liver donors (men/women: 83/56) who underwent MRI between January 2017 and September 2021 were included in this analysis retrospectively. The PDFFs were measured using both MR spectroscopy (MRS) and chemical shift-based MRI (CS-MRI) for each donor in a blinded manner. RESULTS: Significant positive correlations were found between liver biopsy and MRS-PDFF and CS-MRI PDFF in terms of hepatic steatosis detection [r = 0.701, 95% confidence interval (CI): 0.604-0.798, r = 0.654, 95% CI: 0.544-0.765, P < 0.001, respectively). A weak level correlation was observed between liver biopsy, MRI methods, and vibration-controlled transient elastography attenuation parameters in 42 available donors. Based on receiver operating characteristic (ROC) analysis, MRS-PDFF and CS-MRI PDFF significantly distinguished >5% of histopathologically detected hepatic steatosis with an area under the ROC curve (AUC) of 0.837 ± 0.036 (P < 0.001, 95% CI: 0.766-0.907) and 0.810 ± 0.036 (P < 0.001, 95% CI: 0.739-0.881), respectively. The negative predictive values (NPVs) of MRS-PDFF and CS-MRI PDFF were 88.3% and 81.3%, respectively. In terms of distinguishing between clinically significant hepatic steatosis (≥10% on histopathology), the AUC of MRS-PDFF and CS-MRI were 0.871 ± 0.034 (P < 0.001 95% CI: 0.804-0.937) and 0.855 ± 0.036 (P < 0.001, 95% CI: 0.784-0.925), respectively. The NPVs of MRS-PDFF and CS-MRI were 99% and 92%, respectively. CONCLUSION: The methods of MRS-PDFF and CS-MRI PDFF provide a non-invasive and accurate approach for assessing hepatic steatosis in potential living liver donor candidates. These MRI PDFF techniques present a promising clinical advantage in the preoperative evaluation of living liver donors by eliminating the requirement for invasive procedures like liver biopsy.

A combination of non-invasive tests for the detection of significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease is not superior to magnetic resonance elastography alone.

OBJECTIVES: The aims of the present study were to investigate a combination of magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE) or MRE and fibrosis score 4 (FIB-4) in the detection of significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Between November 5, 2021, and March 4, 2022, a total of 119 consecutive patients with MASLD were included. Liver stiffness was measured using liver biopsy, MRE, VCTE, and FIB-4. Data were collected from outpatient visit charts. Significant fibrosis was defined as ≥ stage 2 fibrosis. RESULTS: All 119 MASLD patients were Caucasian, and their median age was 55 years. MRE, VCTE, and FIB-4 demonstrated significant accuracy in the detection of significant fibrosis with an area under the ROC curve (AUC) of 0.848 ± 0.036 (p < 0.001), 0.632 ± 0.052 (p = 0.012), and 0.664 ± 0.051 (p = 0.001), respectively. However, the diagnostic performance of MRE was superior compared to that of VCTE (AUC difference: 0.216 ± 0.053, p < 0.001) and FIB-4 (AUC difference: 0.184 ± 0.058, p = 0.001). With logistic regression analysis, it was determined that when compared to MRE alone, a combination of MRE and TE (p = 0.880) or MRE and FIB-4 (p = 0.455) were not superior for detecting significant fibrosis. CONCLUSIONS: MRE alone is an accurate and non-invasive method for the identification of MASLD patients with significant fibrosis. CLINICAL RELEVANCE STATEMENT: Magnetic resonance elastography alone accurately detects significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. KEY POINTS: • In routine clinical practice, several non-invasive biochemical-based biomarkers and imaging methods are widely used to assess liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. • Magnetic resonance elastography (MRE) is more accurate than vibration-controlled transient elastography (VCTE) or fibrosis score 4 (FIB-4) for assessing liver fibrosis and identifying significant fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. • The combination of MRE and VCTE or MRE and FIB-4 was not superior to MRE alone.

Pantoprazole Induced Acute Interstitial Nephritis in a Patient with Diabetic Ketoacidosis.

Childhood-onset type 1 diabetes mellitus (DM) is a common chronic metabolic disease associated with life-threatening complications. Diabetic ketoacidosis (DKA) is an acute complication of type 1 DM that has significant mortality mostly due to cerebral edema. Other putative complications of DKA include hypokalemia, hypophosphatemia, hypoglycemia, intracerebral and peripheral venous thrombosis, rhabdomyolysis, acute pancreatitis, and acute kidney injury (AKI) (Murdoch IA et al., Acta Paediatr 1993; 82:498-500).

Factors associated with the development of extrahepatic malignancy in patients with nonalcoholic fatty liver disease: a single-center longitudinal study.

BACKGROUND AND AIMS: The aim of the present study was to determine incident cases of extrahepatic malignancy in patients with nonalcoholic fatty liver disease (NAFLD) and to identify whether the factors are associated with cancer development. METHODS: Between 15 January 2001 and 14 March 2021, a total of 1365 patients had been diagnosed with NAFLD were enrolled in the study. RESULTS: The median follow-up period was 59.5 months. The mean age was 50.9 ± 10.9 years. The female gender was predominant (57%). During the follow-up period, 62 extrahepatic malignancies and 11 hepatocellular carcinomas were identified. Of all extrahepatic malignancies, 51 were solid organ malignancies and 11 were hematological malignancies. Female breast cancer was the most frequent (25.8%), followed by thyroid cancer (19.4%), lymphoma (12.9%), and lung cancer (9.7%). In univariate and multivariable analyses, after adjusting for age and sex, the presence of diabetes and high initial baseline gamma glutamyl transpeptidase (GGT) levels were significantly associated with the development of extrahepatic malignancies [hazard ratio (HR) = 1.82, 95% confidence interval (CI): 1.04-3.20, P = 0.036] and HR = 1.96, 95% CI: 1.14-3.38, P = 0.015, respectively). In 424 biopsy-proven NAFLD patients, the development of extrahepatic cancer was significantly associated with the severity of hepatic fibrosis (HR = 3.31, 95% CI: 1.36-8.07; P = 0.008). CONCLUSION: Extrahepatic malignancies are frequently seen in patients with NAFLD. Diabetes mellitus, high baseline GGT levels, and significant hepatic fibrosis are associated with the development of extrahepatic cancer in patients with NAFLD.

Inulin may prevent steatosis by suppressing cannabinoid receptor-1 and patatin-like phospholipase-3 expression in liver.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of liver disease worldwide. Although various molecular mechanisms are effective in the initiation and progression, the exact pathway is not completely clarified. Recent findings suggest a role of the endocannabinoid system in the pathology of NAFLD. Inulin has been shown to be beneficial for NAFLD. With the first study, we investigated the effects of inulin supplementation on NAFLD via the endocannabinoid system in Wistar rats fed high-fat diet. METHODS: Male Wistar rats were fed with control, control plus inulin, high-fat, and high-fat plus inulin diets for 12 wk. Inulin was added to diets in 15% weight/weight. Biochemical parameters, insulin, and adiponectin levels were determined. Steatosis, lobular inflammation, and total NAFLD activity scores (NAS) were determined by histopathological analysis and by magnetic resonance imaging. Anandamide and 2-arachidonylglycerol levels were measured by the liquid chromatography-tandem mass spectrometry method. Gene expression levels were determined by the quantitative polymerase chain reaction method. RESULTS: Our results showed that the NAS of the high-fat diet was 4.16 ± 0.30, which was significantly higher than that of the other groups. Inulin decreased Homeostasis model assessment measuring insulin resistance (HOMA-IR), serum triacylglycerol, total cholesterol, and Aspartate aminotransferaselevels. Inulin also significantly decreased Cannabinoid receptor-1 and Patatin-like phospholipase-3 gene expressions in the liver. The 2-arachidonylglycerol levels in the liver were lower in the inulin-added groups. These effects of inulin were associated with NAS. CONCLUSIONS: Inulin prevented the development of NAFLD, possibly by affecting the expression of genes involved in the pathogenesis of NAFLD in the liver via endocannabinoids. The results of this study show that inulin may be a promising molecule in the treatment/prevention of NAFLD.

Membranous Nephropathy with Lambda Light Chain Restriction: A Rare Form with Serum Negative and Tissue Positive PLA2R Ab.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Subepithelial polyclonal immunoglobulin deposits and >70% M-type phospholipase A2 receptor antibody positivity are typical findings in idiopathic MN. A 58-year-old female patient was admitted with clinical presentation of nephrotic syndrome. Autoimmune diseases, infections, and malignancies were ruled out after clinical and laboratory evaluations. Diagnostic work-up revealed serum PLA2R antibody negativity and diffuse thickening of glomerular capillary wall on biopsy, while glomerular capillary wall IgG, C3, and Lambda monotypic light chain deposition and PLA2R1 positivity were detected by immunofluorescence and immunohistochemical examination, respectively. Following prednisolone treatment, creatinine and proteinuria were markedly regressed. The MN cases with a light chain deposits are rare and experience regarding their treatment are insufficient.

Superficial Acral Fibromyxoma.

Superficial acral fibromyxoma is a rare, benign, slow-growing, soft-tissue tumor commonly located in the acral regions, with a predilection for the great toe, developing from the nail unit. Because of its nonspecific features and rarity, clinical diagnosis is difficult. In this article, we present a case of superficial acral fibromyxoma located in the nail unit with new dermatoscopic and radiologic findings that have not been previously reported in the literature.

Infantile systemic lupus erythematous presenting as nephrotic syndrome in a 12-month-old boy: a case report.

BACKGROUND: Systemic lupus erythematous (SLE) is extremely rare in infants and has been reported to be a much more severe disease with higher prevalence of critical organ involvement. Herein we present the clinical and laboratory features of infantile SLE (iSLE) with an onset of nephrotic syndrome (NS) during the first year of life. CASE: A 12-month-old boy was suffering from generalized edema for two months. He had thrombocytopenia, hemolytic anemia with positive direct and indirect Coombs tests and proteinuria of nephrotic-range. Other laboratory studies revealed slightly decreased C3, low C1q and normal ANA and C4 levels; anti-phospholipid and anti-cardiolipin antibodies were also found to be negative. Renal biopsy revealed Class IV lupus nephritis. The patient also suffered from massive pulmonary thromboembolism. Complete remission was achieved with steroid, cyclophosphamide, mycophenolate mofetil and anticoagulant therapy. CONCLUSION: iSLE should be kept in mind especially in infantile NS with multisystem involvement. Renal biopsy is mandatory for early diagnosis. Although the disease was reported to have poor prognosis, complete remission could be achieved with intensive immunosuppressive therapy.

IgG4-related disease and ANCA positive vasculitis in childhood: a case-based review.

Autoimmune pancreatitis (AIP) type 1 is an IgG4-related disease (IgG4-RD), characterized by inflammatory pseudotumors and histologically by dense lymphoplasmacytic infiltrates rich in IgG4 positive plasma cells, storiform fibrosis, and obliterative phlebitis. Although quite rare, IgG4-RD was found to be associated with medium or small vessel vasculitides. A new overlap syndrome between IgG4-RD and ANCA-associated vasculitis (AAV) has recently been described in the adult population. Here we present a 16-year-old adolescent girl admitted with abdominal pain, episcleritis, palpable purpura, salivary gland enlargement, and bloody diarrhea. Laboratory investigations revealed findings of glomerulonephritis. Abdominal imaging surprisingly revealed a focal mass in the pancreatic tail, while the c-ANCA level was found to be quite high as well as serum IgG4 level. Biopsy of the pancreatic mass showed lymphoplasmacytic IgG4 positive cells infiltrating the pancreas with storiform fibrosis compatible with IgG4-related AIP. The renal biopsy that was done simultaneously showed necrotizing granulomatous vasculitis indicating AAV. Renal biopsy showed IgG4 positive plasma cells very rarely by immunohistochemical examination, which does not indicate any significance for IgG4-RD. Our diagnosis was IgG4-related AIP and AAV overlap syndrome, which has not been reported in the pediatric populations yet. IgG4-RD should be investigated in patients with ANCA-associated vasculitis who shows atypical organ involvement. We searched the Pubmed/Medline and Google Scholar databases to identify clinical findings, treatment, and outcome of the patients with IgG4-related AIP and AAV.

Two patients, two viruses and multiple sites of injury in the kidney.

Viral nephropathy is a term defines glomerular, tubular and/or vascular injury in kidney caused by viruses itself or virus-induced immune mechanisms. It is difficult to prove causality between the renal disease and the viral infection, however, renal biopsy findings can help in this regard. Several viruses such as hepatitis B and C, Human immun deficiciency virus (HIV), Hantavirus, Cytomegalovirus (CMV), an recently Coronavirus are shown to affect the kidney. Treatment of viral nephropathies are unique regarding the diagnosis which can be made only with renal biopsy in most of the situations. We present two patients presented with acute kidney injury and thrombocytopenia caused by different viruses (Hantavirus and HIV) that affect multiple areas in kidney that revealed with kidney biopsy. Supportive treatment in the patient with Hantavirus nephropathy and HIV treatment along with eculizumab and supportive treatment in the patient with HIVAN were successfully implemented.

Gastric and small intestinal traditional serrated adenomas: a detailed morphologic and immunohistochemical analysis.

BACKGROUND/AIMS: Traditional serrated adenomas (TSAs), despite their low incidence in colorectum, may originate in other parts of the gastrointestinal (GI) tract, including stomach and small intestine. Malignant transformation for upper GI TSAs has recently been reported in the literature. Here, we present a series of gastric and small intestinal TSAs with the aim to characterize their morphologic and immunophenotypic features as well as their neoplastic potential in a compartmental manner using digitalized images. MATERIALS AND METHODS: The study comprised 12 GI polyps with TSA features-5 gastric and 7 small intestinal. The extent of the characteristic features of TSA, including eosinophilic cells, ectopic crypt foci (ECF), slit-like serration, foveolar epithelium, goblet cells, together with dysplastic-carcinomatous foci were assessed on digitalized H-E images and were used as reference for immunohistochemical analysis. RESULTS: All polyps in the cohort contained eosinophilic cells as the most extensive morphologic feature followed by ECF and slit-like serration in decreasing order. Serrated dysplasia was more common in gastric polyps, which more frequently showed neoplastic progression compared with the intestinal ones. CK20 was the most widely expressed marker with a preference to eosinophilic cells while ECFs were mostly negative. Ki67 showed the opposite pattern of CK20. MUC6 and MUC2 were selectively expressed in the basal zone and goblet cells, respectively. CONCLUSION: Our results showed that the presence of eosinophilic cells with pencillate nuclei commonly accompanied by ECF and slit-like serration are the defining features of gastric and small intestinal TSAs. They frequently harbor neoplastic foci, particularly in gastric location where serrated dysplasia seems to be more common.

Duodenal bulb biopsy in the diagnostic work-up of coeliac disease.

Coeliac disease (CD) is an autoimmune enteropathy which can present with patchy mucosal lesions. The aim of the present study is to investigate the significance of duodenal bulb biopsy in the diagnostic work-up of CD in both pediatric and adult patients, and to highlight the key points for pathologists. D1 (duodenal bulb) and D2 (distal duodenum) biopsies of 153 newly diagnosed serology-positive CD patients were evaluated for villous/crypt ratio and intraepithelial lymphocyte (IEL) counts on CD3-stained slides and were classified according to Marsh. Mucosal pathology was patchy in 15% (13% only D1 and 2% only D2) of patients, and 85% of patients had diffuse mucosal pathology involving both D1 and D2 biopsies which showed concordant histology in 60% and discordant in 25% of the cases. Though majority of the patients (75%) with only D1 involvement were pediatric cases, no significant difference was found between pediatric and adult patients when all cases were considered (17 vs 14%). Our results clearly indicate that without D1 sampling, diagnosis of CD would have been missed in a significant number of cases (13%), thereby highlighting the importance of taking duodenal biopsies from multiple sites in the diagnostic work-up of CD. We, therefore, conclude that every biopsy piece from both D1 and D2 should be carefully evaluated for the whole spectrum of mucosal changes caused by gluten ingestion and classified using a scheme based on Marsh to allow recognition of mild lesions.