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.

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).

Reversal of deleterious effect of hypertension on the liver by inhibition of endoplasmic reticulum stress.

Hypertension is an important risk factor for cardiovascular diseases. Besides cardiovascular system, it could cause damage to liver. It has been shown that endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of hypertension. ERS inhibitor tauroursodeoxycholic-acid (TUDCA) has favorable effects on various pathologies including cardiovascular, metabolic and hepatic diseases. In this study, the hepatoprotective effect and mechanism of TUDCA were investigated in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Male Wistar rats were used and divided into four groups: Control, DOCA, TUDCA and DOCA + TUDCA. Hypertension was induced by DOCA-salt administration for twelve weeks after the unilateral nephrectomy. TUDCA was given for the last 4 weeks. Systolic blood pressure was measured by using tail-cuff method. At the end of the treatment, liver was isolated and weighed. The expressions of various proteins and histopathological evaluation were examined in the liver. TUDCA markedly decreased systolic blood pressure in the hypertensive animals. Hypertension caused increase in the expressions of glucose-regulated protein-78 (GRP78), matrix metalloproteinase-2 (MMP-2) and phospho-inhibitor κB-α (p-IκB-α) and the decrease in the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and phospho-extracellular signal-regulated kinase (p-ERK) in the liver. Alterations in these protein expressions were not detected in the TUDCA-treated hypertensive group. Also, hepatic balloon degeneration, inflammation and fibrosis were observed in the hypertensive group. TUDCA improved inflammation and fibrosis in the hypertensive liver. Our findings indicate that the detrimental effect of DOCA-salt-induced hypertension on the liver was defended by the inhibition of ERS. Hepatic ERS and its treatment should be taken into consideration for therapeutic approaches to hypertension.

Activation of Liver X Receptors by GW3965 Attenuated Deoxycorticosterone Acetate-Salt Hypertension-Induced Cardiac Functional and Structural Changes.

In this study, the effect of liver X receptor (LXR) activation on hypertension-induced cardiac structural and functional alterations was investigated. Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt administration in uninephrectomized rats for 6 weeks. LXR agonist GW3965 (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid was given for the past week. Rhythmic activity and contractions of the isolated heart tissues were recorded. Biochemical parameters were assessed in ventricular tissue and plasma samples. Cardiac expressions of various proteins were examined, and histopathological evaluation was performed in the left ventricle and liver. GW3965 reduced systolic blood pressure and enhanced noradrenaline-stimulated papillary muscle contraction induced by DOCA-salt + uninephrectomy. Plasma and tissue total antioxidant capacity (TAC) increased and tissue 4-hydroxynonenal (4-HNE) levels decreased in the DOCA-salt group. GW3965 elevated plasma and tissue TAC levels in both of groups. Glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated-protein kinase-like ER kinase (p-PERK), matrix metalloproteinase-2 (MMP-2), and nuclear factor-κB p65 (NF-κB p65) expression was augmented, and inhibitor-κB-α (IκB-α) expression was reduced in hypertensive hearts. The altered levels of all these markers were reversed by GW3965. Also, GW3965 ameliorated DOCA-salt + uninephrectomy-induced cardiac and hepatic inflammation and fibrosis. However, GW3965 unchanged the plasma lipid levels and hepatic balloon degeneration score. These results demonstrated that LXR activation may improve hypertension-induced cardiac changes without undesired effects.

C3 glomerulopathy in NLRP12-related autoinflammatory disorder: case-based review.

Autoinflammatory diseases (AIDs) are a recently described group of conditions caused by mutations in multiple genes that code for proteins of the innate immune system. Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases comprising three clinically overlapping disorders: familial cold urticarial syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). CAPS have been associated with gain-of-function variations in NLRP3 (NOD-like receptor family, pyrin containing domain-3). However, a new class of autoinflammatory disease resembling FCAS or MWS has been described in patients with NLRP12 mutations. Here, we report a 6-year-old boy diagnosed with AID who developed an unexpected C3 glomerulopathy during attacks and carried a novel variation in NLRP12. Following treatment with IL (interleukin) 1 targeting agents, all symptoms and inflammation resolved. This is the first case in the literature affected by both autoinflammatory disease and C3 glomerulopathy.

Non-Diabetic Kidney Disease in Type 2 Diabetic Patients: Prevalence, Clinical Predictors and Outcomes.

BACKGROUND/AIMS: Diabetic kidney disease (DKD) is one of the most frequent microvascular complications of diabetes and is the leading cause of end-stage kidney disease worldwide. In patients with diabetes, non-diabetic kidney disease (NDKD) can also occur. NDKD can be either alone or superimposed with the DKD. In this study, we aimed to investigate the utility of kidney biopsy in patients with type 2 diabetes mellitus (T2DM) and the predictability of diagnosing DKD versus NDKD from clinical and laboratory data. We also evaluated the prevalence and etiology of NDKD in patients with T2DM. METHODS: We retrospectively reviewed type 2 diabetic patients who had kidney biopsy in the last 10 years for diagnosing possible NDKD in our center. In all patients kidney biopsies were performed because of atypical clinical features and biopsy samples were examined by light and immunofluorescence microscopy. Clinical parameters, laboratory workup and office blood pressures were recorded for each patient at the time of biopsy. RESULTS: Eight patients were excluded due to missing data. A total of 48 patients (female/male: 26/22 and mean age: 59±8 years) were included in the study. According to the biopsy findings, 24 (50%) patients had NDKD alone, 20 (41.7%) had DKD alone and 4 (8.3%) had coexisting DKD and NDKD. The most common NDKD diagnoses were membranous nephropathy (29.2%), tubulointerstitial nephritis (20.8%) and IgA nephropathy (12.5%). There were no significant differences in three groups with respect to the duration of diabetes, proteinuria, hematuria and glycated hemoglobin A1c levels. Diabetic retinopathy (DR) was the most significant finding, which was associated with DKD. Positive and negative predictive values of DR for DKD were 88 and 81%, respectively. CONCLUSION: This study demonstrated a high prevalence of NDKD in patients with T2DM. The absence of DR strongly predicted NDKD. Clinical decision alone can lead to wrong diagnosis and delay in appropriate therapy. Clinicians should consider the kidney biopsy more liberally when there is uncertainty on the exact etiology of the kidney disease. However, prospective multicenter studies are needed to clarify the prognosis and outcomes of patients with diabetics.

Anti-VEGF-related thrombotic microangiopathy in a child presenting with nephrotic syndrome.

BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) signaling pathway has become an important approach to current cancer therapy. Anti-VEGF therapy-related renal adverse effects may present as hypertension, non-nephrotic proteinuria, and rarely as nephrotic syndrome (NS) and acute kidney injury. CASE-DIAGNOSIS/TREATMENT: In this report, we present a 15-year-old boy who had developed nephrotic syndrome and thrombotic microangiopathy 26 months after administration of anti-VEGF therapy. Treatment was discontinued and nephrotic syndrome remitted spontaneously within 3 months. CONCLUSIONS: Nephrologists should be aware of the side effects of anti-VEGF therapy. Early diagnosis and prompt management with withdrawal of the agents will result in spontaneous remission.

De novo amyloidosis in a renal transplant patient.

Systemic AA amyloidosis is a serious complication of many chronic inflammatory disorders and chronic infections. Renal involvement is seen in the majority of the patients and can lead to end-stage renal disease. Renal transplantation can be performed in these patients; however, amyloidosis can recur in the transplanted kidneys. On the other hand, de novo AA amyloidosis in renal transplant patients has been rarely reported. We report a 17-yr-old patient with end-stage renal disease due to genitourinary anomalies who developed recurrent pyelonephritis after transplantation. Three yr after transplantation, renal biopsy was performed for proteinuria and AA amyloidosis was identified in the renal allograft. Although rare, chronic infections might cause de novo amyloidosis in renal transplant patients. Therefore, amyloidosis should be kept in mind in those types of patients who present with proteinuria.

Classifying lupus nephritis: an ongoing story.

The role of the renal biopsy in lupus nephritis is to provide the diagnosis and to define the parameters of prognostic and therapeutic significance for an effective clinicopathological correlation. Various classification schemas initiated by World Health Organization in 1974 have been proposed until the most recent update by International Society of Nephrology/Renal Pathology Society in 2004. In this paper, we reviewed the new classification system with the associated literature to highlight the benefits and the weak points that emerged so far. The great advantage of the classification emerged to provide a uniform reporting for lupus nephritis all over the world. It has provided more reproducible results from different centers. However, the studies indicated that the presence of glomerular necrotizing lesion was no longer significant to determine the classes of lupus nephritis leading to loss of pathogenetic diversity of the classes. Another weakness of the classification that also emerged in time was the lack of discussions related to the prognostic significance of tubulointerstitial involvement which was not included in the classification. Therefore, the pathogenetic diversity of the classification still needs to be clarified by additional studies, and it needs to be improved by the inclusion of the tubulointerstitial lesions related to prognosis.

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.

Expression pattern of PAX2 in hyperplastic and malignant endometrium.

BACKGROUND: PAX2 is a member of paired box gene family and expressed during development of urogenital system. This study aimed to evaluate PAX2 expression pattern in hyperplastic and malignant endometrial tissues in comparison to non-pathological endometrial changes and to investigate the presence of any correlation between the PAX2 expression and tumor behavior. METHODS: The study was performed on the archival material of 121 endometrial tissues including complex hyperplasia (n = 18), complex atypical hyperplasia (n = 20), and endometrioid type adenocarcinoma (n = 47) as study groups, and proliferative endometrium (n = 21) and atrophic endometrium (n = 16) as control groups. One representative block for each case was selected for immunohistochemical evaluation. Sections with 4µm thickness were cut from the blocks and incubated with PAX2 rabbit anti-human polyclonal antibody. RESULTS: PAX2 nuclear staining was detected in all of the endometrial tissues. The mean percentages of PAX2 staining cells were 80.8, 96.7, 88.6, 92.7, and 99.2% with proliferative endometrium, atrophic endometrium, complex hyperplasia, complex atypical hyperplasia, and adenocarcinoma, respectively (Kruskal-Wallis; P < 0.001). The frequency of PAX2 staining increased as the pathology progressed in the manner of complex hyperplasia → complex atypical hyperplasia → adenocarcinoma. In cancer cases, there was no correlation between PAX2 expression levels and the stage, histological grade, myometrial invasion, and lymph node status. CONCLUSIONS: PAX2 is expressed in hyperplastic and malignant endometrium as well as proliferative and atrophic endometrium. As the neoplastic lesion progresses from a premalignant state to endometrial cancer, PAX2 expression increases. These findings suggest that PAX2 may contribute to the development of endometrial cancer.

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.

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.

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.

Hepar lobatum carcinomatosum associated with metastatic rectal carcinoma: an unusual cause of liver dysmorphy.

OBJECTIVE: The aim of this study was to present a case of hepar lobatum resulting from metastatic rectal carcinoma. CLINICAL PRESENTATION AND INTERVENTION: A 50-year-old man presented with a 2-year history of bleeding per anum, tenesmus, malaise and weakness. Initially, the patient received neoadjuvant chemoradiotherapy followed by abdominoperineal resection of the rectum. Abdominal computed tomography showed lobar enlargement and lobulated contour, mainly in the left lobe of the liver, but no primary or metastatic lesions were detected. Laparotomy revealed an irregularly lobulated hepatic deformity. Liver biopsy showed a necrotic tumor growth from adenocarcinoma of the rectum in subcapsular localizationof the liver. CONCLUSION: This case showed a patient with hepar lobatum carcinomatosum caused by metastatic rectal carcinoma. The report further highlights the need for clinicians and surgeons to keep in mind the possibility of hepar lobatum carcinomatosum while caring for rectal carcinoma patients, especially when the lobulated contour of the liver is detected at preoperative imaging studies or when the coarsely lobated liver is encountered during surgery for carcinoma of the rectum.