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The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < −5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07–2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17–2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy. [ABSTRACT FROM AUTHOR]

Context.--Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied. Objective.--To define the clinicopathologic and molecular characteristics of PBPGs. Design.--A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed. Results.--The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22-79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1-161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only. Conclusions.--Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma. (Arch Pathol Lab Med. 2017; 141:671-677; doi: 10.5858/arpa.2016-0403-0A), Paragangliomas (PGs) consist of sympathetic and parasympathetic neoplasms, depending on tumor location and catecholamine production. Parasympathetic PGs are located in the head and neck region, and they usually do not [...]

Purpose: Patients with International Metastatic RCC Database Consortium (IMDC) poor risk metastatic renal cell carcinoma (mRCC) rarely respond to first-line tyrosine kinase inhibitors (TKIs) including sunitinib, and carries a very poor prognosis. In recent years, combination therapy involving immune checkpoint inhibitors (ICIs) have demonstrated superior efficacy to sunitinib in poor risk disease. Materials and Methods: In a retrospective study using a cancer chemotherapy registry, 206 consecutive patients with mRCC in the first-line setting were identified between Oct 2019 and Dec 2020. Sixty-one patients had a poor risk mRCC, and were treated with TKI monotherapy (n=36), nivolumab plus ipilimumab (n=16), or pembrolizumab plus axitinib (n=9). Endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), and safety. Results: Patients' median age was 61 years and the median number of risk factors was 3 (range, 3-5). During a median 23.0 months of follow-up, the median OS was 24.3 months with ICI-based combinations and 14.8 months with TKI monotherapy, and the median PFS periods were 9.3 months and 3.4 months, respectively. An objective response occurred in 60% of the patients receiving ICI-based combinations and in 19% of those receiving TKI monotherapy (P=0.001). In the multivariate regression model, number of IMDC risk factors and the ICI-based combination therapy were independent prognostic factors for PFS. All-causality grade 3 or 4 adverse events were 44% for ICI-based combinations and 50% for TKI monotherapy. Conclusions: Among patients with poor risk mRCC, first-line ICI-based therapy showed significantly longer OS and PFS, as well as a higher RR, than TKI monotherapy. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is widely used to predict the clinical responses to immune checkpoint inhibitors (ICIs). However, PD-L1 IHC suffers from the complexity of multiple testing platforms and different cutoff values caused by the current one drug-one diagnostic test co-development approach for ICIs. We aimed to test whether PD-L1 (CD274) mRNA expression levels measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) can represent PD-L1 IHC and predict responses to ICI. The FDA-approved PD-L1 IHC results with 22C3 pharmDx (gastric cancer) and SP142 (urothelial carcinoma) were compared with CD274 mRNA expression levels via qRT-PCR using the same formalin-fixed, paraffin-embedded tissue blocks from 59 gastric cancer and 41 urothelial carcinoma samples. CD274 mRNA expression was identified using three independent sets of primers and TaqMan® probes targeting exon 1–2, exon 3–4, and exon 5–6. CD274 mRNA levels in spanning exon 1–2, exon 3–4, and exon 5–6 junctions of CD274 correlated well with PD-L1 expression (r2=0.81, 0.65, and 0.59, respectively). The area under the curve of exon 1–2 was the highest (0.783), followed by exon 3–4 (0.701), and exon 5–6 (0.671) of the CD274 gene against the PD-L1 combined positive score cutoff of 10. When CD274 mRNA expression was matched for response to immunotherapy, the overall response rate was higher in patients with high CD274 mRNA levels with a cutoff of 0.0722 (gastric cancer) and 0.0480 (urothelial carcinoma) than in those with low CD274 mRNA expression (P < 0.001 and P = 0.018, respectively). These results show that CD274 mRNA levels predicted ICI responses in patients with gastric or urothelial carcinomas and could be used as alternatives for PD-L1 IHC. [ABSTRACT FROM AUTHOR]

Objectives: Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). Methods: Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. Results: Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non‐tolerant group). The CD45RA−FOXP3++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non‐tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA−FOXP3++ Treg cells to CD45RA−FOXP3+ cells indicated good discrimination between the tolerant and non‐tolerant groups. Conclusion: Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT. [ABSTRACT FROM AUTHOR]

The versatility of the intrarenal immunologic micromilieu through dietary modification and the subsequent effects on susceptibility to ischemic acute kidney injury (AKI) are unclear. We investigated the effects of high-salt (HS) or high-fat (HF) diet on intrarenal immunologic micromilieu and development of ischemic AKI using murine ischemic AKI and human kidney-2 (HK-2) cell hypoxia models. Four different diet regimens [control, HF, HS, and high-fat diet with high-salt (HF+HS)] were provided individually to groups of 9-week-old male C57BL/6 mice for 1 or 6 weeks. After a bilateral ischemia-reperfusion injury (BIRI) operation, mice were sacrificed on day 2 and renal injury was assessed with intrarenal leukocyte infiltration. Human kidney-2 cells were treated with NaCl or lipids. The HF diet increased body weight and total cholesterol, whereas the HF+HS did not. Although the HF or HS diet did not change total leukocyte infiltration at 6 weeks, the HF diet and HF+HS diet increased intrarenal CD8 T cells. Plasma cells increased in the HF and HS diet groups. The expression of proinflammatory cytokines including TNF-α, IFN-γ, MCP-1, and RANTES was increased by the HF or HS diet, and intrarenal VEGF decreased in the HS and HF+HS diet groups at 6 weeks. Deterioration of renal function following BIRI tended to be aggravated by the HF or HS diet. High NaCl concentration suppressed proliferation and enhanced expression of TLR-2 in hypoxic HK-2 cells. The HF or HS diet can enhance susceptibility to ischemic AKI by inducing proinflammatory changes to the intrarenal immunologic micromilieu. [ABSTRACT FROM AUTHOR]

Objectives: Androgen receptor splice variants (AR-Vs), especially androgen receptor splice variant 7 (AR-V7), are considered as important factors in developing castration-resistance of prostate cancer and also as candidate predictive factors. Our aim was to evaluate changes in the mRNA expression of full-length AR (AR-FL) and AR-Vs in the primary prostate cancers from the same patients before and after ADT. Methods: We compared morphologic differences and evaluated AR-FL, AR-V7, AR-V4, ARv567es, AR-V3 and AR8 mRNA expression in matched samples of primary hormone-sensitive and castration-resistant prostate cancer (CRPC) from 19 patients. Results: mRNA expression of AR-FL, AR-V7, ARv567es and AR-V3 was present in hormone sensitive prostate cancer (HSPC) and was significantly increased in CRPC in 81.2% (13/16). There were strong positive correlations between AR-FL and AR-V7 (r = 0.93, p <.001), ARv567es (r = 0.72, p <.001) and AR-V3 (r = 0.81, p <.001) mRNA expression. AR-V7/AR-FL ratio was more significantly (>30%) increased after ADT in 25% (4/16) of the patients, who showed significantly (p <.001) worse overall survival. Neuroendocrine differentiation was seen in one patient (5.3%) and the Gleason score was increased in 10 (52.6%) patients. Conclusion: We demonstrated that the expression of AR-V7 is present at low levels in HSPC and is increased in CRPC and the increase is an active process possibly related to aggressive clinical course. [ABSTRACT FROM AUTHOR]

* Context.--CD24, originally described as a B-cell marker, has gained considerable attention in tumor research. High rates of CD24 expression have been found in several types of carcinomas that are [...]

Clinically, acute kidney injury (AKI) episodes in diabetes mellitus (DM) patients are associated with a cumulative risk of developing end-stage renal disease. In this study, we asked whether the severity of AKI induced by renal ischemia-reperfusion injury (IRI) is more prominent in DM than in non-DM control using a cynomolgus monkey (Macaca fascicularis) model. We also investigated whether human bone marrow-derived mesenchymal stem cells (hBM-MSCs) infused via the renal artery could ameliorate renal IRI in DM monkeys. The experimental data, including mortality rate, histologic findings, and urinary albumin secretion indicate that the severity of AKI was greater in DM monkeys than in control animals. Moreover, histological findings and qRT-PCR analysis of Ngal mRNA in renal biopsy tissue showed that hBM-MSC promoted the recovery of tubular damage caused by AKI. Serum analysis also revealed that the level of albumin and ALT was increased 24 and 48 hours after AKI, respectively, suggesting that AKI induced acute liver injury. We suggest that this nonhuman primate model could provide essential information about the renal and nonrenal impairment related to DM and help determine the clinical usefulness of MSCs in AKI. [ABSTRACT FROM AUTHOR]

Abstract: Background: IgA nephropathy (IgAN) is the most frequent primary glomerular disease and the leading cause of end‐stage renal disease. We investigated clinicopathologic predictors of renal survival in patients with IgAN with a focus on glomerular filtration rate (GFR) decline slope. Materials and methods: We screened all patients with primary IgAN between 1995 and 2012. Renal progression was defined as doubling of serum creatinine. Using serial serum creatinine levels during the first‐year, we calculated the GFR decline slopes. Further, we defined patients in the steepest GFR slope quartile as rapid decliners and those in the second steepest GFR slope quartile as slow decliners. Others were defined as nondecliners. Results: Of 214 participants, baseline GFR was 81 (62, 100) mL/min/1.73 m2, which was not different among the 3 groups. Rapid decliners and slow decliners had higher levels of urinary protein/creatinine ratio (0.88, 0.89 and 0.58 g/gCr, respectively, P < .001). Five‐year renal survival was 76% in rapid decliners, 91% in slow decliners and 100% in nondecliners (P < .001, rapid or slow decliners vs nondecliners). After adjustment for clinicopathologic variables, slow decliners were associated with an 8.8‐fold higher risk of progression (P = .011), and rapid decliners were associated with a 10.2‐fold increased risk of progression (P = .007) compared with nondecliners. Conclusions: First‐year GFR slope was associated with increased risk of renal progression, independent of proteinuria and histologic findings. Further studies are needed to investigate whether early GFR change can identify high‐risk patients who benefit from immunosuppressive treatment in IgAN. [ABSTRACT FROM AUTHOR]

Few paraganglioma (PG) cases include frozen section diagnoses and therefore, the accuracy of frozen section diagnosis for PG remains unknown. To better understand the histologic characteristics and pitfalls of frozen section findings for PG, 15 PG cases with frozen section diagnoses were selected from 12 articles through PubMed (1984-2015). In addition, we included 3 cases of PG for which intraoperative consultations were requested during a 5-year period (2012-2016) in 2 hospitals. Seven PGs were from the thyroid; 2 from the pancreas; 4 from the mediastinum, retroperitoneum, or mesentery; 1 from the middle ear and 4 from the urinary bladder (UB). Out of 18 PGs, correct diagnoses were rendered in only 2 cases and no thyroid or UB PGs were correctly diagnosed on intraoperative consultation. Thyroid PGs were frequently misdiagnosed as medullary thyroid carcinomas (4/7, 57%) and UB PGs were frequently misdiagnosed as malignancies. [ABSTRACT FROM AUTHOR]

Crystalline nephropathy is a rare yet well-known condition associated with multiple myeloma and other light chain–secreting disorders. Paraproteins that are resistant to proteolysis crystallize within proximal tubular cells and cause light-chain proximal tubulopathy, which presents clinically as Fanconi syndrome. Podocytes are rarely affected, and the crystalline inclusions within podocytes are typically precipitated, yielding significant glomerular proteinuria. Here we report a case of extensive crystalline inclusions primarily within podocytes and proximal tubules that presented only with Fanconi syndrome and renal insufficiency. Despite the presence of extensive crystalline inclusions in podocytes and diffuse foot process effacement, the patient had no clinical evidence suggestive of podocyte injury. [ABSTRACT FROM AUTHOR]

Renal artery stenosis (RAS) is commonly presented with hypertension and chronic kidney disease. We report a rare case of RAS occurring in a 78-year-old man who presented with nephrotic-range proteinuria. Renal biopsy on the left side was performed, and results showed mesangiopathic glomerulonephritis, which was not compatible with the cause of nephrotic-range proteinuria. Proteinuria was decreased by angiotensin receptor blocker, but azotemia was aggravated. Therefore, angiotensin receptor blocker was discontinued inevitably and thorough evaluation for the possibility of RAS was performed. Computed tomography angiography revealed significant RAS on the left side and a renal artery stent was inserted. After stenting, aortic dissection developed and progressed despite tight control of blood pressure. After inserting another stent graft through the true lumen of the left renal artery, the patient's renal function and proteinuria improved markedly. [ABSTRACT FROM AUTHOR]

Background: IgA nephropathy (IgAN) is not always benign, and some patients at high risk of end-stage renal disease (ESRD) experience a rapid decline in renal function. This study retrospectively examined the beneficial effects of cytotoxic therapy.Methods: We identified 102 patients with progressive IgAN despite optimal conservative management. Of these, 31 who received cytotoxic therapy and 55 who were managed conservatively were included.Results: Median eGFR and urinary protein-to-creatinine ratio (uPCR) at baseline did not differ between the groups (p = 0.475 and 0.259, respectively). Median GFR slope was also similar (p = 0.896). Cumulative renal survival was better in the cytotoxic therapy group than in the control group (p = 0.009). Cytotoxic therapy was associated with lower risk of progression to ESRD, independent of eGFR, uPCR, GFR slope and kidney histologic findings (HR 0.13, 95% CI 0.03–0.66). In the cytotoxic therapy group, the median GFR slope decreased from −7.8 (−10.5, −5.0) mL/min/1.73 m2per year to −3.4 (−5.1, −1.8) mL/min/1.73 m2per year after treatment (p < 0.001). Mortality was not observed, but infection requiring hospitalization occurred at similar rates in both groups (p = 0.886).Conclusions: Cytotoxic therapy attenuated the rate of GFR decline and was associated with a favorable renal outcome in patients with progressive IgAN.Key messagesCytotoxic therapy was associated with a favorable renal outcome in IgA nephropathy patients whose glomerular filtration rate progressively declined despite optimal conservative management.Cytotoxic therapy significantly attenuated the rate of glomerular filtration rate decline as well as the amount of proteinuria in patients with progressive IgA nephropathy.Adverse events following cytotoxic therapy were comparable to conservative management. [ABSTRACT FROM PUBLISHER]

Monoclonal gammopathy with undetermined significance (MGUS) carries a risk of progression to multiple myeloma, and progression is usually diagnosed with changes in M-protein or bone marrow biopsy. We report a case of 62-year-old female patient showing MGUS progression to multiple myeloma without significant changes in M-protein but diagnosed by kidney biopsy. During the follow-ups, azotemia and tubular proteinuria were aggravated without elevation of M-protein. Kidney biopsy showed intratubular and glomerular inclusions associated with plasma cell dysplasia. The progression of MGUS to multiple myeloma was diagnosed by this kidney biopsy. The patient's renal function and tubular proteinuria were markedly improved after chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Urachal cancer is a rare malignancy that accounts for <1% of bladder cancers. There is currently no consensus on the diagnosis and management of urachal cancer and there are very few reports on palliative chemotherapy for unresectable disease. We delineate the clinical features and treatment outcome of urachal cancer, in particular the relevance of palliative chemotherapy in recurrent, metastatic disease. Methods: The clinicopathologic variables and treatment outcome of patients who were treated for urachal cancer were retrospectively reviewed. Results: Among 28 eligible patients, 25 had localized disease and 3 had metastatic disease at initial diagnosis. All patients with localized disease underwent curative resection and there was disease recurrence in 10. Out of 13 patients with metastatic disease either at initial diagnosis or during follow-up, the lung was the most common metastatic site (n = 5), followed by the liver, bone and peritoneum. Ten patients received palliative chemotherapy. A total of 24 chemotherapeutic regimens were administered; regimens with a base of fluoropyrimidine (5-FU), taxane and gemcitabine were the most common. The overall response rate of all chemotherapeutic regimens was 16.7%. The 5-FU-based regimens showed a good response, with 2 of 4 patients who received these showing a partial response. One tumor with a partial small-cell component showed a partial response to both an etoposide-based regimen and a taxane-based regimen. Conclusions: In urachal cancer, curative surgery is still the recommended treatment with respect to overall survival. A 5-FU-based chemotherapy regimen could be considered for metastatic recurrent disease. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Micropapillary carcinoma (MPC) of urinary tract is an uncommon variant of urothelial carcinoma with significant diagnostic and prognostic implications. Though MPC shows characteristic microscopic features, there exists interobserver variability and also it needs to be differentiated from the metastasis from other organs. The prognosis is generally poor, depending on the proportion of the micropapillary component in some reports. Early cystectomy in cases with only lamina propria invasion may be indicated according to recent studies. This review outlines the general features of this entity and briefly comments on the controversies and the recent development. [ABSTRACT FROM AUTHOR]