Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma

BackgroundDiagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.Case presentationA 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.ConclusionThis report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment

Preclinical Testing of Metabolic Inhibitors with Erlotinib in Renal Medullary Carcinoma

https://openworks.mdanderson.org/sumexp23/1099/thumbnail.jp

Burnout and training satisfaction of medical residents in Greece: will the European Work Time Directive make a difference?

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to determine the prevalence of burnout in Greek medical residents, investigate its relationship with training satisfaction during residency and survey Greek medical residents' opinion towards the European Work Time Directive (EWTD).</p> <p>Methods</p> <p>A Multi-centre, cross-sectional survey of Greek residents was performed. The Maslach Burnout Inventory (MBI) was used to measure burnout, which was defined as high emotional exhaustion, combined with high depersonalization or low personal accomplishment. In addition, seven questions were designed for this study to evaluate self-reported resident training satisfaction and three questions queried residents' opinion on the EWTD and its effects on their personal and social life as well as their medical training. Univariate, bivariate and multivariate statistical models were used for the evaluation of data.</p> <p>Results</p> <p>Out of 311 respondents (77.8% response rate), 154 (49.5%) met burnout criteria and 99 (31.8%) indicated burnout on all three subscale scores. The number of residents that were dissatisfied with the overall quality of their residency training were 113 individuals (36.3%). Only 32 residents (10.3%) believed that the EWTD implementation will not have any beneficial effects for them.</p> <p>Conclusions</p> <p>Both burnout and training dissatisfaction were common among Greek residents. Systemic interventions are thus required within the Greek health system, aimed at reducing resident impairment due to burnout and at improving their educational and professional perspectives. Although residents' opinion on the EWTD was not associated with burnout levels, the EWTD was found to be predominantly supported and anticipated by Greek residents and should be implemented to alleviate their workload and stress.</p

Hypoxia inducible factor 1a in kidney cancer

https://openworks.mdanderson.org/sumexp23/1120/thumbnail.jp

Convergent evolutionary trajectories uncover metastatic drivers in renal cancer

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Therapies in Refractory Metastatic Renal Cell Carcinoma

As the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccRCC) expands to include vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immunotherapies, new challenges are in place for evaluating and treating refractory disease. Assessing and managing refractory disease has several elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. These variables all have distinct impact on the biology of refractory or resistant mccRCC. A better understanding of the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker development and therapeutic strategies in the refractory setting. This paper addresses the current understanding of treatment sequencing in refractory mccRCC, focusing on treatment options with prospective clinical trial data, considers refractory mccRCC after adjuvant immunotherapy, and incorporates radiation or surgical resection for oligoprogressive disease

SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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Spermatozoal sensitive biomarkers to defective protaminosis and fragmented DNA

Human sperm DNA damage may have adverse effects on reproductive outcome. Infertile men possess substantially more spermatozoa with damaged DNA compared to fertile donors. Although the extent of this abnormality is closely related to sperm function, the underlying etiology of ensuing male infertility is still largely controversial. Both intra-testicular and post-testicular events have been postulated and different mechanisms have been proposed to explain the presence of damaged DNA in human spermatozoa. Three among them, i.e. abnormal chromatin packaging, oxidative stress and apoptosis, are the most studied and discussed in the present review. Furthermore, results from numerous investigations are presented, including our own findings on these pathological conditions, as well as the techniques applied for their evaluation. The crucial points of each methodology on the successful detection of DNA damage and their validity on the appraisal of infertile patients are also discussed. Along with the conventional parameters examined in the standard semen analysis, evaluation of damaged sperm DNA seems to complement the investigation of factors affecting male fertility and may prove an efficient diagnostic tool in the prediction of pregnancy outcome