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1.
TRIM28 variants and Wilms' tumour predisposition.
Hol, JA, Diets, IJ, de Krijger, RR, van den Heuvel-Eibrink, MM, Jongmans, MC, Kuiper, RP
The Journal of pathology. 2021;(4):494-504
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Abstract
TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context-, species-, and cell-type-specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28-associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28-associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs.
Fogli, S, Porta, C, Del Re, M, Crucitta, S, Gianfilippo, G, Danesi, R, Rini, BI, Schmidinger, M
Cancer treatment reviews. 2020;:101966
Abstract
Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.
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Systemic Treatment of Bone Disease in Metastatic Urinary Malignancies.
Patel, SH, Panian, J, Bree, K, Derweesh, I, Millard, F, Randall, J, Mckay, R
European urology focus. 2020;(1):17-25
Abstract
CONTEXT Bone metastasis is a common site of metastatic disease in patients with genitourinary malignancies. Given that the presence of bone metastasis decreases survival and has a negative impact on quality of life impact, it is critical to optimize management of this patient population. OBJECTIVE To systematically review literature on the systemic treatment of bone metastasis in prostate cancer, renal cell carcinoma, urothelial carcinoma, and germ cell tumors. EVIDENCE ACQUISITION We performed a nonsystematic critical review of PubMed/Medline, clinicaltrials.gov, and the Cochrane Library from January 2001 to February 2019. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials, and selected based on reporting skeletal related events and symptomatic skeletal events for patients with urologic malignancies. EVIDENCE SYNTHESIS Skeletal metastases occur frequently in genitourinary malignancies, at rates around 80% for patients with metastatic prostate cancer and 30% for patients with metastatic renal cell and urothelial carcinoma, and are uncommon in patients with germ cell tumors. Skeletal related events and symptomatic skeletal events can occur in these patients. Optimization of bone health involves dietary and lifestyle modifications, and use of osteoclast-targeted agents in select individuals. Additionally, disease-modifying agents, such as radiopharmaceutical, immunotherapy, and cMET inhibitors, which have activity in the bone, have improved outcomes for patients, including skeletal-related events and symptomatic skeletal events. CONCLUSIONS While the presence of bone metastases is associated with increased mortality and worse outcomes in patients with genitourinary malignancies, strategies have been developed to improve quality of life and survival for patients with skeletal metastases. Future studies investigating novel therapeutic options and bone supporting agents are warranted to target this patient population. PATIENT SUMMARY In this report, we reviewed the current literature and recent clinical trials involving treatment of bone metastases in urinary cancers. The use of bone-targeting agents can improve outcomes for patients, and additional lifestyle modification can optimize bone health in this population.
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The diverse roles of SPOP in prostate cancer and kidney cancer.
Wang, Z, Song, Y, Ye, M, Dai, X, Zhu, X, Wei, W
Nature reviews. Urology. 2020;(6):339-350
Abstract
Multiple studies have confirmed that speckle-type pox virus and zinc finger (POZ) protein (SPOP) functions as a substrate adaptor of cullin 3-based E3 ligase and has a crucial role in various cellular processes via specific targeting of proteins for ubiquitination and subsequent proteasomal degradation. Dysregulation of SPOP-mediated proteolysis might be involved in the development and progression of human prostate and kidney cancers. In prostate cancer, SPOP seems to function as a tumour suppressor by targeting several proteins, including androgen receptor (AR), steroid receptor coactivator 3 (SRC3) and BRD4, for degradation, whereas it might function as an oncoprotein in kidney cancer, for example, by targeting phosphatase and tensin homologue (PTEN) for proteasomal degradation. In addition, nuclear SPOP targets AR for degradation and has a role as a tumour suppressor in prostate cancer; however, in kidney cancer, SPOP largely accumulates in the cytoplasm and fails to promote degradation of AR located in the nucleus, resulting in activation of AR-driven pathways and cancer progression. Owing to the context-dependent function of SPOP in human malignancies, further assessment of the molecular mechanisms involving SPOP in prostate and kidney cancers is needed to improve our understanding of its role in the development of these cancer types. Treatments that target SPOP might become therapeutic strategies in these malignancies in the future.
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5.
Imaging of Renal Cancer.
Krishna, S, Leckie, A, Kielar, A, Hartman, R, Khandelwal, A
Seminars in ultrasound, CT, and MR. 2020;(2):152-169
Abstract
Renal masses are common incidental findings on cross-sectional imaging. Accurate characterization of renal masses is essential to guide management. Renal mass CT protocol comprises of a good quality noncontrast, corticomedullary and nephrographic phases, with each phase providing complementary information for diagnosis. Attenuation measurements in different phases are central to the 'golden-rules' in renal mass imaging in the characterization of renal masses. Newer modalities like dual energy CT scan obviate need for repeat imaging by generation of iodine-overlay image and also help in eliminating artifactual pseudoenhancement which can be problematic, especially in small endophytic cysts. Contrast- enhanced ultrasound (CEUS) is extremely sensitive in identification of enhancing components in indeterminate masses, especially in the setting of renal failure as the microbubbles are not excreted via the renal route. The Bosniak classification for renal cystic masses has been revised in 2019 to standardize terminology and further improve upon the original version. The current version includes CT and MRI, although CEUS is yet to be included. Image- guided biopsy of renal mass helps confirm the diagnosis and also gives information regarding the subtype and grading and is useful in avoiding overtreatment of benign entities, and in active surveillance. Multiparametric MRI can potentially help avoid needle biopsy in a subset of patients by accurate characterization through a previously validated algorithm.
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Reprogramming of Metabolism in Kidney Cancer.
Wettersten, HI
Seminars in nephrology. 2020;(1):2-13
Abstract
Metabolic reprogramming is one of the major steps that tumor cells take during cancer progression. This process allows the cells to survive in a nutrient- and oxygen-deprived environment, to become stress tolerant, and to metastasize to different sites. Recent studies have shown that reprogramming happens in stromal cells and involves the cross-talk of the cancer cell/tumor microenvironment. There are similarities between the metabolic reprogramming that occurs in both noncancerous kidney diseases and renal cell carcinoma (RCC), suggesting that such reprogramming is a means by which renal epithelial cells survive injury and repair the tissue, and that RCC cells hijack this system. This article reviews reprogramming of major metabolism pathways in RCC, highlighting similarities and differences from kidney diseases and potential therapeutic strategies against it.
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Renal Toxicity of Systemic Therapy for Renal Cell Carcinoma.
Jaimes, EA
Seminars in nephrology. 2020;(1):49-58
Abstract
The incidence of kidney cancer has been increasing steadily and, until recently, there was a substantial lack of effective therapies for a cancer that is now among the 10 most common cancers in men and women. During the past 10 years, novel therapies have been developed including antiangiogenic drugs targeting vascular endothelial growth factor and its receptors, immune checkpoint inhibitors, and mammalian target of rapamycin inhibitors that have resulted in a significant improvement in clinical outcomes in a traditionally difficult-to-treat cancer. These new drugs, however, also have important side effects and toxicities that often have an impact on the treatment of these patients. The use of anti-angiogenic drugs often results in the development of hypertension and, less frequently, varying degrees of proteinuria including nephrotic range proteinuria. A variety of agents are used for the treatment of hypertension and proteinuria including blockers of the renin angiotensin system and calcium channel blockers, but there are no randomized clinical trials comparing different therapeutic agents in these patients. Immune checkpoint inhibitors have become one of the cornerstones of therapy in kidney cancer, but their use is linked to a variety of side effects that affect almost every organ and resemble autoimmune diseases. In the kidney, these drugs can induce acute interstitial nephritis in close to 5% of patients with varying degrees of severity that in some cases require discontinuation of treatment and systemic treatment with corticosteroids. Although mammalian target of rapamycin inhibitors now also are part of the therapeutic armamentarium available for these patients, all clinical trials have been performed in patients with normal renal function and therefore their effects in patients with abnormal renal function are not known.
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Englerins: A Comprehensive Review.
Wu, Z, Zhao, S, Fash, DM, Li, Z, Chain, WJ, Beutler, JA
Journal of natural products. 2017;(3):771-781
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Abstract
In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.
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Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.
Pham, MN, Apolo, AB, De Santis, M, Galsky, MD, Leibovich, BC, Pisters, LL, Siefker-Radtke, AO, Sonpavde, G, Steinberg, GD, Sternberg, CN, et al
World journal of urology. 2017;(3):367-378
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Abstract
PURPOSE To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.
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Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.
Zeng, MF, Chen, LL, Ye, HY, Gong, W, Zhou, LN, Li, YM, Zhao, XL
Medicine. 2017;(44):e8426
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Abstract
RATIONALE Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.