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Von Hippel–Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management. [ABSTRACT FROM AUTHOR]

Von Hippel–Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

The detection of genes related to the lifetime of patients with clear cell renal cancer provides information on the mechanisms of the tumor development and can be the basis for creating approaches to predict patient survival. In this paper, the expression of genes regulated by the HIF2α transcriptional factor was studied. Based on the results obtained here and previously identified genes regulated by the transcriptional factor HIF1α, a new panel of 6 genes, including the BAP1 gene, was proposed. Expression of genes of this panel allows predicting the survival of patients with clear cell renal cancer with high sensitivity (93%), specificity (96%), and relative risk (21.5). After verification, the application of this panel can be useful for personalized treatment of patients with clear cell renal cancer, which will increase the effectiveness of therapy. [ABSTRACT FROM AUTHOR]

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view. [ABSTRACT FROM AUTHOR]

Purpose of the study. To evaluate the prognostic significance of biological factors VEGF-A, sVEGF-R1, VEGF-D, FGF, EGF, EGFR, IGF-1, IGF-2, IGFBP-1, IGFBP-2, somatotropin-releasing factor (GHRH) in kidney tissues (tumour tissue, tissue of the perifocal zone and conditionally intact tissue) in local and generalized clear cell renal cancer using ROC analysis.Materials and methods. Two groups of patients were included in the study. Group 1 comprised 50 patients with local kidney cancer (T1–3N0M0), while group 2 comprised 50 patients with metastatic kidney cancer (T1–4N0M1). 10% cytosolic fractions of the kidney tumour tissue were examined. The content of growth factors — somatotropinreleasing factor (GHRH), somatotropin-releasing factor (GHRH) — was determined by the ELISA assay using standard test systems. An assessment of prognostically unfavourable factors that significantly affect the generalization of the tumour process was carried out using binary logistic regression and ROC analysis.Results. The performed ROC analysis revealed diagnostically significant progression biomarkers and their critical values for clear cell renal cancer (for conditionally intact tissue, these values were: VEGF-A ≤ 9107.9 pg/g of tissue; VEGF-R1 ≤ 122.8 ng/g of tissue; FGF ≤ 364.7 pg/g of tissue; IGF-2 ≤ 148 ng/g of tissue; for perifocal tissue, VEGF-A ≤ 5839.6 pg/g of tissue; for tumour tissue, VEGF-A > 9622.5 pg/g of tissue, FGF ≤ 435.1 pg/g of tissue, somatotropin-releasing factor (GHRH) ≤ 158.6 ng/g of tissue). The obtained data contribute to optimization of the disease prognosis.Conclusion. It is established that the most prognostically significant markers of clear cell renal cancer progression include VEGF-A, FGF, somatotropin-releasing factor (GHRH), which can serve as an additional criterion for the differential diagnosis of progression and monitoring of clear cell renal cancer.

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view.

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Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a cause of autoimmune encephalitis and is characterized by epileptic seizures, psychosis, and consciousness impairments. It mostly affects young adults with ovarian cancers. We herein reported a case of anti-NMDAR encephalitis associated with clear cell renal carcinoma.Case Presentation: A 54-year-old male with headache for 1 week and mood and behavioral changes for 3 days was presented, but his clinical presentation and poor response to antiviral treatment did not support a diagnosis of viral encephalitis. Positive anti-NMDAR antibodies in serum and cerebrospinal fluid confirmed autoimmune encephalitis. A subsequent evaluation revealed a paraneoplastic etiology of a renal mass, and this was then resected and pathologically confirmed as clear cell renal carcinoma. The patient's symptoms showed improvement after resection of the mass. The patient relapsed 6 months after discharge, and the symptoms completely disappeared after treatment with corticosteroids and intravenous immunoglobulin.Conclusion: Our findings suggested that NMDAR encephalitis might be associated with clear cell renal carcinoma. When patients present with unexplained seizures, neuropsychiatric disorder, or other brain symptoms, clinicians should be careful with paraneoplastic neurological disorders. Early diagnosis and treatment of primary tumors might show improvement.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a cause of autoimmune encephalitis and is characterized by epileptic seizures, psychosis, and consciousness impairments. It mostly affects young adults with ovarian cancers. We herein reported a case of anti-NMDAR encephalitis associated with clear cell renal carcinoma. Case Presentation: A 54-year-old male with headache for 1 week and mood and behavioral changes for 3 days was presented, but his clinical presentation and poor response to antiviral treatment did not support a diagnosis of viral encephalitis. Positive anti-NMDAR antibodies in serum and cerebrospinal fluid confirmed autoimmune encephalitis. A subsequent evaluation revealed a paraneoplastic etiology of a renal mass, and this was then resected and pathologically confirmed as clear cell renal carcinoma. The patient's symptoms showed improvement after resection of the mass. The patient relapsed 6 months after discharge, and the symptoms completely disappeared after treatment with corticosteroids and intravenous immunoglobulin. Conclusion: Our findings suggested that NMDAR encephalitis might be associated with clear cell renal carcinoma. When patients present with unexplained seizures, neuropsychiatric disorder, or other brain symptoms, clinicians should be careful with paraneoplastic neurological disorders. Early diagnosis and treatment of primary tumors might show improvement. [ABSTRACT FROM AUTHOR]

Background: More than 209,000 patients worldwide are diagnosed with renal cell carcinoma each year, with 6,474 new cases diagnosed in 2012, representing the seventh most common cancer in men and the ninth most common cancer in women. Approximately 75% of renal cancers are diagnosed at over the age of 60, with a plateau reached around 70-75 years, when many patients also have a substantial number of age-associated impairments that need to be considered when planning a treatment. Case presentation: We report the case of a 51-year-old man with a cT4N0 clear cell renal carcinoma that was surgically removed. After four months the patient presented lung, adrenal, and bone metastasis and was treated with sunitinib as first-line treatment. After 16 months the patient had an adrenal progression and everolimus was administered as second-line treatment, and after a pneumonitis the treatment was changed to axitinib. Here we review the available evidence regarding the treatment options for the management of metastatic kidney cancer at each step of the case presentation. Conclusion: Renal cell carcinoma treatment requires a multidisciplinary approach. However, depending on the clinical characteristics of the patient, there are some controversial points in the management of this pathology, so we hope that the scientific data and the clinical trials reviewed in this case report can help to guide physicians to make more rational decisions regarding the management of patients. [ABSTRACT FROM AUTHOR]

Background: among useful tools for management of patients with renal cancer, there are clinical criteria for prognosis and imaging methods to evaluate response to treatment. The most widely used imaging criteria include RECIST 1.1 (Response Evaluation Criteria In Solid Tumors), and more recently MASS (Morphology, Attenuation, Size, and Structure) to objectively evaluate response to treatment with targeted molecular therapy. Objective: compare the usefulness of clinical criteria for prognosis of disease evolution and tomographic criteria to evaluate response to treatment. Materials and methods: a retrospective study from January 2011 through December 2013 of data from patients with confirmed diagnosis of renal cancer, with baseline study and control by tomography at the Centro Médico Nacional Siglo XXI Cancer Hospital. Patients were categorized in accordance with the clinical criteria of Motzer and Heng to establish a prognosis and baseline and control tomograms were analyzed to evaluate in accordance with RECIST 1.1 and MASS criteria; also, an analysis of metastatic disease sites was included. Results: data from 50 patients was analyzed, with mean tomographic monitoring of 298 days, with probability of non-progression of 87% at 223 days with no difference when using RECIST or MASS criteria. Motzer's clinical criteria showed greater consistency in prognosis of disease progression and stability. The most common tumoral diseases were pulmonary and bone adenopathies. Conclusions: the probability of non-progression was 87% at 223 days (p < 0.05); there was no difference when using RECIST 1.1 or MASS evaluation criteria. Motzer's classification showed greater consistency to prognosticate disease progression and stability compared with Heng's classification. [ABSTRACT FROM AUTHOR]

Quantitative methods of gene expression analysis in tumors require accurate data normalization, which allows comparison of different specimens with unknown mRNA/cDNA concentrations. For this purpose, reference genes with stable expression are used (e.g., GAPDH, ACTB, HPRT1, or TBP). The problem of choosing proper reference genes is still a topical issue, because well-known reference genes can be unsuitable for certain cancer types and their inappropriate use without additional testing can lead to wrong conclusions. A recently developed bioinformatical approach was employed to identify a new potential reference gene for lung and kidney tumors, RPN1, located on the long arm of chromosome 3. The method employed the mining of the dbEST and Oncomine databases and functional analysis of genes. RPN1 was selected from approximately 1500 candidate housekeeping genes. Using comparative genomic hybridization with NotI microarrays, we found no methylation, deletions, and/or amplifications in the RPN1-containing locus in 56 nonsmall cell lung and 42 clear cell renal cell cancer specimens. Real-time PCR showed that variation of RPN1 mRNA levels in nonsmall cell lung cancer and clear-cell renal cancer was low and comparable to that of the known reference genes GAPDH and GUSB, respectively. Expression levels of two hyalouronidase genes, HYAL1 and HYAL2, were assessed using the suggested references gene pairs ( RPN1- GAPDH for lung cancer and RPN1- GUSB for kidney cancer), and these combinations were shown to produce accurate and reproducible data. These results suggest that RPN1 is a new, promising reference gene for quantitative data normalization in gene expression studies for lung and kidney cancers. [ABSTRACT FROM AUTHOR]

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view., Competing Interests: Nothing to declare for all authors., (Copyright: Coco D.)