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As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer. [ABSTRACT FROM AUTHOR]

Genetic work-up of unexplained erythrocytosis that is suspected to be inherited in nature currently requires either laborious exon-by-exon gene panel testing by Sanger sequencing or expensive next-generation sequencing. A high prevalence of Chuvash polycythemia (61%) has been previously reported among north Indian erythrocytosis patients. We assessed PCR-RFLP for VHL c.598C > T mutation as a first-line test in 99 persons with JAK2 V617F-negative, unexplained erythrocytosis. We enrolled two groups: Group A (n = 38) had erythrocytosis patients (n = 33) or their first-degree relatives (n = 5), and, Group B with 61 healthy blood donation volunteers who were deferred after the discovery of unexplained high hemoglobin levels. Detailed history and clinical examination, hemogram, erythropoietin levels and PCR–RFLP for the VHL:c.598C > T;p.R200W mutation were done. In Group A, three (8%) persons aged 9, 13 and 30-years were homozygous for VHL:c.598C > T. Two were heterozygous (parents of a known case of Chuvash polycythemia). None of the Group B subjects had the Chuvash mutation. Erythropoietin levels in group A were low in 5/26 cases (19%) and normal in 18/26 (69%). In Group B, seven (11%) donors had normal values while the remaining 54 (89%) had high erythropoietin levels. Despite a lower frequency (8%) compared to literature, our results suggest that the relatively simpler PCR-RFLP for VHL:c.598C > T mutation may be considered for the initial genetic screening of unexplained, suspected congenital erythrocytosis in regions where Chuvash polycythemia comprises a large proportion of inherited erythrocytosis, after polycythemia vera and common acquired secondary causes are excluded. [ABSTRACT FROM AUTHOR]

• Intracranial hemangioblastoma embolization holds promising results. • Intraoperative blood loss was estimated as 464.29 ml (95% CI: 350.63 ml–614.8 ml). • Major complications occurred in 1% (95% CI: 0% to 3%) of patients. • Minor complications in 1% (95% CI: 0% to 4%) of patients. • Further research is needed to confirm its long-term effectiveness and safety. Hemangioblastomas (HBs) are highly vascular tumors linked to substantial morbidity and mortality. Recently, interventional neuroradiology has evolved rapidly, spurring interest in preoperative embolization as a possible HB treatment. This study evaluates the effectiveness and safety of preoperative embolization in managing HB. Adhering to PRISMA guidelines, this meta-analysis considered randomized and nonrandomized studies meeting specific criteria, encompassing intracranial HB and preoperative embolization. Primary outcomes were preoperative embolization efficacy and safety. Complications were classified as major (cerebellar ischemia, ischemic strokes, intratumoral hemorrhage, subarachnoid hemorrhage) and minor (transient nystagmus, slight facial nerve palsy, nausea, transient dysarthria, hemiparesis, hemisensory impairment, thrombotic complications, extravasation). Thirteen studies involving 166 patients with preoperative embolization before HB resection were included. Two studies using the Glasgow Outcome Scale (GOS) showed 5 patients with good recovery, 6 with moderate disability, and 3 with severe disability. Major complications occurred in 1% (95% CI: 0% to 3%), and minor complications occurred in 1% (95% CI: 0% to 4%). Intraoperative blood loss during resection was estimated at 464.29 ml (95% CI: 350.63 ml to 614.80 ml). Preoperative embolization holds promise in reducing intraoperative bleeding risk in neurosurgical intracranial HB treatment, primarily due to its low complication rates. Nonetheless, additional research and larger-scale studies are essential to establish its long-term efficacy and safety. These findings highlight preoperative embolization as a valuable tool for HB management, potentially enhancing future patient outcomes. [ABSTRACT FROM AUTHOR]

We report the case of a 38-year-old man whose diagnostic workup for primary infertility led to the discovery of obstructive azoospermia due to bilateral papillary cystadenoma of the epididymis (PCE). Given the rarity of this finding and because PCE could be a manifestation of Von Hippel-Lindau disease (VHL), although the patient had no family or personal history of VHL, the VHL gene was tested, and a known pathogenetic variant (c.464-1G>A; p.)? was found. Screening for other Von Hippel-Lindau disease-associated neoplasms revealed bilateral retinal capillary hemangioblastomas, clear cell renal cell carcinoma, and multiple pancreatic cysts. In this case, an accurate diagnostic workup for male infertility allowed the detection of a rare life-threatening syndrome, already presenting with several silent neoplasms. For this reason, this case report may be useful for reproductive medicine specialists in the management of male infertility.

Introduction: Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10. Case presentation: Wediagnoseda 9-year-oldgirlofnormal appearance andsevere refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation ofVHLgene(c.414A>G), alsopresent in threemembers ofher family. At age 13, apelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life. Discussion: This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine. [ABSTRACT FROM AUTHOR]

IntroductionVon Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10.Case presentationWe diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of VHL gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life.DiscussionThis family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.

Abstract Background Multiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes. MS cases in the context of genetic diseases may provide different approaches and clues towards identifying novel genes and pathways involved in MS pathogenesis. Here, we present a case series of two related patients with concomitant Von Hippel-Lindau disease (VHLD) and MS. Case presentation We present two patients, a mother (case 1) and daughter (case 2), who developed superimposed relapsing-remitting multiple sclerosis in the background of the autosomal dominant genetic disorder VHLD. Several tumors characteristic of VHLD developed in both cases with pancreatic and renal neoplasms and cerebellar hemangioblastomas. In addition, both patients developed clinical symptoms consistent with multiple sclerosis, supported by radiologic lesions disseminating in time and space. Conclusion Though non-MHC susceptibility genes remain elusive in MS, we present the striking finding of superimposed multiple sclerosis in a mother and daughter with VHLD. The VHL gene is known to be the primary regulator of Nrf2, the well-established target of the FDA-approved therapeutic dimethyl fumarate. These cases provide support for further studies to determine whether VHLD pathway related genes represent a novel genetic link in multiple sclerosis.

Retinal capillary hemangioblastomas (RCH) is a benign tumor that represents the initial manifestation in roughly half of Von Hippel Lindau (VHL) patients. They may also occur sporadically without systemic involvement. A first meta-analysis study was investigated to estimate the prevalence of Retinal capillary hemangioblastoma (RCH) in Von Hippel Lindau (VHL) syndrome, and its relation to type and location of mutations in VHL gene. The electronic databases of PubMed, Scopus, Embase, and Google Scholar were utilized to find eligible papers published up to May 2020. Lastly, after the different prevalence of RCH in Europe compared to other continents was noted, we decided to consider European and non-European patients separately. The Random effect model was used to evaluate the relation between developing RCH and types of mutations. The overall prevalence of RCH among VHL patients is about 47%. The prevalence of RCH was significantly higher in Europe in comparison with non-Europeans (p value < 0.001). Overall, the differences between the prevalence of RCH among different mutation types were not statistically significant. However, in Europe, the prevalence of RCH was significantly higher in patients with truncation mutation (p value = 0.007). In Europe, the RCH in VHL patients who had a mutation in exon 2 was significantly lower in comparison with exon 1 (p value = 0.001); but in non-Europeans, the prevalence of RCH in VHL patients that involved exon 2 was significantly higher in comparison with VHL patients with a mutation in exon1 (p value = 0.012). The highest risk of developing RCH was reported among Europeans. Overall, this study showed that the prevalence of RCH in VHL syndrome is not related to type or location of mutations and difference of RCH prevalence is probably depends on other genetic or environmental factor that should be considered in subsequent studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Thoraco-abdominal paraganglioma and pheochromocytoma (PPGL) are pathogenically linked to mutations in SDH genes. Loss-of-function of SDH has been associated with stabilization of HIF2α, which otherwise would be degraded via oxygen-sensitive mechanisms. SDH dysfunction also predispose to the development of paragangliomas arising at the carotid body or other head and neck paraganglia (HNPGL). Although PPGL and HNPGL share similar features, they have certain clinical and genetic peculiarities. By comparison of HIF2α expression in HNPGL and PPGL, we found that functional HIF2α is overexpressed in 80% of PPGLs, including those with SDH mutations as compared with non-tumor tissue. However, HIF2α is already highly expressed in the carotid body under physiologic conditions, and it is not overexpressed in HNPGL. These data suggest that selective HIF2α inhibitors already in clinical trials may benefit a wide spectrum of PPGL. Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes. MS cases in the context of genetic diseases may provide different approaches and clues towards identifying novel genes and pathways involved in MS pathogenesis. Here, we present a case series of two related patients with concomitant Von Hippel-Lindau disease (VHLD) and MS.Case Presentation: We present two patients, a mother (case 1) and daughter (case 2), who developed superimposed relapsing-remitting multiple sclerosis in the background of the autosomal dominant genetic disorder VHLD. Several tumors characteristic of VHLD developed in both cases with pancreatic and renal neoplasms and cerebellar hemangioblastomas. In addition, both patients developed clinical symptoms consistent with multiple sclerosis, supported by radiologic lesions disseminating in time and space.Conclusion: Though non-MHC susceptibility genes remain elusive in MS, we present the striking finding of superimposed multiple sclerosis in a mother and daughter with VHLD. The VHL gene is known to be the primary regulator of Nrf2, the well-established target of the FDA-approved therapeutic dimethyl fumarate. These cases provide support for further studies to determine whether VHLD pathway related genes represent a novel genetic link in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Protein-protein interactions are vital for a wide range of biological processes. The interactions between the hypoxia-inducible factor and von Hippel Lindau (VHL) are attractive drug targets for ischemic heart disease. In order to disrupt this interaction, the strategy to target VHL binding site using a hydroxyproline-like (pro-like) small molecule has been reported. In this study, we focused on the inhibition mechanism between the pro-like inhibitors and the VHL protein, which were investigated via molecular dynamics simulations and binding free energy calculations. It was found that pro-like inhibitors showed a strong binding affinity toward VHL. Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitors may provide useful information for future drug design. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to report the outcome of early and late vitrectomy for retinal detachment-associated with von Hippel–Lindau (VHL)-related retinal capillary hemangioma (RCH). Materials and Methods: Records of patients diagnosed with VHL-related RCH, from 2016 to 2018, were retrospectively analyzed for patients' age, gender, family history, systemic disorders, previous treatment taken, clinical characteristics of RCH, associated complications, timing of surgery, and surgical outcome. The treatment of RCH depends on its location, size, and clinical expressions. Results: Twenty-one eyes of 15 patients with a median age of 40 years (range, 22–65 years) were seen. Nine patients had central nervous system hemangioblastomas, eight had associated renal complications (four – renal cell carcinoma and four – multiple renal cysts), four had pancreatic cysts, while one had testicular cyst and pheochromocytoma each. Four eyes presented with no perception of light. Eight eyes presented with retinal detachment (RD). Four eyes underwent a combination treatment, four underwent cryotherapy, five underwent laser, and two underwent transpupillary thermotherapy, while four underwent intravitreal bevacizumab. Of eight eyes with tractional RD (TRD), four presented with no perception of light (NPL) . The other four eyes underwent surgery. Of the eyes that underwent surgery, two underwent early vitrectomy for extramacular TRD, whereas the other two underwent surgery in late stage. The two eyes that underwent early vitrectomy gained best-corrected visual acuity (BCVA) of 20/20, and the retina was attached in single surgery. The other two eyes that underwent surgery at an advanced stage had to undergo multiple surgeries and gained BCVA

Background: Conus medullaris tumors are rare, as the majority of all spinal cord tumors occur in the cervical and thoracic regions. Hemangioblastomas of the spinal cord account for 3%–4% of all intramedullary spinal cord tumors and can be sporadic or associated with von Hippel-Lindau disease. There are only fourteen cases of conus medullaris hemangioblastomas published in the literature, herein we present the fifteenth. Case description: A 44-year old male with von Hippel Lindau disease presented with worsening bilateral lower extremity weakness, gait imbalance as well as absent perineal and genital sensation with weak voluntary anal contraction. MRI demonstrated multiple stable spinal tumors and a 6 mm conus medullaris hemangioblastoma with growth and a new peri-tumoral cyst. The patient underwent uncomplicated surgical resection with appreciable improvement in perineal sensation and sphincteric control during post-operative course. Conclusions: Timely resection of conus medullaris tumors can provide symptomatic relief and prevent the progression of devastating neurological deficits. Careful microsurgical dissection with appropriate patient selection allows for safe resection of conus medullaris tumors.

• Hemangioblastoma and radiosurgery. • Cystic Hemangioblastoma and radiosurgery. • Von hipple lindau and radiosurgery. Hemangioblastomas (HB) are benign low grade vascular tumors most frequently occurring in the cerebellum, brain stem, and spinal cord. Often associated with Von Hippel Lindau disease (VHL), the lesions are often multifocal requiring complex resection and are difficult to control. Linear Accelerator (LINAC) Stereotactic Radiosurgery (SRS) has been demonstrated to provide additional tumor control. In this case series, we present our multi-center experience utilizing LINAC SRS in fourteen patients with 23 lesions. We observed a tumor control rate of 87% and found interval changes in the peritumoral enhancement to correlate with treatment outcome. In our study, SRS treatment was also well-tolerated in both cystic and noncystic patients with multifocal disease. Disease control was achieved in all but three patients post-resection and no longitudinal radiation-induced secondary malignancy was observed. SRS response correlated highly with lesion size and radiation dose. We conclude that LINAC SRS is safe and effective for patients with HB and should be considered in addition to surgery in asymptomatic, VHL patients, deep seated lesions and isolated lesions. [ABSTRACT FROM AUTHOR]

Purpose: To determine if non-mydriatic ultra wide-angle digital retinal imaging alone is effective for screening subjects considered to be at 50% or lower risk for developing retinal angiomas. Methods: Digital records and retinal images of subjects attending a regional Von-Hippel-Lindau disease multi-disciplinary clinic over a 12 month period were reviewed. Individuals were stratified for risk of developing retinal angiomas on the basis of age, clinical features and genetic risk. The image quality and necessity for subsequent mydriatic fundoscopy were assessed. Results: Eighty subjects from 55 pedigrees attended the VHL clinic over 12 months. Of these, 44 (55%) were considered to be at lower risk for retinal angiomatosis: 34 (77%) because they had reached at least 30 years of age without developing an angioma, 16 with a presenting solitary tumour of the type associated with VHL but no identifiable gene mutation, and 12 with a family history giving them a 50% risk of carrying a gene mutation. Eighteen patients fulfilled two low risk criteria. All were able to comply with imaging but poor image quality (limited view of the inferior retinal far-periphery) required subsequent dilated fundoscopy in five (6%) eyes of three patients. Conclusions: Non-mydriatic ultra wide-field retinal imaging enabled satisfactory assessment in over 95% of lower-risk VHL subjects. Virtual clinics or remote imaging of lower-risk subjects may improve both the efficiency and flexibility in the provision of multi-disciplinary VHL services and the patient experience. [ABSTRACT FROM AUTHOR]

Abstract Increasing data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. Free iron levels were compared between four VHL-mutant ccRCC cell lines (786-0, A704, 769-P, RCC4) and two benign renal tubule epithelial cell lines (RPTEC, HRCEp) using the Phen Green SK fluorescent iron stain. Intracellular iron deprivation was achieved using two clinical iron chelator drugs, deferasirox (DFX) and deferoxamine (DFO), and chelator effects were measured on cell line growth, cell cycle phase, apoptosis, HIF-1α and HIF-2α protein levels and HIF-α transcriptional activity based on expression of target genes CA9 , OCT4 / POU5F1 and PDGFβ/PDGFB. Similar assays were performed in VHL-mutant ccRCC cells with and without ectopic wild-type VHL expression. Baseline free iron levels were significantly higher in ccRCC cell lines than benign renal cell lines. DFX depleted cellular free iron more rapidly than DFO and led to greater growth suppression of ccRCC cell lines (>90% at ~30–150 µM) than benign renal cell lines (~10–50% at up to 250 µM). Similar growth responses were observed using DFO, with the exception that a prolonged treatment duration was necessary to deplete cellular iron adequately for differential growth suppression of the less susceptible A704 ccRCC cell line relative to benign renal cell lines. Apoptosis and G1-phase cell cycle arrest were identified as potential mechanisms of chelator growth suppression based on their induction in ccRCC cell lines but not benign renal cell lines. Iron chelation in ccRCC cells but not benign renal cells suppressed HIF-1α and HIF-2α protein levels and transcriptional activity, and the degree and timing of HIF-2α suppression correlated with the onset of apoptosis. Restoration of wild-type VHL function in ccRCC cells was sufficient to prevent chelator-induced apoptosis and G1 cell cycle arrest, indicating that ccRCC susceptibility to iron deprivation is VHL inactivation-dependent. In conclusion, ccRCC cells are characterized by high free iron levels and a cancer-specific dependency on iron for HIF-α overexpression, cell cycle progression and apoptotic escape. This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-α dysregulation and ccRCC iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2α and suppressing tumor progression in ccRCC patients. Graphical abstract fx1 Highlights • Free iron levels are elevated in clear cell renal cell carcinoma (ccRCC) cells. • ccRCC cells depend on iron to escape apoptosis and cell cycle arrest. • ccRCC cells depend on iron for HIF-2α protein overexpression and activity. • Clinical iron chelator drugs suppress HIF-2α activity and growth of ccRCC cells. • ccRCC iron dependency is mediated by von Hippel Lindau (VHL) gene inactivation. [ABSTRACT FROM AUTHOR]

Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC.

Abstract Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NEN) are rare and heterogeneous. Therefore, they often remain unrecognized for many years, causing significant disease burden. We here report on four unusual NEN presentations including a metastatic NEN of the kidney, hypoglycemia caused by an insulin-like growth factor-2-oma (previously called non-islet-cell tumor hypoglycemia), multifocal pheochromocytoma in von Hippel Lindau syndrome, and ileal NEN metastatic to the heart. One could say that each one of these tumors were “black swans” and learning about them will increase further awareness of the spectrum of NEN. [ABSTRACT FROM AUTHOR]

Background: Although widely regarded as rare epithelial tumors with a low grade of malignancy, endolymphatic sac tumors (ELST) often lead to disabling petrous bone destruction and significantly impairing symptoms at the time of primary diagnosis and/or recurrence. ELST is not uncommon in von Hippel Lindau (VHL) patients. Although open surgery is regarded as the best treatment option, recurrence remains a challenge, particularly when gross tumor resection (GTR) is deemed unachievable due to topographic conditions. Tumor recurrence successfully treated with fractionated radiotherapy and radiosurgery have been reported in selected cases. We present the case of a patient with recurrent ELST treated with salvage gamma knife radiosurgery (GKRS) adding a review of current literature. Case Description: A 65-year-old patient underwent GKRS of an unresectable, recurrent ELST. Tumor volumetric analysis showed almost 15% increase in tumor volume in the 4 months between the pre-GKRS magnetic resonance imaging (MRI) and the stereotactic MRI (s-MRI) at treatment. Follow-up MRI at 12 and 20 months showed significant decrease in local tumor volume, decreased contrast enhancement and no perifocal edema. The patient's general and neurological status remains stable to the present day. Conclusion: In the present case, GKRS was effective in the management of a recurrent ELST over the course of 20 months. Because of ELSTs recurrence potential, long-term follow up is required. The present case as well as previous reports might suggest a possible salvage/adjunctive role of radiosurgery in the management of ELST. Further studies are deemed necessary. [ABSTRACT FROM AUTHOR]

Objective: A retrospective study detailing the circumstances surrounding diagnosis and treatment of pheochromocytomas with the associated genetic disorders. Materials and Methods: All patients with surgically excised pheochromocytomas in the Health Sciences Center, St. John′s, Newfoundland, Canada between January 2001 and December 2010 were retrospectively analyzed to determine associated familial syndromes, age, tumor size, symptomatology, and percentage of paragangliomas and bilateral pheochromocytomas. Pathology specimen reports, adrenalectomy lists and Meditech (electronic medical record) diagnostic codes provided a comprehensive database for this study. Results: Twenty-four patients were studied; familial disorder patients comprised 42% (10/24). Average age at diagnosis was 57 among the sporadic and 34 in familial disorder groups (P = 0.006). Average tumor size was 4.5 cm in the sporadic group and 3 cm in the familial disorder group (P = 0.19). All atypical cases including bilateral or extra-adrenal tumors and malignancy occurred in familial disorder patients. Conclusions: The proportion of familial disorder patients (42%) was higher in this study than would be expected, likely a result of the relatively high incidence of hereditary autosomal dominant disorders within Newfoundland. Among familial disorder patients, the average younger age at diagnosis and the smaller tumor size suggest syndromic pheochromocytomas may develop earlier, however they are more likely to be diagnosed sooner due to biochemical surveillance testing in known genetic disorder patients. We also demonstrate a relatively high incidence of surgically resected pheochromocytomas of 4.679/million/year in Newfoundland.

Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL. [ABSTRACT FROM AUTHOR]

La enfermedad de von Hippel Lindau es una rara entidad genética que se caracteriza por la predisposición al cáncer, especialmente angiomas de la retina, hemangioblastomas del sistema nervioso central y carcinoma renal de células claras. Los productos del gen presentan un mecanismo de acción peculiar, pues está relacionado con los procesos de adaptación del organismo a la hipoxia. En este trabajo se presenta una panorámica actualizada de esta enfermedad, con énfasis en los aspectos moleculares.The von Hippel Lindau's disease is uncommon genetic entity characterized by a predisposition to cancer, specially the retina angiomas, hemangioblastomas of central nervous system and the clear cells renal carcinoma. Gene products have a typical action mechanism since it is related to organism adaptation processes to hypoxia. In present paper an updated panorama of this disease emphasizing in molecular processes.

Von Hipple-Lindau (vHL) is an autosomal dominant disorder that predisposes individuals to an increased risk of developing multi-organ neoplasms. Pancreatic involvement with subsequent development of type II diabetes mellitus is a well-documented complication of this disorder. In this case report, we present a case of a young man who presented with primary symptoms of polyuria and polydipsia. Patient was later found to be in diabetic ketoacidosis and upon further investigation, was diagnosed with diabetes mellitus type I. Patient's history of persistent abdominal pain prompted further imaging studies, which demonstrated a left sided pheochromocytoma and right sided renal cell carcinoma. Genetic studies confirmed presence of 384delT frame-shift mutation in exon 2 of the tumor suppressor, E3 ubiquitin protein ligase, vHL gene. This case report represents the only one in literature with a rare association of vHL and islet cell autoantibody positive, type I diabetes mellitus. [ABSTRACT FROM AUTHOR]

ABSTRACT Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer predisposition syndromes. We analyzed the frequency and genotype-phenotype correlations of microdeletions in 12 genes ( BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1, and VHL) representing seven tumor predisposition syndromes in 5,897 individuals (2,611 families) from our center. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04-Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next-generation sequencing. [ABSTRACT FROM AUTHOR]

Haemangioblastoma is a rare benign tumour which is known to occur in association with von Hippel Lindau disease in approximately 25% of cases. Occurrence outside the central nervous system is exceptionally rare. This is a case report of a sporadic renal haemangioblastoma occurring in a 32 year old woman. She presented with post-partum fatigue and was found to be polycythaemic with haemoglobin of 19.8 g/dl as well as hypothyroidism. Microscopically this was a highly vascular tumour consisting of densely packed capillary sized blood vessels. Between these were single rows and sheets of polygonal tumour cells with abundant eosinophilic cytoplasm. On immunohistochemistry the tumour cells were positive for S100, CD10, NSE and alpha inhibin and negative for CD34, HMB45, AE1/AE3, MNF116, CAM5.2, RCC, Chromogranin, CD117, synaptophysin, desmin, and melanA. This case also showed focal rhabdoid features and CD10 positivity described only in one other case report in the literature. The differential diagnosis is extensive and includes a variant of renal cell carcinoma, melanoma, paraganglioma, epithelioid leiomyosarcoma and epithelioid angiomyolipoma/PEComa. This is a rare tumour with pseudomalignant appearances and a potential diagnostic pitfall. We have included a literature review of other sporadic haemangioblastomas to characterise the typical immunological and morphological profile of sporadic haemangioblastomas occurring outside the central nervous system. Also of note is the clinical presentation with polycythaemia which has been documented with cases of cerebellar haemangioblastoma and is thought to be a secondary polycythaemia as a result of erythropoietin produced by stromal cells within the tumour. [ABSTRACT FROM AUTHOR]

Objective Clinical characteristics and management of hemangioblastomas of the spinal cord associated with von Hippel-Lindau syndrome have been extensively covered in the literature. This report aims to analyze the characteristics and surgical treatment results of sporadic spinal hemangioblastomas (SSHB). Methods This is a retrospective analysis of 14 patients with SSHB (8 men and 6 women) operated on during a span of 23 years. The median age was 41.5 years (24–70 years). von Hippel Lindau syndrome was excluded by imaging in all patients. The median follow-up was 4 years (1–23 years). We also conducted a meta-analysis of all 271 SSHB cases reported in the English-speaking language literature from 1967 to 2011. Results Nine (64.3%) lesions were cervical, 3 (28.5%) were thoracic, and 1 (7.1%) was lumbar. Eight (57.1%) tumors were dorsal intramedullary, 4 (28.6%) were exophytic, 1 (7.1%) was intradural extramedullary, and 1 (7.1%) was completely extradural. Diffuse segmental cord enlargement was present in 7 patients (50%) and a cyst/syrinx was present in 7 (50%). These 14 patients underwent 15 operations, and gross total resection was achieved in all operations. There was no mortality. Symptoms improved after 8 (53.3%) of 15 operations, remained the same after 5 (33.3%), and worsened after 2 (13.3%). The mean Karnofsky performance score improved from 79.3 (± 17.5) to 87.3 (± 12.2) after 6 months of follow-up. There was one recurrence 15 years after magnetic resonance imaging confirmed total resection. Conclusions The SSHBs occur most often in the upper spinal cord. Excellent surgical results and long-term outcome can be achieved using microsurgery alone with only rare recurrences. [ABSTRACT FROM AUTHOR]

Objective: A retrospective study detailing the circumstances surrounding diagnosis and treatment of pheochromocytomas with the associated genetic disorders. Materials and Methods: All patients with surgically excised pheochromocytomas in the Health Sciences Center, St. John's, Newfoundland, Canada between January 2001 and December 2010 were retrospectively analyzed to determine associated familial syndromes, age, tumor size, symptomatology, and percentage of paragangliomas and bilateral pheochromocytomas. Pathology specimen reports, adrenalectomy lists and Meditech (electronic medical record) diagnostic codes provided a comprehensive database for this study. Results: Twenty-four patients were studied; familial disorder patients comprised 42% (10/24). Average age at diagnosis was 57 among the sporadic and 34 in familial disorder groups (P = 0.006). Average tumor size was 4.5 cm in the sporadic group and 3 cm in the familial disorder group (P = 0.19). All atypical cases including bilateral or extra-adrenal tumors and malignancy occurred in familial disorder patients. Conclusions: The proportion of familial disorder patients (42%) was higher in this study than would be expected, likely a result of the relatively high incidence of hereditary autosomal dominant disorders within Newfoundland. Among familial disorder patients, the average younger age at diagnosis and the smaller tumor size suggest syndromic pheochromocytomas may develop earlier, however they are more likely to be diagnosed sooner due to biochemical surveillance testing in known genetic disorder patients. We also demonstrate a relatively high incidence of surgically resected pheochromocytomas of 4.679/million/year in Newfoundland. [ABSTRACT FROM AUTHOR]

Abstract: Management of pediatric patients with pheochromocytomas associated with genetic syndromes, such as Von Hippel-Lindau (VHL) disease, is complex owing to the need for continuous surveillance, high rates of recurrence, multiple operations during childhood, and the possibility of lifelong exogenous steroid replacement. We report the successful treatment of two siblings with VHL who underwent a total of six cortical-sparing procedures without requiring steroid therapy. [Copyright &y& Elsevier]

Sorrell AD, Lee S, Stolle C, Ellenhorn J, Grix A, Kaelin Jr WG, Weitzel JN. Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma. This report describes clinical characteristics in families with a Type 2A phenotype and functional properties of a novel von Hippel Lindau variant (X214L). Pedigrees were analyzed. Analysis of von Hippel Lindau ( VHL) coding exons and flanking intronic sequences in DNA from a proband with pheochromocytoma and islet cell tumor was performed. Western blot assays for VHL protein (pVHL), HIF α, and Jun B were conducted using VHL null renal clear carcinoma cell lines that were engineered to produce wild-type or X214L mutant pVHL. Pedigree analysis indicated that the variant tracked with disease and the same or similar VHL point mutations were identified in several Type 2A families. The predicted 14 amino acid extended pVHL variant, when reintroduced into VHL null cells, was stable and retained the ability to downregulate HIF α in a hydroxylation-dependent manner. In contrast, the variant was defective with respect to downregulation of JunB. pVHL X214L, like other pVHL variants associated with a low risk of clear cell renal carcinoma, largely preserves the ability to downregulate HIF. In contrast, this variant, like other pVHL variants linked to Type 2A disease, fails to suppress JunB. This underscores that JunB may play a role in the pathogenesis of Type 2A VHL disease. [ABSTRACT FROM AUTHOR]

In the last few years, enhanced understanding of the biology of clear cell renal cell carcinoma has led to the development of molecular signaling inhibitors, which, with their superior anti-tumor activity demonstrated in randomized clinical trials, have led to a paradigm shift in the treatment of advanced renal cell carcinoma from cytokine-based therapy to signaling-inhibitor therapy. Relevant therapeutic signaling pathways that have emerged are VEGF receptor and mammalian target of rapamycin pathways, and signaling inhibitors sunitinib, sorafenib, temsirolimus and, most recently, everolimus are approved by the FDA for treatment of advanced renal cell carcinoma in the USA. Newer agents with promising anti-tumor activity are in continued development, as are efforts to uncover additional therapeutic targets. Currently, the optimal use of available agents, such as sequence and combination strategies, as well as their role in the adjuvant and neoadjuvant setting, remain unclear and investigative efforts are underway. [ABSTRACT FROM AUTHOR]

Gastric bypass and vertical sleeve gastrectomy (VSG) remain the most potent and durable treatments for obesity and type 2 diabetes but are also associated with iron deficiency. The transcription factor HIF2α, which regulates iron absorption in the duodenum, increases following these surgeries. Increasing iron levels by means of dietary supplementation or hepatic hepcidin knockdown does not undermine the effects of VSG, indicating that metabolic improvements following VSG are not secondary to lower iron levels. Gut-specific deletion of Vhl results in increased constitutive duodenal HIF2α signaling and produces a profound lean, glucose-tolerant phenotype that mimics key effects of VSG. Interestingly, intestinal Vhl deletion also results in increased intestinal secretion of GLP-1, which is essential for these metabolic benefits. These data demonstrate a role for increased duodenal HIF2α signaling in regulating crosstalk between iron-regulatory systems and other aspects of systemic physiology important for metabolic regulation. [Display omitted] • Bariatric surgeries result in reduced iron despite upregulation of absorption pathways • Dietary or genetic manipulation to increase iron does not affect VSG effectiveness • Genetic activation of intestinal HIF2α results in improved body fat glucose tolerance • Intestinal HIF2α activation increases GLP-1 secretion, which mediates effects Bariatric surgery remains the most potent treatment for obesity and type 2 diabetes but also reduces iron levels. Evers et al. find that the machinery for absorbing iron is activated after VSG. Activation of this machinery recapitulates multiple effects of VSG. These findings may lead to less invasive therapies. [ABSTRACT FROM AUTHOR]

Objective: This retrospective case series analyzes two cases of hemangioblastomas in the cervicomedullary junction. Methods: A survey of the pediatric staff and of the operative reports from medical records with a review of the literature and medical records of patients with the condition was conducted. Results: Two patients were successfully treated surgically. Conclusion: Surgery is the treatment of choice for hemangioblastomas of the cervicomedullary junction. Careful monitoring for unique complications, treatment of the tumor as a vascular malformation, and screening for von Hippel Lindau must all be employed to safely care for this challenging group of patients. [ABSTRACT FROM AUTHOR]

Central nervous system hemangioblastomas are benign vascular tumours that may present sporadically or as manifestation of the von Hippel-Lindau (VHL) disease. VHL Syndrome is a rare autosomal dominant disorder characterized, besides hemangioblastomas, by susceptibility to multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumours. Germline mutations of VHL tumour suppressor gene cause the VHL disease, while somatic mutations have been associated with sporadic hemangioblastomas and clear-cell renal carcinomas. We identified an 11-bp duplication in the promoter region of the VHL gene in a VHL-affected individual. Functional analysis revealed that this variant affects the binding or the binding affinity of one or more transcription factors that regulate the transcription of VHL in vivo, reducing the endogenous levels of VHL mRNA. Moreover, consistent with the “two hits” model, microsatellite analysis of hemangioblastoma tissue from this patient revealed Allelic Imbalance for the chromosomal region near the VHL gene. We propose that these molecular events, through a loss of pVHL function, lead to the onset of the VHL-related tumours in that individual. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia inducible factor-1alpha (HIF1α) plays a key role in the regulation of genes controlling oxygen supply, glucose metabolism and angiogenesis. Its expression in tumors appears to confer an adaptive advantage to their hypoxic microenvironment. We have evaluated the effect of the immunophilin ligands FK506 and cyclosporin A on HIF1α levels in different tumor cell lines. Our results indicate that both drugs are potent suppressors of HIF1α expression by accelerating the proteasomal degradation of the protein. Unexpectedly, the suppressive effect of these compounds was found to be independent of the presence of von Hippel Lindau factor and the degree of hydroxylation of the HIF1α protein. Moreover, HIF1α degradation induced by these compounds did not required ubiquitination, as it was also induced in E1 ligase-incompetent cells. [Copyright &y& Elsevier]

Abstract: Herein, we review the associations between the kidney, renal cancers, and the eye. Renal cancers have been reported to metastasize to the eye and the orbit. As these tumors can be confused with other amelanotic or vascular tumors, a high index of suspicion is required for early detection and management of the primary tumor. We discuss the physiology of metastases, clinical features and management of metastatic disease. A variety of ocular anomalies have been associated with renal disease. Wilms tumor, a renal tumor of childhood, can present with aniridia, which may be the first clue leading to the diagnosis of the primary tumor. Paraneoplastic syndromes are common manifestations of renal cancers and can present as retinopathies and neuro-ophthalmic disorders. Multiple cancer syndromes involve both the eye and the kidney. For example, the diagnosis of von Hippel retinal tumors can lead to a systemic evaluation and discovery of associated visceral tumors. The prognosis, screening, and counseling of such patients is discussed. Newer systemic treatments available for renal tumors, such as interferon alfa, may lead to ocular side effects including retinopathy. These patients require periodic ophthalmic examinations. This review demonstrates the essential role of the ophthalmologist, for early diagnosis and treatment that can help reduce the morbidity and mortality associated with kidney tumors and renal-associated disease. [Copyright &y& Elsevier]

This survey reviews selected medical disorders in which the ophthalmologist has a unique opportunity of anticipating the existence of asymptomatic, life-threatening disease simply by recognizing that certain benign conditions involving the eye or adnexa represent clues to occult non-ocular cancer and other neoplasias. Having knowledge that these clues are associated with specific types of neoplasia, the ophthalmologist can then initiate a goal-directed oncologic investigation designed to identify the underlying neoplasm with the hope of providing potentially life-saving therapy. The survey is organized to feature each clue separately. The clinical characteristics of the clue are described and illustrated with color photographs when possible. A discussion reviews associated malignancies and other important medical features. The survey begins with clues expressed anteriorly in the lids, progressively reviewing those clues located more posteriorly, concluding with clues involving the retinal pigment epithelium and choroid. [Copyright &y& Elsevier]

Renal cell carcinoma incidence is rising worldwide with increasing subtype stratification by the World Health Organization. Each subtype has unique genetic alterations, cell biology changes and clinical findings. Such genetic alterations offer the potential for individualized therapeutic approaches that are rapidly progressing. This review highlights the most common subtypes of renal cell carcinoma, including both hereditary and sporadic forms, with a focus on genetic changes, clinical findings and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The two main renal tumours, Wilms' tumour and renal cell carcinoma, are associated with distinct molecular genetic abnormalities. The genes involved behave as Knudson oncosuppressor genes. Further dissection of the molecular biology pathways involving WT1 and VHL genes is providing fascinating insight into the biology of these genes, the development and cell biology of the kidney and its tumours. [ABSTRACT FROM AUTHOR]

Introduction: Patients with a confirmed germline mutation in the von Hippel-Lindau (VHL) tumor suppressor gene have been followed at the National Cancer Institute since the 1980s. In this study, we identify VHL patients with pheochromocytoma and long-term follow-up to determine the best candidates for active surveillance and surgical resection.Methods: A prospectively collected database of patients with a confirmed germline VHL mutation was reviewed to identify patients with a history of pheochromocytoma and at least 10 years of follow up. The presence of symptoms was assessed at the time of resection. Imaging data obtained at each clinic visit was reviewed to evaluate mass size and annual growth rate. Catecholamine data were reviewed to evaluate for data above the upper limit of the reference range. Masses that underwent imaging at least 3 months apart were considered in our surveillance cohort.Results: Median follow up was 16.7 years. There was a size-dependent increase in catecholamine production (P<0.05). For 36 masses on active surveillance, growth rate increased exponentially from 0.03 cm/y when masses were <1 cm to 0.32 cm/y when masses were greater than 2 cm. Approximately 1/3 of patients developed another pheochromocytoma after initial resection with a median time of 7.9 years. Partial adrenalectomy was associated with no metastatic events and a steroid-free rate of 97%.Conclusion: Active surveillance is a safe strategy for management of VHL associated pheochromocytoma in masses less than 2 cm. [ABSTRACT FROM AUTHOR]

Patients with von Hippel Lindau (VHL) disease develop multiple central nervous system hemangioblastomas (HB). The surgical resection of VHL-HBs is the standard of clinical care when these HBs become symptomatic due to tumor growth, edema, or cyst formation. VHL-HBs frequently present at the obex of the brainstem, making this a challenging surgical problem. Here, we present a case of a large symptomatic brainstem VHL-HB that was resected using a dorsal midline approach and midline myelotomy. This 35-year-old man with VHL disease and multiple prior resections of cerebellar hemangioblastomas presented with progressive bilateral upper extremity weakness, ataxia, and dysphagia. The accompanying two-dimensional (2D) video demonstrates the key techniques for resection of this brainstem hemangioblastoma, including recognizing the pial presentation, sharp pial/subpial dissection, and en bloc removal. Subsequently, we discuss circumferential dissection, identification, and division of feeding vessels. We also demonstrate key maneuvers to recognize and divide the main arterial pedicle while preserving the anterior spinal artery. The patient tolerated the resection without complication and the patient was discharged home after 6 days at his baseline neurologic function. This work was supported by the Intramural Research Program of the National Institutes of Health. The link to the video can be found at: https://youtu.be/mb2VqcLpxDQ. [ABSTRACT FROM AUTHOR]