[Von Hippel-Lindau disease].

von Hippel‐Lindau (VHL) disease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene. VHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations. We analyzed genotype–phenotype correlations in 573 individuals with VHL disease. Routine clinical and radiological surveillance of VHL patients and at‐risk relatives was associated with increased detection of retinal angiomatosis (73 vs. 59% of cases) and a reduction in age at diagnosis of renal cell carcinoma (RCC) (44.0±10.9 vs. 39.7±10.3 years). We confirmed the association of pheochromocytoma with missense mutations described previously, but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk. Age at first manifestation of VHL disease was significantly earlier (P=0.001), and age‐related risks of retinal angiomas and RCC were higher (P=0.022 and P=0.0008, respectively) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product (pVHL). These results extend genotype–phenotype–protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in VHL disease. Hum Mutat 28(2), 143–149, 2007. © 2006 Wiley‐Liss, Inc.

Genotype-Phenotype Correlations in von Hippel-Lindau disease

Percutaneous cryoablation is gaining in popularity as a viable treatment option for renal cell carcinoma (RCC). We present the 5-year oncologic outcomes of a prospective trial. Over a 5-year period, we treated 134 consecutive patients with biopsy-proven RCC with CT-guided percutaneous cryoablation. All were treated while under conscious sedation. Technical objective was for the ice ball to cover the lesion plus a 5-mm margin. Hydro- or air dissection was utilized to aid in technical success as needed. Efficacy was defined as the lack of enhancement and/or enlargement of a previously enhancing lesion on follow-up imaging. Safety was assessed by the common terminology criteria for adverse events (CTCAE), version 4.0. The 1-, 2-, 3-, 4-, and 5-year efficacy of percutaneous cryoablation for RCC was 99.2, 99.2, 98.9, 98.5, and 97.0 %, respectively. Median tumor size was 2.8 ± 1.4 cm. All-cause mortality during the study period was 3 (none from RCC), yielding an overall 5-year survival of 97.8 %. The cancer-specific 5-year survival was 100 %. No patient developed metastatic disease during the follow-up period. The overall significant CTCAE version 4.0 complication rate was 6 %, with the most frequent being transfusion-requiring hemorrhage, at 1.6 %. There was one 30-day mortality unrelated to the procedure. CT-guided percutaneous cryoablation for renal cancer offers very high efficacy, approaching that of the gold standard, with a more favorable safety profile.

Efficacy and Safety of Percutaneous Cryoablation for Stage 1A/B Renal Cell Carcinoma: Results of a Prospective, Single-Arm, 5-Year Study

Understanding of molecular mechanisms of tumor growth has an increasing impact on the development of diagnostics and targeted therapy of human neoplasia. In this review, we summarize the current knowledge on molecular mechanisms and their clinical implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syndrome usually manifests in young adulthood and predisposes affected patients to the development of benign and malignant tumors of different organ systems mainly including the nervous system and internal organs. A consequent screening and timely preventive treatment of lesions are crucial for patients affected by VHL disease. Surgical indications and treatment have been evaluated and optimized over many years. In the last decade, pharmacological therapies have been evolving, but are largely still at an experimental stage. Effective pharmacological therapy as well as detection of biomarkers is based on the understanding of the molecular basis of disease. The molecular basis of von Hippel-Lindau disease is the loss of function of the VHL protein and subsequent accumulation of hypoxia-inducible factor with downstream effects on cellular metabolism and differentiation. Organs affected by VHL disease may develop frank tumors. More characteristically, however, they reveal multiple separate microscopic foci of neoplastic cell proliferation. The exact mechanisms of tumorigenesis in VHL disease are, however, still not entirely understood and knowledge on biomarkers and targeted therapy is scarce.

/pdf/von-hippel-lindau-disease-current-challenges-and-future-7ogz8r1t8c.pdf

Von Hippel-Lindau Disease: Current Challenges and Future Prospects.

BACKGROUND: The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs). METHODS: Our methods were the review and discussion of the pertinent literature. RESULTS: About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently. CONCLUSION: All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested. (c) 2013 Wiley Periodicals, Inc. Head Neck 36: 907-916, 2014.

Genetics of hereditary head and neck paragangliomas.

We evaluated the clinicopathological outcome of von Hippel-Lindau (VHL)-patients who had mainly undergone nephron sparing surgery (NSS) for renal cell carcinoma (RCC) when the tumour diameter has reached 4.0 cm. Multiple, bilateral RCC with high recurrence rates and subsequent repeated interventions, followed by increasing risk for end-stage renal failure and metastases is characteristic for VHL. NSS is widely used for VHL-associated RCC at 3.0 cm cut-off. 54 VHL patients underwent NSS, nephrectomy or thermal ablation for RCC. We analysed time to second treatment, overall and cancer specific survival, intra- and post-operative data as well as tumour characteristics. We also examined the effects of delaying removal of RCC to 4.0 cm cut-off. Median follow-up was 67 months. 54 patients underwent 97 kidney treatments. 96 % of first and 67 % of second interventions comprised of NSS. 0 % metastases were observed in the group with largest tumour size ≤4 cm. The probability for second surgery was 21 %, at 5 years and 42 % at 10 years. Median time to second NSS was 149.6 months. The overall and cancer specific survival rate was 96.5 and 100 % at 5-year follow-up, and 82.5 and 90.5 % respectively at 10-year follow-up. Median delay to second NSS at 4.0 cm cut-off versus 3.0 cm was 27.8 months. NSS was both successfully used in first and second surgery and to some extent even in third surgery. By following a strict surveillance protocol it is possible to support a 4.0 cm-threshold strategy for NSS, based on the assumption that delaying time to second NSS prevents patients from premature renal failure.

Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up

Von Hippel-Lindau disease is an important hereditary tumor syndrome with a clear option for effective treatment if diagnosed in time. Interdisciplinary cooperation is the key to successful management. Major components of the disease are retinal capillary hemangioblastomas, hemangioblastomas of cerebellum, brain stem and spine, renal clear cell carcinomas, pheochromocytomas, multiple pancreatic cysts and islet cell carcinomas, tumors of the endolymphatic sac of the inner ear, and cystadenomas of the epididymis and broad ligament. A well structured screening program should be performed at yearly intervals.

[Von Hippel-Lindau disease. Interdisciplinary patient care].

Das Von-Hippel-Lindau-Syndrom ist eine hereditare Tumorerkrankung. Die interdisziplinare Versorgung der Patienten ist von zentraler Bedeutung, weil die Erkrankung nicht nur die Augen, sondern zahlreiche weitere Zielorgane betrifft. Klassische Veranderungen sind Hamangioblastome von Kleinhirn, Medulla oblongata und Ruckenmark, Nierenkarzinome, Phaochromozytome, Pankreaszysten und Inselzelltumoren sowie Tumoren des Endolymphsacks des Innenohrs. Das Untersuchungsprogramm umfasst die augenarztliche Untersuchung, MRT von Kopf, Ruckenmark und Abdomen. Jahrliche Kontrollen werden empfohlen. Die Durchfuhrung der Untersuchungen, die die Grundlage einer rechtzeitigen und meist erfolgreichen Therapie darstellen, ist eine organisatorische Herausforderung.

Von-Hippel-Lindau-Erkrankung

Objective: To evaluate the growth kinetics of renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease in a large trial by CT/MRI scan. VHL disease is a multisystemic disorder predisposing to renal cysts and cancer. There is a general assumption that VHL-associated RCC presents slower growth rates than sporadic RCC. Patients and Methods: We describe growth kinetics of 96 renal tumours in 64 VHL patients with analysed germline mutation (54/64 treated, 10/64 active surveillance) over a mean follow-up of 54.9 months. We calculated tumour volume, growth rate, multiplication of tumour volume per year and overall, as well as tumour volume doubling time. Results: The mean growth rate of 96 tumours was 4.4 mm/year (SD 3.2, median 4.1 mm/year), mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). We saw a median 1.4-fold increase in tumour volume per year. At treatment time point, VHL kidneys comprised 39% tumour and 15.7% cyst volume fraction. We saw no correlation between tumour size and growth parameters. Conclusion: VHL-associated RCC show large variances in tumour growth behaviour. Compared to the literature, in our study the growth rates (mm/year) of RCC in VHL disease did not differ from those of sporadic RCC. Fast tumour growth increases the risk for metastases.

/pdf/growth-kinetics-in-von-hippel-lindau-associated-renal-cell-20s5k3zlja.pdf

Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma.

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Papers

Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up

[Von Hippel-Lindau disease. Interdisciplinary patient care].

Von-Hippel-Lindau-Erkrankung

Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma.