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Biomedical subjects

H P Neumann

Publications and source records attributed to H P Neumann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Novel mutations of the MET proto-oncogene in papillary renal carcinomas.

Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.

3T3 Cells↗
PubMed1999

[Retinal capillary angioma. Clinical and molecular genetic studies].

UNLABELLED: Capillary retinal angiomas are rare vascular tumors that frequently occur in von Hippel-Lindau syndrome (vHL) but may also be sporadic. In all patients presenting with this tumor a thorough search for other vHL-associated lesions must be performed. After identification of the vHL gene on the short arm of chromosome 3 (3p25-26), the diagnosis is supported by molecular genetic analysis. PATIENTS: In 20 patients with retinal angioma a clinical search for other manifestations of vHL was performed. In 5 patients only one angioma was present. In all patients molecular genetic tests for a mutation of the vHL gene were performed by SSCP and direct sequencing. RESULTS: In 16 (80%) patients vHl was present, and in 15 it could be diagnosed by clinical findings or a positive family history. Organ lesions in vHL patients were CNS hemangioblastoma in 10 (63%), pancreatic cysts in 7 (43%) and renal cysts in 7 (43%) patients. In two patients (13%) renal carcinoma could be detected; in one patient a pheochromocytoma was present. A mutation could be detected in all 15 patients with clinically confirmed vHL. In three patients a new mutation of vHL disease was diagnosed genetically. In one of these patients a single retinal angioma was the only sign of vHL. CONCLUSION: In patients presenting with capillary retinal angioma a careful search for other vHL lesions has to be performed. A mutation of the vHL gene can be detected in the majority of patients; thus, molecular genetic testing is a powerful tool for diagnosis and detection of asymptomatic gene-carriers.

Adolescent↗
PubMed1999

Adrenal-sparing surgery for phaeochromocytoma.

BACKGROUND: Adrenalectomy is the current treatment for phaeochromocytoma. Consequently, patients with bilateral adrenal phaeochromocytoma become steroid dependent. An adrenal-sparing surgical technique was introduced in 1985. The results of this treatment have been reviewed. METHODS: Since 1985, 39 patients with adrenal phaeochromocytoma (16 men and 23 women, aged 10-76 years) have been treated. Thirty-three patients had unilateral and six had bilateral phaeochromocytomas. Seven of the former 33 had a contralateral adrenal tumour resected previously. All 39 patients were re-evaluated biochemically and clinically for ipsilateral recurrence. RESULTS: Adrenal-sparing surgery was performed successfully in 37 of the 39 patients. In one, adrenal-sparing resection was impossible anatomically and total adrenalectomy was necessary. Another patient with bilateral tumours had retroperitoneal haemorrhage and became steroid dependent. None of the remaining 12 patients who had bilateral adrenal surgery required steroid replacement. Adrenocortical function was normal in eight and mildly impaired in two of the ten patients who had evaluation by adrenocorticotrophic hormone stimulation. After a mean follow-up of 73 months, one patient with von Hippel-Lindau disease developed a recurrence in the ipsilateral adrenal gland. Genetic testing revealed that 26 of the 39 patients, including half of those with a unilateral tumour, had hereditary phaeochromocytoma. CONCLUSION: Adrenal-sparing surgery is safe and effective, and may become the treatment of choice in patients with hereditary phaeochromocytoma.

Adolescent↗
PubMed1999

Expression of the von Hippel-Lindau-binding protein-1 (Vbp1) in fetal and adult mouse tissues.

The von Hippel-Lindau (VHL) tumour suppressorgene product is believed to be involved in the down-regulation of transcriptional elongation by preventing the association of elongin B and C with the catalytic subunit elongin A. Alterations in the human VHL gene lead to VHL disease which is associated with various rare neoplasias, including haemangioblastoma of the central nervous system, retinal angioma, clear cell renal carcinoma and pheochromocytoma. Recently, a protein (VBP1) was isolated that was found to bind to the VHL protein in vivo. We have used the murine Vbp1 homologous cDNA to investigate the expression of the Vbp1 mRNA in the mouse by in situ hybridization and northern blot analysis. In fetal stages between days 9 and 18 of gestation, Vbp1 was expressed mainly in the central nervous system, retina and liver. In addition, at day 12, high expression was observed in the labyrinthine region of the placenta. In later stage placentas, Vbp1 expression was, however, considerably reduced. Northern blot analysis of adult mouse tissues showed that Vbp1 was ubiquitously expressed. In situ analysis on several adult tissues showed that in most tissues, transcripts were evenly distributed. In brain, eye, kidney and intestine, however, Vbp1 was expressed in specific cell types. Moreover, expression of the human VBP1 gene was investigated in cerebellum and in various tumours of VHL patients encompassinghaemangioblastomas, renal cell carcinomas and pheochromocytomas. In all of these tissues, VBP1 was ubiquitously expressed at low levels. However, no consistent differences in VBP1 expression levels could be detected between tumours and normal tissue. Mapping of the murine Vbp1 gene revealed conserved chromosomal localization between mouse and human in a region homologous to human Xq28.

Animals↗
PubMed1999

Multiple intracranial aneurysms in a patient with autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is usually characterized by early onset chronic renal failure due to innumerable dilated collecting ducts. Hepatic fibrosis is an obligate sign. Here, for the first time, we report a 31-year-old female with ARPKD who was diagnosed with symptomatic multiple intracranial aneurysms, a manifestation previously only known to be associated with autosomal dominant polycystic kidney disease (ADPKD).

Adult↗
PubMed1999

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system.

OBJECTIVES: Haemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with the major additional components retinal angioma, renal cancer, and pheochromocytoma. Genetic testing for germline mutations predisposing to von Hippel-Lindau disease has been available since identification of the VHL tumour suppressor gene. The impact of this testing was evaluated in patients with haemangioblastomas seen in this centre. METHODS: A register and database of patients with symptomatic haemangioblastomas for the last 15 years was evaluated. The VHL gene was analysed by the SSCP method for all exons and Southern blotting for mutations and deletions of the gene. RESULTS: 141 patients with haemangioblastoma of the CNS were registered. In 81 patients (57%) there was a disease predisposing germline mutation including eight novel mutations. Population related calculation of patients from the administrative district of Freiburg disclosed VHL germline mutations in 22% of the patients with haemangioblastoma. Analysis of mutation carriers for clinical information suggestive of the syndrome showed (1) a positive family history of a brain tumour in 50%, (2) a history for the patient of extracranial manifestations in 36% (retinal angioma 30%, pheochromocytoma 6%), and (3) 19% presenting with multiple brain tumours when first admitted. By genetic testing of haemangioblastoma patients without any indications of von Hippel-Lindau disease mutation carriers were identified in 14%. Sensitivity of VHL germline testing was 86%. CONCLUSIONS: DNA analysis for VHL germline mutations is clearly superior to clinical information in the diagnosis of von Hippel-Lindau disease. Although the percentage of von Hippel-Lindau disease associated haemangioblastoma decreases after the fourth decade of life and is infrequent in patients without other symptomatic lesions and a negative family history, it is recommended that every patient with CNS haemangioblastoma should be screened for von Hippel-Lindau disease germline mutations. This provides the key information and enables screening for extraneurological tumours of the patients and investigations of the patient's family to ameliorate management of von Hippel-Lindau disease.

Adolescent↗
PubMed1999

Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma.

BACKGROUND: Familial pheochromocytoma, increasingly diagnosed in asymptomatic subjects with inherited syndromes such as multiple endocrine neoplasia type 2 and Von Hippel-Lindau disease, is frequently bilateral and multifocal, but very rarely malignant. Therefore, bilateral adrenalectomy and subsequent lifelong steroid replacement, with its attendant side effects, is not desirable. Minimally invasive adrenal sparing surgery by means of laparoscopy was explored for the treatment of bilateral pheochromocytoma. We report on the cure rate and adrenocortical function in a series of patients treated accordingly. PATIENTS AND METHODS: Four patients (three male, one female, ages 9-60 yr) with hereditary bilateral adrenal pheochromocytoma were treated by laparoscopic surgery in an organ sparing fashion. Postoperatively, all patients were reevaluated for complete tumor removal and for adrenocortical function. RESULTS: Two to 24 months after surgery, all patients were normotensive, had normal sodium potassium, glucose, aldosterone, renin, and cortisol serum concentrations, 24-h excretion of norepinephrine, epinephrine, and vanillylmandelic acid. Abdominal magnetic resonance imaging (n = 3) and computed tomographic scan (n = 1) disclosed no remnant or relapsing tumor tissue. ACTH stimulation testing resulted in normal cortisol responses. CONCLUSION: By adrenal sparing laparoscopic surgery not only bilateral pheochromocytoma can be successfully removed, but also adrenocortical function preserved. This may become the treatment of choice for familial pheochromocytoma.

Adrenal Cortex↗
PubMed1998

Laparoscopic surgery for pheochromocytoma: adrenalectomy, partial resection, excision of paragangliomas.

PURPOSE: Surgical treatment of pheochromocytoma includes adrenalectomy, adrenal sparing surgery and excision of extraadrenal paragangliomas. We report our experience using laparoscopy for these procedures. MATERIALS AND METHODS: Between June 1992 and November 1997, 19 patients underwent laparoscopic surgery for pheochromocytoma. Of the patients 14 had solitary tumors, and 4 presented with bilateral pheochromocytomas and 1 or 2 additional paragangliomas. In 1 patient a recurrent pheochromocytoma was found in the contralateral adrenal following previous right adrenalectomy. One patient each had myocardiopathy, amaurosis and stroke secondary to severe hypertension. Two patients were pregnant. RESULTS: All solitary tumors were treated with laparoscopic adrenalectomy. Laparoscopic adrenal sparing surgery (4 cases, 2 bilateral) and bilateral adrenalectomy (1) were performed for multiple familial pheochromocytoma, and all paragangliomas were excised simultaneously. The pregnant patients underwent surgery at 16 and 20 weeks of gestation, respectively. All procedures were completed as planned. The rate of minor intraoperative and postoperative complications was 11% and 16%, respectively, and there were no major complications. In all patients the catecholamine levels returned to normal and no residual tumors were found at followup. None of the patients undergoing partial resection required steroid replacement therapy. CONCLUSIONS: In experienced hands, laparoscopic surgery for solitary and multiple pheochromocytoma and paraganglioma is feasible and safe, and does not increase the specific risks associated with pheochromocytoma surgery.

Adrenal Gland Neoplasms↗
PubMed1998

Renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex.

Tuberous sclerosis is a multisystem syndrome characterized by neurological symptoms and tumors in multiple organs, including kidney, brain, skin, eyes, heart, and lung. The kidney and brain are the two most frequently affected organs in TSC, and renal disease is a leading cause of death in TSC patients. Three types of tumors occur in TSC kidneys: (1) angiomyolipomas, which are benign tumors composed of smooth muscle, fat, and vessels; (2) epithelial cysts; and (3) malignant tumors. This review focuses on the clinical, pathological, and molecular features of these tumors.

Angiomyolipoma↗
PubMed1998

Endolymphatic sac tumours.

This review article surveys clinical and pathological literature on endolymphatic sac tumours (ELST) and summarizes characteristics that describe the entity. ELST are rare neuroectodermal neoplasms in the petrous bone, originating from inner ear structures. They can be encountered sporadically or in von Hippel-Lindau disease. The most prominent symptom is sensorineural deafness. Historically, nomenclature of invasive adenoid tumours in the petrous bone has been divergent, the term papillary adenocarcinoma used most frequently. Histologically, they have a follicular or papillary and adenoid pattern that can be easily confused with various other neoplastic conditions including metastatic carcinoma. It remains to be verified whether similar tumours (papillary adenocarcinomas) can originate from the middle ear. Middle ear adenomas have a similar appearance but probably originate from neural crest cells in the middle ear. ELST can express a variety of epitopes (including cytokeratin and neuroectodermal markers) which can be detected immunohistochemically. In cases in von Hippel-Lindau disease the cerebello-pontine angle should be included in routine radiological examinations to detect ELST before the tumours lead to deafness. In apparently sporadic cases of ELST, genetic testing for von Hippel-Lindau disease should be considered. Correct distinction of ELST from metastatic carcinoma prevents futile searches for unknown primary tumours.

Diagnosis, Differential↗
PubMed1998

Genotype-phenotype correlations in von Hippel-Lindau disease.

A total of 146 intragenic germline mutations of the von Hippel-Lindau (VHL) gene are known and this figure is still increasing. To date, information for mutation-specific genetic counselling is insufficient, since either the total number of carriers is very low or clinical information and investigation of symptomatic and asymptomatic is incomplete. This review summarizes all known mutations and includes the centres which performed the mutation analyses and may provide further information regarding specific mutations.

Genetic Counseling↗
PubMed1998

Gene conversion is a likely cause of mutation in PKD1.

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.

Gene Conversion↗
PubMed1998

Frequent progesterone receptor immunoreactivity in tuberous sclerosis-associated renal angiomyolipomas.

Angiomyolipomas can occur sporadically or in association with tuberous sclerosis complex (TSC). TSC is an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the brain, heart, kidney, and skin. Angiomyolipomas are more common in women than in men, suggesting a possible hormonal influence on tumor growth. In this study, 35 angiomyolipomas from 23 patients were immunostained with antibodies to estrogen receptor (ER) and progesterone receptor (PR). Eleven angiomyolipomas (31%) contained clusters of PR-immunoreactive smooth muscle cells. None contained ER-immunoreactive cells. Of the 21 tumors from patients with TSC, 11 (48%) were PR immunoreactive. All of the PR-immunoreactive angiomyolipomas were from women younger than 50 years of age, and all except one of these women had TSC. This study suggests that hormonal factors play a role in the pathogenesis of TSC-associated angiomyolipomas.

Adult↗
PubMed1998

Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.

PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm. CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.

Adult↗
PubMed1997

Results of renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are at risk for the development of end-stage renal failure from the treatment of localized renal cell carcinoma. Transplantation with its attendant immunosuppression may predispose patients to tumor recurrence; however, there is little information regarding the outcome with this approach. In this article, we review the North American and European experience with renal transplantation in this patient population. METHODS: The study group comprises 32 patients who have VHL rendered anephric secondary to localized renal cell carcinoma and who have undergone renal transplantation. Patients were identified from North American (n=18) and European (n=14) registries. The outcome of the study group is compared with a cohort of 32 renal transplant recipients without VHL from the Cleveland Clinic Unified Transplant Data Base, who were matched for donor source, gender, age, transplant status (primary vs. regraft), and date of transplantation. RESULTS: The 23 men and 9 women in the study group received transplants between 1974 and 1996. The average age at transplantation was 36 years, and the average duration of dialysis before transplantation was 26 months. Patients have been followed for 48+/-35 months. There was no statistically significant difference in graft survival, patient survival, or renal function between the study and control groups. There were five deaths in both the study and control groups. In the study group, three patients died with metastatic disease. There was no difference in the duration of dialysis before transplantation between patients who developed metastatic disease and those who did not. CONCLUSION: These data support the utility of renal transplantation as an effective form of renal replacement therapy in this unique population, with a limited risk of recurrent cancer.

Carcinoma, Renal Cell↗