Publications by authors named "McClellan M Walther"

46 Publications

Management of von Hippel-Lindau-associated kidney cancer.

Nat Clin Pract Urol 2005 May;2(5):248-55

Urologic Oncology at the Urologic Oncology Branch of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Von Hippel-Lindau disease (VHL) is an autosomal-dominant inherited condition that predisposes patients to develop renal cysts and tumors, most commonly in the second to fourth decades of life. Renal cysts and tumors have historically been a major cause of disease-related morbidity and mortality, so urologists are often called on to manage patients with VHL. Knowledge of the extrarenal manifestations of VHL (hemangioblastomas of the central nervous system and retina, endolymphatic sac tumors, pancreatic cysts, epididymal and broad-ligament cysts, and pheochromocytomas) and integration of nonurologic specialties into management teams for VHL patients will help to achieve successful outcomes. Screening for renal manifestations of VHL, by regular imaging of the abdomen, begins late in the second decade of life. Because renal tumors in VHL can be multifocal and bilateral, management can be complex. Radical nephrectomy removes all tissue at risk for forming renal tumors; however, this necessitates renal replacement therapy. In an effort to control cancer effectively while preserving native renal function and minimizing intervention, some researchers have proposed an observational strategy. Patients are screened until the largest tumor reaches 3 cm in diameter, at which time operative intervention is recommended. Nephron-sparing surgery is undertaken, whenever technically feasible, with the goal of removing all tumors in that renal unit. The role of minimally invasive technologies is currently being evaluated in selected patients with VHL renal masses. Elucidation of molecular pathways associated with VHL renal tumors may facilitate development of effective medical treatments for these lesions in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncpuro0179DOI Listing
May 2005

Partial adrenalectomy: the National Cancer Institute experience.

Urology 2005 Jul;66(1):19-23

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

Objectives: To report our experience of partial adrenalectomy and demonstrate whether adrenal function can be preserved in patients with hereditary adrenal pheochromocytoma. Total adrenalectomy has largely been used in the treatment of patients with hereditary adrenal pheochromocytomas. Adrenal cortical-sparing surgery is an alternative approach that aims to balance tumor removal with preservation of adrenocortical function.

Methods: From 1995 to 2004, 33 patients with hereditary pheochromocytoma presented with adrenal masses. Partial adrenalectomy (open or laparoscopic) was performed if normal adrenocortical tissue was evident on preoperative imaging or intraoperative ultrasonography. Various operative parameters, as well as postoperative function of the residual adrenal remnants, were determined.

Results: Of the 33 patients, 8 underwent open partial adrenalectomy and 25 laparoscopic partial adrenalectomy during a 10-year period. Ten patients underwent simultaneous, bilateral partial adrenalectomy and 8 underwent surgery on a solitary adrenal gland, 4 of whom received postoperative steroid replacement (stopped in 3 after 1 to 3 months). All other patients had normal catecholamine levels and remained tumor free by imaging at a mean follow-up of 36 months (range 3 to 102).

Conclusions: Partial adrenalectomy can preserve adrenal function in patients with adrenal masses. The laparoscopic approach is technically safe and associated with less morbidity without compromising tumor removal. With careful surgical planning, especially in patients with tumors in solitary glands, adrenocortical function may be preserved, thereby avoiding the morbidity associated with medical adrenal replacement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2005.01.009DOI Listing
July 2005

High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors.

J Natl Cancer Inst 2005 Jun;97(12):931-5

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

The Birt-Hogg-Dubé (BHD) syndrome is an inherited genodermatosis characterized by a predisposition to hamartomatous skin lesions, pulmonary cysts, and renal carcinoma. Seventy-seven renal tumors from 12 patients with germline BHD mutations were examined by DNA sequencing to identify somatic mutations in the second copy of BHD. Sequence alterations were detected in the majority of renal tumors (41 of 77, 53%), with loss of heterozygosity at the BHD locus in a minority of additional tumors (14 of 77, 17%). The somatic mutations were distributed across the entire gene, and the majority resulted in frameshifts that are predicted to truncate the BHD protein. These results support a role for BHD as a tumor suppressor gene that predisposes to the development of renal tumors when both copies are inactivated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/dji154DOI Listing
June 2005

Metastatic renal cell carcinoma to contralateral ureter presenting as acute obstructive renal failure after radical nephrectomy.

Urology 2005 May;65(5):1001

Department of Urology, Washington Hospital Center, Washington, DC, USA.

Metastatic renal cell carcinoma commonly involves the lungs, bone, liver, adrenal glands, and brain. Less commonly affected organs include the gallbladder, thyroid, and pancreas. Even metastatic spread to the contralateral kidney and the bladder has been reported. Computed tomography is the standard imaging technique to evaluate for contralateral involvement. One of the disadvantages of computed tomography as a screening modality is its difficulty in identifying small ureteral lesions. We report a rare case of metastatic renal cell carcinoma in the contralateral ureter presenting as acute obstructive renal failure after radical nephrectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2004.11.036DOI Listing
May 2005

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.

Am J Hum Genet 2005 Jun 25;76(6):1023-33. Epub 2005 Apr 25.

Basic Research Program, Science Applications International Corporation-Frederick Inc., Frederick, MD, USA.

Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/430842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196440PMC
June 2005

Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome.

J Urol 2005 May;173(5):1482-6

Urologic Oncology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute and Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland, USA.

Purpose: Herein we describe the evaluation and management of renal tumors in Birt-Hogg-Dubé (BHD), an autosomal dominant disorder predisposing to cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal tumors.

Materials And Methods: A total of 124 affected individuals underwent comprehensive clinical evaluation, including body computerized tomography, to determine cutaneous, pulmonary and renal manifestations of BHD. Of these individuals 14 had their renal tumors managed at our institution.

Results: Of the 124 BHD affected individuals 34 (27%) had renal tumors of various histologies, most commonly hybrid oncocytic tumor and chromophobe renal carcinoma. Average age at renal tumor detection was 50.4 years and multiple tumors were found in a majority of patients. Some patients with renal tumors were identified that did not have the characteristic cutaneous hallmarks of BHD. In 4 of the 14 patients treated at our institution small (less than 3 cm) renal tumors were observed, while 10 others underwent a total of 12 renal procedures, including 4 radical and 8 partial nephrectomies. At a median of 38 months of followup 5 of these 10 patients remained free of disease, 3 had small renal tumors and 2 died of metastatic renal cancer.

Conclusions: Patients with BHD are at risk for multiple renal tumors that are often malignant and can metastasize. Individuals at risk or affected by BHD should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches. Genetic testing for this syndrome is now available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000154629.45832.30DOI Listing
May 2005

Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.

J Clin Endocrinol Metab 2005 Jun 15;90(6):3747-51. Epub 2005 Mar 15.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D-37, Bethesda, Maryland 20892-1414, USA.

Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2004-1899DOI Listing
June 2005

The genetic basis of cancer of kidney cancer: implications for gene-specific clinical management.

BJU Int 2005 Mar;95 Suppl 2:2-7

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1464-410X.2005.05189.xDOI Listing
March 2005

Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines.

Clin Chem 2005 Apr 17;51(4):735-44. Epub 2005 Feb 17.

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA.

Background: Measurements of plasma free metanephrines (normetanephrine and metanephrine) provide a useful test for diagnosis of pheochromocytoma and may provide other information about the nature of these tumors.

Methods: We examined relationships of tumor size, location, and catecholamine content with plasma and urinary metanephrines or catecholamines in 275 patients with pheochromocytoma. We then prospectively examined whether measurements of plasma free metanephrines could predict tumor size and location in an additional 16 patients.

Results: Relative proportions of epinephrine and norepinephrine in tumor tissue were closely matched by relative increases of plasma or urinary metanephrine and normetanephrine, but not by epinephrine and norepinephrine. Tumor diameter showed strong positive relationships with summed plasma concentrations or urinary outputs of metanephrine and normetanephrine (r = 0.81 and 0.77; P <0.001), whereas relationships with plasma or urinary catecholamines were weaker (r = 0.41 and 0.44). All tumors in which increases in plasma metanephrine were >15% of the combined increases of normetanephrine and metanephrine either had adrenal locations or appeared to be recurrences of previously resected adrenal tumors. Measurements of plasma free metanephrines predicted tumor diameter to within a mean of 30% of actual diameter, and high plasma concentrations of free metanephrine relative to normetanephrine accurately predicted adrenal locations.

Conclusions: Measurements of plasma free metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help predict tumor size and location. This additional information may be useful for clinical decision-making during tumor localization procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1373/clinchem.2004.045484DOI Listing
April 2005

Genetic basis of cancer of the kidney: disease-specific approaches to therapy.

Clin Cancer Res 2004 Sep;10(18 Pt 2):6282S-9S

Urologic Oncology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-1501, USA.

Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2alpha for ubiquitin-mediated degradation. VHL-/- clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor alpha. Both hypoxia-inducible factor 1alpha and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dubé syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-050013DOI Listing
September 2004

Radiofrequency ablation of cancer.

Cardiovasc Intervent Radiol 2004 Sep-Oct;27(5):427-34. Epub 2004 Jun 3.

Diagnostic Radiology Department, Special Procedures Division, National Institutes of Health, Clinical Center, Bethesda, MD 20892, USA.

Radiofrequency ablation (RFA) has been used for over 18 years for treatment of nerve-related chronic pain and cardiac arrhythmias. In the last 10 years, technical developments have increased ablation volumes in a controllable, versatile, and relatively inexpensive manner. The host of clinical applications for RFA have similarly expanded. Current RFA equipment, techniques, applications, results, complications, and research avenues for local tumor ablation are summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00270-004-0062-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408956PMC
August 2006

Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene.

J Urol 2004 Oct;172(4 Pt 1):1256-61

Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland, USA.

Purpose: Hereditary papillary renal carcinoma (HPRC) is characterized by a predisposition to multiple, bilateral papillary type 1 renal tumors caused by inherited activating missense mutations in the tyrosine kinase domain of the MET proto-oncogene. In the current study we evaluated the clinical phenotype and germline MET mutation of 3 new HPRC families. We describe the early onset clinical features of HPRC.

Materials And Methods: We identified new HPRC families of Italian (family 177), Spanish (family 223) and Cuban (family 268) descent. We evaluated their clinical features, performed MET mutation analysis by denaturing high performance liquid chromatography and DNA sequencing, and estimated age dependent penetrance and survival using Kaplan-Meier analysis. We characterized renal tumors by histology and fluorescence in situ hybridization.

Results: Identical germline MET c.3522G --> A mutations (V1110I) were identified in families 177 and 268 but no evidence of a founder effect was found. Affected members of family 223 carried a germline c.3906G --> C.3522G --> A MET mutation (V1238I). Age dependent penetrance but not survival was significantly earlier for the c.3522G -->A mutation than for the c.3906G --> A mutation in these HPRC families. Trisomy of chromosome 7 and papillary renal carcinoma type 1 histology were detected in papillary renal tumors.

Conclusions: HPRC can occur in an early onset form. The median age for renal tumor development in these 3 HPRC families was 46 to 63 years. HPRC associated papillary renal tumors may be aggressive and metastasize, leading to mortality. Median survival age was 60 to 70 years. Families with identical germline mutations in MET do not always share a common ancestor. HPRC is characterized by germline mutations in MET and papillary type 1 renal tumor histology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000139583.63354.e0DOI Listing
October 2004

Risk factors for skin breakdown after renal and adrenal surgery.

Urology 2004 Aug;64(2):246-9

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA.

Objectives: To perform a retrospective review in patients undergoing urologic operations during a 10-year period. Patient positioning is important before surgery to avoid pressure sores and other iatrogenic injuries. The reported risk factors have included a long operative time, diabetes, and malignancy. We have noted skin breakdown in patients placed on stabilizing devices and in patients with germline von Hippel-Lindau (VHL) gene mutations (a gene important in angiogenesis).

Methods: We performed a retrospective review in patients undergoing urologic operations during a 10-year period. Patient sex, age, blood loss, position, use of belt or Vac Pac, and diagnosis of VHL were correlated with skin breakdown.

Results: During a 10-year period, 382 patients underwent primarily renal and adrenal surgery. Fifty-five patients (14.4%) developed skin breakdown after surgery. Ninety-six patients had VHL gene mutations. Patient position and operative time were both significantly related to skin breakdown (both P <0.0001). The odds ratio for the position effect indicated that patients in the lateral position were at much greater risk than patients in the supine position (estimated odds ratio 8.1, P <0.0001). The odds ratio for operative time confirmed that patients experiencing longer operative times were also at increased risk of skin breakdown (estimated odds ratio 3.7 for each doubling of the operative time, P <0.0001). Patient sex, patient age, estimated blood loss, diagnosis of VHL, and use of belt or Vac Pac were not associated with an increased risk of skin breakdown.

Conclusions: Patients with longer operative times were at greater risk of skin breakdown and required greater care during preoperative positioning. The other factors studied were not significantly associated with skin breakdown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2004.03.024DOI Listing
August 2004

Thermal protection during percutaneous thermal ablation of renal cell carcinoma.

J Vasc Interv Radiol 2004 Jul;15(7):753-8

Diagnostic Radiology Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Thermal injury to collateral structures is a known complication of thermal ablation of tumors. The authors present the use of CO(2) dissection and inserted balloons to protect the bowel during percutaneous radiofrequency (RF) ablation and cryotherapy of primary and locally recurrent renal cell carcinoma. These techniques offer the potential to increase the number of tumors that can be treated with RF ablation or cryotherapy from a percutaneous approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408950PMC
http://dx.doi.org/10.1097/01.rvi.0000133535.16753.58DOI Listing
July 2004

The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease.

J Urol 2004 Jul;172(1):63-5

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Purpose: Patients with von Hippel-Lindau disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with von Hippel-Lindau disease.

Materials And Methods: Screening affected kindred or retrospective review of medical records identified 181 patients with von Hippel-Lindau disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors.

Results: A total of 108 patients with von Hippel-Lindau disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with von Hippel-Lindau disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p <0.0001). Metastases developed in 20 of 73 (27.4%) patients in group 2. The frequency of renal tumor metastases increased with increasing tumor size.

Conclusions: No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm threshold for parenchymal sparing surgery in patients with von Hippel-Lindau disease to decrease the risk of metastatic disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with von Hippel-Lindau disease and vigilant followup thereafter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000132127.79974.3fDOI Listing
July 2004

Parenchymal sparing surgery for central renal tumors in patients with hereditary renal cancers.

J Urol 2004 Jul;172(1):49-53

Urologic Oncology Branch and Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.

Purpose: Nephron sparing surgery has become accepted surgical practice for removing of renal tumors. The resection of central lesions has been thought to be more surgically challenging than that of peripheral tumors. We analyzed our experience with renal preservation surgery in patients with small hereditary central renal tumors.

Materials And Methods: From 1992 to 2000 we performed 116 partial nephrectomies with 44 kidneys (38%) demonstrating central renal masses. Central renal tumors were defined radiologically as those completely encircled by parenchyma or transgressing the interpapillary line on computerized tomography. We compared this group to a similar series of 67 patients with hereditary renal cancer with only peripheral based tumors.

Results: Mean tumor size was 3.2 cm (range 1.5 to 7.5). Mean operative time was 352 minutes (range 70 to 830). Renal hypothermia and vascular clamping were used in 19 of 44 procedures (41%). Mean ischemic time was 55 minutes (range 16 to 143). Mean blood loss was 4.6 l (range 0.1 to 23). The complication rate was 23% (10 of 44 cases) and with 18% (8 of 44) directly related to surgical technique. The mean transfusion requirement was 6.7 U (range 0 to 32) and 12 of 44 procedures (27%) required no blood products. Mean preoperative and postoperative serum creatinine was 1.05 (range 0.6 to 1.8) and 1.08 mg/dl (range 0.6 to 2.1), respectively. Mean followup was 33.7 months. No metastasis developed during followup.

Conclusions: Central renal tumors are a common manifestation of hereditary renal cell carcinoma. There was no statistical difference found between common operative parameters when central and peripheral nephron sparing surgeries were compared. However, mean operative blood loss and transfusion requirements were increased in the central tumor group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000130930.70356.28DOI Listing
July 2004

Bilateral testicular adrenal rests after bilateral adrenalectomies in a cushingoid patient with von Hippel-Lindau disease.

Urology 2004 May;63(5):981-2

Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.

We report a case of bilateral testicular masses in a 25-year-old man with von Hippel-Lindau disease presenting with cushingoid symptoms. His medical history was significant for bilateral adrenalectomies secondary to pheochromocytomas, and he began steroid therapy at that time. After exhaustive endocrinologic, radiographic, and physical examinations, the testicular masses were postulated to be active adrenal rest tissue. Bilateral testicular venous sampling found elevated glucocorticoids that were responsive to dexamethasone suppression, which confirmed the testicular masses as testicular adrenal rests without the need for surgical intervention. Successful conservative management consisted of appropriate steroid manipulation and radiographic evaluation and resulted in the resolution of presenting symptoms, a decrease in size of the bilateral testicular masses, and testicular conservation in this young man.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2004.01.023DOI Listing
May 2004

Surgical images: Soft tissue laparoscopic resection of a renal hilar pheochromocytoma.

Can J Surg 2004 Feb;47(1):52-3

Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211801PMC
February 2004

Update on minimally invasive approaches to kidney tumors.

Curr Urol Rep 2004 Feb;5(1):13-8

Division of Urology, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, MEB 588, New Brunswick, NJ 08903, USA.

Renal tumors are being detected at increasing rates because of widespread use of modern imaging techniques such as ultrasonography and computed tomography. Typically, these tumors, many of which are discovered incidentally, tend to be small and are confined to the kidney. Advances in ablative and imaging technology have led to the application of minimally invasive therapy in the treatment of small renal tumors. Although still evolving as a cancer treatment, minimally invasive treatment potentially offers several advantages over conventional open renal surgery: shorter convalescence, improved cosmesis, reduced postoperative pain, and renal preservation. This article reviews the status and recent progress of minimally invasive approaches to renal neoplasm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11934-004-0005-yDOI Listing
February 2004

Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location.

Hum Mutat 2004 Jan;23(1):40-6

Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.

von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30-kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs. 18.9%, p <0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. Careful correlation of genotypic data with objective phenotypic measures will provide further insight into the mechanisms of tumor formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.10302DOI Listing
January 2004

Hereditary kidney cancer.

Urol Clin North Am 2003 Nov;30(4):831-42

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bldg#10, Room 2B47, Bethesda, MD 20892, USA.

Significant advances have been made in the understanding of the genetic basis of familial renal neoplasia. Identification of key genes in the pathogenesis of various hereditary renal cancer syndromes has provided opportunities to screen family members at risk and to explore the significance of these genetic abnormalities in the development and genesis of much more common sporadic counterparts. As researchers continue to delineate critical carcinogenic pathways and accumulate expansive knowledge on oncogenic mechanisms driving cancer initiation and progression at the cellular and molecular levels, this information will be integrated and translated into effective diagnostic and therapeutic strategies that will dictate clinical management of all renal cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0094-0143(03)00054-5DOI Listing
November 2003

Laparoscopic management of extra-adrenal pheochromocytoma.

J Urol 2004 Jan;171(1):72-6

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Purpose: Laparoscopic management of extra-adrenal pheochromocytoma presents a unique surgical challenge due to variable anatomical presentation and potential catecholamine surge during operative manipulation. We report our experience with laparoscopic removal of extra-adrenal pheochromocytomas.

Materials And Methods: Between 1999 and 2002, 5 patients presented with retroperitoneal extra-adrenal pheochromocytomas. Of the patients 2 had a history of von Hippel-Lindau disease, and the remaining 3 patients were diagnosed with sporadic extra-adrenal pheochromocytoma during hypertension evaluation. Although 4 patients had a history of hypertension, only 2 reported symptoms (episodic flushing, headaches, blurred vision) associated with excess catecholamine production. All patients had markedly increased preoperative urinary and plasma normetanephrine and/or norepinephrine levels, and 3 had positive I131 metaiodobenzylguanidine scan. In each case tumor was accurately identified on computerized tomography before surgery.

Results: Laparoscopic resection of extra-adrenal pheochromocytoma was successful in 4 patients. Open conversion was required in 1 patient, who also had von Hippel-Lindau related bilateral adrenal pheochromocytomas due to significant adhesion of the extra-adrenal tumor to the aorta and renal hilum, and a concern for possible local invasion. Mean laparoscopic operative time and blood loss were 273 minutes (range 240 to 350) and 119 cc (range 75 to 200), respectively. Three 10 mm ports in a standard triangular fashion were used for the left side tumors, in which the tumors were found lateral to the aorta. For the right side tumors located either in the inter-aortacaval or para-caval region, a fourth port (10 mm) was inserted for liver retraction as needed. Laparoscopic ultrasound was used to localize the tumor and to assess the retroperitoneum for possible metastasis (none detected) in 3 cases. None of the patients had a hypertensive crisis intraoperatively, and all had unremarkable postoperative recovery with an average hospital stay of 3.8 days (range 3 to 4). Plasma and/or urinary norepinephrine and normetanephrine levels returned to normal range postoperatively in all cases. One patient was noted to have left lower extremity lymphedema and gluteal hematoma due to a positional injury related to prolonged pressure from the operating table and was treated conservatively. There has been no tumor recurrence at a median followup of 14 months (range 9 to 36).

Conclusions: With careful surgical planning and appropriate preoperative pharmacological blockade, laparoscopic surgery can be safely performed in patients with extra-adrenal pheochromocytomas with minimal morbidity. Laparoscopic ultrasound may be helpful in precise localization and evaluation of tumor extension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000102081.46348.a4DOI Listing
January 2004

The genetic basis of cancer of the kidney.

J Urol 2003 Dec;170(6 Pt 1):2163-72

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

Purpose: The types of epithelial renal tumors are clear cell, types I and II papillary, chromophobe and oncocytoma. We identified the genetic basis of these different types of kidney cancer to provide better methods for early diagnosis of this disease as well as provide the foundation for the development of molecular therapeutic approaches.

Materials And Methods: To identify the genetic basis of kidney cancer we studied families with an inherited predisposition to kidney cancer. Families in which 2 or more individuals had kidney cancer underwent a comprehensive evaluation to determine whether they were affected with a hereditary form of renal carcinoma. Genetic linkage analysis was performed to identify the gene for inherited forms of renal carcinoma.

Results: The gene for the inherited form of clear cell renal carcinoma associated with von Hippel-Lindau gene was identified. This gene has been found to be a tumor suppressor gene. A new form of inherited renal carcinoma, hereditary papillary renal carcinoma, was identified. The gene for this condition was identified and found to be the proto-oncogene c-Met. A previously unidentified form of familial renal oncocytoma was found. A familial form of chromophobe renal carcinoma and oncocytoma associated with Birt Hogg Dubé syndrome was found. The gene for this condition was localized on the short arm of chromosome 17 and it has been identified. We studied families with cutaneous leiomyomas, uterine leiomyomas and papillary renal carcinoma. We identified mutations in the fumarate hydratase gene in patients affected with this disorder, namely hereditary leiomyoma renal cell carcinoma.

Conclusions: Kidney cancer used to be considered a single disease. It is now known that there are a number of different types of cancers of the kidney with different histological patterns and different clinical courses that appear to respond differently to therapy. These different types of kidney cancer are caused by different genes, ie they each have a distinct genetic basis. Understanding the molecular pathways of these cancer genes should provide insight into their varying clinical courses and responses to treatment as well as provide the foundation for the development of disease specific molecular therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000096060.92397.edDOI Listing
December 2003

Surgical management of lumbosacral nerve root hemangioblastomas in von Hippel-Lindau syndrome.

J Neurosurg 2003 Jul;99(1 Suppl):64-9

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.

Object: Hemangioblastomas in the lumbosacral region are rare, and the authors of prior reports have not defined the surgical management, histopathological features, or outcome in a group of patients after resection of these tumors. To identify features that will help guide the operative and clinical management of these lesions, the authors reviewed data obtained in a series of patients with von Hippel-Lindau syndrome who underwent resection of lumbosacral nerve root hemangioblastomas.

Methods: Six consecutive patients (three men and three women; mean age at surgery 39 years [range 31-48 years]) who underwent operations for resection of lumbosacral nerve root hemangioblastomas were included in this study. The mean follow-up period was 23 months (range 6-45 months). Data derived from examination, hospital charts, operative findings, histopathological analysis, and magnetic resonance imaging were used to analyze surgical management and clinical outcome. The resected tumors were located in the lumbar (five cases) or sacral (one case) regions; the mean tumor size was 2728 mm3 (range 80-15,022 mm3). Consistent with central nervous system (CNS) regional variation of space available to accommodate the neural compressive effect of the hemangioblastoma size, the mean tumor volume (2728 mm3) of these symptomatic lesions was much larger than that of symptomatic hemangioblastomas resected in the other regions of the CNS. Histopathological examination showed infiltration of the associated nerve root by the hemangioblastoma in each case. In five of the six patients complete resection was achieved, and in one patient intradural exploration of two hemangioblastomas was performed, but resection was not achieved because of motor root involvement. In all cases involving complete resections the patients experienced symptomatic improvement.

Conclusions: Lumbosacral nerve root hemangioblastomas can be safely removed in most patients with von Hippel-Lindau syndrome. Generally, hemangioblastomas of the lumbosacral nerve roots should be resected when they become symptomatic. Because these neoplasms appear to originate from the nerve root, it is necessary to sacrifice the nerve root from which the hemangioblastoma originates to achieve complete resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/spi.2003.99.1.0064DOI Listing
July 2003

Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results.

J Clin Endocrinol Metab 2003 Jun;88(6):2656-66

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true- from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true- from false-positive results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2002-030005DOI Listing
June 2003

Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor.

Proc Natl Acad Sci U S A 2003 Jun 30;100(12):6958-63. Epub 2003 May 30.

Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.

To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression "profile" from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1131754100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165812PMC
June 2003

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Am J Hum Genet 2003 Jul 22;73(1):95-106. Epub 2003 May 22.

Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180594PMC
http://dx.doi.org/10.1086/376435DOI Listing
July 2003

Surgical management of multi-organ visceral tumors in patients with von Hippel-Lindau disease: a single stage approach.

J Urol 2003 Mar;169(3):895-8

Urological Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA.

Purpose: We assessed surgical feasibility of a 1-stage multi-organ approach for multiple visceral tumors in patients with von Hippel-Lindau disease.

Materials And Methods: A total of 14 men and 15 women with von Hippel-Lindau disease underwent simultaneous multi-organ surgery for multiple adrenal, renal and pancreatic tumors at the National Cancer Institute between 1988 and 2001. Perioperative and followup data were analyzed retrospectively. The Mann-Whitney U test was used for statistical analysis.

Results: Surgery involving 2 or more organs (mean 2.4 procedures per patient, range 2 to 4) was performed in all patients and concurrent pancreatic operations were performed in 12 (41%). Overall a combined 71 procedures, were performed including 4 cases (13%) treated laparoscopically. Mean +/- SD operative time and estimated blood loss were 464 +/- 142 minutes (range 206 to 830) and 2,798 +/- 4,285 cc (300 to 20,000), respectively. In 16 patients (55%) blood transfusion was administered intraoperatively. At a median followup of 21 months (range 5 to 151) renal tumors recurred in 8 patients (28%), requiring further kidney operations, but no patient had pancreatic or adrenal recurrence. The overall complication rate was 38%, and there was no operative mortality.

Conclusions: A single stage surgical approach for multi-organ visceral tumors is a viable option for patients with von Hippel-Lindau disease. With careful patient selection and surgical planning combined procedures can be safely performed in 1 operative setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000049518.15260.1fDOI Listing
March 2003

Hereditary renal cancers.

Radiology 2003 Jan;226(1):33-46

Imaging Sciences Program, National Institutes of Health, Bethesda, MD 20892-1182, USA.

Hereditary renal cancer syndromes can lead to multiple bilateral kidney tumors that occur at a younger age than do nonhereditary renal cancers. Imaging plays an important role in the diagnosis and management of these syndromes. During the past decade, several new hereditary renal syndromes have been discovered but are not yet widely known. Whereas previously, the list of hereditary renal cancers in adults included von Hippel-Lindau disease and a rare form of chromosomal translocation, the list now includes the following syndromes: tuberous sclerosis, hereditary papillary renal cancer, Birt-Hogg-Dubé syndrome, hereditary leiomyoma renal cell carcinoma, familial renal oncocytoma, hereditary nonpolyposis colon cancer, and medullary carcinoma of the kidney. In addition, a number of newly described but poorly understood syndromes are under investigation. Even at this early stage, it is clear that elucidation of the underlying genetic mutations that cause hereditary renal cancer syndromes will have profound implications for understanding the origins of nonhereditary renal tumors. These studies will likely culminate in a better understanding of the causes of renal cancer, its prevention, and, ultimately, its cure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2261011296DOI Listing
January 2003

A phase I study of intravesical suramin for the treatment of superficial transitional cell carcinoma of the bladder.

J Urol 2003 Jan;169(1):357-60

Urologic Oncology Therapeutic Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA.

Purpose: Suramin is a polysulfonated naphthylurea that inhibits proliferation and DNA synthesis of transitional cell carcinoma cell lines. Its large molecular size and negative charge inhibit bladder absorption, making suramin an excellent candidate for intravesical chemotherapy. Intravesical suramin was evaluated in a phase I study to define dose limiting toxicity and systemic absorption, determine a starting dose and regimen for phase II studies and provide a preliminary assessment of in vivo antitumor activity.

Materials And Methods: Intravesical suramin treatment was administered in 9 patients with histologically identified transitional cell carcinoma (Tcis, Ta or T1) in whom at least 1 course of standard intravesical chemotherapy (bacillus Calmette-Guerin, thiotepa or mitomycin C) had failed. Suramin was administered once weekly for 6 weeks. Patients were treated in groups of 3 using a 60 cc volume and intrapatient dose escalation schedule. Suramin doses of 0.3 to 614.4 mg./ml. were administered intravesically. The last group was treated with the same weekly dose for 6 weeks.

Results: The 9 patients underwent 54 treatments with suramin. Plasma suramin concentration after treatment was 1.9 to 38.0 microg./ml. and was not related to treatment dose. The dose escalation phase was limited by the solubility of suramin in solution. Complications included self-limited bladder spasms (less than 24 hours) in 4 of 54 treatments (7%) and new or worsening vesicoureteral reflux in 3 ureters (17%). Another patient who was treated after the Foley balloon was inflated in the urethra experienced bladder spasms, skin flushing and fever (39C). Mean bladder capacity before and after treatment was 600 and 540 ml., respectively. At followup 7 patients had stage Ta tumors and 2 had carcinoma in situ.

Conclusions: An intravesical suramin dose of 153 mg./ml was defined as a safe treatment parameter with acceptable plasma concentrations and minimal side effects. Phase II studies are needed to assess the antitumor activity of suramin in patients with transitional cell carcinoma of the bladder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ju.0000032745.90528.dcDOI Listing
January 2003
-->