Biomedical subjects

W Marston Linehan

Publications and source records attributed to W Marston Linehan.

101 records · Page 6Linked to original sources

PubMed2002

Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.

Amino Acid Sequence↗

PubMed2002

Post-analysis follow-up and validation of microarray experiments.

Measurement of gene-expression profiles using microarray technology is becoming increasingly popular among the biomedical research community. Although there has been great progress in this field, investigators are still confronted with a difficult question after completing their experiments: how to validate the large data sets that are generated? This review summarizes current approaches to verifying global expression results, discusses the caveats that must be considered, and describes some methods that are being developed to address outstanding problems.

Animals↗

PubMed2002

Specimen morcellation after laparoscopic radical nephrectomy: confirmation of histologic diagnosis using needle biopsy.

BACKGROUND AND PURPOSE: Laparoscopic radical nephrectomy (LRN) is being increasingly offered for the management of renal-cell carcinoma (RCC). Specimen removal may be performed through a small or hand-port incision or by specimen morcellation. Limited studies exist addressing the accuracy of histopathologic diagnosis in morcellated renal tumors. Because of concerns about the lack of a diagnosis secondary to the morcellation process, we performed premorcellation needle biopsies to obtain nondisrupted tissue for pathologic analysis. Herein, we compare the histopathologic diagnosis achieved via needle biopsy prior to morcellation with that of the final specimen. PATIENTS AND METHODS: Following successful laparoscopic resection, specimens were entrapped in a Lapsac. Needle biopsies were performed manually through the mouth of the Lapsac, and morcellation was then done in some patients using manual and mechanical methods. The histopathologic diagnoses in the needle biopsy specimens and the morcellated material were compared. RESULTS: Laparoscopic radical nephrectomy with specimen morcellation was performed in 15 patients. Nine patients had premorcellation needle biopsies. Eight of these biopsies had sufficient tissue for diagnosis of RCC. This finding correlated with final diagnosis from the morcellated material. Perinephric fat invasion was identified in three morcellated specimens. CONCLUSIONS: Needle biopsy prior to specimen morcellation confirmed the histologic diagnosis of the morcellated specimen. This finding suggests that such histopathology material is adequate for diagnosis and may make premorcellation needle biopsy redundant.

Biopsy, Needle↗

PubMed2002

Renal tumors in the Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant genodermatosis characterized by the development of small dome-shaped papules on the face, neck, and upper trunk (fibrofolliculomas). In addition to these benign hair follicle tumors, BHD confers an increased risk of renal neoplasia and spontaneous pneumothorax. To date, there has been no systematic pathologic analysis of the renal tumors associated with this syndrome. We reviewed 130 solid renal tumors resected from 30 patients with BHD in 19 different families. Preoperative computed tomography scans demonstrated a mean of 5.3 tumors per patient (range 1-28 tumors), the largest tumors averaging 5.7 cm in diameter (+/- 3.4 cm, range 1.2-15 cm). Multiple and bilateral tumors were noted at an early age (mean 50.7 years). The resected tumors consisted predominantly of chromophobe renal cell carcinomas (44 of 130, 34%) or of hybrid oncocytic neoplasms that had areas reminiscent of chromophobe renal cell carcinoma and oncocytoma (65 of 130, 50%). Twelve clear cell (conventional) renal carcinomas (12 of 130, 9%) were diagnosed in nine patients. These tumors were on average larger (4.7 +/- 4.2 cm) than the chromophobe (3.0 +/- 2.5 cm) and hybrid tumors (2.2 +/- 2.4 cm). Microscopic oncocytosis was found in the renal parenchyma of most patients, including the parenchyma of five patients with evidence of clear cell renal cell carcinoma. Our findings suggest that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear cell renal cell carcinomas in patients with BHD syndrome. Recognition by the pathologist of the unusual renal tumors associated with BHD may assist in the clinical diagnosis of the syndrome.

Adenocarcinoma↗

PubMed2002

Neuroendocrine tumors of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison.

PURPOSE: To demonstrate the imaging characteristics of neuroendocrine tumors (NETs) of the pancreas in patients with von Hippel-Lindau (VHL) disease to establish diagnostic criteria. MATERIALS AND METHODS: Twenty-five patients with VHL disease and 29 surgically confirmed pancreatic NETs were included. Screening computed tomographic (CT) and/or magnetic resonance (MR) imaging findings were reviewed, and tumor number, diameter, growth rates (doubling time), location, presence of metastatic disease, and attenuation or enhancement properties were determined. RESULTS: Eighteen of 29 (62%) pancreatic NETs were smaller than 3.0 cm in diameter and enhanced homogeneously on contrast material-enhanced CT and MR images. No tumor smaller than 3.0 cm metastasized. Tumors 3.0 cm or larger (11 [38%] of 29) more often enhanced heterogeneously, and two of 11 were associated with hepatic metastases. Smaller (<3.0 cm) tumors displayed longer mean doubling times (mean, 927 vs 351 days) than did larger (> or =3.0 cm) tumors; however, there was considerable overlap. Fifteen (52%) tumors were located in the pancreatic head; eight (28%), in the tail; and six (21%), in the body. Ten (40%) patients with pancreatic NETs had associated pheochromocytomas, and 22 (88%) had no or mild pancreatic cystic disease, which is substantially more than the general population of patients with VHL disease. CONCLUSION: Pancreatic NETs in VHL have characteristic features at CT and MR imaging: Most are small, located in the pancreatic head, and enhance homogeneously. Tumors larger than 3.0 cm are prone to metastasize and enhance heterogeneously.

Adult↗

PubMed2002

Pheochromocytoma in von hippel-lindau disease: distinct histopathologic phenotype compared to pheochromocytoma in multiple endocrine neoplasia type 2.

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel- Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL pheochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas.

Adrenal Gland Neoplasms↗

PubMed2002

National Cancer Institute intramural approach to advanced prostate cancer.

Adenocarcinoma of the prostate is the most common cancer diagnosed in men in the United States, with approximately 189,000 new cases estimated to be diagnosed in 2002. It is believed that men with this disease pass through a series of clinical states. In the intramural program of the National Cancer Institute, we have designed clinical trials that have addressed each disease state. In addition to clinical endpoints, each trial also encompasses molecular or immunologic endpoints in an attempt to determine if our therapy is acting on its presumed target. In patients with localized disease, we are evaluating cancer vaccines in combination with radiation therapy as well as comparing this vaccine against second-line hormonal therapy in patients with rising serum prostate-specific antigen (PSA) but no radiographically measurable disease. We are also evaluating the ability of the antiangiogenesis agent thalidomide to prolong the rest period in patients with a biochemical recurrence (stage D0) that are receiving intermittent hormonal therapy. In patients with metastatic prostate cancer, we are evaluating the addition of the bisphosphonate alendronate when added to ketoconazole for impact on matrix metalloproteinase (MMP)-2 and MMP-9 as well as traditional clinical endpoints. In addition, we have 3 ongoing trials involving the chemotherapeutic agent docetaxel. One trial is examining the combination of thalidomide with docetaxel. The other 2 trials are exploring the PSA vaccine with docetaxel and the combination of docetaxel with ketoconazole. As we obtain information from these ongoing studies, we will be able to take this information and integrate it in the development of newer and more successful treatment regimens as well as look for novel agents that may help in the fight against this disease.

Adenocarcinoma↗

PubMed2002

Percutaneous radio frequency ablation of small renal tumors: initial results.

PURPOSE: Thermal tissue ablation with radio frequency energy is an experimental treatment of renal tumor. We report early results of an ongoing trial of percutaneous radio frequency ablation for small renal tumors. MATERIALS AND METHODS: Patients with percutaneously accessible renal tumors were evaluated for radio frequency ablation. Tumors were solid on computerized tomography (CT), 3 cm. or less in diameter and enlarging during at least 1 year. Ablation was performed at the Interventional Radiology suite under ultrasound and/or CT guidance. A 50 W., 460 kHz. electrosurgical generator delivered radio frequency energy via a percutaneously placed 15 gauge coaxial probe. At least 2, 10 to 12-minute ablation cycles were applied to each lesion. Patients were observed overnight before discharge from hospital and reevaluated 2 months later. RESULTS: A total of 24 ablations were performed in 21 patients with renal tumor, including solid von Hippel-Lindau clear cell tumor in 19 and hereditary papillary renal cancer 2. Most (22 of 24) procedures were performed with patients under conscious sedation. At 2 months postoperatively mean tumor diameter plus or minus standard deviation decreased from 2.4 +/- 0.4 to 2.0 +/- 0.5 cm. (p = 0.001), and a majority of tumors (19 of 24, 79%) ceased to be enhanced on contrast CT. Mean serum creatinine plus or minus standard deviation was unchanged during this interval (1.0 +/- 0.2 mg./dl.). No major and 4 minor complications were encountered, including 2 episodes each of transient psoas pain and flank skin numbness. CONCLUSIONS: Percutaneous radio frequency ablation of small renal tumor is well tolerated and minimally invasive. It will remain experimental until procedural and imaging parameters that correlate with tumor destruction are validated.

Adult↗

PubMed2002

Intentional resection of the diaphragm during cytoreductive laparoscopic radical nephrectomy.

PURPOSE: Laparoscopic radical nephrectomy is being performed more commonly. To our knowledge intentional resection of the diaphragm during laparoscopic radical nephrectomy for large renal tumors has not yet been described. We detail the laparoscopic management of diaphragmatic resection. MATERIALS AND METHODS: From March 1996 to February 2001, 36 patients underwent cytoreductive laparoscopic radical nephrectomy at our institution in preparation for systemic immunotherapy. Charts and operative tapes were reviewed and cases were identified in which diaphragmatic resection was performed for locally invasive tumors. RESULTS: In 3 patients a portion of the diaphragm was dissected via laparoscopy during debulking nephrectomy. All patients had renal cell carcinoma with documented metastatic disease. The diaphragm was repaired laparoscopically using intracorporeal suturing techniques in 2 of the 3 patients and a chest tube was placed in all 3. Transient systolic hypotension and hypercarbia in 1 case resolved with manual ventilation. The chest tube was removed on postoperative days 2 to 4. There were no complications and no ipsilateral pleural metastasis was identified at an average of 6 weeks (range 2 to 23) of followup. CONCLUSIONS: A portion of the diaphragm may be intentionally resected during laparoscopic radical nephrectomy. This maneuver may be successfully managed without conversion to an open procedure. In cases of a large diaphragmatic defect or the potential for coagulopathy postoperatively a chest tube should be inserted. Potential invasion of the diaphragm by large tumors should not be considered a contraindication to cytoreductive laparoscopic radical nephrectomy.

Adult↗

PubMed2002

Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.

The Birt-Hogg-Dubé syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dubé syndrome, in 13 Birt-Hogg-Dubé haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and approximately 9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dubé syndrome. The Birt-Hogg-Dubé syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.

Adult↗

PubMed2001

Studying cancer families to identify kidney cancer genes.

We studied families with multiple members affected with renal cancer to delineate clinically distinct forms of inherited renal cancer, and to identify and characterize the genes responsible for these disorders. Today, cancer geneticists recognize seven clinically distinct, inherited forms of epithelial renal cancer; genes responsible for five inherited predispositions have been found. Positional cloning efforts for one kidney cancer gene are nearing completion. These discoveries will provide diagnostic tests for these diseases, a foundation for studies of the relationship between genotype and phenotype, and a basis for studies of the pathophysiology of the diverse types of epithelial renal cancer.

Animals↗