McClellan Walther - Academia.edu (original) (raw)

Papers by McClellan Walther

PubMed, Dec 1, 1996

Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal le... more Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC.

The Journal of Urology, Oct 1, 1999

Purpose: We characterize the genetic abnormalities associated with pathological subtypes of renal... more Purpose: We characterize the genetic abnormalities associated with pathological subtypes of renal tumors, which may help diagnosis or prognostication. Materials and Methods: A comprehensive literature review of genetic abnormalities associated with different renal tumor subtypes was performed. Results: Studies of sporadic and hereditary forms suggest that abnormalities in the von Hippel-Lindau and met genes are the earliest changes in conventional (clear cell) and papillary basophilic renal cancers, respectively. Renal oncocytoma and chromophobe carcinoma have common genetic abnormalities, suggesting a relationship. A similar finding has been observed between papillary adenoma and papillary basophilic renal cancer. Conclusions: These findings suggest that molecular diagnostic testing will help determine histopathological diagnosis, identify tumor types with similar genetic abnormalities suggesting a common origin and indicate potential prognostic markers for future study.

The Journal of Urology, Dec 1, 1995

We sought to describe the earliest renal lesions in patients with von Hippel-Lindau disease to ga... more We sought to describe the earliest renal lesions in patients with von Hippel-Lindau disease to gain insight into the genesis of renal neoplasms in this condition. Grossly normal renal parenchyma from von Hippel-Lindau disease patients was examined microscopically and compared to findings in similar tissues obtained from patients with sporadic renal cancer and from autopsy subjects with no renal disease. Microscopic renal cystic and solid neoplasms containing only clear cell cytological features were found in patients with von Hippel-Lindau disease. Benign cysts with clear cell cytological features were found only in patients with von Hippel-Lindau disease. Benign cysts lined by cuboidal cells with eosinophilic cytoplasm, similar to renal tubular cells, were present only in patients with renal cancer. The extrapolated number of clear cell lesions in an average kidney with von Hippel-Lindau disease was estimated as 1,100 cysts (benign or atypical) with clear cell lining and 600 clear cell neoplasms. These findings support the hypothesis that abnormalities in the von Hippel-Lindau gene in a kidney results in the cytological cell type of clear cell renal cancer as the initial product of cellular transformation.

Humana Press eBooks, Nov 15, 2003

ABSTRACT

The Journal of Urology, Apr 1, 1999

The Journal of Urology, Feb 1, 2000

We describe the earliest renal lesions associated with hereditary papillary renal cancer and esti... more We describe the earliest renal lesions associated with hereditary papillary renal cancer and estimate the prevalence of microscopic papillary renal tumors. Grossly normal tissue was obtained from 12 kidneys during renal surgery in 9 patients with hereditary papillary renal cancer. Tissue was examined microscopically and findings were compared to those previously reported to be associated with von Hippel-Lindau disease and sporadic renal cell carcinoma. A total of 92 microscopic papillary renal cell carcinoma lesions were identified on 46 of 88 slides (53%). No other lesions were identified. All tumors were solid and displayed the basophilic papillary histology characteristic of hereditary papillary renal cancer. Extrapolation of the data predicted the prevalence of 1,100 to 3,400 microscopic papillary tumors in a single kidney in a patient with hereditary papillary renal cancer. The basophilic papillary histology characteristic of clinically apparent renal tumors in patients with hereditary papillary renal cancer also characterizes the multiple microscopic lesions seen in the kidneys. These findings suggest that the earliest renal tumor in patients with an activating hereditary mutation of the met gene is papillary basophilic renal cancer. The large number of microscopic tumors in patients with hereditary papillary renal cancer was comparable to or greater than that seen in those with von Hippel-Lindau disease.

The Journal of Urology, Apr 1, 2004

RESULTS: Baseline fluorescence of 49 selected NRK52E is shown in the top panel below; fluorescenc... more RESULTS: Baseline fluorescence of 49 selected NRK52E is shown in the top panel below; fluorescence of the identical cells increased after 12 minutes of pressurization, as shown in the bottom panel. Mean per cell fluorescent intensities were 130 :t 38 random fluorescent units (RFU) prior to pressurization, and 176 :t 41 RFU after pressurization (p<.OOOI, paired t-test). All cells demonstrated elevated fluorescence in response to pressurization. The mean increase in per cell average intensity was 42%. Fluorescence of non-pressurized cells did not change over time. Cells incubated with L-NAME showed markedly attenuated fluorescence. N0213 in supernatants derived from NRK52E cells pressurized for 60 minutes was 2.9 uM, versus 0.7 uM in control supernatant. iNOS mRNA band density from HKC-8 cells pressurized for 60 minutes was markedly increased compared to non-pressurized controls. CONCLUSIONS: This study represents the first characterization of NO production in the kidney in response to pressure. Within minutes of exposure to elevated pressure, renal epithelial cells, of both human and rats, increased NO production and elevated expression of iNOS mRNA. These results demonstrate that pressure is a direct stimulus of NO synthesis in renal tubules, which could have profound consequences to the renal response to UO.

The Journal of Urology, Oct 1, 2002

Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic par... more Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic partial nephrectomy is a technically feasible but challenging operation. We describe the use of intraoperative ultrasound to facilitate laparoscopic partial nephrectomy in a population with a hereditary predisposition to multifocal pheochromocytoma. All patients underwent a history, physical examination, serum and urine catecholamine determinations, abdominal computerized tomography-magnetic resonance imaging and metaiodobenzylguanidine scan. The adrenal gland was exposed using a standard 3 or 4 port approach. Intraoperative ultrasound was performed using a 7.5 MHz. 10 mm. transducer placed through a 12 mm. port. After imaging the whole gland and adjacent structures partial adrenalectomy was performed based on intraoperative ultrasound images using a harmonic scalpel or alternatively using a cut and sew technique that provided a 5 mm. margin. Tumors were removed intact and sent for pathological examination. Since 1998, 11 patients have undergone laparoscopic partial adrenalectomy. Intraoperative ultrasound was performed in 7 patients with suspected multiple adrenal masses, including 4 and 3 who underwent unilateral and bilateral laparoscopic partial nephrectomy, respectively. Six of the 7 patients had germline defects in the von Hippel-Lindau disease gene and 1 had no identifiable alteration in the von Hippel-Lindau disease or RET gene. A solitary tumor was identified in 3 cases and multiple lesions were noted in 4. In 1 case intraoperative ultrasound localized a tumor not identified on preoperative imaging that was not readily visible via laparoscopy. Intraoperative ultrasound guided surgical dissection in all cases and identified an extra-adrenal mass in 1 patient with bilateral adrenal masses. There were no complications due to intraoperative ultrasound and no conversions to open surgery. Mean operative time was 335 minutes and mean estimated blood loss was 179 ml. Histological study demonstrated pheochromocytoma in 14 lesions and the extra-adrenal mass proved to be a splenic rest. At short-term followup no recurrences have been noted. All patients retained sufficient adrenal cortical function to avoid steroid replacement therapy. Laparoscopic ultrasound differentiates normal adrenal parenchyma from adrenal tumors and facilitates laparoscopic partial adrenalectomy.

The Journal of Urology, Mar 1, 1995

The Journal of Urology, Jul 1, 1989

To the Editor. I fully support the suggestion that ultrasound be used as the initial diagnostic t... more To the Editor. I fully support the suggestion that ultrasound be used as the initial diagnostic test in patients with asymptomatic microscopic hematuria. However, as well as minimizing cost and morbidity I would propose that it has greater accuracy to detect renal cell carcinoma and contest the assumption that ultrasound would miss 5 of 100 patients with renal carcinoma. I refer the reader to a study of 253 patients that investigated the use of real-time ultrasound as the primary imaging method of renal disease. 1 Compared to excretory urography ultrasound proved to be more reliable in the diagnosis of renal tumors and renal cysts.

The Journal of Urology, Jul 1, 1993

The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expan... more The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expanding. Among patients who achieve significant responses to these regimens the subsequent development of isolated recurrences raises difficult management questions. We report 2 unusual cases of isolated recurrence in the remaining kidney following a sustained, complete response to interleukin-2 based adoptive immunotherapy. Both patients were treated with interleukin-2 based therapy following surgical resection of the primary renal tumor. The disease course of each patient is described and the literature is reviewed. Both patients were free of disease after relatively shortterm followup. Surgery for patients with limited recurrence of renal cell carcinoma following an objective response to immunotherapy may, in select cases, be a reasonable treatment alternative.

Cancer, Feb 1, 1993

Suramin is an anthelmintic drug that recently has been shown to have clinical efficacy in the tre... more Suramin is an anthelmintic drug that recently has been shown to have clinical efficacy in the treatment of patients with some advanced malignancies, including prostate carcinoma. The current study was done to assess the effect of suramin at clinically relevant doses on the growth in culture of a human prostatic carcinoma cell line, PC-3. The antiproliferative effect of varying doses of suramin on PC-3 was assessed. Northern blot analysis was done to assess the potential changes in genetic expression at different times after the initiation of treatment. Suramin inhibited the proliferation of PC-3 in a dose-related manner (concentration range, 30-300 microM). Compared with fetal calf serum 2%, when the cells were grown in fetal calf serum 10%, higher concentrations of suramin were required to inhibit tritiated thymidine incorporation. When grown in RPMI without supplement, the PC-3 cell number remained the same. When 100 microM suramin was included, the cell number decreased. By contrast, when RPMI was supplemented with insulin, transferrin, and selenium (ITS), PC-3 grew well. The inhibition of the proliferation of PC-3 cells by suramin was decreased when ITS were added to the cells grown under serum-free conditions. These results were consistent with the hypothesis that in vitro inhibition of the growth of PC-3 cells by suramin may be caused, at least in part, by the growth factor antagonism of the drug. In fetal calf serum 2%, the suramin inhibition was reversible after 3 days. If the treatment was extended to 6 days, however, the PC-3 cells were unable to recover. Cell-cycle analysis revealed that, after 6 days of treatment, there was a decrease in the number of cells in G1 that corresponded with an increased number of cells in G2/M. This suggested that critical antineoplastic events were occurring during this time. Molecular analysis did not detect any altered expression of actin, transforming growth factors alpha or beta, or histone compared with untreated control samples.

The Journal of Urology, Apr 1, 1987

Cystitis cystica was studied with the aid of electron and immunofluorescence microscopy. By elect... more Cystitis cystica was studied with the aid of electron and immunofluorescence microscopy. By electron microscopy, the epithelium demonstrated morphologic features suggestive of an active metabolism. Secretory-type granules were seen in the cytoplasm just beneath the luminal membrane of surface columnar cells. Microvilli of the plasma membrane also were seen at the luminal surface. Rough endoplasmic reticulum and Golgi apparatuses were present. The cells were rich in mitochondria. By immunofluorescence microscopy, IgA, secretory piece and IgM were localized in the epithelial cells, especially at the luminal surfaces. IgG was occasionally found. These findings contrast markedly with the transitional cells and their relatively scanty content of secretory-type organelles. In addition, they may explain the large amounts of IgA in the urine of patients with cystitis cystica.

Urology, Aug 1, 1997

Objectives. A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transit... more Objectives. A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. Methods. Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01% intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. Results. Twenty patients underwent 2 1 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. Conclusions. An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.

Molecular and Cellular Biology of Prostate Cancer, 1991

Both prostate as well as kidney cancer are common malignancies in the United States. It is projec... more Both prostate as well as kidney cancer are common malignancies in the United States. It is projected that in 1990, prostate carcinoma will be the most common cancer in men and will result in 20,000 deaths. Although hormonal manipulation is the mainstay of therapy of patients with advanced prostate carcinoma, there is no currently available effective therapy for patients with this malignancy. Over 20,000 patients develop kidney cancer per year in the United States, and there are over 9,500 deaths from this cancer. Recent studies have reported approximately a 95%, 5 year survival for patients with Stage T1, No renal cell carcinoma and a 92% survival for patients with Stage T2, No disease (1,2). While the five year survival for patients with N + (local nodal involvement) renal cell carcinoma is 20% (3,4), patients with distant renal cell carcinoma metastases have only a 20% five year survival (5).

The Journal of Urology, 1996

American Journal of Pathology, Jul 1, 1998

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been rep... more Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported , their pathological features have not been characterized. In addition , it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients , we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based singlestrand conformational polymorphism analysis. Morphologically , the tumors were characterized by solid, trabecular , and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide , somatostatin , insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.

Urology, Aug 1, 1997

Objectives. Tumors are thought to metastasize by a process involving tumor cell attachment to ext... more Objectives. Tumors are thought to metastasize by a process involving tumor cell attachment to extracellular matrix, degradation of matrix components by tumor-associated proteases, and cellular movement into the area modified by protease activity. Type IV collagen comprises the major element tumor cells must degrade to gain access to the rest of the body. Renal cancer cell line progelatinase A (E.C. 3.4.24.24; 72-kDa type IV collagenase; MMP-2) mRNA expression was correlated with patient survival. Methods. Total cellular mRNA was extracted from tumor cell lines derived from patients with metastatic renal cell carcinoma. The results of the densitometric analysis of Northern blots were correlated with patient survival. Formalin-fixed, paraffin-embedded tissue sections of primary renal cancers were examined for immunohistochemical expression of MMP-2. Results. Cell lines established from 23 primary renal tumors and six metastatic sites in 26 patients with metastatic renal carcinoma were studied. Variable expression of progelatinase A, relative to A2058 melanoma cells (mean 2 SEM, 0.60 I+_ 0.2 1; median, 0.082; range, 0 to 4.78), was found. There was a significant inverse association between patient survival and the log of the MMP-2 expression (P = 0.045 by the Cox proportional-hazards model). Using a cutoff value of 0.10, the closest round number to the median expression of MMP-2, a significant difference between survival of patients with lower and higher MMP-2 expression in their primary renal cell line was found (P = 0.0054). Cell lines with low, intermediate, and high expression of MMP-2 mRNA all had primary tumors with high tissue immunohistochemical expression of MMP-2. Conclusions. These studies demonstrate an inverse relationship between renal cancer cell line MMP-2 mRNA expression and patient survival. lmmunohistochemical studies of the primary tumors from which the cell lines were derived uniformly showed high MMP-2 expression. Previous work suggests local renal factors upregulate cellular expression of MMP-2 in the primary tumor, and are not active at extrarenal sites. UROLOGY 50: 295-301, 1997. P rimary renal tumors are thought to metastasize by a process involving tumor cell attachment and penetration of the vascular endothelial cell

The Journal of Urology, Sep 1, 1997

The role of nephrectomy in the management of hypercalcemia in metastatic renal carcinoma is not k... more The role of nephrectomy in the management of hypercalcemia in metastatic renal carcinoma is not known. Hypercalcemia in patients with renal cell carcinoma frequently mimics primary hyperparathyroidism and has been attributed to tumor secretion of parathyroid hormone related protein. We determined the role of cytoreductive surgery in patients with metastatic renal cell carcinoma and hypercalcemia, identified factors that predict patient benefit from surgery, and evaluated the mechanisms of hypercalcemia in these patients. A total of 15 patients with metastatic renal cell carcinoma and hypercalcemia underwent metabolic and laboratory evaluation followed by nephrectomy. Post-operatively they were followed for changes in serum calcium levels. We selected 18 normocalcemic patients with metastatic renal cell carcinoma and 4 normocalcemic patients without renal cancer to serve as control groups for survival and parathyroid hormone related protein expression. A decrease in serum calcium corrected for albumin occurred in 9 of 11 patients at 1 to 4 weeks after nephrectomy and in 7 of 12 patients at 5 to 16 weeks after nephrectomy. Clinical evaluation supported a parathyroid hormone related protein mechanism of hypercalcemia in 5 of 8 patients. Two patients had evidence of local osteolytic hypercalcemia and 1 had prostaglandin mediated hypercalcemia. Nephrectomy temporarily ameliorated hypercalcemia in a subgroup of patients with metastatic renal cancer and hypercalcemia. Parathyroid hormone related protein expression was commonly found to be associated with hypercalcemia. Nonparathyroid hormone related protein mechanisms of hypercalcemia in renal carcinoma may be more common than previously thought.

PubMed, Dec 1, 1996

Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal le... more Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC.

The Journal of Urology, Oct 1, 1999

Purpose: We characterize the genetic abnormalities associated with pathological subtypes of renal... more Purpose: We characterize the genetic abnormalities associated with pathological subtypes of renal tumors, which may help diagnosis or prognostication. Materials and Methods: A comprehensive literature review of genetic abnormalities associated with different renal tumor subtypes was performed. Results: Studies of sporadic and hereditary forms suggest that abnormalities in the von Hippel-Lindau and met genes are the earliest changes in conventional (clear cell) and papillary basophilic renal cancers, respectively. Renal oncocytoma and chromophobe carcinoma have common genetic abnormalities, suggesting a relationship. A similar finding has been observed between papillary adenoma and papillary basophilic renal cancer. Conclusions: These findings suggest that molecular diagnostic testing will help determine histopathological diagnosis, identify tumor types with similar genetic abnormalities suggesting a common origin and indicate potential prognostic markers for future study.

The Journal of Urology, Dec 1, 1995

We sought to describe the earliest renal lesions in patients with von Hippel-Lindau disease to ga... more We sought to describe the earliest renal lesions in patients with von Hippel-Lindau disease to gain insight into the genesis of renal neoplasms in this condition. Grossly normal renal parenchyma from von Hippel-Lindau disease patients was examined microscopically and compared to findings in similar tissues obtained from patients with sporadic renal cancer and from autopsy subjects with no renal disease. Microscopic renal cystic and solid neoplasms containing only clear cell cytological features were found in patients with von Hippel-Lindau disease. Benign cysts with clear cell cytological features were found only in patients with von Hippel-Lindau disease. Benign cysts lined by cuboidal cells with eosinophilic cytoplasm, similar to renal tubular cells, were present only in patients with renal cancer. The extrapolated number of clear cell lesions in an average kidney with von Hippel-Lindau disease was estimated as 1,100 cysts (benign or atypical) with clear cell lining and 600 clear cell neoplasms. These findings support the hypothesis that abnormalities in the von Hippel-Lindau gene in a kidney results in the cytological cell type of clear cell renal cancer as the initial product of cellular transformation.

Humana Press eBooks, Nov 15, 2003

ABSTRACT

The Journal of Urology, Apr 1, 1999

The Journal of Urology, Feb 1, 2000

We describe the earliest renal lesions associated with hereditary papillary renal cancer and esti... more We describe the earliest renal lesions associated with hereditary papillary renal cancer and estimate the prevalence of microscopic papillary renal tumors. Grossly normal tissue was obtained from 12 kidneys during renal surgery in 9 patients with hereditary papillary renal cancer. Tissue was examined microscopically and findings were compared to those previously reported to be associated with von Hippel-Lindau disease and sporadic renal cell carcinoma. A total of 92 microscopic papillary renal cell carcinoma lesions were identified on 46 of 88 slides (53%). No other lesions were identified. All tumors were solid and displayed the basophilic papillary histology characteristic of hereditary papillary renal cancer. Extrapolation of the data predicted the prevalence of 1,100 to 3,400 microscopic papillary tumors in a single kidney in a patient with hereditary papillary renal cancer. The basophilic papillary histology characteristic of clinically apparent renal tumors in patients with hereditary papillary renal cancer also characterizes the multiple microscopic lesions seen in the kidneys. These findings suggest that the earliest renal tumor in patients with an activating hereditary mutation of the met gene is papillary basophilic renal cancer. The large number of microscopic tumors in patients with hereditary papillary renal cancer was comparable to or greater than that seen in those with von Hippel-Lindau disease.

The Journal of Urology, Apr 1, 2004

RESULTS: Baseline fluorescence of 49 selected NRK52E is shown in the top panel below; fluorescenc... more RESULTS: Baseline fluorescence of 49 selected NRK52E is shown in the top panel below; fluorescence of the identical cells increased after 12 minutes of pressurization, as shown in the bottom panel. Mean per cell fluorescent intensities were 130 :t 38 random fluorescent units (RFU) prior to pressurization, and 176 :t 41 RFU after pressurization (p<.OOOI, paired t-test). All cells demonstrated elevated fluorescence in response to pressurization. The mean increase in per cell average intensity was 42%. Fluorescence of non-pressurized cells did not change over time. Cells incubated with L-NAME showed markedly attenuated fluorescence. N0213 in supernatants derived from NRK52E cells pressurized for 60 minutes was 2.9 uM, versus 0.7 uM in control supernatant. iNOS mRNA band density from HKC-8 cells pressurized for 60 minutes was markedly increased compared to non-pressurized controls. CONCLUSIONS: This study represents the first characterization of NO production in the kidney in response to pressure. Within minutes of exposure to elevated pressure, renal epithelial cells, of both human and rats, increased NO production and elevated expression of iNOS mRNA. These results demonstrate that pressure is a direct stimulus of NO synthesis in renal tubules, which could have profound consequences to the renal response to UO.

The Journal of Urology, Oct 1, 2002

Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic par... more Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic partial nephrectomy is a technically feasible but challenging operation. We describe the use of intraoperative ultrasound to facilitate laparoscopic partial nephrectomy in a population with a hereditary predisposition to multifocal pheochromocytoma. All patients underwent a history, physical examination, serum and urine catecholamine determinations, abdominal computerized tomography-magnetic resonance imaging and metaiodobenzylguanidine scan. The adrenal gland was exposed using a standard 3 or 4 port approach. Intraoperative ultrasound was performed using a 7.5 MHz. 10 mm. transducer placed through a 12 mm. port. After imaging the whole gland and adjacent structures partial adrenalectomy was performed based on intraoperative ultrasound images using a harmonic scalpel or alternatively using a cut and sew technique that provided a 5 mm. margin. Tumors were removed intact and sent for pathological examination. Since 1998, 11 patients have undergone laparoscopic partial adrenalectomy. Intraoperative ultrasound was performed in 7 patients with suspected multiple adrenal masses, including 4 and 3 who underwent unilateral and bilateral laparoscopic partial nephrectomy, respectively. Six of the 7 patients had germline defects in the von Hippel-Lindau disease gene and 1 had no identifiable alteration in the von Hippel-Lindau disease or RET gene. A solitary tumor was identified in 3 cases and multiple lesions were noted in 4. In 1 case intraoperative ultrasound localized a tumor not identified on preoperative imaging that was not readily visible via laparoscopy. Intraoperative ultrasound guided surgical dissection in all cases and identified an extra-adrenal mass in 1 patient with bilateral adrenal masses. There were no complications due to intraoperative ultrasound and no conversions to open surgery. Mean operative time was 335 minutes and mean estimated blood loss was 179 ml. Histological study demonstrated pheochromocytoma in 14 lesions and the extra-adrenal mass proved to be a splenic rest. At short-term followup no recurrences have been noted. All patients retained sufficient adrenal cortical function to avoid steroid replacement therapy. Laparoscopic ultrasound differentiates normal adrenal parenchyma from adrenal tumors and facilitates laparoscopic partial adrenalectomy.

The Journal of Urology, Mar 1, 1995

The Journal of Urology, Jul 1, 1989

To the Editor. I fully support the suggestion that ultrasound be used as the initial diagnostic t... more To the Editor. I fully support the suggestion that ultrasound be used as the initial diagnostic test in patients with asymptomatic microscopic hematuria. However, as well as minimizing cost and morbidity I would propose that it has greater accuracy to detect renal cell carcinoma and contest the assumption that ultrasound would miss 5 of 100 patients with renal carcinoma. I refer the reader to a study of 253 patients that investigated the use of real-time ultrasound as the primary imaging method of renal disease. 1 Compared to excretory urography ultrasound proved to be more reliable in the diagnosis of renal tumors and renal cysts.

The Journal of Urology, Jul 1, 1993

The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expan... more The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expanding. Among patients who achieve significant responses to these regimens the subsequent development of isolated recurrences raises difficult management questions. We report 2 unusual cases of isolated recurrence in the remaining kidney following a sustained, complete response to interleukin-2 based adoptive immunotherapy. Both patients were treated with interleukin-2 based therapy following surgical resection of the primary renal tumor. The disease course of each patient is described and the literature is reviewed. Both patients were free of disease after relatively shortterm followup. Surgery for patients with limited recurrence of renal cell carcinoma following an objective response to immunotherapy may, in select cases, be a reasonable treatment alternative.

Cancer, Feb 1, 1993

Suramin is an anthelmintic drug that recently has been shown to have clinical efficacy in the tre... more Suramin is an anthelmintic drug that recently has been shown to have clinical efficacy in the treatment of patients with some advanced malignancies, including prostate carcinoma. The current study was done to assess the effect of suramin at clinically relevant doses on the growth in culture of a human prostatic carcinoma cell line, PC-3. The antiproliferative effect of varying doses of suramin on PC-3 was assessed. Northern blot analysis was done to assess the potential changes in genetic expression at different times after the initiation of treatment. Suramin inhibited the proliferation of PC-3 in a dose-related manner (concentration range, 30-300 microM). Compared with fetal calf serum 2%, when the cells were grown in fetal calf serum 10%, higher concentrations of suramin were required to inhibit tritiated thymidine incorporation. When grown in RPMI without supplement, the PC-3 cell number remained the same. When 100 microM suramin was included, the cell number decreased. By contrast, when RPMI was supplemented with insulin, transferrin, and selenium (ITS), PC-3 grew well. The inhibition of the proliferation of PC-3 cells by suramin was decreased when ITS were added to the cells grown under serum-free conditions. These results were consistent with the hypothesis that in vitro inhibition of the growth of PC-3 cells by suramin may be caused, at least in part, by the growth factor antagonism of the drug. In fetal calf serum 2%, the suramin inhibition was reversible after 3 days. If the treatment was extended to 6 days, however, the PC-3 cells were unable to recover. Cell-cycle analysis revealed that, after 6 days of treatment, there was a decrease in the number of cells in G1 that corresponded with an increased number of cells in G2/M. This suggested that critical antineoplastic events were occurring during this time. Molecular analysis did not detect any altered expression of actin, transforming growth factors alpha or beta, or histone compared with untreated control samples.

The Journal of Urology, Apr 1, 1987

Cystitis cystica was studied with the aid of electron and immunofluorescence microscopy. By elect... more Cystitis cystica was studied with the aid of electron and immunofluorescence microscopy. By electron microscopy, the epithelium demonstrated morphologic features suggestive of an active metabolism. Secretory-type granules were seen in the cytoplasm just beneath the luminal membrane of surface columnar cells. Microvilli of the plasma membrane also were seen at the luminal surface. Rough endoplasmic reticulum and Golgi apparatuses were present. The cells were rich in mitochondria. By immunofluorescence microscopy, IgA, secretory piece and IgM were localized in the epithelial cells, especially at the luminal surfaces. IgG was occasionally found. These findings contrast markedly with the transitional cells and their relatively scanty content of secretory-type organelles. In addition, they may explain the large amounts of IgA in the urine of patients with cystitis cystica.

Urology, Aug 1, 1997

Objectives. A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transit... more Objectives. A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. Methods. Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01% intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. Results. Twenty patients underwent 2 1 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. Conclusions. An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.

Molecular and Cellular Biology of Prostate Cancer, 1991

Both prostate as well as kidney cancer are common malignancies in the United States. It is projec... more Both prostate as well as kidney cancer are common malignancies in the United States. It is projected that in 1990, prostate carcinoma will be the most common cancer in men and will result in 20,000 deaths. Although hormonal manipulation is the mainstay of therapy of patients with advanced prostate carcinoma, there is no currently available effective therapy for patients with this malignancy. Over 20,000 patients develop kidney cancer per year in the United States, and there are over 9,500 deaths from this cancer. Recent studies have reported approximately a 95%, 5 year survival for patients with Stage T1, No renal cell carcinoma and a 92% survival for patients with Stage T2, No disease (1,2). While the five year survival for patients with N + (local nodal involvement) renal cell carcinoma is 20% (3,4), patients with distant renal cell carcinoma metastases have only a 20% five year survival (5).

The Journal of Urology, 1996

American Journal of Pathology, Jul 1, 1998

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been rep... more Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported , their pathological features have not been characterized. In addition , it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients , we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based singlestrand conformational polymorphism analysis. Morphologically , the tumors were characterized by solid, trabecular , and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide , somatostatin , insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.

Urology, Aug 1, 1997

Objectives. Tumors are thought to metastasize by a process involving tumor cell attachment to ext... more Objectives. Tumors are thought to metastasize by a process involving tumor cell attachment to extracellular matrix, degradation of matrix components by tumor-associated proteases, and cellular movement into the area modified by protease activity. Type IV collagen comprises the major element tumor cells must degrade to gain access to the rest of the body. Renal cancer cell line progelatinase A (E.C. 3.4.24.24; 72-kDa type IV collagenase; MMP-2) mRNA expression was correlated with patient survival. Methods. Total cellular mRNA was extracted from tumor cell lines derived from patients with metastatic renal cell carcinoma. The results of the densitometric analysis of Northern blots were correlated with patient survival. Formalin-fixed, paraffin-embedded tissue sections of primary renal cancers were examined for immunohistochemical expression of MMP-2. Results. Cell lines established from 23 primary renal tumors and six metastatic sites in 26 patients with metastatic renal carcinoma were studied. Variable expression of progelatinase A, relative to A2058 melanoma cells (mean 2 SEM, 0.60 I+_ 0.2 1; median, 0.082; range, 0 to 4.78), was found. There was a significant inverse association between patient survival and the log of the MMP-2 expression (P = 0.045 by the Cox proportional-hazards model). Using a cutoff value of 0.10, the closest round number to the median expression of MMP-2, a significant difference between survival of patients with lower and higher MMP-2 expression in their primary renal cell line was found (P = 0.0054). Cell lines with low, intermediate, and high expression of MMP-2 mRNA all had primary tumors with high tissue immunohistochemical expression of MMP-2. Conclusions. These studies demonstrate an inverse relationship between renal cancer cell line MMP-2 mRNA expression and patient survival. lmmunohistochemical studies of the primary tumors from which the cell lines were derived uniformly showed high MMP-2 expression. Previous work suggests local renal factors upregulate cellular expression of MMP-2 in the primary tumor, and are not active at extrarenal sites. UROLOGY 50: 295-301, 1997. P rimary renal tumors are thought to metastasize by a process involving tumor cell attachment and penetration of the vascular endothelial cell

The Journal of Urology, Sep 1, 1997

The role of nephrectomy in the management of hypercalcemia in metastatic renal carcinoma is not k... more The role of nephrectomy in the management of hypercalcemia in metastatic renal carcinoma is not known. Hypercalcemia in patients with renal cell carcinoma frequently mimics primary hyperparathyroidism and has been attributed to tumor secretion of parathyroid hormone related protein. We determined the role of cytoreductive surgery in patients with metastatic renal cell carcinoma and hypercalcemia, identified factors that predict patient benefit from surgery, and evaluated the mechanisms of hypercalcemia in these patients. A total of 15 patients with metastatic renal cell carcinoma and hypercalcemia underwent metabolic and laboratory evaluation followed by nephrectomy. Post-operatively they were followed for changes in serum calcium levels. We selected 18 normocalcemic patients with metastatic renal cell carcinoma and 4 normocalcemic patients without renal cancer to serve as control groups for survival and parathyroid hormone related protein expression. A decrease in serum calcium corrected for albumin occurred in 9 of 11 patients at 1 to 4 weeks after nephrectomy and in 7 of 12 patients at 5 to 16 weeks after nephrectomy. Clinical evaluation supported a parathyroid hormone related protein mechanism of hypercalcemia in 5 of 8 patients. Two patients had evidence of local osteolytic hypercalcemia and 1 had prostaglandin mediated hypercalcemia. Nephrectomy temporarily ameliorated hypercalcemia in a subgroup of patients with metastatic renal cancer and hypercalcemia. Parathyroid hormone related protein expression was commonly found to be associated with hypercalcemia. Nonparathyroid hormone related protein mechanisms of hypercalcemia in renal carcinoma may be more common than previously thought.