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Objective: To assess the potential benefit of treating patients with acute ischemic stroke using intra-arterial methods. Methods: A meta-analysis of published randomized controlled trials that compared standard therapy with intravenous tissue plasminogen activator (IVtPA) for thrombolysis to intra-arterial therapies in patients with acute stroke was performed. All studies reported were analyzed as one group and studies documenting patients with large vessel obstruction were analyzed as a second group. The standardized mean difference (SMD) and the odds ratio (OR) of the dichotomized outcomes of Modified Rankin Scale (mRS) of these trials was calculated. Results: Nine trials were identified with 2,711 patients treated. Meta-analysis of all studies, with and without large vessel obstruction documented, showed a significant benefit with intra-arterial therapy (SMD: 0.22 + 0.041; P=0.003). The dichotomized outcomes of mRS of these trials showed significant improvement (OR: 1.66 -2.43 in four of the five treatment arm groups examined). Meta-analysis of all publications with large vessel obstruction documented as an entry criteria showed a greater significant benefit with intra-arterial therapy (SMD: 0.35 + 0.05; P

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.

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.

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.

Pheochromocytomas in von Hippel–Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrine- and epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine- versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2α, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2α in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.

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 2α for ubiquitin-mediated degradation. VHL−/− clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor α. Both hypoxia-inducible factor 1α 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.

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).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.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 P0.0001). 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, P0.0001). 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, P0.0001). 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.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.

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.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.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.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.

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.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.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.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.

Summary von Hippel-Lindau disease is a heritable multisystem cancer syndrome that is associated with a germline mutation of the VHL tumour suppressor gene on the short arm of chromosome 3. This disorder is not rare (about one in 36 000 livebirths) and is inherited as a highly penetrant autosomal dominant trait (ie, with a high individual risk of disease). Affected individuals are at risk of developing various benign and malignant tumours of the central nervous system, kidneys, adrenal glands, pancreas, and reproductive adnexal organs. Because of the complexities associated with management of the various types of tumours in this disease, treatment is multidisciplinary. We present an overview of the clinical aspects, management, and treatment options for von Hippel-Lindau disease.

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

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 administer...

Purpose: Abdominal wall adhesions at laparoscopy may predispose patients to access related injuries and increase the complexity of the procedure. We have observed concern from referring physicians regarding the safety of laparoscopy in patients who previously underwent surgery because of the risk of abdominal adhesions. To assess the risk of adhesions at laparoscopy a retrospective cohort study was performed.Materials and Methods: All patients who underwent a transperitoneal urological laparoscopic procedure in a 6-year period at our institution were included in this study. A chart review was performed to obtain demographic/surgical data and identify preoperative risk factors for adhesions, such as previous abdominal or pelvic surgery, radiation and/or intra-abdominal inflammatory disease. Operative videotapes were reviewed to determine the presence and location of adhesions. Standard statistical analyses were performed.Results: During the study period 127 patients underwent transperitoneal laparo...

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.

Purpose: 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.Materials and Methods: 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 s...

Pheochromocytoma is a rare, surgically correctable cause of hypertension. Modern medical blockade has significantly improved patient survival and morbidity. The last decade has seen the identification of the genes responsible for several hereditary causes of pheochromocytoma. Evaluation of these patients has demonstrated different catecholamine profiles associated with the different syndromes. Genetic testing and new, more sensitive catecholamine tests are allowing better, earlier diagnosis of affected patients. Some patients with small tumors deemed nonfunctional by traditional methods may be safely observed until function is demonstrated. Laparoscopic surgery has supplanted the use of open surgery in the management of these tumors. Adrenocortical-sparing surgery may be performed using laparoscopy in patients with hereditary forms of pheochromocytoma.

Birt-Hogg-Dube (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.

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.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.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.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.

The management of advanced renal cell carcinoma (RCC) continues to evolve. With the advent of laparoscopic radical nephrectomy (LRN), minimally invasive approaches to kidney cancer have developed. Laparoscopic resection of locally advanced RCC yields a similar cancer-control rate with the advantage of decreased morbidity. Although cytoreductive LRN is a technically challenging procedure, it may be completed safely in selected patients. Further prospective study of the role of LRN for advanced RCC is warranted.

Solid tissue tumors traditionally have been treated with systemic chemotherapy, surgical resection, or local radiation therapy. Many tumors, however, remain poorly responsive to these therapeutic modalities and necessitate the use of alternative treatments. Recent technical advancements in radiofrequency thermal ablation may provide one such option for certain cancer patients. Heat has been used clinically for thousands of years dating back to ancient Hindu and Greek healers who used it for hemostasis. In fact, Hippocrates is reported as saying that “those diseases that medicine cannot cure, the knife cures; those which the knife cannot cure, fire cures.”1 More recently, heat has been utilized in the surgical setting as electrocautery to control bleeding and to cut tissue. Percutaneous thermal tissue ablation is performed with radiofrequency current by, in effect, transforming the patient into an electrical circuit with adhesive grounding pads on the thighs or back. A needle with a plastic-insulated shaft is placed into the tumor with imaging guidance, in a fashion similar to a routine percutaneous biopsy. Alternating radiofrequency current agitates ions in the tissue surrounding the needle, creating frictional heat, which denatures and destroys tissue at predictable temperatures, in a relatively predictable volume. Multiple percutaneous image-guided therapies currently are available for thermal ablation of localized solid tumors. Thermal sources for these treatment modalities include high-intensity ultrasound, laser, microwave, and radiofrequency.2,3 Radiofrequency ablation (RFA) is a safe, predictable, and inexpensive option and has emerged as the thermal modality that most easily can create large volumes of tissue necrosis. The predictability of RFA is adequate to limit collateral damage and complications, however, is limited by biologic and anatomic variability of tissue. RFA has been used over many years for the treatment of cardiac conduction abnormalities, trigeminal neuralgia4 and osteoid osteomas.5 In addition, RFA recently has been used in the treatment of neoplasms in the liver,6–14 kidney,15–17 adrenal,18 spleen,19 prostate,20,21 bone and soft tissue,22 lung,23 and breast.24 The ablation of metastatic pheochromocytomas has been described as well.25 However, the most promising and most common clinical application has been for liver tumors. Three RFA systems are 510-K cleared by the Federal Drug Administration (FDA) for soft tissue tumor ablation (Radionics Inc., Burlington, MA; RadioTherapeutics Corp., Mountain View, CA; RITA Medical Systems, Mountain View, CA). Two of these also are cleared by the FDA (510-K) for unresectable liver tumor ablation specifically. Thus, although the technique is in its infancy, it is not an experimental procedure for the liver.

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.

Purpose: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life.Materials and Methods: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calcul...

This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.

Purpose: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dube syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm., then performing parenchymal sparing surgery. We present a 5-year update on our experience.Materials and Methods: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including von Hippel-Lindau disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dube syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205).Results: A total of 50 patien...

We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers.Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but 1 of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map.A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm. to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat.Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery.

von Hippel-Lindau disease (VHL) is an autosomal dominant familial syndrome that predisposes to the formation of tumors in multiple organ systems, including adrenal and extra-adrenal pheochromocytomas. However, fewer than 30% of VHL families develop pheochromocytomas. In recent years, this clinical heterogeneity has been correlated with missense mutations. The VHL patient requires vigilant, lifelong biochemical and radiographic screening for pheochromocytoma. Half of VHL pheochromocytomas present bilaterally, and there is a high incidence of recurrence after surgery. Because of the morbidity of bilateral total adrenalectomy with subsequent steroid replacement therapy, the recent therapeutic trend has been toward observation and minimally invasive adrenal-sparing procedures.

Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1-2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21-22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs. Published 2001 Wiley-Liss, Inc.

Suramin has been shown to have an effect on bone resorption in in vitro models. It is not clear if a similar effect is seen in patients treated with suramin. The clinical effect of suramin treatment on total serum calcium was examined in two groups of patients with hormone-refractory prostate cancer. In all, 28 patients in group 1 were examined within 2 weeks before and 2 weeks after suramin treatment and 72 patients in group 2 were examined within 2 weeks before, during, and after treatment with suramin. In addition, calcium controls spiked with suramin were run in three different commercially available assays for evaluation of the effect of suramin dose on calcium determination. Group 1 patients showed a decrease in serum calcium after treatment with suramin. The mean uncorrected serum calcium level was 2.29 +/- 0.025 mmol/l before treatment and 2.09 +/- 0.025 mmol/l after treatment (P < 0.0001, paired Wilcoxon test). The mean serum calcium value corrected for albumin was 2.33 +/- 0.02 mmol/l before treatment and 2.24 +/- 0.02 mmol/l after treatment (P = 0.0022, paired Wilcoxon test). Group 2 patients also displayed a decrease in serum calcium after treatment with suramin. The mean baseline value was 2.23 mmol/l (median 2.26 mmol/l, range 1.20-2.54 mmol/l). The mean level of serum calcium corrected for albumin as determined at the end of treatment was 2.14 mmol/l (median 2.16 mmol/l, range 0.98 2.46 mmol/l). In all, 48 patients for whom pre- and post-treatment values were available for analysis displayed a median calcium decrease of 0.09 mmol/l (P = 0.0005, Wilcoxon signed-rank test for the null hypothesis of no change). For 68 patients in group 2, data on serial serum calcium measurements during treatment were available for analysis. A projected median decrease in serum calcium of 0.06 mmol/l (range 0.43 to 0.72 mmol/l) over an 8-week interval of suramin therapy was found. Overall, 47 of the 68 slopes were negative (P = 0.0022, Wilcoxon signed-rank test). Nine patients were treated with suramin for less than 6 weeks. These patients' calcium levels were significantly higher than those of 50 patients treated for longer periods (median value 2.24 versus 2.16 mmol/l, P = 0.035, Wilcoxon rank-sum test). No correlation was found between suramin dose and calcium level using the Kodak Ektachem, Hitachi 914, or Synchron Clinical System CX3 method. In conclusion, suramin treatment was consistently associated with decreases in serum calcium in two groups of patients with hormone-refractory cancer. Suramin placed in calcium controls did not affect calcium determination using three commercially available methods.

Purpose: Patients with von Hippel-Lindau disease are predisposed to multiple bilateral adrenal pheochromocytoma. In these patients partial adrenalectomy may preserve adrenocortical function and avoid the morbidity associated with medical adrenal replacement. We report our experience with such cases.Materials and Methods: Laparoscopic partial adrenalectomy was performed in patients with von Hippel-Lindau disease and pheochromocytoma when there was evidence of normal adrenocortical tissue on preoperative imaging or intraoperative examination. Suture ligature or a harmonic scalpel was used to excise the tumors, leaving a 2 to 3 mm. margin of normal tissue.Results: Two patients underwent laparoscopic partial adrenalectomy and 1 laparoscopic bilateral partial adrenalectomy with preservation of normal adrenocortical tissue. Seven pheochromocytomas were removed. Laparoscopic ultrasound was essential for localizing 2 pheochromocytomas that were not visualized by the camera. Median operative time was 324 minutes, ...

Summaryvon Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease.

Purpose:: We review the literature and characterize the clinical findings of von Recklinghausen’sassociated pheochromocytoma.Materials and Methods:: A Grateful Med search for the years 1966 to 1999 was performed on the subjects, “von Recklinghausen” and “neurofibromatosis.” Articles from the Grateful Med search were then reviewed to identify older publications. Of 325 articles 118 are included in this review.Results:: Pheochromocytomas have been clinically identified in 0.1 to 5.7% of patients with von Recklinghausen’s disease. Mean patient age was 42 years (range 1.5 to 74) in 87 women and 61 men at presentation with pheochromocytoma. Of the 148 patients 84% had solitary adrenal tumors, 9.6% bilateral adrenal disease and 6.1% ectopic pheochromocytomas. Symptoms related to pheochromocytoma or hypertension were noted in 78% of the patients. Tumors secreted epinephrine and norepinephrine, and 87% demonstrated metaiodobenzylguanidine uptake. Of the 148 patients 6% died during pregnancy or a medical procedure...

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.

Purpose: Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with von Hippel-Lindau disease and hereditary papillary renal cancer.Materials and Methods: Patients with von Hippel-Lindau disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the large renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.Results: The 3 cm. surgical threshold was evaluated in 52 patients with von Hippel-Lindau disease (group 1) at a median followup of 60 months (range...

Objectives. Cytoreductive nephrectomy is commonly performed in patients with metastatic renal cell carcinoma before systemic interleukin-2 (IL-2) therapy. Open nephrectomy is associated with prolonged recovery during which metastatic disease can progress. The feasibility of laparoscopic cytoreductive surgery in these patients with large renal tumors was examined. The role of tumor morcellation in reducing the recovery period and allowing earlier treatment with IL-2 was investigated. Methods. Patients with metastatic renal cancer underwent either open nephrectomy (group 1, n=19) or laparoscopic cytoreductive nephrectomy (n = 11; 6 with tumor morcellation [group 2], 5 with removal of the tumor through a small incision [group 3]). The three groups were compared to evaluate relative recovery, suitability for treatment with IL-2, and laparoscopic port site seeding. Results. A group of 19 patients underwent open nephrectomy (group 1). Eleven patients with a median tumor volume of 377 cm 3 (median tumor diameter 9 cm) underwent laparoscopic cytoreductive nephrectomy. Six of these patients underwent tumor morcellation (group 2) and 5 underwent laparoscopic assisted nephrectomy (group 3). There was no difference in patient age, sex, sites of metastatic disease, ECOG status, size of renal tumor, or surgical complication rates among groups. Patients whose tumor was morcellated had reduced postoperative parenteral narcotic requirements and were discharged sooner than patients undergoing open cytoreductive nephrectomy. Time to treatment with IL-2 was shortest in the morcellation group (median time to treatment 37 days). No port site seeding was observed. Conclusions. Laparoscopic cytoreductive nephrectomy in patients with bulky renal disease is a safe procedure in selected patients. This pilot study demonstrated a significant association of laparoscopic tumor morcellation with less postoperative pain, faster time to discharge, and shorter time to treatment with IL-2. A randomized study is warranted to determine the role of laparoscopic cytoreductive nephrectomy with tumor morcellation.

Purpose: In patients with von Hippel-Lindau disease multiple bilateral adrenal pheochromocytoma can develop, which has traditionally been treated with adrenalectomy. Partial adrenalectomy can preserve normal adrenal function and avoid the morbidity associated with medical adrenal replacement. We demonstrate whether adrenal function could be preserved by partial adrenalectomy in patients with von Hippel-Lindau disease.Materials and Methods: From 1995 to 1998, 13 consecutive von Hippel-Lindau disease patients with pheochromocytoma underwent 14 partial and 6 complete unilateral adrenalectomies. Function of residual normal adrenal and recurrence of adrenal pheochromocytoma were determined at followup.Results: Of the patients 2 had undergone unilateral adrenalectomy and 1 had undergone complete and partial adrenalectomy previously. Following surgery residual normal adrenal tissue consisted of 1 partial adrenal in 3 patients, bilateral partial adrenal in 5, partial and complete adrenal gland in 1, 1 com...

Purpose: We analyzed familial renal oncocytoma to provide a foundation for studies aimed at defining genes involved in the pathogenesis of renal oncocytoma.Materials and Methods: We describe 5 families with multiple members affected with renal oncocytoma. Tumors were analyzed pathologically, and affected and nonaffected members were screened clinically and genetically.Results: We identified 12 affected male and 3 affected female (ratio 4:1) individuals in the 5 families. In affected family members renal oncocytomas were often multiple and bilateral. No metastatic disease was observed. Most renal oncocytomas were detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal oncocytoma families. One identical twin pair was affected with bilateral multiple renal oncocytomas.Conclusions: Renal oncocytoma may be inherited in some families.

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 single-strand 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.

Purpose: After renal parenchymal sparing surgery, residual defects may persist on imaging studies at the sites of resection. These “pseudotumors” may lead to confusion as to whether a lesion was removed or has recurred. We describe the imaging appearances and behavior of renal pseudotumors following renal parenchymal sparing surgery.Materials and Methods: From 1988 to 1997, 32 patients underwent 46 renal parenchymal sparing surgeries for removal of renal cancers, including von Hippel-Lindau disease in 27, hereditary papillary cancer in 2 and sporadic disease in 3. A median of 14 tumors (range 1 to 114) were removed in each operation. Thrombin soaked absorbable gelatin sponge was placed in the tumor bed after resection to aid hemostasis. We reviewed all imaging studies performed after these operations to characterize these lesions and gain further understanding into the prevalence and etiology.Results: Of the patients, 9 had a total 13 pseudotumors on initial postoperative imaging studies, includin...

Purpose: We sought to determine the frequency of interleukin-6 (IL-6) expression in renal cancer cell lines, the frequency of the detection of IL-6 in the serum of patients with metastatic renal cell carcinoma, whether serum IL-6 level correlates with the development of paraneoplastic syndromes and whether serum IL-6 level in patients with metastatic renal cancer correlates with response to treatment with interleukin-2 (IL-2) or patient survival.Materials and Methods: Conditioned media from 21 cell lines from 20 patients were examined for IL-6. We identified 2 matched groups of patients with metastatic renal cancer (30 responders and 29 nonresponders) to IL-2 based immunotherapy. Stored pretreatment serum specimens were evaluated for IL-6. Medical records were reviewed to determine the presence of paraneoplastic syndromes.Results: IL-6 was detected in 19 of 21 renal cancer cell lines (90%) obtained from 20 patients with metastatic renal cancer as well as in the serum of 33 of 59 patients (56%) wit...

von Hippel-Lindau disease (VHL) is an inherited neoplastic disorder characterized by the development of tumors in the eyes, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis. The VHL tumor suppressor gene was identified in 1993. Initial studies reported the detection of germline mutations in the VHL gene in 39–75% of VHL families. We used tests that detect different types of mutations to improve the frequency of detection of germline mutations in VHL families. The methods included quantitative Southern blotting to detect deletions of the entire VHL gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization (FISH) to confirm deletions, and complete sequencing of the gene. Here we report that we have detected germline mutations in the VHL gene in 100% (93/93) of VHL families tested. In addition, we describe 13 novel intragenic VHL germline mutations. With the methodology described in this article, it is now possible to identify germline mutations in virtually all families with VHL. Hum Mutat 12:417–423, 1998. © 1998 Wiley-Liss, Inc.

To evaluate the use of dual-phase three-dimensional magnetic resonance (MR) angiography in the preoperative staging of renal cancer.MR angiography was performed in 18 patients before performance of partial (n = 7), radical (n = 10), or laparoscopic (n = 1) nephrectomy to treat renal cancer. Dynamic, three-dimensional MR angiograms were obtained with gadoteridol enhancement, breath holding, and a three-dimensional spoiled gradient-echo sequence. Images were obtained at 15-second intervals to achieve opacification of arteries and veins. Source, maximum intensity projection, and multiplanar reconstruction images were evaluated. Imaging results were compared with surgical findings.Renal arterial phase MR angiograms depicted 30 of 31 (97%) surgically confirmed renal arteries, with one false-positive result (an artery that arose from an early-branching single main renal artery, interpreted as a separate accessory artery). Renal venous phase MR angiograms depicted all seven instances of renal vein involvement, including extension to the inferior vena cava in two patients. Collateral vessels around the tumor, including prominent gonadal veins in three patients, were demonstrated. Additional findings included adenopathy and adrenal and pulmonary metastases.Dual-phase MR angiography of the kidney may be a useful technique in depicting renal vessels before nephrectomy.

We defined the outcome of a strategy using cytoreductive surgery before high dose interleukin-2 (IL-2) therapy in patients with metastatic renal cell carcinoma.During an 11-year period, 195 patients underwent cytoreductive surgery as preparation for high dose IL-2 based therapy. The renal primary and locoregional metastatic disease that could be safely resected was removed.Because of the large size 176 of 195 renal tumors (90%) were resected through transabdominal incision and in 45 patients (23%) a second additional significant procedure was performed. Five cases (2.6%) were unresectable and 2 (1%) perioperative deaths occurred. After surgery 121 of 195 patients (62%) were eligible for treatment with high dose IL-2 based protocols. Overall response rate to IL-2 based protocols was 18%.Cytoreductive surgery can be performed safely in patients with metastatic renal cell carcinoma. Although the impact of cytoreductive surgery on response to immunotherapy remains undefined, this combination of primary debulking and systemic IL-2 can result in durable complete tumor regression in some patients with metastatic renal cell carcinoma.

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 ± SEM, 0.60 ± 0.21 ; 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. Immunohistochemical 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.

BACKGROUND Combined androgen blockade (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow-up, had been maintained for more than 46 months. METHODS A 71-year-old man with a positive family history of prostate carcinoma presented in 1989 with urinary frequency and a suspicious digital rectal examination. He was found to have a poorly differentiated adenocarcinoma (Gleason 4+4). He was started on CAB and his prostate specific antigen (PSA) concentration declined from 96 ng/mL to the normal range and was maintained for the next 24 months. In 1991 his PSA began to rise, and reached 64 ng/mL by 1993. The patient was enrolled on a clinical trial that discontinued the flutamide administration and hydrocortisone was initiated. RESULTS Physical examination at the time of enrollment was unremarkable. His PSA declined to below the limits of detection after this maneuver and at last follow-up had been maintained there for more than 46 months. In 1995, the patient underwent a repeat biopsy of the prostate and all six tissue cores were negative for carcinoma. At last follow-up in December 1996, the patient had no evidence of disease and was being followed routinely; however, the authors were continuing treatment with testicular suppression (leuprolide) plus hydrocortisone. CONCLUSIONS The authors believe the residual androgens and steroids produced by the adrenal cortex play a meaningful role in prostate carcinoma cell proliferation. Based on this case and data from trials supporting the activity of flutamide withdrawal plus adrenal suppression, it appears reasonable to evaluate prospectively the discontinuation of antiandrogen versus antiandrogen withdrawal plus adrenal suppression in individuals failing CAB. Cancer 1997; 79:1964-8. © 1997 American Cancer Society.

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.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.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 p0.0001). Metastases developed in 20 of 73 (27.4%) patients in group 2. The frequency of renal tumor metastases increased with increasing tumor size.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.

Reduced expression of nm23 has been associated with increased metastases and decreased survival in a variety of malignancies. In the present study, the expression of nm23 was examined by Northern and Western blot analyses in a series of cell lines derived from patients with metastatic renal cell carcinoma. Two of twelve (17%) informative cell lines derived from 9 patients had loss of heterozygosity at Nm23-H1. Twenty-two renal cancer cell lines derived from primary tumors, 5 cell lines derived from metastatic tumors and 4 short-term cultures of normal proximal renal tubular cells all expressed Nm23 mRNA in varying amounts. On average, the level of expression of Nm23 mRNA in short-term cultures of benign proximal renal tubular cells was found to be similar to the level seen in renal cancer cell lines. Twenty-eight cell lines derived from renal primary tumors and 8 cell lines derived from metastatic tumors expressed both the Nm23-H1 and Nm23-H2 proteins. High or low relative expression of nm23 at the mRNA or protein level did not correlate with survival. The absence of any anomalous pattern of expression of the nm23 genes and the lack of correlation of expression with survival suggests that nm23 does not play a central role in the progression of this tumor type.

Tumor suppressor genes have been found to have loss of function in a number of malignancies. This loss of function is believed to contribute to malignant transformation or metastatic spread. In the present study, expression of the retinoblastoma (RB) tumor suppressor gene was examined in cell lines and tumor tissue obtained from primary renal and metastatic sites in patients with metastatic renal cell carcinoma.Three of fifteen (20 percent) of informative renal carcinoma cell lines had loss of heterozygosity (LOH) in the RB gene (intron 20) detected by polymerase chain reaction analysis. Using restriction fragment length polymorphism (RFLP) analysis, 7 of 22 (32 percent) informative cell lines had LOH centromeric to the RB gene at the D13S1 locus. No LOH (0 of 7) was seen telomeric to the RB gene at the D13S2 locus. None of the 28 cell lines examined had decreased RB mRNA expression compared with short-term cultures of proximal renal tubular cells. Western blotting demonstrated phosphorylated and ...

The combined efforts of a number of investigators have led to the identification of the VHL gene, which appears to function as a tumor suppressor gene and is implicated in both sporadic and familial forms of RCC. These findings should increase our understanding of the molecular biology of this malignancy; however, there is much work to be done. Identification of the mechanism of inactivation of the VHL gene, as well as the structure and function of the VHL gene product, ultimately may provide clinicians with greater understanding of this malignancy as well as with methods for earlier diagnosis. The role of other tumor suppressor genes, such as p53, is incompletely understood. It is hoped that the techniques that have been applied to the study of RCC also will result in advances in our knowledge of other urologic malignancies.