The detrimental effect of poor early graft function after laparoscopic live donor nephrectomy on graft outcomes.

We undertook this study to assess the rate of poor early graft function (EGF) after laparoscopic live donor nephrectomy (lapNx) and to determine whether poor EGF is associated with diminished long-term graft survival. The study population consisted of 946 consecutive lapNx donors/recipient pairs at our center. Poor EGF was defined as receiving hemodialysis on postoperative day (POD) 1 through POD 7 (delayed graft function [DGF]) or serum creatinine >/= 3.0 mg/dL at POD 5 without need for hemodialysis (slow graft function [SGF]). The incidence of poor EGF was 16.3% (DGF 5.8%, SGF 10.5%), and it was stable in chronologic tertiles. Poor EGF was independently associated with worse death-censored graft survival (adjusted hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.34-3.47, p = 0.001), worse overall graft survival (HR 1.62, 95% CI 1.10-2.37, p = 0.014), worse acute rejection-free survival (HR 2.75, 95% CI 1.92-3.94, p < 0.001) and worse 1-year renal function (p = 0.002). Even SGF independently predicted worse renal allograft survival (HR 2.54, 95% CI 1.44-4.44, p = 0.001). Risk factors for poor DGF included advanced donor age, high recipient BMI, sirolimus use and prolonged warm ischemia time. In conclusion, poor EGF following lapNx has a deleterious effect on long-term graft function and survival.

Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation. A mechanism for irradiation erythema.

Acute ultraviolet light B (UVB) injury is associated with dermal mast cell histamine release. The possibility that histamine-stimulated prostaglandin (PG) synthesis could be a mechanism for irradiation erythema was therefore examined using human skin explants. Explants responded to UV irradiation (120 mJ/cm2) with a fivefold increase in synthesis of prostaglandins E2, F2 alpha and 6-keto PGF1 alpha. Incubating explants with the H1 antihistamines brompheniramine (50 microM) or pyrilamine (30 microM) inhibited PG release from irradiated explants 63 +/- 4.9% (mean +/- SEM) 6 h after UV exposure. Antihistamines did not affect PG synthesis in control explants. Irradiation increased the histamine concentration in explant conditioned medium only 50% over basal values, suggesting that irradiation enhanced histamine responsiveness. Explants were therefore incubated with exogenous histamine. In irradiated explants, PG synthesis was stimulated threefold by 3 microM histamine. Unirradiated explants' PG synthesis was unaffected by histamine. Enhanced histamine sensitivity was also examined in epidermal cell cultures. In irradiated cultures, histamine sensitivity was again markedly potentiated: as little as 1 microM histamine stimulated significant PGE2 release and the response to 10-30 microM histamine was increased six to eight times compared with that of unirradiated cultures. These studies demonstrate that endogenous histamine stimulates PG synthesis in human skin after UV injury by potentiation of histamine-induced prostaglandin release. Potentiated agonist responses induced by UV exposure may contribute to the effects of UVB irradiation injury and in particular to irradiation erythema.

Suramin, an active drug for prostate cancer: interim observations in a phase I trial.

BACKGROUND: Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotoxicity of this agent is closely related to sustained plasma drug concentrations of 350 micrograms/mL or more. PURPOSE: This phase I clinical trial in patients with solid tumors was designed to determine whether plasma concentrations resulting in both antitumor activity and manageable toxicity could be achieved with short, intermittent infusions of suramin. METHODS: Thirty-seven patients, including 33 with metastatic, hormone-refractory prostate cancer, collectively received 43 courses of suramin designed to maintain a plasma concentration range of 200-300, 175-275, or 150-250 micrograms/mL. Patients received a test dose of 200 mg and an initial loading dose of 1000 mg/m2 on day 1 of therapy. Subsequent suramin doses and schedules were individually determined using a strategy of adaptive control with feedback, which used a maximum a posteriori Bayesian algorithm to estimate individual pharmacokinetic parameters. Patients were treated until dose-limiting toxicity or progressive disease developed. RESULTS: Thirty-five of the 37 study patients and 31 of the 33 with prostate cancer were assessable for toxicity and response. Treatment was discontinued in 28 patients because of dose-limiting toxicity consisting of a syndrome of malaise, fatigue, and lethargy; recurrent reduction in creatinine clearance of 50% or more; or axonal neuropathy. Evidence of major antitumor activity was observed in patients with prostate cancer treated at all three plasma drug concentrations. Measurable responses (one complete response and five partial responses) were noted in six of 12 patients with measurable disease. Twenty-four (77%) of 31 patients had a reduction in prostate-specific antigen of 50% or more, and 17 (55%) of 31 had a reduction of 75% or more. Twenty (83%) of 24 patients reported reduction in pain. CONCLUSIONS: Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible. Suramin is active against hormone-refractory prostate cancer. IMPLICATIONS: Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types.

Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in human prostate cancer.

Allelic loss studies have been instrumental in identifying tumor suppressor gene loci in a variety of cancers. In this study we analyzed prostate cancer specimens from 52 patients for allelic loss using 8 polymorphic probes for the short arm of chromosome 8. Overall, 32 of 51 (63%) informative tumors showed loss of at least one locus on chromosome 8p. The most frequently deleted region is observed at chromosome 8p22-8p21.2. Loss of one allele is identified in 14 of 23 (61%) tumors at D8S163, in 15 of 32 (47%) tumors at lipoprotein lipase, and in 20 of 29 (69%) tumors at MSR, all on 8p22. Loss of one allele is identified in 16 of 27 (59%) tumors at D8S220 at 8p21.3-8p21.2. In addition to frequent loss of one allele at the MSR locus, one metastatic prostate cancer sample demonstrated homozygous deletion of MSR sequences. Loci telomeric and centromeric to this region are largely retained. A chromosome 8p deletion map is constructed and defines the smallest region of overlap to a 14-cM interval at 8p22 between D8S163 and lipoprotein lipase, flanking the MSR locus. Evidence of chromosome 8q multiplication at locus D8S39 was detected in 5 of 32 (16%) tumors, all of which demonstrated loss with at least one probe on chromosome 8p. This study extends the previous finding of frequent loss of chromosome 8p in prostate cancer by defining a common region of loss of heterozygosity at 8p22 and a homozygous deletion of the MSR locus contained within this region. This is the first homozygous deletion identified in the genome of a human prostate cancer and the highest rate of loss yet reported on chromosome 8p in cancer. These results strongly suggest the presence of a tumor suppressor gene in this region which is frequently inactivated in prostate cancer.

Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer.

PURPOSE: This phase I study was designed with the following objectives: (1) to describe the overall and dose-limiting toxicity (DLT) of suramin administered by intermittent short intravenous infusions until DLT or disease progression; (2) to determine the ability of an adaptive control with feedback (ACF) dosing strategy to maintain suramin plasma concentrations within a preselected range; (3) to develop a population model of suramin pharmacokinetics; and (4) to identify preliminary evidence of antitumor activity. PATIENTS AND METHODS: Seventy-three patients with advanced, incurable, solid tumors (including 69 with hormone-refractory prostate cancer) received an initial 5- to 7-day daily loading treatment followed by intermittent infusions individually determined by ACF using a Bayesian algorithm and relying on population models of suramin pharmacokinetics. Treatment was given to three cohorts of patients based on target plasma suramin concentration ranges (peak, 30 minutes postsuramin, and trough on morning of the treatment day), as follows: cohort 1, 175 to 300 micrograms/mL (27 patients); cohort 2, 150 to 250 micrograms/mL (23 patients); and cohort 3, 100 to 200 micrograms/mL (23 patients). All patients were to receive suramin until DLT or disease progression. RESULTS: The DLT was most commonly seen in cohort 1 and included a syndrome of malaise and fatigue, associated with weight loss, anorexia, and changes in taste. Other reversible toxicities were neurologic, renal, cutaneous, edema, lymphopenia and anemia, ophthalmologic, and alopecia. Forty of 67 assessable patients (60%) had a 50% reduction and 25 of 67 (37%) a 75% reduction in prostate-specific antigen (PSA) levels that lasted more than 4 weeks, seven of 18 (40%) had measurable responses, and 18 of 37 (49%) demonstrated major pain improvement. The overall times to disease progression and survival were 170 and 492 days, respectively. CONCLUSION: We have characterized all toxicities with suramin in a pharmacologically guided phase I study designed to maintain plasma suramin concentrations of 100 to 300 micrograms/mL (cohorts 1 to 3). The incidence of grade 3 to 4 neurologic abnormalities was relatively low, particularly in cohorts 2 and 3 (100 to 250 micrograms/mL). Evidence of significant and durable antitumor activity was seen in all three cohorts.

Urinary free cortisol and separation anxiety early in the course of bereavement and threatened loss.

Among 56 persons who were acutely bereaved or threatened with a loss, a group with worsening separation anxiety over a period of a month early after the event had higher urinary free cortisol output than a group experiencing improvement in grief. Although not tested in this study, both these psychological and physiological measures may have potential for serving as early predictors of poor outcome in bereavement for the 15%-20% of exposed persons who are at risk for unresolved grief or persistent depressive syndromes.

Adverse life events and cognitive-personality characteristics in the prediction of major depression and antidepressant response.

OBJECTIVE: Stressful life events are known to precipitate major depression. However, it remains unclear why some individuals who experience adverse events develop depression whereas others do not, and how the occurrence of life events affects treatment outcome. Emerging models posit that the effect of adverse life events varies by cognitive-personality style. This study examines the direct and interactive effects of stressful life events and cognitive-personality style in predicting 1) episode onset in patients with DSM-IV unipolar depression versus community comparison subjects and 2) depressive symptom severity at the completion of a 6-week standard antidepressant regimen. METHOD: Multivariate models were used to test the effects of adverse life events, cognitive-personality style, and the congruence of event type (interpersonal versus achievement) with cognitive-personality style on depressive onset and treatment outcome in 43 patients with major depression and 43 healthy comparison subjects. Cognitive-personality characteristics were assessed by using Beck's measures of sociotropy (interpersonal dependency) and autonomy (need for independence and control). RESULTS: Adverse life events, sociotropy, and an autonomy factor need for control were each significantly related to depressive onset and predicted group status for 88% of the subjects. Event types affected outcome differently, and specific life event types interacted with cognitive-personality styles in predicting response to treatment. A multivariate model accounted for 65% of the variance in predicting outcome. CONCLUSIONS: Adverse life events are a potent factor in predicting depression. However, cognitive-personality characteristics also confer susceptibility to depression. Better outcome is associated with occurrence of adverse interpersonal events (e.g., death of a loved one) rather than adverse achievement events (e.g., loss of job) and occurs when the event type is congruent with cognitive-personality style.

Influence of traumatic grief on suicidal ideation among young adults.

OBJECTIVE: The purpose of this study was to examine the influence of traumatic grief on suicidal ideation. METHOD: The Beck-Kovacs Scale for Suicidal Ideation was administered to 76 young adult friends of suicide victims. RESULTS: Traumatic grief was associated with a 5.08 times greater likelihood of suicidal ideation, after control for depression. Comorbid traumatic grief and depression were not associated with a greater likelihood of suicidal ideation. CONCLUSIONS: Syndromal traumatic grief heightens vulnerability to suicidal ideation.

Apoptotic versus proliferative activities in human benign prostatic hyperplasia.

Cell growth in the normal prostate is regulated by a delicate balance between cell death and cell proliferation (ie, apoptotic v proliferative activity). Disruption of the molecular mechanisms that regulate these two processes may underline the abnormal growth of the gland leading to benign prostatic hyperplasia (BPH). In this study, the incidence of programmed cell death (apoptosis) and cell proliferation was comparatively analyzed among the various cell subpopulations in the normal and benign hyperplastic human prostate. The authors also examined the relative expression of two proteins involved in the regulation of prostate apoptosis: (1) transforming growth factor (TGF)-beta1, a negative growth factor able to induce prostate apoptosis under physiological conditions; and (2) bcl-2, a potent apoptosis suppressor. Analysis of the incidence of "spontaneous" apoptosis in situ, using the end-labeling terminal transferase staining technique for the detection of nucleosomal DNA fragmentation, revealed infrequent apoptotic staining in isolated basal and secretory prostate epithelial cells. The basal level of cell proliferation was determined on the basis of the Ki-67 nuclear antigen staining, a nuclear protein that appears primarily during the proliferative phases of the cell cycle. The Ki-67-positive nuclei were equally distributed among the basal and secretory epithelial cells of the hyperplastic prostatic acini. The apoptotic index of the secretory and basal cells of the prostate epithelium was higher in the normal prostate compared with BPH tissue, whereas there was a significant increase in the proliferative index of the respective cell populations in the hyperplastic prostate. Balancing the apoptotic versus the proliferative activities revealed a substantial net decrease (fourfold) in the total number of cells dying via apoptosis in both the glandular and basal epithelial cell compartments of the hypertrophic prostate (BPH) when compared with the normal gland. TGF-beta staining was exclusively identified in the secretory epithelial cells, lining the prostatic lumen with minimal involvement of the basal cells and total lack of immunoreactivity among the stroma elements. Statistical analysis revealed a significant elevation in TGF-beta expression in the epithelial cells of BPH tissue compared with the normal prostate (P < .001). Expression of bcl-2 was topologically restricted to the glandular epithelium of the prostate. In the normal prostate, bcl-2 immunoreactivity was predominantly identified in the basal cell layer. An increase in both the intensity of immunoreactivity for bcl-2 and the number of positive epithelial cells (basal and secretory) was detected in BPH specimens relative to the normal prostate (P < .02). These results suggest a potential involvement of enhanced expression of this antiapoptosis protein in deregulation of the normal apoptotic cell death mechanisms in the human prostate, thus resulting in a growth imbalance in favor of cell proliferation that might ultimately promote prostatic hyperplasia.

Seizures associated with antidepressants: a review.

BACKGROUND: Seizures are uncommon, but serious, adverse effects of antidepressant drugs. A better understanding of drug-related seizure risk, its predictors, and its neurophysiologic basis might help clinicians avoid this adverse event. A better understanding of the factors involved in the determination of seizure risk would be helpful for interpretation of seizure rates reported. METHOD: The authors review case reports, series of cases, and information from clinical trials of antidepressants to determine antidepressant-related seizure risk. Predisposing factors are identified. Effects of dose, blood levels, and duration of treatment on seizure risk are examined. Electrophysiologic and in vitro models of drug-related seizure induction are discussed. RESULTS: A significant proportion of drug-related seizures occurs in individuals with an identifiable predisposition, such as previous seizures, sedative or alcohol withdrawal, and multiple concomitant medications. Seizure risk for most antidepressants increases with dose (or blood level), and comparisons between drugs should consider seizure rates at the effective dose (or blood level) for each drug. For imipramine, the most frequently studied tricyclic, the literature indicates a seizure rate between 0.3% and 0.6% at effective doses. In unselected patients and at higher doses, these rates may be higher. Fluoxetine, sertraline, fluvoxamine, trazodone, nomifensine, and the monoamine oxidase inhibitors have a lower seizure risk. Estimates for recently marketed antidepressants with intermediate seizure risk are complicated by the fact that effective doses and blood levels are not well established. CONCLUSION: Assessment of seizure risk in individuals involves consideration of predisposing factors, the antidepressant selected, and the bioavailability of the drug. Future studies of seizure risk would benefit from the use of specified criteria for determination of probable seizure events, a priori definition of predisposing exclusions, samples sufficiently large to provide adequate power, blood level monitoring, and inclusion of duration of drug treatment in the calculation of risk.

Prostatic ultrasound in the patient without a rectum.

Digital rectal examination, measurement of prostatic-specific antigen, and transrectal ultrasound, with or without prostate biopsy, are the urologist's primary tools for diagnosing carcinoma of the prostate. However, in the patient who has previously undergone abdominoperineal resection of the rectum such procedures are not possible. We therefore describe a simple, cost-effective method for evaluating the prostate in the patient without a rectum, via transperineal ultrasound and prostate biopsy. This procedure provides the urologist with a solution to a heretofore difficult problem.

Mitogenic factor in human prostate extracts.

Extracts of human benign prostatic hyperplasia, well-differentiated prostatic adenocarcinoma, and normal post-pubertal prostate stimulate 3H-thymidine incorporation by resting phase cultures of fetal rat osteoblasts and fibroblasts. The stimulation is concentration dependent and reaches a maximum at twenty-four hours of incubation. Prostatic extracts are also mitogenic in cell cultures of newborn human foreskin fibroblasts and the human cell lines, BUD-8 and DoT. The growth-stimulating factor is both heat and trypsin sensitive indicating that the factor is either a protein or contains a protein moiety. The growth-stimulating activity is not related to prostatic polyamine concentration. Experiments also show the activity is not due to human prostatic acid phosphatase. A prostatic growth factor may explain the growth of fibrous nodules in benign prostatic hyperplasia and the osteoblastic response of bone to prostatic cancer.

Reversion of human prostate tumorigenic growth by azatyrosine.

OBJECTIVES: Azatyrosine, an antibiotic isolated from a Streptomyces species, has been previously shown to have antitumor activity against ras- and neu-transformed fibroblasts and human epithelial cells. In this study, we investigated the effect of azatyrosine on human prostate cancer cell growth and the reversion potential of this antibiotic on prostate tumorigenic cell lines. METHODS: Three androgen-independent human prostate cancer cell lines (TSU-Prl, DU-145, and PC-3) were cultured in the presence of azatyrosine and their growth rates were determined over a 7-day period. Following exhaustive treatment with azatyrosine for 5 weeks, three azatyrosine-resistant colonies were cloned from the PC-3 cell line and were subsequently established as stable cell lines. The growth characteristics of these azatyrosine-resistant clones were examined both in vitro and in vivo to establish their "potentially revertant" profiles. RESULTS: Incubation with azatyrosine (for 7 days) resulted in greater than 95% in vitro growth inhibition of the three parental prostate cancer cell lines. Analysis of the biologic properties of these azatyrosine-resistant cell lines revealed: (1) a significant reduction in in vitro growth rates; (2) a decreased rate of DNA synthesis as measured by thymidine uptake; and (3) a decreased ability for colony formation in soft agar. Moreover all three azatyrosine-resistant clones exhibited suppressed tumorigenicity in severe combined immunodeficient (SCID) mice when compared with the parental cell line. An important observation was that one revertant clone demonstrated complete loss of tumorigenicity. On the basis of this biologic behavior, these cell lines were characterized as revertants. Cytogenetic analysis revealed gross chromosomal differences between the revertant clones and the parental cell line. Northern hybridization analysis demonstrated elevated expression of the K-rev-1 and bcl-2 but not the rrg mRNA transcripts in the revertant cell lines. CONCLUSIONS: These results suggest that azatyrosine inhibits prostate tumorigenic growth; it has a high reversion efficiency on human prostate cancer cells; and the K-rev-1 suppressor gene and the bcl-2 proto-oncogene could be potentially involved in the reversion mechanism mediated by azatyrosine. This reversion of prostate cancer cells to an apparently nontumorigenic phenotype points to a potentially significant therapeutic role for azatyrosine in the treatment of advanced prostate cancer.

Rare incidence of human papillomavirus types 16 and 18 in primary and metastatic human prostate cancer.

OBJECTIVES: The reported data regarding the incidence and significance of human papillomavirus (HPV) in prostate cancer have been inconsistent. In the present study the incidence of HPV 16 and 18 was evaluated in an expanded series of primary as well as metastatic prostate cancer specimens, in order to evaluate a potential role of HPV infection in development and progression of prostate cancer. This is the first study attempting to establish the significance of HPV in metastatic prostate cancer. METHODS: The presence of high risk human papillomaviruses HPV 16 and 18 was analyzed using the polymerase chain reaction (PCR) amplification method and Southern blot hybridization analysis in a total of 61 prostatic tissue specimens: 43 primary prostate adenocarcinoma formalin-fixed, paraffin-embedded specimens, with varying degrees of differentiation (mean Gleason score 5.8, range 3 to 9); 17 pelvic lymph nodes positive for metastatic deposits; and 1 normal prostate specimen. RESULTS: This human papillomavirus typing indicates that only 1 out of the 43 prostatic specimens analyzed was positive for HPV 16 and 1 metastatic lymph node was positive for HPV 18, as revealed by Southern analysis. These results demonstrate the infrequent detection of HPV 16 and 18 DNA in all the primary prostatic adenocarcinoma specimens and metastatic lymph nodes analyzed in this study population. CONCLUSIONS: The negative HPV status for primary and metastatic prostate cancer demonstrated in this study provides a strong argument against an etiological role of HPV infection in the development and progression of the disease.

Digital subtraction angiography for renal donor evaluation.

A consecutive series of 52 living related renal donors were evaluated preoperatively by angiography. The preoperative angiographic interpretation was compared with the anatomy found at donor nephrectomy. Standard selective renal arteriography was found to be 100 per cent accurate in defining single (25) or multiple (1) renal arteries. Digital subtraction angiography (DSA) alone performed with an intra-arterial injection of contrast material was found to be 82 per cent accurate in determining the number of renal arteries. In five kidneys with multiple renal arteries, only two had the correct number of vessels identified. The errors are inherent in the DSA technology. DSA at the present time is not accurate enough to replace the standard arteriogram in the evaluation of the donor nephrectomy patient.

Primary renal carcinoid tumor.

A case of primary renal carcinoid tumor in a sixty-seven-year-old man is presented. Radical nephrectomy removed the primary disease, but hepatic metastases developed and the patient subsequently died. Review of the literature disclosed 8 other cases of primary renal carcinoid. Three of these had metastatic spread.

Topical testosterone therapy for penile growth.

Three prepubertal males were treated with daily applications to the penis of 5 per cen topical testosterone cream. Penile growth occurred in all 3 patients. Serum testosterone values rose dramatically in 2 of the patients. Topical testosterone probably causes penile growth via its systemic action, not merely through its local effect.

Ureteral injury due to blunt and penetrating trauma.

In a period of twenty-seven months, 15 patients with ureteral trauma were encountered, leading us to believe that there is an increasing incidence of these injuries. The injuries were caused by blunt trauma in 3 patients and gunshot wounds in 12. All patients sustained injuries to other organs as well as the ureter. The diagnosis of ureteral injury was frequently delayed beyond the day of presentation (33%) primarily due to the number and severity of associated injuries. The most accurate methods of diagnosis were surgical exploration and retrograde pyelography. Intravenous pyelography and abdominal computerized tomography scanning were diagnostic in only 33 percent of cases. Hematuria was present in only 63 percent of patients who had no other genitourinary injuries, emphasizing the lack of reliability of this sign in ureteral trauma.

Priapism due to solid malignancy.

Although priapism secondary to hematologic malignancies has been well described, review of the literature reveals 75 case reports of priapism due to local corporeal involvement by solid tumors. Our recent experience with 6 cases of local invasion of the corporeal bodies is reviewed. Three transitional cell carcinomas, one prostatic adenocarcinoma, one rectal carcinoma, and one sarcoma comprise the series. Three patients presented with priapism as their chief complaint, and 3 patients presented with priapism as their first sign of recurrence. Therapy included corporeal curettage, surgery, radiotherapy, or chemotherapy. None of the modalities was entirely effective, although chemotherapy seemed to offer the best palliation.

Transforming growth factor-alpha expression in human renal cell carcinoma: TGF-alpha expression in renal cell carcinoma.

OBJECTIVES: To characterize the expression of transforming growth factor-alpha (TGF-alpha) in various histologic types of renal cell carcinomas. METHODS: Immunohistochemistry of renal cell carcinoma and adjacent normal tissue was performed on formalin-fixed tissue using a specific monoclonal antibody to TGF-alpha. RESULTS: Clear and distinct staining was present in normal distal convoluted tubules and collecting ducts. The growth factor was not observed in the glomerulus or the proximal tubule. In tumors composed of clear cells, staining was evident only in endothelial cells but not in the tumor cells themselves. In granular cell type tumors, the tumor cells as well as endothelial cells stained for TGF-alpha. When mixed cell type tumors were studied, a heterogenous pattern of growth factor expression was found. Endothelial cells and granular cells but not clear cells demonstrated positive staining. CONCLUSIONS: These studies suggest that TGF-alpha is likely to play a major role in neovascularization of clear cell carcinomas and that the growth factor may be more important in supporting proliferation of granular cell type tumors.