Computer-Generated R.E.N.A.L. Nephrometry Scores Yield Comparable Predictive Results to Those of Human-Expert Scores in Predicting Oncologic and Perioperative Outcomes.

PURPOSE: We sought to automate R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry scoring of preoperative computerized tomography scans and create an artificial intelligence-generated score (AI-score). Subsequently, we aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to expert human-generated nephrometry scores (H-scores). MATERIALS AND METHODS: A total of 300 patients with preoperative computerized tomography were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors, and geometric algorithms were developed to estimate components of R.E.N.A.L. nephrometry score. Tumors were independently scored by medical personnel blinded to AI-scores. AI- and H-score agreement was assessed using Lin's concordance correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using areas under the curve. RESULTS: Median age was 60 years (IQE 51-68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors, including 27%, 37% and 24% with high stage, grade and necrosis, respectively. There was significant agreement between H-scores and AI-scores (Lin's ⍴=0.59). Both AI- and H-scores similarly predicted meaningful oncologic outcomes (p <0.001) including presence of malignancy, necrosis, and high-grade and -stage disease (p <0.003). They also predicted surgical approach (p <0.004) and specific perioperative outcomes (p <0.05). CONCLUSIONS: Fully automated AI-generated R.E.N.A.L. scores are comparable to human-generated R.E.N.A.L. scores and predict a wide variety of meaningful patient-centered outcomes. This unambiguous artificial intelligence-based scoring is intended to facilitate wider adoption of the R.E.N.A.L. score.

Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling. METHODS: We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model. RESULTS: We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model. CONCLUSIONS: Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.

Evaluating prostate cancer mortality and competing risks of death in patients with localized prostate cancer using a comprehensive nomogram.

BACKGROUND: The aim of this study was to determine the optimal treatment for a patient with newly diagnosed prostate cancer weighing the individual's risk of disease progression against his risk of non-cancer death. METHODS: We developed a predictive model incorporating clinicopathological tumor variables, patient age, comorbidity status, and primary treatment modality. We identified 6091 patients with clinically-localized prostate cancer managed with radical prostatectomy (n=4117) or radiation therapy (n=1974) from the Cancer of the Prostate Strategic Urologic Research Endeavor database. Fine and Gray competing-risks proportional hazards regression models were used to calculate the risks of prostate cancer-specific mortality (PCSM) and non-prostate cancer death and to generate a nomogram. RESULTS: The median follow-up after treatment was 53 months (interquartile range 30, 80 months). In total, 983 men died during follow-up, including 167 who died of prostate cancer and 816 who died of non-prostate cancer causes. On multivariate analysis, higher Cancer of the Prostate Risk Assessment score and primary treatment with radiation were associated with an increased risk of PCSM, whereas older age, African-American race, and treatment with radiation predicted non-prostate cancer death. The number of comorbidities and receipt of androgen deprivation therapy correlated with an increased risk of non-prostate cancer death, but not PCSM. The resulting nomogram allows quantification and comparison of the 10-year risk of PCSM and non-prostate cancer death. CONCLUSIONS: Integrating clinicopathological variables with comorbid conditions in a competing-risks model affords quantification and comparison of relative probabilities of PCSM and non-prostate cancer death following treatment. Our model thereby facilitates an individualized approach for counseling patients regarding prostate cancer management.

Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome- and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP.

The treatment of non-metastatic prostate cancer with external beam radiation therapy.

Multiple treatment options exist for men with non-metastatic prostate cancer. For nearly 50 years, external beam radiation therapy (EBRT) has been an important means of treating men with this disease. Improvements in technology and better use of pre-treatment variables including prostate specific antigen (PSA), Gleason score and prediction nomograms have steadily improved biochemical and clinical outcomes. This article reviews the current status of EBRT in the treatment of prostate cancer. Differences in technique as well as clinical results using conventional, 3D conformal and intensity modulated radiation therapy are compared and contrasted. The appropriate use of adjuvant hormones as well as the complications of these treatments will also be discussed.

Prevalence and patterns of self-initiated nutritional supplementation in men at high risk of prostate cancer.

OBJECTIVE: To define the prevalence and patterns of self-initiated herbal and vitamin supplementation among men at high risk of developing prostate cancer, as there is increasing public awareness of prostate cancer screening, risk-factor assessment and prevention, leading to increasing interest in the use and systematic study of nutritional therapies for prostate cancer prevention. SUBJECTS AND METHODS: Since 1996 our institution has prospectively maintained a prostate cancer-risk registry through its Prostate Cancer Risk Assessment Program (PRAP). Eligibility includes African-American men, any man with at least one first-degree relative or two or more second-degree relatives with prostate cancer, or men who tested positively for the BRCA1 gene mutation. A 420-item self-administered questionnaire was completed and included the use of nutritional supplements and complementary therapies. We divided men into groups who used supplements to lessen their cancer risk and those who did not. The prevalence and patterns of use were evaluated and the two groups then compared for differences in demographic, socio-economic and risk-perception variables. RESULTS: In all, 345 high-risk men were enrolled in the PRAP over a 5-year period. Data on the use of dietary or herbal supplements were available on 333 men (97%), of whom over half (170) reported taking one or more supplements to prevent prostate cancer. Supplement use was divided into eight categories, including vitamins, minerals, extracts from fruits/seeds, organic compounds, flowers/bulbs, leaves/bark, roots, or animal products. Most commonly used for self-initiated chemoprevention were vitamins (95%), minerals (28%), and fruit/seed extracts (18%). More than a quarter of men (27%) took three or more agents. Men taking proactive preventative measures were statistically more likely to be Caucasian and aged > 60 years (P < 0.05). African-Americans were less likely to self-initiate preventative steps. Men taking supplements tended to return more often for follow-up and participate in PRAP longer, while those not taking supplements tended to earn less and report less self-perceived risk. CONCLUSIONS: A significant proportion of men at risk of developing prostate cancer initiate measures they perceive to reduce their risk. Although the chemopreventative efficacy of many of these supplements remains unsubstantiated, they are widely perceived by the public to reduce the risk of developing prostate cancer. These data provide an insight into patient perceptions and misconceptions of chemopreventative strategies, and may help to refine recruitment efforts in multi-institutional prostate cancer prevention trials.

The T cell death knell: immune-mediated tumor death in renal cell carcinoma.

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.

Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes.

Alterations in intracellular Zn(2+) concentrations are believed to play a crucial role in modulating apoptosis. The observation that Zn(2+) deficiency can induce cell death both in vivo and in vitro has been attributed to the fact that exchange of Zn(2+) for Ca(2+) and Mg(2+) within the nuclei may directly activate endogenous endonucleases therefore inducing DNA fragmentation independent of cytoplasmic factors. Here we show that the membrane-permeable zinc chelator, N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces translocation of cytochrome c from the mitochondrial intramembranous space into the cytosol in human peripheral blood T lymphocytes (PBL) with subsequent activation of caspases-3, -8, and -9. Pretreatment of T lymphocytes with caspase inhibitors Z-VAD.fmk or DEVD.fmk prevented DNA fragmentation in response to TPEN indicating that apoptosis triggered by zinc deficiency is entirely dependent on activation of caspase family members. The release of cytochrome c and activation of downstream caspases precedes changes in the mitochondrial transmembrane potential (Delta Psim). Therefore, cytoplasmic and mitochondrial events are critical to this process.

Inhibition of NFkappaB induces caspase-independent cell death in human T lymphocytes.

Nuclear factor kappaB (NFkappaB) regulates the expression of various genes essential for cell survival. Here we demonstrate that suppression of NFkappaB nuclear import with SN50 peptide carrying the nuclear localization sequence (NLS) of the NFkappaB p50 subunit induces apoptosis in human peripheral blood T lymphocytes (T-PBL), which can be blocked with the pan-caspase inhibitor Z-VAD.fmk. However, even when caspase function is blocked, the addition of SN50 induces irreversible cell loss due to the reduction in the mitochondrial transmembrane potential (DeltaPsim) followed by disruption of the cell membrane, hallmarks of necrosis. These observations demonstrate that although inhibition of NFkappaB nuclear translocation by SN50 peptide can induce caspase-dependent apoptosis in T-PBL, cell death may still proceed in the absence of functional caspase activity. The availability of downstream caspases appears to determine the mode of cell death in NFkappaB defective cells.

Nephron sparing surgery for renal tumors: indications, techniques and outcomes.

PURPOSE: A contemporary review of the indications, techniques and outcomes is presented for nephron sparing approaches to solid renal masses, emphasizing their role for the treatment of renal cell carcinoma. We also reviewed the evolving role of minimally invasive forms of parenchymal sparing renal surgery. MATERIALS AND METHODS: MEDLINE and CANCERLIT computerized literature searches, and manual bibliographic reviews were performed to identify published peer reviewed articles pertaining to nephron sparing surgery or partial nephrectomy from 1980 to 2000. Pertinent articles were collated and reviewed. RESULTS: Nephron sparing surgery is increasingly being used to treat patients with solid renal lesions. The technical success rate of nephron sparing surgery is excellent, and operative morbidity and mortality are low. For renal cell carcinoma long-term cancer-free survival is comparable to that after radical nephrectomy, particularly for low stage disease. The overall incidence of local recurrence is low at 0% to 10%. For tumors 4 cm. or less local recurrence rates are even less at 0% to 3%. The risk of local recurrence depends primarily on the initial local pathological tumor stage. The reported incidence of multifocal renal cell carcinoma is approximately 15% and it also depends on tumor size, histology and stage. The risk of multifocal disease is low at less than 5% when the maximal diameter of the primary tumor is 4 cm. or less. Recent advances in renal imaging limit the radiographic evaluation necessary when planning complex nephron sparing approaches. Three-dimensional, volume rendered computerized tomography integrates all of the necessary information previously obtained by conventional computerized tomography, angiography, venography and pyelography into a single preoperative test, allowing better operative planning with maximal preservation of unaffected parenchyma in the remnant kidney. Minimally invasive modalities of tumor resection or destruction should be reserved for highly select patients and await improvements in technology, standardization of technique and long-term outcomes data before they may be completely integrated options. CONCLUSIONS: Nephron sparing surgery provides effective therapy for patients in whom preservation of renal function is a relevant clinical consideration. The importance of meticulous operative technique for achieving acceptable oncological and functional outcomes is emphasized. Accumulating data in appropriately select patients suggest a long-term functional advantage gained by the maximal preservation of unaffected renal parenchyma without sacrificing cancer control.

Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor-kappaB suppression.

Antitumor immunity fails to adequately develop in many cancer patients, including those with renal cell carcinoma (RCC). A number of different mechanisms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display increased sensitivity to apoptosis. Tumor-infiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated nick end labeling in situ, and the number of apoptotic TILs further increases after 24 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals undergo activation-induced cell death (AICD) upon in vitro stimulation with phorbol myristate acetate and ionomycin. This is in contrast to T cells from normal individuals, which are resistant to AICD. TILs and peripheral blood T cells from RCC patients also exhibit impaired activation of the transcription factor, nuclear factor (NF)-kappaB. Additional findings presented here indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, and in some instances directly induce, normal T cells to apoptosis. These same supernatants also inhibit NF-kappaB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to apoptosis. Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-kappaB activation and apoptosis. Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-kappaB activation but also sensitized T cells to AICD. These findings demonstrate that tumor-derived soluble products, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.

Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue.

OBJECTIVES: To analyze the quality of life and psychological adjustment after surgical therapy for localized renal cell carcinoma. METHODS: Postal questionnaires including measures of quality of life (SF-36) and the impact of the stress of cancer (Impact of Events Scale) were completed by 97 patients who had undergone radical or partial nephrectomy for localized renal cell carcinoma. Data were analyzed for the group as a whole and comparing the partial nephrectomy and radical nephrectomy groups. The variables examined included the impact of the type of partial nephrectomy (elective versus mandatory) and the amount of self-reported renal tissue remaining. RESULTS: The quality of life for the group as a whole was good, with no significant differences between the sample and U.S. norms for an age and sex-matched community sample on both the mental and physical health composite scores. Having undergone a partial versus a radical nephrectomy did not influence the patients' overall quality of life. Multiple linear regression modeling demonstrated that having more remaining renal parenchyma was an independent predictor of better self-reported physical health on the SF-36 (P <0.001). The entire sample had low mean scores on both avoidance and intrusion on the Impact of Events Scale, suggesting a lack of daily anxiety about cancer. Multiple linear regression modeling showed that patients who reported having more remaining renal parenchyma had lower intrusion and avoidance scores (P = 0.002 and 0.01, respectively). Multiple logistic regression modeling also demonstrated that the patients' perception of their remaining renal parenchyma was associated with less concern about cancer recurrence (P = 0.018) and less impact of cancer on patients' overall health (P <0.001). CONCLUSIONS: Most survivors of localized kidney cancer have normal physical and mental health regardless of the type of nephrectomy performed. The quality of life is better for patients with more renal parenchyma remaining after surgery for localized renal cell carcinoma.

Strategies for transplantation of cadaveric kidneys with congenital fusion anomalies.

PURPOSE: The dire shortage of cadaveric kidneys has led to a gradual expansion of donor criteria in the transplant community. The use of kidneys with anatomical fusion anomalies is uncommon and has not been well defined in the literature. We evaluated the surgical strategies and postoperative outcomes of transplanting cadaveric kidneys with congenital fusion anomalies. MATERIALS AND METHODS: Three cadaveric kidneys with congenital fusion anomalies were procured and transplanted between May 1994 and November 1999. None of the 3 donors had any significant urological history. All fusion anomalies were identified during the organ procurement process. RESULTS: Anomalies included 1 L-shaped cross-fused ectopic and 2 horseshoe kidneys. All 3 kidneys were procured en bloc. One horseshoe kidney with a narrow isthmus was split and the 2 kidneys were transplanted into separate recipients, while the other horseshoe kidney was transplanted en bloc into a single recipient. The L-shaped kidney was transplanted en bloc into 1 patient. All transplants were successful with a serum creatinine of 1.1 to 1.9 mg/dl. CONCLUSIONS: To our knowledge we present the initial case of transplantation of an L-shaped kidney. Cadaveric kidneys with congenital fusion anomalies may be transplanted successfully using various individual technical strategies based on the specific renal anatomy. As such, these kidneys may be used to maximize the increasingly inadequate donor pool.

23 assessment of T-cell immune dysfunction in patients with renal cell carcinoma.

Functional T cells are the central component of an effective antitumor immune response. However, in patients with renal cell carcinoma (RCC), the growth of antigenic tumors proceeds in the absence of significant T-cell responses, posing a distinct obstacle to the development of effective immunotherapy strategies and cancer vaccines. The minimum required elements of a functional antitumor immune T-cell response have been identified, including T cells that can preferentially recognize tumor-associated antigens (1). However, despite increasing evidence that T-cells recognize discrete tumor antigen, transformed cells continue to evade immune destruction, and tumors thereby progress. There is now little doubt that the immune response to tumor antigens is altered in patients with cancer (2). This rarely manifests clinically as generalized immune suppression, which may reflect the antigen specificity of the immune dysfunction in the initial stages of the disease.

Laparoscopic retroperitoneal live donor right nephrectomy for purposes of allotransplantation and autotransplantation.

PURPOSE: We report the technique of and initial experience with retroperitoneal laparoscopic live donor right nephrectomy for purposes of renal allotransplantation and autotransplantation. MATERIALS AND METHODS: A total of 5 patients underwent retroperitoneoscopic live donor nephrectomy of the right kidney for autotransplantation in 4 and living related renal donation in 1. Indications for autotransplantation included a large proximal ureteral tumor, a long distal ureteral stricture and 2 cases of the loin pain hematuria syndrome. In all cases a 3-port retroperitoneal laparoscopic approach and a pelvic muscle splitting Gibson incision for kidney extraction were used. In patients undergoing autotransplantation the same incision was used for subsequent transplantation. RESULTS: All procedures were successfully accomplished without technical or surgical complications. Total mean operating time was 5.8 hours and average laparoscopic donor nephrectomy time was 3.1 hours. Mean renal warm ischemia time, including endoscopic cross clamping of the renal artery to ex vivo cold perfusion, was 4 minutes. Average blood loss for the entire procedure was 400 cc. Radionuclide scan on postoperative day 1 confirmed good blood flow and function in all transplanted kidneys. Mean analgesic requirement was 58 mg. fentanyl. Mean hospital stay was 4 days (range 2 to 8), and convalescence was completed in 3 to 4 weeks. CONCLUSIONS: In the occasional patient requiring renal autotransplantation live donor nephrectomy can be performed laparoscopically with renal extraction and subsequent transplantation through a single standard extraperitoneal Gibson incision, thus, minimizing the overall operative morbidity. Furthermore, these data demonstrate that live donor nephrectomy of the right kidney can be performed safely using a retroperitoneal approach with an adequate length of the right renal vein obtained for allotransplantation or autotransplantation.

Preoperative use of 3D volume rendering to demonstrate renal tumors and renal anatomy.

With increased use of computed tomography (CT) and abdominal ultrasonography, the indications for nephron-sparing surgery are also increasing. Triphasic helical CT and three-dimensional (3D) volume rendering can be combined into a single noninvasive test to delineate renal tumors and normal and complex renal anatomy prior to nephron-sparing surgery. This combination technique has proved accurate and very useful for both preoperative and intraoperative planning by demonstrating renal position, tumor location and depth of tumor extension into the kidney, relationship of the tumor to the collecting system, and renal vascular anatomy. Knowledge of the position of the kidney relative to the lower rib cage, iliac crest, and spine helps in planning the initial surgical incision. By depicting tumor location and depth of extension, helical CT with 3D volume rendering helps ensure complete tumor excision and conservation of adjacent normal renal parenchyma. Depiction of the relationship of the tumor to the collecting system helps anticipate further tumor extension and minimize postoperative complications. Identification of normal renal vasculature and anatomic variants can help minimize ischemic injury and intraoperative bleeding. Radiologists should be familiar with current indications for nephron-sparing surgery and understand what information is required prior to surgery.

Tumor-induced dysfunction in interleukin-2 production and interleukin-2 receptor signaling: a mechanism of immune escape.

PURPOSE: The development of an effective antitumor immune response is compromised in patients with renal cell carcinoma. Despite significant infiltration by T lymphocytes into renal tumors, no detectable induction of gene expression is associated with the generation of an antitumor immune response. Tumor-induced down-regulation of interleukin (IL)-2 expression may contribute to the impaired development of the T cell-mediated antitumor immune response. Within renal tumors, there is no detectable expression of IL-2 or the IL-2 receptor alpha chain, and only low levels of interferon gamma (IFN-gamma) mRNA are detected. Products in the tumor environment may suppress the expression of these genes, thus inhibiting production of type 1 helper T cell cytokines. METHODS: Peripheral blood lymphocytes obtained from healthy volunteers were exposed to supernatants from renal cell carcinoma explants, and the immunologic consequences of this were assessed using a variety of molecular assays. RESULTS: Soluble products from renal tumor explants can inhibit the production of IL-2 and IFN-gamma by peripheral blood lymphocytes and can suppress T-cell proliferation. Soluble products from renal cell carcinoma explants appear to block the nuclear translocation of nuclear factor kappa B (NFkappaB) proteins p50 and RelA without affecting cytoplasmic levels of these proteins. In some experiments, a reduction in the nuclear translocation of other transcription factors involved in IL-2 gene expression, including nuclear factor of activated T cells and accessory protein-1, was observed. Gangliosides isolated from tumor supernatants blocked the production of IL-2 and IFN-gamma in response to ionomycin plus phorbol myristate acetate stimulation. These gangliosides also inhibited stimulus-dependent activation and nuclear accumulation of NFkappaB. Coculture experiments demonstrated that renal cell carcinoma lines known to express gangliosides could inhibit the activation of NFkappaB in normal T cells and the Jurkat T-cell line. Supernatants from renal cell carcinoma explants and renal cell carcinoma cell lines can also suppress the proliferation of normal T cells, thus reproducing another defect observed in tumor-infiltrating lymphocytes. Supernatants from renal cell carcinoma tumors also appear to inhibit signaling through the IL-2 receptor. Although tumor supernatants had little effect on IL-2 receptor (alpha, beta or gamma) expression, they did block expression of JAK3, a key kinase involved in signaling through the IL-2 receptor pathway. Moreover, downstream events in IL-2 receptor signaling linked to JAK3 were impaired in T cells treated with tumor supernatants. CONCLUSION: These findings suggest that soluble products from renal tumors may suppress T-cell responses by blocking both IL-2 production and normal IL-2 receptor signaling.