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A C Novick

Publications and source records attributed to A C Novick.

At least 37 records · Page 2Linked to original sources
PubMed2001

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.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Renal outcome 25 years after donor nephrectomy.

PURPOSE: The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS: From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS: Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS: Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.

Adult↗
PubMed2000

Laparoscopic renal cryoablation in 32 patients.

OBJECTIVES: Laparoscopic renal cryoablation is a developmental minimally invasive nephron-sparing treatment alternative for highly select patients with small renal tumors. We present our evolving experience with this procedure. METHODS: Thirty-two patients (34 tumors) with a mean tumor size of 2.3 cm on preoperative computed tomography underwent laparoscopic renal cryoablation. As dictated by the tumor location, cryoablation was performed by either the retroperitoneal (n = 22) or the transperitoneal (n = 10) laparoscopic approach using real-time ultrasound monitoring. A double freeze-thaw cycle was routinely performed. RESULTS: The mean surgical time was 2.9 hours, cryoablation time 15.1 minutes, and blood loss 66.8 mL. For a mean intraoperative ultrasonographic tumor size of 2 cm, the mean cryolesion size was 3.2 cm. The hospital stay was less than 23 hours in 22 (69%) of 32 patients. Sequential magnetic resonance imaging scans demonstrated a gradual contraction in the mean diameter of the cryolesions. Of the 20 patients who underwent a 1-year follow-up magnetic resonance imaging scan, the cryoablated tumor was no longer visible in 5. Of note, 23 patients have now undergone a 3 to 6-month follow-up computed tomography-directed biopsy of the cryoablated tumor site; the biopsy was negative for cancer in all 23 patients. No evidence of local or port-site recurrence was found during a mean follow-up of 16.2 months. CONCLUSIONS: Critical long-term data regarding laparoscopic renal cryoablation, a developmental technique, are awaited. However, our initial experience is cautiously optimistic. Despite its significant potential for false-negative results, it is encouraging that the follow-up computed tomography-directed needle biopsies at 3 to 6 months were negative for cancer in 23 of 23 patients.

Adenoma, Oxyphilic↗
PubMed2000

Association between a positive flow cytometry crossmatch and the development of chronic rejection in primary renal transplantation.

OBJECTIVES: With the current repertoire of immunosuppressants available, the results of organ transplantation are now very good in the short term. However, many grafts continue to be lost in the long term because of chronic rejection. This study examined the effect of kidney transplantation against a positive flow cytometry crossmatch (FCXM) on the subsequent development of chronic rejection and graft failure. METHODS: We examined 187 primary renal transplantations performed at our institution between 1993 and 1996. All of these patients had a negative cytotoxicity crossmatch. All had a pretransplant FCXM, and patients were divided according to the results of the FCXM into three categories: FCXM negative, FCXM class I positive, and FCXM class II positive. RESULTS: We found that a positive FCXM at the time of transplantation was strongly associated with the ultimate development of chronic rejection. In FCXM-negative individuals, 16.9% developed chronic rejection compared with 80% of those with an HLA class I (T and B-cell) reaction and 40.9% of those with a class II (B-cell-only) reaction (P <0.001). The 3-year graft survival rate was 93% for FCXM-negative patients compared with 86% for FCXM class II positive and 80% for FCXM class I positive patients (P = 0.001). CONCLUSIONS: A strong association between a positive FCXM and subsequent development of chronic rejection was identified. This finding raises the possibility that more aggressive treatment of patients with a positive FCXM might ultimately result in a lower incidence of chronic rejection and improve overall graft survival.

Acute Disease↗
PubMed2000

Contemporary management of renal cell carcinoma with coexistent renal artery disease: update of the Cleveland Clinic experience.

OBJECTIVES: To treat concurrent renal cell carcinoma (RCC) and renal artery disease (RAD), which pose an unusual and challenging management dilemma. METHODS: Before June 1998, 48 patients presented with localized RCC and RAD affecting all the functioning renal parenchyma. These patients were grouped into four distinct categories: group 1, a solitary kidney with RCC and RAD (n = 8); group 2, bilateral RCC and coexistent RAD (n = 9); group 3, unilateral RCC and contralateral RAD (n = 15); and group 4, unilateral RCC and bilateral RAD (n = 16). The most common cause of RAD was atherosclerosis (n = 40), followed by medial fibroplasia (n = 5), renal artery aneurysm (n = 2), and arteriovenous malformation (n = 1). RESULTS: All patients underwent complete surgical excision of RCC. A nephron-sparing operation was performed preferentially (44 patients), and bilateral renal cancer operations were staged. Eleven patients underwent surgical renal vascular reconstruction in conjunction with either partial (n = 9) or radical (n = 2) nephrectomy. In 2 patients, renal revascularization was accomplished by percutaneous transluminal angioplasty before tumor excision. No perioperative deaths occurred. Postoperatively, preservation of renal function was achieved in 47 patients; 1 patient required chronic dialysis. The overall and cancer-specific 5-year patient survival rates in this series were 66% and 90%, respectively. At a mean follow-up of 58 months, 28 patients were alive with no evidence of malignancy. Six patients died of metastatic RCC, and 14 died of unrelated causes with no evidence of malignancy. CONCLUSIONS: Nephron-sparing surgery combined with selective renal arterial reconstruction can yield gratifying results in this complex patient population.

Adult↗
PubMed2000

A randomized prospective trial of low-dose OKT3 induction therapy to prevent rejection and minimize side effects in recipients of kidney transplants.

BACKGROUND: We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation. METHODS: One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7-14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored. RESULTS: No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Formation of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 and 1. CONCLUSIONS: Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.

Acute Disease↗
PubMed2000

Early increased chemokine expression and production in murine allogeneic skin grafts is mediated by natural killer cells.

BACKGROUND: Increased expression of chemokine mRNA is observed in allogeneic but not syngeneic skin grafts 3-4 days after transplantation. The recipient cells mediating this early inflammatory response in allografts remain unidentified. METHODS: Isogeneic and allogeneic skin grafts were transplanted to euthymic and athymic nude mice. mRNA expression and protein production of macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and the murine homolog of Gro(alpha), i.e. KC, from graft homogenates retrieved 3-4 days posttransplantation was tested by Northern blot hybridization and ELISA. To deplete NK cells, recipients were treated with antiasialo GM1 (ASGM1) antisera or with anti-NK1.1 mAb before transplantation. RESULTS: Expression of KC, MIP-1alpha, and MIP-1beta mRNA was equivalent in C57BL/6 allogeneic skin grafts and BALB/c isografts at day 2 posttransplant. At day 3 posttransplant, chemokine mRNA levels decreased in isografts but were maintained at high levels in the allografts. Increased early chemokine mRNA was also observed in C57BL/6, but not BALB/c++ grafts on BALB/c athymi(nu/nu) recipients. Treatment of allograft recipients with ASGM1 or with anti-NK1.1 antibody eliminated NK cells from the spleen and allograft infiltrating cell populations and decreased early chemokine mRNA levels in allografts 60-70%. Analyses of allograft homogenates indicated increased levels of KC, MIP-1alpha, and MIP-1beta protein at day 4 posttransplant that were decreased in recipients depleted of NK cells. Early chemokine mRNA levels were equivalent in isogeneic and semiallogeneic F1 grafts. CONCLUSIONS: Early chemokine mRNA expression and protein production in allogeneic skin grafts is amplified by recipient natural killer (NK) cells. These results indicate a novel function for infiltrating NK cells in mediating early increased intra-allograft chemokine production and inflammation during the initiation of acute rejection.

Animals↗
PubMed2000

Laparoscopic urinary diversion.

Urinary diversion, in conjunction with cystectomy or as an isolated procedure, has traditionally been performed using open surgical technique. Laparoscopic urinary diversion has only recently been reported. We review the available literature on laparoscopic urinary diversion and present some of the experimental and clinical studies that have attempted to overcome the technical difficulties of the procedure. In addition, the indications, results, and future directions of laparoscopic urinary diversion are discussed.

Animals↗
PubMed2000

Retroperitoneal laparoscopic radical nephrectomy: the Cleveland clinic experience.

PURPOSE: Laparoscopic radical nephrectomy is usually performed by the transperitoneal approach. At our institution the retroperitoneoscopic approach is preferred. We confirm the technical feasibility of retroperitoneoscopic radical nephrectomy, even for large specimens, and compare its results with open surgery in a contemporary cohort. MATERIALS AND METHODS: A total of 47 patients underwent 53 retroperitoneoscopic radical nephrectomies. Data from the most recent 34 laparoscopic cases were retrospectively compared with 34 contemporary cases treated with open radical nephrectomy. RESULTS: For the 53 retroperitoneoscopic radical nephrectomies mean tumor size was 4.6 cm. (range 2 to 12), surgical time was 2.9 hours (range 1.2 to 4.5) and blood loss was 128 cc. Mean specimen weight was 484 gm. (range 52 to 1,328), and concomitant adrenalectomy was performed in 72% of patients. Mean analgesic requirement was 31 mg. morphine sulfate equivalent. Average hospital stay was 1.6 days, with 68% of patients discharged from the hospital within 23 hours of the procedure. Minor complications occurred in 8 patients (17%) and major complications occurred in 2 (4%) who required conversion to open surgery. Various parameters, including patient age, body mass index, American Society of Anesthesiologists status, tumor size (5 versus 6.1 cm.), specimen weight (605 versus 638 gm.) and surgical time (3.1 versus 3.1 hours), were comparable between patients undergoing laparoscopic (34) and open (34) radical nephrectomy. However, laparoscopy resulted in decreased blood loss (p <0.001), hospital stay (p <0.001), analgesic requirements (p <0.001) and convalescence (p = 0.005). Complications occurred in 13% of patients in the laparoscopic group and 24% in the open group. CONCLUSIONS: Retroperitoneoscopy is a reliable, effective and, in our hands, the preferred technique of laparoscopic radical nephrectomy. At our institution retroperitoneoscopy has emerged as an attractive alternative to open radical nephrectomy in patients with T1-T2N0M0 renal tumors.

Adult↗
PubMed2000

Laparoscopic radical cystoprostatectomy with ileal conduit performed completely intracorporeally: the initial 2 cases.

OBJECTIVES: To present the initial 2 patients who underwent laparoscopic radical cystoprostatectomy, bilateral pelvic lymphadenectomy, and ileal conduit urinary diversion, with the entire procedure performed exclusively by intracorporeal laparoscopic techniques. METHODS: Two male patients, 78 and 70 years old, with muscle-invasive, organ-confined, transitional cell carcinoma of the urinary bladder underwent the procedure. The entire procedure, including radical cystoprostatectomy, pelvic node dissection, isolation of the ileal loop, restoration of bowel continuity with stapled side-to-side ileoileal anastomosis, retroperitoneal transfer of the left ureter to the right side, and bilateral stented ileoureteral anastomoses were all performed exclusively by intracorporeal laparoscopic techniques. Free-hand laparoscopic suturing and in situ knot-tying techniques were used exclusively. RESULTS: The surgical time was 11.5 hours in the first patient and 10 hours in the second. The respective blood loss was 1200 mL and 1000 mL. In both patients, ambulation resumed on postoperative day 2, bowel sounds on day 3, and oral intake on day 4; the hospital stay was 6 days. Narcotic analgesia comprised 108.3 mg and 16.5 mg of morphine sulfate equivalent, respectively. Pathologic examination revealed pT4N0M0 (prostate) and pT2bN0M0 transitional cell carcinoma of the bladder with the surgical margins negative for cancer in both patients. No intraoperative or postoperative complications occurred in either patient. CONCLUSIONS: To our knowledge, this is the initial report of laparoscopic radical cystoprostatectomy with intracorporeal ileal conduit urinary diversion. We believe that with further experience and refinement in the operative technique, laparoscopic radical cystoprostatectomy with ileal conduit urinary diversion may become an attractive treatment option for selected candidates with localized muscle-invasive bladder cancer.

Aged↗
PubMed2000

Laparoscopic cryoablation of renal masses.

Laparoscopic cryoablation seems to be an effective treatment modality for small peripheral renal tumors. The technique is minimally invasive, has a rapid learning curve, results in minimal blood loss and morbidity, and, to date, has demonstrated precise reliable ablation of small renal neoplasms. Long-term follow-up is necessary to confirm the absence of local tumor recurrence or distant or port-site metastases.

Adult↗
PubMed2000

Management of synchronous renal neoplasm and abdominal aortic aneurysm.

OBJECTIVES: Renal neoplasm (RN) and abdominal aortic aneurysm (AAA) are occasionally discovered concurrently. The approach to synchronous malignancy and aortic aneurysm is controversial. METHODS: Between 1981 and 1999, concurrent RN and AAA were diagnosed in 50 patients at the Cleveland Clinic Foundation. Twenty-three patients were managed conservatively because of small asymptomatic AAA or metastatic disease; these patients were excluded from the study. The remaining 27 patients underwent operative management of both entities with a staged or simultaneous approach, and they form the basis of this article. RESULTS: AAA diameter ranged from 4.8 to 13 cm (mean, 6.0+/-1.8 cm). RNs were managed with radical nephrectomy in 11 patients (41%), partial nephrectomy in 10 patients (37%), or both in 6 patients with bilateral renal tumors (22%). The AAA repair was performed at the time of the urologic procedure in 11 patients (41%), before the urologic procedure in 13 patients (48%), or after the urologic procedure in 3 patients (11%). The AAA was addressed with open surgical repair in 24 patients (89%); recently, three patients (11%) underwent endovascular repair of the aneurysm and staged partial nephrectomy. The incidence of major perioperative complications was 23% (6 patients). Acute renal failure was the most common complication (3 [11%]) followed by acute respiratory failure (2 [7.4%]), pulmonary embolism (1 [3.7%]), and stroke (1 [3.7%]). At the mean follow-up of 57 months, there were no graft infections reported. The 5-year overall and cancer-specific survival rates were 62% and 81%, respectively. There was a significant difference in 5-year cancer-specific survival when comparing patients managed simultaneously versus staged (80% versus 35%, P =.007). CONCLUSIONS: The concurrent presentation of RN and AAA should not discourage one from treating both entities simultaneously because long-term survival is common. Endovascular repair of AAA holds promise as an attractive strategy in these complex patients.

Aged↗
PubMed2000

Laparoscopic aortorenal bypass.

BACKGROUND AND PURPOSE: Open surgical renovascular repair, although producing excellent results, confers significant operative morbidity. As a result, less morbid procedures such as percutaneous balloon angioplasty and stenting have gained increasing acceptance. Laparoscopic techniques have not previously been applied to renal revascularization. The aim of this study was to demonstrate the technical feasibility and the long-term clinical and pathologic outcomes of laparoscopic aorto-left renal artery bypass in a chronic porcine model. MATERIALS AND METHODS: Eight animals were used in the study. All laparoscopic suturing and knot-tying were performed intracorporeally using free-hand techniques. The following operative steps were employed: (1) aortic dissection and cross-clamping; (2) transection and refashioning of the left renal artery ostium; (3) in-situ renal hypothermia; (4) end-to-side aorto-left renal artery anastomosis; and (5) aortic unclamping. In situ renal hypothermia was achieved laparoscopically by infusion of ice-cold heparinized saline into the renal artery through a balloon catheter. RESULTS: All eight pigs underwent laparoscopic aortorenal bypass successfully. The median surgical time was 110 minutes, and the aortic cross-clamping time was 45.5 minutes. The median anastomotic time was 40 minutes, and the renal warm ischemia time was 9 minutes. The median estimated blood loss was 30 mL. An intraoperative complication of suture breakage leading to anastomotic hemorrhage occurred in one animal; the problem was corrected laparoscopically. Postoperatively, one animal died from pneumonia. The remaining seven animals experienced no postoperative complications and were euthanized, one each at postoperative day 0 and 1 and week 1, 2, 3, 4, and 6. The median preoperative and postoperative (at euthanasia) serum creatinine values (1.15 mg/dL v 1.2 mg/dL; P = 0.39) were similar. However, compared with preoperative peripheral renin activity (0.25 microg/L per hour), the postoperative peripheral renin activity was elevated (0.9 microg/L per hour; P = 0.047). Autopsy revealed a grossly normal left kidney, with Doppler confirmation of flow in the repaired renal artery in all seven animals. Ex vivo angiography confirmed a patent anastomosis. On histopathology examination, the early left renal parenchymal specimens revealed transient, mild acute tubular necrosis that resolved over sequential specimens without significant long-term sequelae. Histologic analysis of the aorto-left renal artery anastomotic site revealed gradual endothelialization with time. CONCLUSIONS: Laparoscopic aortorenal artery revascularization is technically feasible. Our chronic animal model has demonstrated durable success over a 6-week follow-up. This study represents the initial report in the literature.

Anastomosis, Surgical↗
PubMed2000

Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup.

PURPOSE: Partial nephrectomy is effective for renal cell carcinoma when preservation of renal function is a concern. We present the 10-year followup of patients treated with nephron sparing surgery at our institution. MATERIALS AND METHODS: Partial nephrectomy was performed in 107 patients with localized sporadic renal cell carcinoma before December 1988. Tumors were symptomatic in 73 patients (68%) and indications for surgery were imperative in 96 (90%). Of the patients 42 (39%) had renal insufficiency preoperatively. All patients were followed a minimum of 10 years or until death. RESULTS: At the end of the followup interval 32 patients (30%) had no evidence of recurrence, 28 (26%) died of metastatic renal cell carcinoma and 46 (42%) died of unrelated causes. Cancer specific survival was 88.2% at 5 and 73% at 10 years, and was significantly affected by tumor stage, symptoms, tumor laterality and tumor size. Long-term renal function was stable in 52 patients (49%). CONCLUSIONS: Partial nephrectomy is effective for localized renal cell carcinoma, providing long-term tumor control with preservation of renal function.

Adult↗
PubMed2000

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.

Carcinoma, Renal Cell↗