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The role of aggressive surgery for metastatic renal cancer in the era of biological therapy is not clear. Therefore, we reviewed 17 patients who, between February 1987 and August 1990, underwent surgical resection of residual masses following initial response to interferon-alpha-based therapy. Viable tumor persisted in 15 patients (88%), whereas only inflammatory response was detected in 2. Of the patients 11 (65%) remained disease-free at a median of 12 months postoperatively (range 5 to 29), with an overall median survival of 26 months (range 6 to 34) from treatment initiation. These data suggest that surgery may be of therapeutic benefit in select patients with renal cell carcinoma who do not meet traditional criteria for surgical resection. Prospective trials are being performed to determine whether there is a role for aggressive surgical resection of persistent disease in patients with advanced renal cell carcinoma who have previously responded to interferon-alpha-based therapy.
PURPOSE - To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2.
PATIENTS AND METHODS - We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2.
RESULTS - A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response).
CONCLUSION - The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.
Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine. Patients received oral acrivastine at doses of 400 mg every 4 hours for 6 days and a 96-hour continuous infusion of vinblastine at a dose of 1.6 mg/m2/24 h. Of 15 evaluable patients, no tumor responses were seen. The regimen was well-tolerated with the majority of toxicities being gastrointestinal and hematologic. Serum levels of acrivastine, its principal metabolite (270C81) and vinblastine were measured during the study. Based on in vitro data, the plasma levels of acrivastine were within a range adequate to block P-glycoprotein activity. High doses of acrivastine were well-tolerated clinically, however, the combination of acrivastine and vinblastine was not active against renal cell carcinoma.
Renal cell carcinoma is unusual in children. We report a case of anaplastic renal cell carcinoma arising in a 7-year-old girl following treatment for Stage III neuroblastoma. The renal cell carcinoma has unusual histologic and ultrastructural features, which are discussed. The case is further unusual in that few children with advanced stage neuroblastoma survive long enough to develop second malignant neoplasms.
Secondary tumors of the gastrointestinal (GI) tract are unusual but are probably more common than clinically suspected. Comparison of surgical pathologic findings and autopsy experience over a 14-yr period revealed a different spectrum of tumors, which may reflect clinical practice issues and the pathophysiology of individual tumors. Seventy-three surgical resection or biopsy cases with clinically evident secondary tumors were compared with 108 autopsy cases with secondary malignancies involving the GI tract. The most common tumors in surgical specimens were melanoma (22 cases), ovary (11 cases), bladder (eight cases), breast (six cases), and lung (five cases). The most common primary tumors at autopsy were lung (21 cases), gynecologic malignancies (18 cases), breast (14 cases), and pancreas (nine cases). In most cases, routine histologic examination yielded clues to the primary tumor. Metastatic breast carcinoma cases had a high potential for misinterpretation because most metastases consisted of infiltrating strands of pleomorphic cells without gland formation. Signet ring cells were present in most metastases (all six surgical cases and seven of 14 autopsies), regardless of the histologic type of the primary breast carcinoma. The time from diagnosis of the primary tumor to development of GI involvement varied widely, from presentation with GI metastases to more than 30 yr for metastatic malignant melanoma. Survival after development of GI involvement was generally poor, with most patients surviving less than 1 yr. However, long-term palliation may be achieved in a small subset of patients, chiefly those with single small bowel deposits of malignant melanoma or patients with breast carcinoma responsive to tamoxifen.
A phase I trial of repetitive weekly cycles of human recombinant interleukin-2 (IL-2) was performed in 23 patients with metastatic carcinoma. Patients received 4 days of IL-2 each week, followed by 3 days of observation, for 4 consecutive weeks. IL-2 was administered iv at 1.0 or 3.0 X 10(6) U/m2/day by one of three schedules involving continuous or bolus infusions. All treatment was carried out in a general hospital ward without intensive care unit monitoring or support. Seventeen patients had metastatic renal cell carcinoma; three of these demonstrated measurable (greater than 50% shrinkage) partial responses. This study demonstrates that IL-2 given alone without lymphokine-activated killer cells in this manner can induce antitumor effects with acceptable toxicity.
Expression of the low-affinity interleukin-2 (IL-2) receptor molecule (TAC) has been associated with lymphocyte activation, in vitro and in vivo [Greene WC (1987) Clin Res 35:439]. We have used an enzyme-linked immunosorbent assay (ELISA) to quantify the role of released and cell-bound IL-2 receptor following in vitro or in vivo activation of human lymphocytes with IL-2. In vitro experiments, culturing fresh peripheral blood lymphocytes in 30 U/ml IL-2 (corresponding to the steady-state IL-2 concentration achieved in patients receiving IL-2 in our clinical trials), showed that the levels of IL-2 receptor released into the culture media exceeded the levels of cell-associated receptor, with both rising in parallel to the cytotoxic activity of the peripheral blood lymphocytes (PBL) against cultured tumor cells. In 12 patients receiving high-dose IL-2 for the treatment of various malignant neoplasms, the levels of IL-2 receptor released into the serum rose dramatically during the IL-2 infusion, and then fell following cessation of the IL-2 infusion. This heightened release of IL-2 receptor into the serum occurred during the episodes of profound lymphopenia that developed within hours after patients began an IL-2 infusion. Following each 4-day infusion of IL-2, a rebound lymphocytosis was observed, as has been previously reported. Serum IL-2 receptor levels do not rebound in parallel; rather, they reach a plateau near the end of the 4-day infusion and then decrease upon cessation of IL-2. These changes in serum IL-2 receptor levels accompany changes in lytic activity of circulating PBL on Daudi target cells. These results suggest that lymphocyte populations exposed to IL-2 in vivo are activated to become cytotoxic, release TAC, and relocate in non-peripheral blood compartments. Following cessation of the IL-2 infusion these activated lymphocytes return to the peripheral circulation and do not secrete TAC as vigorously as while influenced directly by the IL-2 infusion.
Twenty patients with refractory malignancies were treated with a protocol evaluating the addition of ex vivo-activated autologous lymphokine-activated killer (LAK) cells to a clinically tolerable interleukin-2 (IL-2) regimen (four weekly cycles of human recombinant IL-2 at 3 x 10(6) U/m2/day by continuous infusion for 4 days/week). Sixteen patients completed their induction month of therapy, two had a partial response, six had stable disease, and eight had progressive disease. Four patients had clinical toxicity preventing completion of the induction month of therapy, and one of these patients died during therapy. Significant clinical toxicities included decreased performance status, weight gain, catheter-related thromboses, infectious complications, fever, hypotension, and dyspnea or hypoxemia requiring oxygen. Thus, the addition of LAK cell infusions to this IL-2 regimen did not cause a noticeable change in antitumor response rate but did not cause more severe toxicity.
Preliminary studies involving small numbers of patients have suggested that interleukin-2 (IL-2) administered by continuous infusion in repetitive weekly cycles using doses of 3 x 10(6) U/M2/day is immunologically active and can induce tumor responses in patients with renal cell carcinoma. This study was designed to examine both the immunological and clinical effects of prolonged infusion IL-2 given by repetitive weekly cycles; first at moderate doses for 4 weeks as an impatient followed by lower doses of IL-2 for up to 5 months. Prolonged IL-2 treatment was investigated because previous studies revealed that patients had a return to their baseline immune status within 4 weeks after completing IL-2 treatment. Twenty-five patients (including 18 with renal cell carcinoma) were treated with one of two regimens utilizing IL-2 as sole therapy. These regimens were designed to induce augmented and prolonged immune activation based upon in vitro and in vivo data. Though patients on both arms of the study demonstrated sustained lymphocytosis, increase in numbers of natural killer cells, and induction of lymphokine-activated killer activity with prolonged IL-2 administration, only 1 out of the 18 patients with renal cell carcinoma demonstrated a sustained partial antitumor response to therapy. Furthermore, several patients demonstrated profound immune activation, without any evidence of tumor regression. The lack of clinical responses in these patients showing marked activation of LAK cytotoxicity suggests that other variables must also influence the likelihood of antitumor effects for patients receiving IL-2 therapy.
A sarcomatoid renal cell carcinoma has been isolated from a patient with Stauffer's syndrome. The tumor, designated BA1119, has been established in tissue culture over 80 passages. Subcutaneous deposition of BA1119 in athymic mice induced splenomegaly and hepatic dysfunction which became fatal within four weeks without metastasis. Suramin is a synthetic polyanionic compound which is capable of altering the function of a number of biologic systems and inhibiting the activity of a variety of protein and growth factors. In this study we attempted to study the effect of suramin on growth of BA1119 in culture and in nude mice. Suramin, at 300 micrograms/ml., had a profound inhibitory effect on cell growth during a six-day culture period. Suramin given i.p. weekly to nude mice at clinically relevant doses (200 mg./kg.) caused significant shrinkage of subcapsular tumor deposits. Splenic hypertrophy secondary to BA1119-induced Stauffer's syndrome was inhibited by suramin. Synergistic effect with enhanced cytotoxicity on BA1119 cells was observed when suramin (100 micrograms/ml.) was used in combination with lymphokines, such as gamma interferon (500 units/ml.) and alpha tumor necrosis factor (300 ng./ml.). These results may suggest a therapeutic efficacy of suramin in renal cell carcinoma patients with Stauffer's syndrome.