A phase I trial of fluorouracil, leucovorin, and recombinant interferon alpha-2b in patients with advanced malignancy.

We conducted a phase I trial of fluorouracil (5-FU), leucovorin, (LCV), and recombinant interferon-alpha-2b (rIFN-alpha-2b). The doses of each of the three agents were escalated sequentially. 5-FU and LCV were administered by IV bolus, weekly for 6 weeks and rIFN-alpha-2b was administered by subcutaneous injection, three times weekly for 6 weeks. Twenty-nine patients with advanced cancer (75% colon or pancreatic cancer) were treated. Partial remissions were observed in three patients (10%) with previously untreated colon cancer, colon cancer refractory to 5-FU plus LCV and previously untreated pancreatic cancer, respectively. An additional three patients with pancreatic, prostate, and rectal cancer had a 50% reduction in tumor markers but no change in objective tumor measurements. The toxicity of this regimen was tolerable. The most common toxicities were diarrhea, fatigue, flu-like symptoms, nausea/vomiting, and mucositis. However, no fatal or life-threatening toxicities were observed. We conclude that the combination of 5-FU, LCV, and rIFN-alpha-2b can be safely administered and recommend further evaluation of this regimen in patients with tumors of gastrointestinal origin using doses of 5-FU 600 mg/m2, LCV 500 mg/m2, and rIFN-alpha-2b 10 x 10(6) U.

Neutrophil-derived serine proteinases enhance membrane type-1 matrix metalloproteinase-dependent tumor cell invasion.

BACKGROUND: Matrix metalloproteinase-2 degrades a variety of basement membrane components and is essential for tumor invasion. We have previously reported that membrane type-1 matrix metalloproteinase (MT1-MMP) cooperates with neutrophil-derived serine proteinases (NDPs; elastase, cathepsin G, protease-3) to activate matrix metalloproteinase-2. We therefore hypothesized that NDPs enhance tumor-cell invasion. METHODS: Clones of human HT1080 fibrosarcoma cells transfected with MT1-MMP sense (HT-SE) or antisense CDNA (HT-AS) were used. These cells express either high (HT-SE) or extremely low levels (HT-AS) of MT1-MMP relative to nontransfected HT1080 cells (HT-WT). The cells were incubated in the presence or absence of purified NDP, with or without alpha 1-antitrypsin or the MMP inhibitor batimastat. Cell invasion was measured with the use of Boyden chambers with polycarbonate membranes coated with a reconstituted extracellular matrix. RESULTS: Under control conditions HT-WT and HT-SE cells were 4-fold more invasive than HT-AS cells. The addition of NDP increased HT-WT and HT-SE cell invasion 60% to 100% but had no effect on HT-AS cells. alpha 1-antitrypsin or batimastat did not decrease the baseline invasiveness of HT-WT and HT-SE cells; however, they abrogated the stimulatory effect of NDP. CONCLUSIONS: HT1080 cell invasion depends on MT1-MMP expression. MT1-MMP overexpression does not increase invasiveness by itself. NDPs increase invasion by MT1-MMP expressing cells by activating matrix metalloproteinase-2.

Activation of tumor cell matrix metalloproteinase-2 by neutrophil proteinases requires expression of membrane-type 1 matrix metalloproteinase.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. METHODS: Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. RESULTS: Ht-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme from (72 kd). Ht-1080 cells with high levels of MT1-MMP (HT-SE) secreted pro MMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose-dependent generation of active, 62 kd MMP-2. In contrast, when PMN-conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. CONCLUSIONS: PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion.

Hepatic abscess in cancer patients. Characterization and management.

OBJECTIVE: To identify factors that may aid in the diagnosis and treatment of patients with malignant neoplasms in whom hepatic abscesses develop. DESIGN: Retrospective review of medical records. PATIENTS: Thirty-seven oncology patients in whom hepatic abscesses developed at the National Cancer Institute, Bethesda, Md, between June 1954 and October 1989. RESULTS: Among 37 cancer patients, bacterial abscesses developed in 17 and fungal abscesses developed in 20. Among the patients with bacterial abscesses, 12 (71%) had a solid-tissue malignant neoplasm, 10 (59%) had a prior invasive procedure, and six (35%) had prior chemotherapy. In comparison, among the patients with fungal abscesses, 15 (75%) had a hematologic malignant neoplasm and five (25%) had a solid-tissue malignant neoplasm (P2 = .014). Two patients with fungal abscesses (10%) had a prior invasive procedure (P2 = .004) and 19 (95%) had prior chemotherapy (P2 < .0001). As compared with fungal abscesses, bacterial abscesses were larger (P2 < .00001) and fewer (P2 = .004). Antibiotics and percutaneous or surgical drainage effectively treated bacterial abscesses. Amphotericin B usually eradicated hepatic fungal infections. CONCLUSIONS: The results of this study reveal the importance of the clinical setting in the diagnosis of hepatic abscesses in cancer patients. Aggressive treatment of these abscesses is indicated and is frequently effective.

Decreasing length of stay after pancreatoduodenectomy.

HYPOTHESIS: Decreased length of stay (LOS) after pancreatoduodenectomy is due to multiple factors, including a lower complication rate and more efficient perioperative care for all patients, with and without complications. DESIGN: A retrospective review, validation cohort. SETTING: A single university hospital referral center. PATIENTS: A consecutive sample of patients undergoing pancreatoduodenectomy from January 9, 1986, to December 21, 1992 (group 1 [n = 104]) and from February 16, 1993, to November 9, 1998 (group 2 [n = 111]). INTERVENTION: Mann-Whitney test and linear [correction of logistic] regression analysis applied to clinical variables and LOS. MAIN OUTCOME MEASURES: Difference in median LOS between early and late groups and identification of factors predictive of decreased LOS. RESULTS: Total LOS decreased between the 2 groups (26 days [range, 13-117 days] vs 15 days [range, 5-61 days]; P<.001), with a decrease in preoperative (4 days [range, 0-28 days] vs 2 days [range, 0-36 days]; P<.001) and postoperative (19 days [range, 11-95 days] vs 12 days [range, 4-58 days]; P<.001) LOS (data given for group 1 vs group 2). Major complications decreased from 49% in group 1 to 25% in group 2 (P<.001). Postoperative LOS decreased for patients with (25 days [range, 15-95 days] vs 20 days [range, 8-58 days]; P = .05) and without (15 days [range, 11-47 days] vs 11 days [range, 4-55 days]; P<.001) major complications (data given for group 1 vs group 2). Multivariate analysis identified age (P = .01), pancreatic fistula (P<.001), delayed gastric emptying (P<.001), biliary complications (P<.001), operative time (P<.005), extra-abdominal infection (P<.005), use of a percutaneous stent (P = .04), and year of operation (P<.001) as independent predictors of total LOS. CONCLUSION: A reduction in complications in combination with factors leading to a streamlining of perioperative care has contributed to the decreased LOS after pancreatoduodenectomy.

Long-term outcome in 87 patients with low-grade soft-tissue sarcoma.

OBJECTIVE: To describe the long-term clinical outcome of patients with low-grade soft-tissue sarcoma and identify factors that may predict or determine their prognosis. DESIGN: Retrospective chart review with multivariate analysis. SETTING: Large research hospital and referral center. PATIENTS: All patients treated between 1975 and 1990 at the National Cancer Institute (Bethesda, Md) who had a confirmed diagnosis of low-grade soft-tissue sarcoma. INTERVENTIONS: Surgery and radiation therapy. MAIN OUTCOME MEASURES: Local recurrence and overall survival. RESULTS: For patients with nonretroperitoneal lesions, overall survival was excellent, with a history of recurrence, a positive surgical margin, and an absence of adjuvant radiation therapy significantly associated with increased risks of local recurrence. Patients with retroperitoneal lesions not only had an increased risk of local recurrence, but significantly poorer overall survival. CONCLUSIONS: Low-grade soft-tissue sarcomas are associated with excellent overall survival, especially those confined to nonretroperitoneal sites. The risk of local recurrence after resection with negative margins and/or adjuvant radiation therapy is very low and most recurrences can be controlled with further therapy.

Review of experience with interferon and drug sensitivity testing of ovarian carcinoma in semisolid agar culture.

Studies were performed with a semisolid agar culture system to determine the in vitro sensitivity of human ovarian carcinoma to human leukocyte interferon (IFN-alpha) and standard chemotherapeutic agents (adriamycin, cis-platinum, hexamethylmelamine, melphalan, and velban). Growth in culture occurred in 67% of samples derived from ascitic fluid and 71% of these exhibited reduction in tumor colony number by greater than or equal to 25% in response to 300 units interferon/ml. The responsiveness of the ascitic fluid samples to interferon ran parallel to the overall responsiveness to the other agents tested. Sensitivity to interferon was not related to the histology or grade of the tumor or to the stage of the disease. As compared with cell suspensions prepared from ascitic fluid samples, solid tumor samples had markedly lower viability, 39% vs 89%, and had more tumor cells, 81% vs 28%. Also, colonies derived from solid tumor samples were less sensitive to interferon and more sensitive to cis-platinum and adriamycin than were ascitic fluid-derived colonies. Three of four ascitic fluid samples showed a reduction in tumor colony number of greater than or equal to 25%, whereas none of the solid tumor samples obtained from the same donors were affected by interferon to that degree. Retrospective analysis of drug testing (exclusive of interferon) for in vitro: in vivo correlations revealed that in 58% of 12 evaluable situations, when a single drug (or at least one of a group of drugs) gave a positive response in vitro, stabilization or regression of the tumor occurred in vivo after treatment with the drug. These studies prove the utility of the semisolid agar culture system for assessing the antiproliferative effects of interferon against ovarian carcinoma, and will be of utility in the future for assessing whether various types of interferon have the same degree, range, and mechanism of action of antitumor effect.

Topical hepatic hypothermia attenuates pulmonary injury after hepatic ischemia and reperfusion.

BACKGROUND: Prolonged periods of hepatic ischemia are associated with hepatocellular injury and distant organ dysfunction in experimental models. Neutrophils (PMN) and tumor necrosis factor (TNF)-alpha have been implicated, mostly because of their local deleterious effects on the hepatocyte after hepatic ischemia and reperfusion (I/R) injury. We hypothesize that topical hepatic hypothermia (THH) reduces ischemia and reperfusion-induced hepatic necrosis, PMN infiltration, TNF-alpha release, and consequent acute pulmonary injury. STUDY DESIGN: Sprague-Dawley rats (250 to 300g) were evenly divided into three groups: 90 minutes of normothermic (37 degrees C) partial hepatic ischemia (normothermic I/R), 90 minutes of hypothermic (25 degrees C) partial hepatic ischemia (hypothermic I/R), and sham laparotomy (without ischemia). There were six animals in each experimental group per time point unless otherwise specified. Hepatic necrosis and PMN infiltration were evaluated and scored on hematoxylin and eosin-stained liver specimens 12 hours after reperfusion. Serum TNF-alpha levels were determined by ELISA at 0 minutes, 15 minutes, 30 minutes, 1 hour, and 12 hours postreperfusion. Pulmonary PMN infiltration and vascular permeability were measured by myeloperoxidase activity and Evans blue dye extravasation, respectively, to quantitate pulmonary injury 12 hours after reperfusion. RESULTS: Normothermic I/R results in a significant increase in TNF-alpha at 15 and 30 minutes (p < 0.005), PMN infiltration (p < 0.001), and hepatic necrosis (p < 0.001), compared with sham. Institution of THH reduced peak serum TNF-alpha levels by 54% at 15 minutes (p < 0.005) and by 73% at 30 minutes (p < 0.001) postreperfusion compared with normothermic I/R. Similarly, hepatic PMN infiltration and necrosis at 12 hours were reduced by 60% (p < 0.05) and 47% (p < 0.05), respectively. Myeloperoxidase activity and Evans blue extravasation (measures of acute lung injury) were reduced by 42% and 39%, respectively, with institution of THH compared with animals undergoing normothermic I/R (p < 0.001). CONCLUSIONS: These results demonstrate that THH protects the liver from ischemia and reperfusion-induced necrosis and PMN infiltration. In addition, THH reduces the serum levels of TNF-alpha and associated pulmonary injury. These data suggest that the ischemic liver is a potential source of inflammatory mediators associated with hepatic ischemia and reperfusion-induced pulmonary injury.

Serial MR in gene therapy for recurrent glioblastoma: initial experience and work in progress.

PURPOSE: To describe the MR imaging findings in a pilot study evaluating gene therapy for treatment of patients with recurrent glioblastoma. METHODS: Serial MR examinations were evaluated retrospectively in patients treated with gene therapy that included a retroviral vector containing the herpes simplex virus thymidine kinase gene and intravenous ganciclovir. Images were obtained after tumor resection and after each cycle of treatment, at approximately 40-day intervals. The volume of enhancing tissue was measured on serial MR images. RESULTS: Eleven patients with recurrent glioblastoma were entered into the clinical trial of gene therapy and seven patients completed at least two cycles of treatment. Of these seven, three patients had an early (between 40 and 80 days) increase in the volume of enhancing tissue followed by a decrease or plateau in enhancing tissue volume. A fourth patient had a stable volume of enhancing tissue for 132 days. The remaining three patients had continuous increases in volume of enhancement on all subsequent MR examinations. CONCLUSION: Although animal data show striking tumor regression in response to similar gene therapy, only limited regression was observed among the seven patients we studied. The transient increases in enhancement seen in three of seven patients might reflect an inflammatory response to local injection of the viral vector.

Magnetic resonance imaging with magnetic resonance cholangiopancreatography accurately predicts resectability of pancreatic carcinoma.

Accurate preoperative staging of pancreatic malignancy aids in directing appropriate therapy and avoids unnecessary invasive procedures. We evaluated the accuracy of magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) in determining resectability of pancreatic malignancy. Twenty-one patients with suspected pancreatic malignancy underwent dynamic, contrast-enhanced breath-hold MRI with MRCP prior to surgical evaluation. Results of this study were correlated with operative results and pathologic findings. The sensitivity, specificity, and accuracy of MRI with MRCP in detecting a mass, determining the nature of the mass, and predicting lymph node involvement and resectability were determined. MRI with MRCP correctly identified the presence of a pancreatic mass in all 21 of these patients. Following pathologic correlation, it was determined that MRI with MRCP was 81% accurate in determining the benign or malignant nature of the pancreatic mass and 43% accurate in predicting lymph node involvement. In predicting resectability, MRI with MRCP had a sensitivity of 100%, specificity of 83%, positive predictive value of 94%, negative predictive value of 100%, and accuracy of 95%. MRI with MRCP is an accurate, noninvasive technique in the preoperative evaluation of pancreatic malignancy. Information obtained from MRI with MRCP including identification of a mass and predicting tumor resectability may be of value in staging and avoiding unnecessary invasive diagnostic procedures in patients with pancreatic cancer.

Magnetic resonance cholangiopancreatography accurately predicts the presence or absence of choledocholithiasis.

Accurate common bile duct (CBD) imaging in patients with biliary calculi is an important determinant of specific therapy. Noninvasive methods to evaluate calculi in the CBD have limited accuracy and rely mainly on ultrasonography and computed tomography. Magnetic resonance cholangiopancreatography (MRCP) is a new noninvasive modality available to evaluate the biliary system. This study was undertaken to assess the accuracy of MRCP in predicting the presence or absence of CBD stones in patients at increased risk for choledocholithiasis. The medical records of 48 patients with a final diagnosis of biliary calculous disease undergoing MRCP between November 1995 and April 1997 were retrospectively reviewed. Three groups were identified: choledocholithiasis (n = 19), gallstone pancreatitis (n 5 11), and uncomplicated cholelithiasis (n = 18). In all patients the presence or absence of CBD calculi, as determined by MRCP, was correlated with the final diagnosis obtained from endoscopic retrograde cholangiopancreatography (ERCP) (n = 19), intraoperative cholangiography (n = 6), CBD exploration (n = 13), or clinical follow-up (n = 10). Sensitivity, specificity, and accuracy of MRCP were determined. The major clinical indications for MRCP in the 48 patients ware abnormal liver function tests followed by hyperamylasemia. Twenty patients were diagnosed with CBD stones and 28 were not. MRCP correctly predicted the presence of CBD stones in 19 of 20 patients and failed to detect CBD stones in one patient with gallstone pancreatitis. MRCP incorrectly predicted the presence of CBD stones in 3 of 28 patients ultimately found to have gallstones and no CBD stones. MRCP correctly predicted the absence of CBD stones in the other 25 patients including 10 patients with gallstone pancreatitis. Overall, MRCP had a sensitivity of 95%, a specificity of 89%, and an accuracy of 92%. MRCP is an accurate, noninvasive test for evaluating the CBD duct for the presence or absence of calculi in patients suspected of having CBD stones. Our data support the use of MRCP in the preoperative evaluation of these patients as findings may influence therapeutic decisions.

Breakdown of P.G.E. 1 synthesis is responsible for the acquired immunodeficiency syndrome.

This hypothesis suggests that repeated viral infections disrupt the biosynthesis of P.G.E. 1 and nullify a major system by which t lymphocytes are regulated. It is hypothesized that a breakdown of P.G.E. 1 synthesis is responsible for the acquired immunodeficiency syndrome and the frequently associated Kaposi's sarcoma. A means of restoring P.G.E. 1 synthesis and reversing the immunodeficiency is proposed.

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer.

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor cyclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m-2 combined with CsA 10 mg kg-1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m-2 week-1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.

Optimal management of the pancreatic remnant after pancreaticoduodenectomy.

OBJECTIVE: The authors evaluated methods of operative management of the pancreatic remnant after pancreaticoduodenectomy. SUMMARY BACKGROUND DATA: Despite reductions in mortality after pancreaticoduodenectomy, leakage from the pancreatic remnant still may cause significant morbidity. Patients with small, unobstructed pancreatic ducts or soft, friable pancreata are at particularly high risk. Although numerous surgical techniques have been described to avoid such complications, no single method is suitable for all patients. METHODS: The authors retrospectively reviewed the medical records of 114 consecutive patients who underwent pancreaticoduodenectomy. Sixty-nine patients were men (61%) and 45 were women (39%), with median age 66 years. Underlying disease was malignant in 87 (76%) and benign in 27 (24%). Patients were divided into groups based on risk for postoperative pancreatic fistula and on the operative management of the pancreatic remnant. Sixty-eight patients underwent end-to-side pancreaticojejunostomy, 13 of whom were high risk (group 1A) and 55 of whom were low risk (group 1B). Thirty-seven patients, all high risk, had either pancreatic duct closure by oversewing (N = 19, group 2) or end-to-end pancreaticojejunal invagination (N = 18, group 3). Nine patients underwent total pancreatectomy (group 4). Morbidity related to prolonged pancreatic drainage (PPD) of greater than 20 days was determined. RESULTS: Overall incidence of PPD was 17% and caused the only death. Patients considered high risk for postoperative pancreatic fistula had a 36% incidence of PPD compared with 2% in patients considered low risk (p < 0.0001). Prolonged pancreatic drainage frequency related to the method of pancreatic remnant management was as follows: group 1A, 15%; group 1B, 2%; group 2, 79%; and group 3, 6% (p < 0.001 for group 2 vs. other groups). No serious sequelae followed PPD in 15 patients (79%); however, 4 patients required reoperation for pseudocyst or abscess drainage; one in group 1A (who died) and three in group 2. Multivariate analysis revealed that operative technique (oversewing of the pancreatic duct) and male sex were significant factors predisposing a patient to the development of PPD. CONCLUSION: After pancreaticoduodenectomy, pancreatic remnant management by end-to-side pancreaticojejunostomy appeared safe in low-risk patients. In high-risk patients, end-to-end pancreaticojejunal invagination was the safest option. Morbidity was greatest after pancreatic duct closure without anastomosis.

Phase II trial of recombinant beta (IFN-betaser) interferon in the treatment of metastatic breast cancer.

Nine patients with metastatic breast cancer received 30 x 10(6) I.U. of Interferon - Betaser (Betaseron) intravenously daily times five for two consecutive weeks followed by a two week rest period. Only one patient received more than one such cycle of Betaseron. The drug was well tolerated in eight of these patients. One patient, with liver metastases and liver dysfunction, developed hepatic decompensation during therapy. Toxicity consisted of anorexia, chills, fever, fatigue and nausea with an occasional patient having emesis. One patient developed severe thrombocytopenia, two, significant leukopenia and nine, mild elevations of serum transaminase. Two patients developed beta interferon binding antibodies but none developed neutralizing antibodies. No anti-tumor responses were seen and disease progression occurred rapidly during the four week cycle in eight of nine patients.

Recombinant beta-serine-interferon in hairy cell leukemia compared prospectively with results with recombinant alpha-interferon.

Ten patients with hairy cell leukemia (HCL) requiring therapy were treated with recombinant beta-serine-interferon (rIFN-beta ser) (90 x 10(6) units [U] subcutaneously three times a week). Eight patients were evaluable for response and nine for toxicity. Five patients (63%) showed normalization of peripheral blood counts, and an additional two patients (25%) showed improvement in at least one hematologic variable. Persistent hairy cells were detected in the bone marrow of all patients at the completion of therapy. All patients experienced influenza-like symptoms which were not dose limiting and which resolved with continued therapy. Erythema and induration at interferon injection sites developed in five patients (56%); one required dose reduction and another was removed from the study for this reason. Data from matched historical controls treated with recombinant alpha-interferon are presented for comparison. We conclude that rIFN-beta ser has activity in HCL.