Effects of anti-phencyclidine and anti-(+)-methamphetamine monoclonal antibodies alone and in combination on the discrimination of phencyclidine and (+)-methamphetamine by pigeons.

RATIONALE: Drug-specific monoclonal antibodies against phencyclidine (PCP) and (+)-methamphetamine [(+)-METH] should bind to these drugs to block their discriminative stimulus effects. OBJECTIVES: To determine if mouse monoclonal antibodies against PCP and (+)-METH can block the discriminative stimulus effects of the drugs in pigeons. MATERIALS AND METHODS: Pigeons were trained to discriminate among intramuscular injections of saline, 1 mg/kg PCP, and 2 mg/kg (+)-METH. After responding stabilized, cumulative dose-response curves were obtained for PCP and (+)-METH. Doses of an anti-PCP antibody at 620 mg/kg (anti-PCP mAb6B5) with a K (D) of 1.3 nM for PCP and no measurable affinity for (+)-METH and 1,000 mg/kg doses of anti-(+)-METH antibody (anti-METH mAb6H7) with a K (D) of 41 nM for (+)-METH and no measurable affinity for PCP were subsequently administered, first alone and later in combination after which the dose-response curves were redetermined. RESULTS: When the antibodies were given alone, the anti-PCP antibody blocked the discriminative stimulus effects of PCP, but not those of (+)-METH, and the anti-(+)-METH antibody blocked the discriminative stimulus effects of (+)-METH, but not those of PCP. The anti-PCP antibody shifted the PCP dose-response curve further to the right and for a longer time than the anti-(+)-METH antibody shifted the dose response curve for (+)-METH. When the anti-PCP and anti-(+)-METH antibodies were administered on the same day, the discriminative stimulus effects of both drugs were completely blocked 1 day after antibody administration. CONCLUSIONS: These experiments demonstrate the high specificity of the antibodies for the drugs to which they bind and show that monoclonal antibodies can be combined to antagonize the effects of more than one drug.

Hepatic chemoembolization combined with systemic infusion of 5-fluorouracil and bolus leucovorin for patients with metastatic colorectal carcinoma: A Southwest Oncology Group pilot trial.

BACKGROUND: Rates of response to systemic chemotherapy among patients with advanced colorectal carcinoma rarely exceed 25- 30%, and complete responses are rare. The liver is the most common site of metastasis; however, regional therapies have not improved survival rates. The Southwest Oncology Group designed a clinical trial combining hepatic arterial chemoembolization with systemic infusion of 5-fluorouracil chemotherapy in an attempt to increase the complete response rate and prolong the time to disease progression. METHODS: Patients with documented liver metastasis from colorectal carcinoma were treated with two or three cycles of chemoembolization using a collagen suspension with doxorubicin, mitomycin C, and cisplatin. Subsequently, systemic chemotherapy with continuous infusion of 5-fluorouracil and weekly leucovorin was initiated. Patients were assessed for response at 12-week intervals, with treatment continuing until disease progression. RESULTS: Thirty-one eligible, evaluable patients were treated. One complete and 8 partial responses were observed, for an overall response rate of 29%. Fifty-eight percent of patients survived 1 year, and the median survival for the whole cohort was 14 months. The median time to progression was 8 months. Seven patients (23%) experienced Grade 4 toxicity and 21 patients (67%) had Grade 3 toxicity. CONCLUSIONS: The response rate in this trial was comparable to that achieved with systemic chemotherapy consisting of a fluorinated pyrimidine-based regimen for patients with this disease. No improvement in complete response rate or time to progression was observed compared with the Southwest Oncology Group's experience with systemic therapy. The authors are not planning to study this regimen further as a treatment for patients with metastatic colorectal carcinoma.

The detection of changes in mammographic densities.

We previously reported reductions in mammographic densities in women participating in a trial of a gonadotropin-releasing hormone agonist (GnRHA)-based regimen for breast cancer prevention. In our previous report, we compared (by simultaneous evaluation) three basic elements of mammographic densities. The purpose of the present study was to evaluate whether a standard (expert) method of measuring mammographic densities would detect such changes in densities and whether a novel nonexpert computer-based threshold method could do so. Mammograms were obtained from 19 women at baseline and 12 months after randomization to the GnRHA-based regimen. The extent of mammographic densities was determined by: (a) a standard expert outlining method developed by Wolfe and his colleagues (Am. J. Roentgenol., 148: 1087-1092, 1987); and (b) a new computer-based threshold method of determining densities. The results from both the expert outlining method and the computer-based threshold method were highly consistent with the results of our original (simultaneous evaluation) method. All three methods yielded statistically significant reductions in densities from baseline to the 12-month follow-up mammogram in women on the contraceptive regimen. The difference between the treated and the control group was statistically significant with the expert outlining method and was of borderline statistical significance with the computer-based threshold method. The computer-based results correlated highly (r > 0.85) with the results from the expert outlining method. Both the standard expert outlining method and the computer-based threshold method detected the reductions we had previously noted in mammographic densities induced by the GnRHA-based regimen.

Is cryosurgical ablation appropriate for treating hepatocellular cancer?

OBJECTIVE: To examine the feasibility and efficacy of cryosurgical ablation as treatment for patients with cirrhosis with unresectable hepatocellular carcinoma. DESIGN: Retrospective case series. SETTING: A tertiary public hospital and a cancer center. PATIENTS: Twelve patients with cirrhosis with hepatocellular carcinoma (stage II, 2; stage III, 1; stage IVA, 7; stage IVB, 2). INTERVENTIONS: Cryosurgical ablation of all identifiable tumors. Nine patients treated with curative intent were included in the survival analysis, and 3 were treated for palliation. Five patients were treated with preoperative intra-arterial chemoembolization. MAIN OUTCOME MEASURES: Perioperative complications and the effects of tumor stage and chemoembolization were examined. Patient survival and disease-free interval were calculated by life-table analysis. RESULTS: No perioperative deaths occurred and 1 patient had 2 postoperative complications: pneumonia and biloma. The mean survival has been 19 months after cryosurgical ablation and 29 months after diagnosis. Three of the 9 patients treated with curative intent died with recurrence at a mean of 17 months after cryosurgical ablation. Four patients are alive with recurrence at a mean of 19 months after cryosurgical ablation and 38 months after diagnosis. Two patients with stage II disease have no evidence of recurrence 10 and 32 months after cryosurgical ablation. CONCLUSIONS: Cryosurgical ablation is feasible and safe for treatment of hepatocellular carcinoma in patients with cirrhosis. The technique is primarily palliative but may provide a possibility of cure in patients with lower-stage disease.

Prevalence of infection following hepatic chemoembolization with cross-linked collagen with administration of prophylactic antibiotics.

PURPOSE: The authors present their experience with 494 hepatic chemoembolization (HCE) procedures in 236 patients with administration of a mixture of cross-linked collagen and chemotherapeutic agents. The prevalence of infectious complications was compared in patients who did and did not receive prophylactic administration of antibiotics as part of the HCE procedure. PATIENTS AND METHODS: Fourteen HCE procedures in nine patients were performed without prophylactic antibiotics (PA). These patients underwent embolization with cross-linked collagen alone or with low-dose cisplatinum. All of the remaining 480 procedures in 227 patients were performed with PA. RESULTS: One of the nine patients (11%) who did not receive PA experienced fatal sepsis within 24 hours of HCE. Of the 227 patients who did receive antibiotics, six (2.6%) developed hepatic abscess and no fatal sepsis was encountered. CONCLUSION: Use of PA decreases the prevalence of infectious complications following HCE.

Hepatic chemoembolization: safety with portal vein thrombosis.

PURPOSE: Nine patients with unresectable hepatic malignancy and portal vein thrombosis underwent hepatic chemoembolization. PATIENTS AND METHODS: Six patients had primary malignancies (hepatocellular carcinoma in five, hepatoblastoma in one), and three had metastatic tumor (adenocarcinoma of the colon in two, glucagonoma in one). Chemoembolization was performed with 10 mg/mL of cross-linked collagen, 10 mg/mL of mitomycin, 3 mg/mL of doxorubicin, and 3 mg/mL of cisplatin. Each patient was treated until flow in the hepatic artery ceased completely. RESULTS: All treatments were technically successful. Eight patients responded to treatment, including two long-term survivors (> 2 years). One patient died 31 days after treatment of progressive hepatic malignancy and atherosclerotic disease. No patient developed hepatic infarction or insufficiency as a result of treatment. Follow-up ranged from 1 to 26 months (mean, 13 months). CONCLUSION: Portal vein thrombosis should not be considered an absolute contraindication to hepatic chemoembolization. Hepatic chemoembolization can be performed safely in the presence of adequate collateral circulation.

The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial.

We assigned 91 patients with deeply invasive, pathological stage P3, P4 or N+ and Mo transitional cell carcinoma of the bladder (with or without squamous or glandular differentiation) to adjuvant chemotherapy or to observation after radical cystectomy and pelvic lymph node dissection. For most patients chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M.2 cisplatin, 60 mg./M.2 doxorubicin and 600 mg./M.2 cyclophosphamide. A significant delay was shown in the time to progression (p = 0.0010) with 70% of the patients assigned to chemotherapy free of disease at 3 years compared to 46% in the observation group. Median survival time for patients in the chemotherapy group was 4.3 years compared to 2.4 years in the observation group (p = 0.0062). In addition to treatment groups, important prognostic factors included age, gender and lymph node status. The number of involved lymph nodes was the single most important variable. We recommend adjuvant chemotherapy for patients with invasive transitional cell carcinoma after definitive surgical resection.

Intraarterial administration of lidocaine for analgesia in hepatic chemoembolization.

Hepatic chemoembolization (HCE) routinely results in severe pain requiring massive doses of intravenously administered narcotics. This study examines the efficacy and safety of lidocaine administered intraarterially for analgesia in HCE. In 45 HCE procedures, lidocaine was injected into hepatic arterial branches just prior to and during chemoembolization. Adjunctive analgesic doses given during the procedure and the need for a morphine sulfate drip infusion for postprocedural pain control were recorded and compared with those in 20 procedures performed previously without lidocaine. In procedures with lidocaine, an average of 0.13 mg of morphine sulfate and 1.3 mg of midazolam were required. This is significantly lower than the 11.7 mg of morphine sulfate and 3.7 mg of midazolam used during procedures without lidocaine. A postprocedural morphine drip infusion was required for control of severe pain in 16 of 20 (80%) procedures performed without lidocaine compared with nine of 45 (20%) of those performed with lidocaine. Peripheral blood levels of lidocaine were well below the toxic level, and no complications referable to lidocaine toxicity occurred. Marked reductions in the amount of narcotic analgesia in HCE procedures may be safely achieved with the administration of intraarterial lidocaine.

Effect of antimicrobial protection on tolerance to hepatic chemoembolization with a fibrous collagen carrier.

The effect of antimicrobial prophylaxis on tolerance to hepatic embolization and chemoembolization with collagen particles was examined in porcine liver. Embolization in the 36 animals consisted of hepatic artery injection of 3 mL of collagen (10 mg/mL) alone or combined with one to three drugs (cisplatin, mitomycin, and doxorubicin). Embolization was performed with or without antimicrobial protection, and the animals were killed at 5 days for gross and histologic evaluation of liver and for bacterial culture. When present, liver damage consisted of focal to whole-lobe necrosis. Liver damage was correlated with positive bacterial culture (P less than .002) and was reduced by antimicrobial protection. Vessel recanalization was inhibited by addition of drug to collagen (P less than .001) and by lack of antimicrobial protection (P less than .001). Perivascular necrosis was directly related to vessel size (P = .0001). Antimicrobial prophylaxis is recommended to enhance hepatic chemoembolization safety.

Renal cisplatin chemoembolization with Angiostat, Gelfoam, and Ethiodol in the rabbit: renal platinum distributions.

Renal platinum distributions were determined in rabbits after administration of 0.4 mL of 1 mg/mL cisplatin by intravenous infusion, by injections into the left renal artery with aqueous contrast material and with lipid contrast material (Ethiodol), and by chemoembolization of the left renal artery with concurrent administration of various concentrations of two collagen carriers, Angiostat collagen for embolization and Gelfoam gelatin. Renal platinum concentration was measured in tissue homogenates at 2 1/2 hours with atomic absorption spectrometry. Target-kidney platinum levels were 5.4 and 6.9 times the contralateral-kidney levels after intraarterial infusion of aqueous and lipid contrast media, respectively. With Angiostat and Gelfoam chemoembolization, renal platinum retention and collagen concentration were linearly related (r = .87 and .81, P less than .001). Target-kidney-contralateral-kidney platinum ratios were 57:1 for 30 mg/mL Gelfoam and 220:1 for 10 mg/mL Angiostat. The difference in regional drug retention for Angiostat versus Gelfoam reflects the stable fiber integrity of Angiostat.

Unusual antiproliferative effects of transforming growth factors-beta 1 and beta 2 against primary cells from human tumors.

Transforming growth factors beta 1 and beta 2 (TGF-beta 1 and beta 2), tested in a clonogenic assay against primary cells from human tumors, suppress proliferation to different extents. In nineteen of twenty-six cell cultures, proliferation was less than 50% of control with factor at 0.04 or 0.4 nM. Of these, TGF-beta 2 was more active than TGF-beta 1 in fourteen; and TGF-beta 1 was more active than TGF-beta 2 in five. In seven of the nineteen, proliferation was 0% with one or the other factor. In contrast, cisplatin was much less effective in inhibiting proliferation of some of the same cells even at 1,000 or more times the molar concentration of the factors. Surprisingly, when TGF-beta 1 and TGF-beta 2 were combined at equal concentrations, the antiproliferative effect of one was cancelled or markedly inhibited by the other.

Collagen chemoembolization: pharmacokinetics and tissue tolerance of cis-diamminedichloroplatinum(II) in porcine liver and rabbit kidney.

Pharmacokinetics of chemoembolization with a fibrous collagen carrier was studied in rabbit kidney and porcine liver models. Cisplatin (1 mg/ml) chemoembolization of liver and kidney was compared with i.v. and intraarterial cisplatin infusion. Tissue platinum concentration [Pt] was measured at 2.5 h by atomic absorption spectrometry. Renal platinum retention and Angiostat (collagen for embolization) concentration were linearly related (r = 0.87, p less than 0.001). At 10 mg/ml collagen for embolization, chemoembolized kidney [Pt] was 220 +/- 50 (SE; n = 4) times contralateral kidney [Pt], and 62 and 23 times renal [Pt] by i.v. and intraarterial infusion, respectively. At 10 mg/ml collagen for embolization, chemoembolized liver [Pt] was 2 times hepatic [Pt] by i.v. and intraarterial infusion. Since hepatic tumor vasculature is end arterial, chemoembolization should yield high [Pt] in tumor (as in kidney) but lower levels in normal liver.

Transpancreatic catheterization of the right hepatic artery for chemoembolization using a new infusion system.

The right hepatic artery was catheterized for chemoembolization in a patient with liver-dominant metastatic breast carcinoma and occlusion of the celiac artery by tumor compression. This was accomplished by use of a new coaxial infusion catheter-steerable guidewire system passed through the superior mesenteric artery and posterior pancreatic arcade.

Reevaluation of the maximum tolerated dose of continuous venous infusion of 5-fluorouracil with pharmacokinetics.

5-Fluorouracil (5-FU) was administered as a continuous ambulatory venous infusion to 25 patients in a Phase I trial. The principal dose limiting toxic effect observed was mucositis. Skin rash and diarrhea occurred less frequently. Hematological toxicity was modest, and no hepatic toxicity was seen. One partial remission of 138 days duration was seen in a patient with metastatic breast carcinoma who was previously refractory to a 5-FU combination regimen. Patient tolerance of 5-FU delivered in this manner appeared highly variable. On the basis of this trial, we recommend that future studies evaluating the efficacy of long-term venous infusion of 5-FU should utilize a dosage of 450 mg/m2/day.

Reassessment of the role of adjunctive surgical therapy in the treatment of advanced germ cell tumors.

We treated 30 patients for stage B3 or B3C germ cell tumors between December 1978 and December 1983. After initial, high dose, platinum-based combination chemotherapy, all patients underwent adjunctive resection of all clinically evident residual disease. Residual malignant elements were found in the retroperitoneum in 35 per cent of 26 nonseminomatous germ cell tumor patients and in 40 per cent of those with residual lesions beyond the retroperitoneum following chemotherapy. After additional chemotherapy, including platinum plus etoposide for patients with residual malignant elements, 80 and 75 per cent of those with stages B3 and B3C disease, respectively, achieved a complete sustained remission at a mean followup of 30 to 38 months, respectively. The strongest predictors of ultimate treatment failure were the presence of extensive pulmonary disease at presentation and the finding of residual malignant elements in resected lesions. Of 4 patients with seminoma 3 achieved sustained complete remission, while 1 died of recurrent embryonal carcinoma. These data support the role of adjunctive resection of clinically evident residual lesions following initial platinum-based chemotherapy in advanced metastatic germ cell tumors, and demonstrate the efficacy of additional platinum-etoposide-based chemotherapy in the 35 to 40 per cent of patients who harbor residual malignant disease in resected lesions.

Correlation of meningioma hormone receptor status with hormone sensitivity in a tumor stem-cell assay.

Several investigators have detected progesterone receptors in a high percentage of meningioma specimens and have noted progesterone receptors to be more common than estrogen receptors in these specimens. However, a functional significance of such hormone receptor positivity in control of meningioma growth has not been described. This paper describes a paired test of the estrogen and progesterone receptor assay as the biochemical assay and of the human tumor stem-cell clonogenic assay (HTSCCA) as the functional assay in 17 meningioma specimens. Only one (6%) of the 17 specimens was estrogen receptor-positive, while 11 (69%) of 16 specimens were progesterone receptor-positive. The HTSCCA revealed that only two (15%) of 13 specimens were sensitive to estradiol while five (31%) of 16 specimens were sensitive to progesterone. Comparison of progesterone results for the 15 specimens on which both hormone receptor assay and HTSCCA were performed revealed correlation in a majority of cases; four specimens were positive for both assays and five specimens were negative for both assays. No specimen that was negative for progesterone receptors was sensitive to progesterone by HTSCCA. These results suggest that the hormone receptor and sensitivity pattern of meningiomas may differ from that of breast cancer, and that progesterone addition or ablation may be a reasonable therapeutic approach for meningiomas.

Peripheral hepatic arterial embolization with crosslinked collagen fibers.

Hepatic artery embolization with a nonimmunogenic, crosslinked microfibrillar collagen preparation (Angiostat, Collagen for Embolization, Target Therapeutics, Los Angeles, CA) was studied in mongrel dogs. Flow-directed technique was used to achieve complete distal arterial occlusion. Serial liver function evaluation demonstrated marked alterations at 48 to 72 hours, partial correction at one week, and resolution of abnormalities by one month. Restoration of large vessel blood flow was angiographically demonstrable at one week. Follow-up arteriograms showed no persistent arterial occlusion. Collagen was demonstrated in vessels of 20 to 250 micron. Recanalization was achieved by migration of endothelial cells around the collagen, development of a new vascular channel within an endothelial cell cleft, and subsequent complete removal of the collagen over a three- to four-month period. Three months after embolization with a single dose, normal hepatic vascular and tissue anatomy and hepatic function were restored completely. Repeated embolization at two weekly intervals was well tolerated.

Recombinant interferon alpha-2 (INTRON A) in a phase II study of renal cell carcinoma.

Because two of five patients with renal cell carcinoma in a Phase I study had partial response to recombinant alpha-2 interferon (IFN), we treated 26 patients with advanced renal cell carcinoma with a 3-month regimen of IFN. Patients were randomized to receive IFN either subcutaneously (2 X 10(6) IU/m2 3 times a week) or intravenously (3 X 10(7) IU/m2 for 5 consecutive days every 2-3 weeks). Patients whose disease was responding or stable were treated further, while those with progressive disease on subcutaneous treatment were offered intravenous therapy. Sites of metastasis included lung (14 patients), bone (7 patients), soft tissue (7 patients) and liver (2 patients). Twenty patients were evaluable for response. One patient had a partial response at the end of the third course of intravenous IFN and subsequently had complete disappearance of a 12 X 7 cm subcutaneous mass after the seventh course of treatment. The disease was stable in 13 patients including two minor responses, and six patients had progressive disease (5 with subcutaneous treatment; 1 with intravenous treatment) including one mixed response. All patients experienced early flu-like symptoms of fever, chills, and rigors during the first few days of treatment and most had mild to moderate fatigue. Three patients left the study because of fatigue, and one had an urticarial rash. From these results and our previous experience, it appears that IFN has activity against renal cell carcinoma with acceptable toxicity.

Indium-111 oxine platelet survival in dogs: effect of doxorubicin and Dacron grafts.

The cytotoxic chemotherapeutic agent doxorubicin was found to acutely decrease platelet survival times in beagle dogs as determined using platelets labeled with [111In]oxine. Recovery was rapid, with platelet survival times returning to normal within 3 wk of cessation of treatment. Doxorubicin (1.5 mg/kg i.v. every 3 wk for a total of four doses) also delayed the return of platelet survival times to normal when given to beagle dogs following placement of thoracoabdominal aortic Dacron grafts. It is not known whether or not this may have clinical significance.