Etoposide (VP-16) and cisplatin at maximum tolerated dose in non-small cell lung carcinoma: a Cancer and Leukemia Group B study.

A multi-institutional cooperative group trial was undertaken by the Cancer and Leukemia Group B (CALGB) to evaluate the efficacy of the combination of cisplatin and intravenous etoposide for the treatment of metastatic or recurrent non-small cell lung cancer (NSCLC). The doses used were those previously determined to be the maximally tolerated dose of this drug combination. Forty patients were entered into the trial, 37 of whom were eligible for evaluation. Cisplatin (35 mg/M2/day for 3 days) and etoposide (200 mg/M2/day for 3 days) were administered every 28 days for a planned 6 cycles of therapy. Sixteen of 37 evaluable patients (43%) responded to therapy. Myelosuppression was the dominant toxicity, with 89% of the patients experiencing grade 4 neutropenia, and nearly half grade 3 or 4 thrombocytopenia. Median survival was 8.5 months, with 30% of the patients alive at 1 year and 10% alive at 2 years. Malaise, fatigue, and peripheral neuropathy were the other major toxicities. The combination of etoposide at the dose of 200 mg/M2/day for 3 days and cisplatin at 35 mg/M2/day for 3 days is a highly potent combination against metastatic non-small cell carcinoma.

Nonoperative management of non-small cell lung cancer: the current cancer and leukemia group B experience.

The Cancer and Leukemia Group B (CALGB) is studying nonoperative management in two subgroups of patients with advanced non-small cell lung cancer. In patients with regional disease, primarily those with bulky N2 or T4 disease or those with contralateral mediastinal involvement (N3), a phase III trial is under way to explore concurrent carboplatin as intensification of local therapy and additional systemic treatment. This builds on prior CALGB work demonstrating the benefits of induction chemotherapy prior to radiation for selected patients with stage III disease. For patients with still more advanced disease, a trial evaluating efficacy and cost of two supportive care modalities during intensive chemotherapy is about to begin accrual. Following its completion, the CALGB plans to evaluate new chemotherapy combinations based on one or more of the exciting new agents now being tested for the nonoperative management of non-small cell lung cancer.

Rapid and sustained hematopoietic reconstitution by peripheral blood stem cell infusion alone following high-dose chemotherapy.

We utilized mobilized peripheral blood stem cells (PBSC) as sole support for hematologic reconstitution following high-dose chemotherapy in 52 patients with advanced solid tumors and lymphoma. PBSC were collected by large scale leukapheresis after mobilization with chemotherapy. Each apheresis product was analysed for total nucleated cells, CFU-GM and CD34+ content. Disease-specific high-dose chemotherapy regimens were administered followed by thawed PBSC. Colony-stimulating factors were not administered. The median time to an absolute neutrophil count > 0.5 x 10(9)/l was 13 days (range 9-26 days) and median time to a sustained platelet count > 20 x 10(9)/l without transfusion support was 10 days (range 5-43 + days). There was no difference in time to recovery by dose-intensive regimen or underlying disease. The times to recover ANC and platelets both correlated significantly with increasing doses of PBSC as assayed by CD34+ cells and CFU-GM. All four patients with prolonged platelet recovery times received < 20 x 10(4) CFU-GM/kg, establishing this as a threshold value for PBSC infusion. There were no late transient or sustained graft failures. For 26 patients alive 1 year after infusion, the mean total leukocyte count is 6.3 x 10(9)/l, mean hematocrit 35.5% and mean platelet count 182 x 10(9)/l. Thirteen patients followed at least 24 months after PBSC infusion have essentially normal blood counts. Mobilized peripheral blood progenitors are an effective source of stem cells which afford rapid and complete hematopoietic engraftment after myelo-suppressive chemotherapy regimens. Engraftment appears sustained with no late failures.(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of the susceptibility patterns of gram-negative organisms isolated in cancer centres with aminoglycoside usage.

This study in 12 cancer treatment centres across the United States was designed to evaluate the potential for increased resistance to amikacin with unrestricted use. An initial 3-month baseline period during which the use of amikacin was restricted and that of tobramycin and gentamicin unrestricted was followed by a period of at least 12 months when amikacin was the primary aminoglycoside. Resistance of Gram-negative bacilli to these aminoglycosides from hospitalized patients was monitored and compared for the two periods. Amikacin usage increased from a mean of 20.1% to a mean of 83.9% of aminoglycoside patient-days. A reduction in the use of tobramycin and gentamicin were observed with means of 66.1 and 10%, and 13.9 and 6.1%, respectively for the two periods. Resistance to amikacin was 0.85% at baseline and 1.3% at end-point which was not clinically significant (P = 0.614). Baseline resistance was 6.5 and 7.6%, while final resistance was 2.6 and 4.8%, respectively for tobramycin (P = 0.001) and gentamicin (P = 0.052).

Phase I clinical evaluation of cytarabine and cisplatin in patients with advanced cancer.

Studies in cell culture systems and tumor-bearing animals have demonstrated synergistic cytotoxicity of cytarabine (ara-C) and cisplatin. We have conducted a phase I trial to assess the toxic effects and tolerable doses of these drugs in patients with advanced cancer. Forty-five such patients were treated with varying dosages of ara-C infused continuously during Days 1-3 of a 28-day cycle. Cisplatin at a dose of 100 mg/m2 was administered on Day 2 of the cycle. Using this schedule, the maximally tolerated dose of ara-C in previously untreated patients was 60 mg/m2/day (180 mg/m2). Hematologic toxicity was dose-limiting with median wbc and granulocyte count nadirs of 1800 and 168/mm3, respectively. Reduction of the cisplatin dose while maintaining the ara-C dose at 60 mg/m2/day resulted in less myelosuppression, suggesting that these drugs may have synergistic effects on the bone marrow. Objective responses were seen in six of 41 evaluable patients, including five of 12 patients with non-small cell lung cancer. The severe bone marrow toxicity observed at relatively low drug doses and the 42% response rate in patients with non-small cell lung cancer suggest that the combination of ara-C and cisplatin has substantial clinical activity. Phase II trials are warranted in non-small cell lung cancer and other tumors.

Sperm phagocytosis by human peritoneal macrophages: a possible cause of infertility in endometriosis.

The mechanism of infertility in women with endometriosis is unknown, but it is independent of mechanical factors that affect fallopian tube function. Increased numbers of peritoneal macrophages are present in women with endometriosis and have access to the female reproductive tract via the oviducts. To determine whether peritoneal macrophages might phagocytize sperm and thereby contribute to infertility in women with endometriosis, we examined peritoneal macrophages from 32 fertile and infertile women; the infertile group was separated into those with and those without visible endometriosis. Peritoneal macrophages from infertile patients with endometriosis phagocytized more normal sperm in vitro (84% +/- 4%) than did those from fertile women (43% +/- 4%) or infertile women without endometriosis (46% +/- 8%) (p less than 0.002). The sperm phagocytosis occurred rapidly and reached a peak by approximately 6 hours. Incubation at 0 degrees C, lysing the macrophages by freezing and thawing, or fixing the macrophages with glutaraldehyde inhibited the sperm uptake by macrophages. The process occurred in cultures with or without serum, thereby indicating that the sperm phagocytosis was not dependent on sperm opsonization with a serum factor. Electron microscopy showed internalization of the spermatozoa into phagosomes with subsequent intravacuolar degradation. These data demonstrate that: (1) peritoneal macrophages phagocytize and degrade sperm in vitro and (2) peritoneal macrophages isolated from women with endometriosis exhibit greater phagocytosis in vitro than do macrophages from fertile women or infertile women without endometriosis. These results suggest that, if peritoneal macrophages from women with endometriosis enter the reproductive tract via the oviducts, they might adversely influence fertilization by phagocytizing sperm.

Treatment of small cell carcinoma of the lung with methotrexate, doxorubicin, cyclophosphamide, and lomustine: a community-based study.

Forty-four patients with undifferentiated small cell carcinoma of the lung (SCCL) were diagnosed and treated at community hospitals. Patients with limited disease were treated with surgical resection or primary radiation therapy (RT) followed by chemotherapy; those with extensive disease received chemotherapy followed by RT if there was not a complete primary response. The chemotherapy used was a combination of methotrexate, doxorubicin, cyclophosphamide, and lomustine. Median survival for patients with both limited and extensive disease was 12 months, with a six-month survival of 89%. Half of the patients had recurrence in the lung. The toxicity was moderate and tolerable. We conclude that this combination chemotherapy plus radiation therapy carries acceptable toxicity and can be used in a community hospital to achieve response rates and survival of SCCL equivalent to that obtained in large cancer centers.

Monocyte chemotactic peptide receptor. Functional characteristics and ligand-induced regulation.

Monocytes, macrophages, and neutrophils will demonstrate several important cellular functions in response to synthetic formylated oligopeptides. N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine (fNLPNTL) was a potent chemoattractant for human blood monocytes; a 1.0-nM concentration induced a maximal chemotactic response. Binding of 125I-labeled fNLPNTL to the monocyte formyl peptide receptor was rapid, specific, and saturable at 4, 24, or 37 degrees C. At 4 degrees C, monocytes from several different donors demonstrated between 10,000 and 18,000 receptors/cell with a dissociation constant (Kd) of 1.7-2.7 nM. The association of the 125I peptide with the cells was irreversible at the elevated temperatures and exceeded the amount of surface receptor by approximately four-fold, suggesting receptor-mediated peptide endocytosis. Processing of rhodamine-labeled fNLPNTL by monocytes was observed directly by video intensification microscopy. At 37 degrees C, diffuse membrane fluorescence was seen initially, followed by rapid aggregation and internalization of the peptide. Monocytes incubated with fNLPNTL displayed a temperature dependent loss of surface binding capacity (receptor down-regulation). This decrease was due to a decrease in surface receptor number rather than to a decrease in receptor affinity. A dose-response curve for peptide-induced receptor down-regulation correlated with a dose-response curve for 125I-labeled fNLPNTL uptake, suggesting that each uptake event led to the loss of one surface receptor. Surface receptor replenishment following down-regulation was rapid and not dependent on new protein synthesis, but was inversely related to both the time and peptide concentration used to induce down-regulation. An exact correlation between receptor down-regulation and functional deactivation of the chemotactic response could not be demonstrated.