Early hypophosphatemia in preterm infants receiving aggressive parenteral nutrition.

OBJECTIVE: To report the prevalence of hypophosphatemia during the first week of life in preterm infants receiving aggressive parenteral nutrition and to analyze population variables associated with severe hypophosphatemia. STUDY DESIGN: A retrospective cohort of 61 neonates below 1250 g birth weight consecutively born at Hospital Italiano de Buenos Aires exposed to high caloric and protein intake from the first day of birth. Primary outcome was hypophosphatemia (phosphate <4 mg dl(-1)). A one-sample mean comparison test was used to compare our sample with a hypothesized population mean. RESULTS: The prevalence of hypophosphatemia was 91% (95% confidence interval (CI) 82 to 97%). The mean phosphatemia value was 2.52 mg dl(-1) (95% CI 2.18 to 2.86), significantly different from the hypothesized population mean (P<0.001). Patients with severe hypophosphatemia (<2 mg dl(-1)) were smaller. They presented with sepsis more frequently and received more vasoactive drugs and mechanical ventilation. CONCLUSION: The prevalence of hypophosphatemia in this group of preterm infants is high. The potential association with adverse clinical outcomes deserves further research.

Ventilatory management in neonates. Science or art?

Conventional mechanical ventilation continues to be the standard mode of support for neonates with respiratory failure. Controversies regarding the selection of optimal ventilatory strategies still abound. A deep understanding of physiologic concepts as well as a critical appraisal of the literature is needed to optimize the ventilatory management of the newborn. Principles of gas exchange, pulmonary mechanics and control of breathing are reviewed in the context of their relevance during mechanical ventilation. The application of these concepts to the ventilatory strategies for the management of infants with respiratory distress is presented, and current controversies are emphasized.

Phase I study of simultaneous dose escalation and schedule acceleration of cyclophosphamide-doxorubicin-etoposide using granulocyte colony-stimulating factor with or without antimicrobial prophylaxis in patients with small-cell lung cancer.

A phase I study was designed to assess whether dose intensity of an 'accelerated' cyclophosphamide-doxorubicin-etoposide (CDE) regimen plus granulocyte colony-stimulating factor (G-CSF) could be increased further, in an outpatient setting, by escalating the dose of each single drug of the regimen. Patients with previously untreated small-cell lung cancer (SCLC) received escalating doses of cyclophosphamide (C) 1100-1300 mg m-2 intravenously (i.v.) on day 1, doxorubicin (D) 50-60 mg m-2 i.v. on day 1, etoposide (E) 110-130 mg m-2 i.v. on days 1, 2, 3 and every 14 days for at least three courses. Along with chemotherapy, G-CSF (filgastrim) 5 micrograms kg-1 from day 5 to day 11 was administered subcutaneously (s.c.) to all patients. Twenty-five patients were enrolled into the study. All patients at the first dose level (C 1100, D 50, E 110 x 3) completed three or more cycles at the dose and schedule planned by the protocol and no 'dose-limiting toxicity' (DLT) was seen. At the second dose level (C 1200, D 55, E 120 x 3) three out of five patients had a DLT consisting of 'granulocytopenic fever' (GCPF). Another six patients were treated at this dose level with the addition of ciprofloxacin 500 mg twice a day and only two patients had a DLT [one episode of documented oral candidiasis and one of 'fever of unknown origin' (FUO) with generalised mucositis]. Accrual of patients proceeded to the third dose level (C 1300, D 60, E 130 x 3) with the prophylactic use of ciprofloxacin. Four out of six patients experienced a DLT consisting of GCPF or documented non-bacterial infection. Accrual of patients at the third dose level was then resumed adding to ciprofloxacin anti-fungal prophylaxis (fluconazole 100 mg daily) and anti-viral prophylaxis (acyclovir 800 mg twice a day) from day 5 to 11. Out of five patients treated three experienced a DLT consisting of severe leucopenia and fever or infection. With a simultaneous dose escalation and schedule acceleration it is indeed possible to take maximum advantage of G-CSF activity and to increase CDE dose intensity by a factor 1.65-1.80 for a maximum of 3-4 courses. The role of antimicrobial prophylaxis in this setting deserves to be investigated further.

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer.

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.

Recombinant interferon alpha-2b in the treatment of diffuse malignant pleural mesothelioma.

Fourteen patients with diffuse malignant pleural mesothelioma (DMPM) were enrolled in a Phase II study to assess activity and toxicity of the systemic administration of recombinant (r)-alpha-interferon (IFN)-2b. The IFN schedule was: 3 x 10(6) IU i.m. days 1-4, 6 x 10(6) IU days 5-8, 10 x 10(6) IU days 9-12; then IFN was administered at 10 x 10(6) IU 3 days/week. If grades II-III toxicity occurred, IFN dose was reduced and drug continued at the previous dose level. All patients were evaluated by CT scan. Only one patient was not evaluable for response and toxicity because of inadequate follow-up. Of 13 evaluable patients, we observed 1 objective response, 6 stable disease, and 6 failures (3 progressive disease and 3 early interruptions due to subjective toxicity). The median time to progression was 19 weeks, and the median overall survival was 62 weeks. Toxicity was mild: of 13 patients evaluable for toxicity we observed fever (9 patients), flu-like syndrome (3 patients), fatigue (4 patients), anorexia (2 patients), myelosuppression (3 patients), and muscle pain (1 patient). The results of this study indicate only marginal activity of r-alpha-IFN in the treatment of DMPM.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) allows acceleration and dose intensity increase of CEF chemotherapy: a randomised study in patients with advanced breast cancer.

A randomised study was conducted in 62 patients with advanced breast cancer to assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) would yield an increase in the dose intensity of a standard-dose CEF regimen through an acceleration of chemotherapy administration. Patients received CEF (cyclophosphamide 600 mg m-2, epidoxorubicin 60 mg m-2 and fluorouracil 600 mg m-2) i.v. on day 1 or the same chemotherapy, plus GM-CSF 10 micrograms kg-1 s.c. starting from day 4, repeated as soon as haematopoietic recovery from nadir occurred. Patients in the CEF + GM-CSF group received chemotherapy at a median interval of 16 days compared with 20 days in the control group. This led to a significant increase (P = 0.02) in the dose intensity actually administered in the third, fourth and sixth cycles: +28%, +25%, +20% respectively. Non-haematological toxicity was mild. GM-CSF had to be reduced or suspended in 50% of patients because of toxicity. Haematological toxicity, mainly cumulative anaemia and thrombocytopenia, was manageable. An increase in response rate for patients with measurable disease, of borderline statistical significance (P = 0.088, P for trend = 0.018), from 42% in the CEF group to 69% in the CEF + GM-CSF group, was observed. This randomised trial indicates that GM-CSF is useful for chemotherapy acceleration. Accelerated CEF + GM-CSF is a moderately dose-intensive regimen that can be administered in an outpatient clinic and is associated with a high objective response.

Combination of chemotherapy and recombinant alpha-interferon in advanced non-small cell lung cancer. Multicentric Randomized FONICAP Trial Report. The Italian Lung Cancer Task Force.

BACKGROUND: Preclinical data suggested that alpha-interferon (IFN) may potentiate chemotherapy cytotoxicity. METHODS: A prospective multicentric randomized trial was initiated to assess the clinical benefit of adding recombinant alpha-2-IFN to combination chemotherapy in patients with metastatic non-small cell lung cancer. A total of 182 patients were randomized to receive either cisplatin-epidoxorubicin-cyclophosphamide (CEP) combination chemotherapy (cisplatin, 60 mg/m2; epidoxorubicin, 50 mg/m2; and cyclophosphamide, 400 mg/m2 intravenously) alone on day 1 or the same chemotherapy plus recombinant alpha-2-IFN at the dose of 5 MU intramuscularly from day -2 to +4, then 3 times weekly. RESULTS: The median survival was 6 months in the CEP plus IFN arm versus 5.5 months in the control arm. The log-rank test showed a marginal statistically significant difference (P = 0.045) in favor of CEP chemotherapy, which disappeared when survival curves were adjusted for prognostic factors. Progression-free survival was similar in the two treatment arms. Considering all eligible patients, the response rate was 7.6% in the CEP arm versus 18.9% in the CEP plus IFN arm (P = 0.042). Nearly 40% of the patients receiving IFN had grade 3-4 nadir leukopenia versus 15% in the control arm (P = 0.01) and 12.5% versus 4.2% had grade 3-4 thrombocytopenia. Apart from the usual constitutional symptoms, IFN was also responsible for increased emesis and mucositis. CONCLUSIONS: This study indicates that the addition of recombinant alpha-IFN to CEP chemotherapy can increase response rate and toxicity to treatment without a positive effect on progression-free survival and survival.

Potentiation of TNF-mediated cell killing by mitoxantrone. Relationship to DNA single-strand break formation.

Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates different cellular responses including cytotoxicity, cytostasis, proliferation, differentiation and expression of specific genes. Recent studies have demonstrated that chemotherapeutic drugs that inhibit the nuclear enzyme DNA topoisomerase II synergize with TNF in tumor cell killing in vitro and in vivo. We now report that a combination of TNF and the topoisomerase II inhibitor Mitoxantrone produced dose-dependent synergistic cytotoxicity against the human ovarian cancer cell line A2774 in a clonogenic assay (1 hr treatment). This result was obtained with simultaneous administration of the drug and the cytokine under test, and is independent of modification of Mitoxantrone uptake. This combination is responsible for an evident augmentation of "cleavable complex" formation. From isolated nuclei, we have isolated also the topoisomerase II activity; we observed an increment when the cells were previously treated with TNF, 2.5 min before nuclear extraction. After 10-30 min of treatment with TNF, the topoisomerase II activity returned to normal values. If TNF is not given with but 30 min before Mitoxantrone, no potentiation of cytotoxicity or break induction is observed. These results suggest that specific timing of the association may be needed also when attempting to translate it to animals and humans.

[Feasibility of a cyclophosphamide methotrexate and 5-fluorouracil regime intravenously administered with and without granulocyte-colony stimulating factor in surgically treated breast carcinoma]. / Studio di fattibilità del regime ciclofosfamide methotrexate e 5-fluorouracile somministrati per via endovenosa con e senza "granulocyte-colony stimulating factor" nel carcinoma mammario operato.

The aim of this study was to evaluate the feasibility of CMF 1.8-28 regimen, with all three drugs administered intravenously (IV), and to compare the hematologic toxicity of this regimen with or without G-CSF. Patients aged 18 to 65 years with histologically proven breast cancer treated by surgery and without distant metastases were eligible for the study. All patients had to have normal white blood cells (WBC) count (WBC > or = 3000/mm3 and/or neutrophils > or = 2000), and platelets (Plt) counts (> or = 100,000/mm3), and adequate renal and hepatic function. The toxicity was recorded according to World Health Organization Scale. CMF 1.8 regimen was: cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2. The drugs were given IV on day 1 and 8, and cycles repeated every 28 days. G-CSF (5 micrograms/kg/day) was administered subcutaneously from day 9 to 20, starting from the second cycle of chemotherapy. A complete blood count with white-cell differential and platelet count was obtained twice a week. For each patient bone marrow toxicity variables recorded during the first cycle (without G-CSF) were compared with values during the second cycle (with G-CSF). One of 10 entered patients, 1 was not evaluated due to missing data on hematologic toxicity. All patients received chemotherapy with or without G-CSF at the scheduled 28th day. Treatment with G-CSF after CMF 1.8 regimen resulted in a significantly WBC's earlier nadir (average day of nadir 14 vs 17; p = 0.0005), while there was no difference in the average values of WBC at the nadir. Moreover, the average value of platelets recorded at the nadir was significantly lower with the use of G-CSF (average No. of platelets/mm3; 185,111 vs 116,000; p = 0.001). Complete hematologic recovery without and with G-CSF was reached on day 25 and 20 respectively (p = 0.001). CMF 1.8 with IV cyclophosphamide is a feasible regimen with and without G-CSF and can be used in adjuvant setting instead of "classic" CMF in order to improve the low compliance observed when cyclophosphamide is given by mouth. As reported by others, we observed that after standard chemotherapy G-CSF anticipated the nadir of WBC and hastened hematologic recovery (WBC > 3000 and Plt > or = 100,000).(ABSTRACT TRUNCATED AT 400 WORDS)

Potentiation of tumour necrosis factor-mediated cell killing by VP16 on human ovarian cancer cell lines. In vitro results and clinical implications.

Synergism between recombinant human tumour necrosis factor (rHuTNF) and DNA topoisomerase II inhibitor VP16 during the killing of cells has been studied in six human ovarian cancer cell lines (A2774, A2780, SW626, IGROV-1, SKOV3, Pa1) and a cervical carcinoma cell line (Me180). Studies were performed using an assay of colony formation inhibition (drug treatment for 1 h) and a growth inhibition assay (continuous exposure for 20 h). Concomitant treatment of cells with VP16+rHuTNF enhanced cell killing in all the cell lines tested--an effect observed in both short- and long-term cytotoxicity assays. This study suggests that the activity of VP16 in ovarian cancer cell lines might be enhanced by rHuTNF in in vitro models.

High dose-intensity chemotherapy, with accelerated cyclophosphamide-doxorubicin-etoposide and granulocyte-macrophage colony stimulating factor, in the treatment of small cell lung cancer.

15 patients with small-cell lung cancer were treated with an "accelerated" chemotherapy consisting of standard-dose cyclophosphamide-doxorubicin-etoposide administered every 15 days (as opposed to the usual 21-day intervals) along with granulocyte-macrophage colony stimulating factor (10 micrograms/kg/day) administered prophylactically subcutaneously from day 4 to 13. The primary objective of this study was to examine the possibility of achieving a 50% dose-intensity increase by a shortening of chemotherapy intervals. 9 patients were not able to complete the planned six courses of chemotherapy owing to cumulative haematological toxicity. In fact, while leukopenia was acceptable and constant during treatment, both thrombocytopenia and anaemia progressively worsened with subsequent courses, becoming particularly severe after the 4th cycle when interruption of the treatment was often required. 13 patients who completed four courses of chemotherapy received a median of 96% of the planned dose-intensity. This corresponded with an average relative dose-intensity actually delivered of 1.44 compared with the planned dose-intensity of a standard cyclophosphamide-doxorubicin-etoposide every 21 days. In conclusion, acceleration of cyclophosphamide-doxorubicin-etoposide chemotherapy combined with granulocyte-macrophage colony stimulating factor can lead to a significant increase of dose-intensity but it is feasible only for a limited number of courses.

An outpatient phase I study of a subcutaneous interleukin-2 and intramuscular alpha-2a-interferon combination in advanced malignancies.

The aim of this phase I study was to exploit the potential efficacy of an alpha-2a-interferon (alpha-2a-IFN)-subcutaneous interleukin-2 (IL-2) combination, bypassing the toxicity usually associated with bolus or continuous infusion of IL-2. Therefore, nineteen patients with metastatic malignancies (7 melanomas, 6 renal cell carcinomas and 6 soft tissue sarcomas) were treated according to a dose escalating schedule of subcutaneous IL-2 combined with intramuscular alpha-2a-IFN for 5 days/week for 3 consecutive weeks. Cycles were repeated every 2-4 weeks unless disease progressed. Alpha-2a-IFN (3 MU/die) was given continuously, including during the rest weeks. IL-2 doses were started at 2 MIU/day/sqm and the MTD of 6 MIU/day/sqm was progressively reached. The dose of IL-2 was given twice daily every 12 hours. Both of the cytokines were administered in an outpatient setting. The main side effects were fever, chills, fatigue, hypotension, nausea and vomiting. Toxicity was correlated with IL-2 dose level. It was found to be mild at 2 and 4 MIU/day/sqm, while, in contrast, grade III toxicity was observed only at the highest dose of 6 MIU/day/sqm. However, this grade III toxicity was manageable and did not prevent continuation of the treatment as long as the dose was not increased above 6 MIU/day/sqm. Three patients, one with melanoma and two with renal cell carcinomas, obtained clinical partial responses. In eight patients, stable disease, and in the remaining eight, progression, were observed. The data suggest that the combined use of the two BRMs has manageable side effects and would seem to be efficacious. A phase II study at the recommended dose of 6 MIU/day is now necessary.

A pilot study of mitomycin, ifosfamide and cisplatin as outpatient combination chemotherapy for advanced non-small cell lung cancer.

Twenty-one patients with advanced stage, non-small-cell lung carcinoma were treated with a chemotherapy regimen including: mitomycin (6 mg/m2), ifosfamide (3 g/m2), cisplatin (80 mg/m2). The regimen was administered on an outpatient basis. Two patients were lost to follow-up. Among the 29 patients evaluable for response we registered a response rate of 36.8%; 36.8% of patients had stable disease, and 15.7% progressed during treatment. Median duration was 8.7 months and median survival was 11 months. Toxicity was low and easily manageable on an out-patient basis.

Human granulocyte-macrophage colony-stimulating factor is a growth factor active on human ovarian cancer cells.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a regulatory glycoprotein that stimulates the production of granulocytes and macrophages from committed hematopoietic progenitor cells both in vitro and in vivo. In this report, we show that recombinant human GM-CSF enhances colony formation by nonhematopoietic human ovarian cancer cell lines, IGROV-1, A2774, ME-180, Pa-1 and A2780. GM-CSF also enhanced the colony formation by cells obtained from fresh ascites of a patient with ovarian mucinous cystadenocarcinoma and a patient with serous papillary ovarian carcinoma. Our observations were made with GM-CSF concentrations between 0.1 to 1 ng/ml; these concentrations are equivalent to the dosages generally used for bone marrow recovery after chemotherapy.