Pulmonary microvascular fat: the significance?

OBJECTIVE: To determine the effects of fat emboli on cardiopulmonary function in critically ill patients. DESIGN: A prospective study. SETTING: Tertiary referral medical/surgical shock/trauma intensive care unit (ICU). PATIENTS: A total of 51 critically ill medical and surgical (including acute trauma) patients who required supplemental oxygen (FIO2 of > or = 0.35) to maintain arterial blood oxyhemoglobin saturation of > or = 90% and who had 62 pulmonary artery catheters placed for patient care reasons. INTERVENTIONS: Pulmonary capillary blood samples were obtained via the pulmonary artery catheters in the "wedged position" at insertion and postinsertion at 8, 24, 48, and 72 hrs. Cytospun smears of the buffy coat aspirates of these samples were made and were stained with Oil Red-O for fat. MEASUREMENTS AND MAIN RESULTS: One investigator, without knowledge of the patients' cardiopulmonary function, examined all smears and graded them 0 to 4+ for amount of fat. Fat scores were correlated with chest radiograph appearance, hemodynamic and respiratory parameters, complete blood cell counts with differential white blood cell counts, whether the patient was receiving lipid-containing parenteral nutrition, principal organ system failure, and reason for ICU admission. Samples from 27 pulmonary artery catheter insertions had no fat, 13 samples had low-grade (1+) episodic fat, and 22 samples had repeated episodes of > or = 2+ fat or isolated episodes of 4+ fat. There was a significant association between the amount of pulmonary microvascular fat and trauma as the reason for ICU admission. Of the other parameters, only chest compliance and body temperature showed unequivocal significant associations. These associations were opposite to the expected findings, but would support a conclusion that fat emboli did not cause the observed cardiopulmonary dysfunction. The inconsistent associations for the FIO2, PCO2, and mixed venous blood oxyhemoglobin saturation may be random events. CONCLUSION: Cardiopulmonary dysfunction commonly attributed to fat emboli is likely due to other causes.

Predictors of 5-year survival and curability in small cell lung cancer.

A retrospective analysis of various characteristics in 81 small cell lung cancer patients treated at the Mount Sinai Medical Center, New York, from 1974 to 1982 was carried out to identify factors which had prognostic significance for long-term survival, defined as actual disease-free survival for at least 5 years from initiation of therapy. Six patients, five female patients (16.7%) and one male patient (2%), including four limited disease (9.7%) and two extensive disease patients (5%) were long-term survivors (73 to 96+ months from onset of therapy), and among them three remain alive and disease-free at 84, 84, and 96 months from first treatment, respectively. Although several factors, including sex, stage of disease (limited versus extensive), and occurrence of herpes zoster predicted overall survival duration, female sex and an occurrence of herpes zoster were the only variables which were statistically significantly related to 5-year survival. Herpes zoster was a relatively late occurrence whereas female sex was an independent positive prognostic factor.

Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia.

A comparison of the late effects on intellectual and neuropsychologic function of three different CNS "prophylaxis" regimens was conducted in 104 patients treated for childhood acute lymphocytic leukemia. Of the children studied, 33 were randomized to treatment with intrathecal (IT) methotrexate alone, 36 to IT methotrexate plus 2,400 rad cranial irradiation, and 35 to IT methotrexate plus intravenous intermediate dose methotrexate. All patients were in their first (complete) continuous remission, were a minimum of one year post-CNS prophylaxis and had no evidence of CNS disease at the time of evaluation. In contrast to the other two treatment groups, children whose CNS prophylaxis included cranial irradiation attained significantly lower mean Full Scale IQs (P less than .001), performed more poorly on the Wide Range Achievement Test, a measure of school abilities, and exhibited a greater number of difficulties on a variety of other neuropsychologic measures. The poorer performance of the irradiated group was independent of sex of the patient, time since treatment and age at diagnosis. These data suggest that the addition of 2,400 rad cranial irradiation to CNS prophylaxis in ALL puts these children at greater risk for mild global loss in intellectual and neuropsychologic ability.

A comparison of intermittent vs. continuous and of adriamycin vs. methotrexate 5-drug chemotherapy for advanced breast cancer. A Cancer and Leukemia Group B study.

The therapeutic effectiveness of intermittent vs. continuous combination chemotherapy and of the substitution of adriamycin for methotrexate in a 5-drug regimen was evaluated in women with metastatic breast carcinoma. Patients were randomly allocated to receive continuous therapy with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone ( CMFVP -C, 86 patients), intermittent CMFVP ( CMFVP -I, 109 patients), or intermittent CAFVP (107 patients). The CR + PR rate with CAFVP (71%) was superior to CMFVP -C (50%, p = 0.003) and to CMFVP -I (50%, p = 0.002). The remission duration with CAFVP (14 months, median) was superior to CMFVP -I (7 months) (p less than 0.01), and tended to be superior to CMFVP -C (9 months) (p = 0.07). There was a survival advantage of CAFVP (19 months, median) over CMFVP -I (13 months) (p = 0.01), but not over CMFVP -C (16 months) (p = 0.24). Among CR + PR patients, the survival with CAFVP (29 months, median) was superior (p = 0.02) to both CMFVP -I (18 months) and CMFVP -C (21 months). The CMFVP -C regimen was associated with the highest incidence of leukopenia and neurologic toxicity, but the lowest incidence of GI toxicity. The results indicate that the CAFVP regimen is well tolerated and is superior to the CMFVP regimens.

A randomized trial of five and three drug chemotherapy and chemoimmunotherapy in women with operable node positive breast cancer.

Women with breast carcinoma and four or more involved ipsilateral axillary lymph nodes were randomly assigned to receive an induction course and 2 yr of maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF, 150 patients), CMF plus vincristine and prednisone (CMFVP, 166 patients), or chemoimmunotherapy with CMF plus the methanol extraction residue of BCG (CMF-MER, 85 patients). After 5 yr of accrual and a median follow-up of 34 mo, CMFVP is superior to CMF (p less than 0.01) with disease-free survival estimates at 4 yr of 60% for CMFVP compared to 45% for CMF. The disease-free survival advantage of CMFVP over CMF was greater in postmenopausal (p = 0.02) than in premenopausal patients (p = 0.09). CMF-MER was similar to CMF alone. CMF related side effects were similar in each regimen (see text), except for a greater incidence of leukopenia during induction with CMF than with CMFVP (p less than 0.01).

Effect of age on therapeutic response and survival in advanced Hodgkin's disease.

Although age is a recognized prognostic factor in advanced Hodgkin's disease, there are few data concerning the use of combination chemotherapy in patients greater than 60 years. In two phase III trials of the Cancer and Leukemia Group B, 385 previously untreated patients with stage III or IV Hodgkin's disease received multidrug chemotherapy. All patients received a combination of either mechlorethamine or a nitrosourea, as well as a vinca alkaloid, procarbazine, and prednisone. Two hundred and five patients were less than 40 years of age, 107 were 40-59 years, and 73 were greater than or equal to 60 years. The overall response rates in these three age groups were 70%, 66%, and 40%, respectively. Age at the time of diagnosis was the predominant factor affecting response, and the response rate was not significantly higher in those older patients who received full doses of chemotherapy. Age was also associated with an increased frequency of serious leukopenia and thrombocytopenia. The group of patients greater than or equal to 60 years of age experienced the shortest median time to recurrence, 33 months. The intermediate age group also had a shorter time to recurrence (median, 44 months) than patients less than 40 years (median not yet reached). The low complete response rate and the short duration of response in the patients greater than or equal to 60 years of age resulted in a median survival time of 18 months. Even when the analysis of restricted to just the older patients who received greater than or equal to 90% of the projected drug doses, the complete remission rate, the median time to recurrence (20 months), and the duration of survival (27 months) are still much shorter than in younger patients.

Chemotherapy and combined modality therapy for Hodgkin's disease: a progress report on Cancer and Leukemia Group B studies.

Between 1974 and 1977, the Cancer and Leukemia Group B (CALGB) initiated four studies which address current major questions in the therapy for Hodgkin's disease. The efficacy of chemotherapy alone as compared with combined modality therapy in patients with poor-prognostic stages I and II is evaluated in CALGB 7751. Currently, both therapies produce very high complete remission rates in asymptomatic patients; the remission rate is better with combined modality therapy in symptomatic patients. Single and combined modality therapies are compared for stage III patients in CALGB 7451. Complete remission rates have been similar, but relapse-free survival is superior for patients treated with local nodal radiotherapy followed by chemotherapy (P = 0.04). In particular, stage IIIA patients with nodular sclerosis seem to benefit from the inclusion of radiotherapy in their initial treatment. In CALGB 7551, the efficacy of chemotherapy alone versus chemotherapy plus radiotherapy to areas of bulky disease is under study in patients with stages IIIB and IV. Currently, a relapse rate of less than 10% has been seen among sites irradiated, and survival is best for patients treated with radiotherapy bracketed by chemotherapy. Finally, the role of two alternating non-cross-resistant combination chemotherapy programs is being studied in CALGB 7552. Relapse-free and overall survival is better with the doxorubicin-containing regimen than with either the alternating or alternate chemotherapy program. At present, the median followup for each of these studies is less than 5 years. Further observation is required to answer the critical questions relating to prolonged disease-free survival and cure.

A randomized trial of postoperative five-versus three-drug chemotherapy after mastectomy: a Cancer and Leukemia Group B (CALGB) study.

The Cancer and Leukemia Group B (CALB) has conducted a randomized study of adjuvant chemotherapy in patients with breast cancer who have involved axillary nodes at the time of mastectomy. Five-drug treatment (CMFVP) was compared with three-drug treatment (CMF). For patients with more than three involved nodes, the CMFVP regimen produced a significantly prolonged disease-free survival in comparison to the CMF regimen.

A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease.

Five hundred and sixty-six patients with either Stage III or IV Hodgkin's disease were prospectively randomized to test whether CCNU and/or vinblastine are more effective than mechlorethamine and/or vincristine with procarbazine and prednisone. The combination of CCNU, vinblastine, procarbazine, and prednisone (CVPP) was shown to be a highly effective program with a complete response frequency of 69%. The use of CCNU as part of the induction program was also shown to be the most significant determinant of prolonged remissions (P = .025). Reduced vomiting and neurotoxicity, as well as the oral administration, were the chief advantages of the CVPP as compared with MOPP. These factors resulted in improved patient and physician compliance. The MVPP regimen was also shown to be a highly effective regimen with a complete response frequency of 73% in patients without prior exposure to chemotherapy. However, the induction regimens containing vinblastine were associated with a significantly higher frequency of fatal hematopoietic toxicities than the induction regimens containing vincristine (P = .05). This higher frequency was almost exclusively seen in the elderly or in patients previously treated with both chemotherapy and radiotherapy. At this time, the remission durations maintained by vinblastine with periodic reinforcement are longer when compared with vinblastine maintenance alone (P = .06), but there is no corresponding increase in survival.

A comparative trial of daunorubicin, cytosine arabinoside, and thioguanine, and a combination of the three agents for the treatment of acute myelocytic leukemia.

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M2 daily X 3, cytosine arabinoside and thioguanine 100 mg/M2 each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M2 given on dav 1 and cytosine arabinoside plus thioguanine each given at a dose of 100 mg/M2 every 12 hours for five days. All patients received cyclophosphamide 600 mg/M2 followed in 24 hours by hydroxyurea 500 mg/M2 every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M2 daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M2 of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.