Madeline Bauer

Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update.

The current findings completely affirm the validity of our original observations indicating the appropriateness of grouping primary breast cancer patients into those with negative, 1 to 3, or ≫4 positive nodes. Results, however, reveal that there is a risk in combining all patients with ≫4 positive nodes into a single group. Since there was a 25% greater disease‐free survival and an 18% greater survival in those with 4 to 6 than in those with ≫13 positive axillary nodes, such a unification may provide misleading information regarding patient prognosis, as well as the worth of a therapeutic regimen when compared with another from a putatively similar patient population. Of particular interest were findings relating the conditional probability, i.e., the hazard rate, of a treatment failure or death each year during the 5‐year period following operation to nodal involvement with tumor. Whereas the hazard rate for those with negative, or 1 to 3 positive nodes, was relatively low and constant, in those with ≫4 positive nodes the risk in the early years was much greater, but by the fifth year it was similar to that occurring when 1‐3 nodes were involved, and not much different from negative node patients. The same pattern existed whether 4 to 6 or ≫13 nodes were positive. When the current findings are considered relative to other factors with predictive import, it is concluded that nodal status still remains the primary prognostic discriminant.

Early Mycological Treatment Failure in AIDS-Associated Cryptococcal Meningitis

Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.

Refining the indications for arteriography in penetrating extremity trauma: A prospective analysis

PURPOSE Five hundred fourteen consecutive patients with an isolated upper or lower extremity penetrating injury were entered into a prospective study designed to refine the indications for diagnostic arteriography. METHODS Twenty-two (4%) patients with limb-threatening ischemia who required immediate operation and 23 (4%) who refused arteriography were excluded from subsequent analyses. The remaining 469 patients were classified as being at high, intermediate, or low risk for an arterial injury. RESULTS Two hundred thirteen patients who were at low risk were observed for 24 hours, discharged, and monitored as outpatients. No delayed complications of an arterial injury developed in any patient in this group. The intermediate-risk group of 151 patients and the high-risk group of 105 patients underwent arteriography. Seventy-seven injuries were identified; 24 were major (limb-threatening) and 53 were minor. Fourteen major injuries required operative repair or transcatheter embolization; the remaining 10 nonocclusive major injuries were observed without sequelae. CONCLUSIONS By step-down logistic regression only pulse deficit (p < 0.01) and an ankle/brachial or wrist/brachial index less than 1.00 in the injured extremity (p < 0.03) were found to be significant predictors of an arterial injury. The presence of either of these two clinical variables successfully predicted all major arterial injuries. This prospective study supports the proposition that arteriography that is limited only to those patients who have either a pulse deficit or minimum ankle/brachial or wrist/brachial index less than 1.00 successfully detects all significant arterial injuries.

Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis

ABSTRACT We evaluated the antifungal activities of amphotericin B, fluconazole, and flucytosine, alone and in combination, in a murine model of cryptococcal meningitis. The objectives were to determine the greatest antifungal effects achievable with these drugs alone or in combination. Meningitis was established in male BALB/c mice weighing 23 to 25 g by intracerebral injection of Cryptococcus neoformans. Treatment was started on day 2. Amphotericin B was tested at 0.3 to 1.3 mg/kg of body weight/day by slow intravenous injection. Fluconazole at 10 to 40 mg/kg/day and flucytosine at 20 to 105 mg/kg/day were administered in the sole source of drinking water. The mice were killed at 16 days, and the numbers of fungal colonies in the brain were quantified. The association between the response and the dose combination was evaluated by local nonparametric response surface methods; 99% confidence intervals were used to evaluate the antifungal effects. Ninety-five percent of the mice treated with amphotericin B at 0.5 mg/kg survived to the end of the experiment, regardless of the fluconazole or flucytosine dose used. The greatest activity was seen with amphotericin B plus fluconazole with or without flucytosine. However, the addition of flucytosine did not increase the antifungal activity. Given the widespread availability of amphotericin B and fluconazole and the relative safety profile of fluconazole compared to that of flucytosine, the full potential of this two-drug combination deserves further evaluation.

A phase II trial of human recombinant lnterleukin‐2 administered as a 4‐day continuous infusion for children with refractory neuroblastoma, non‐Hodgkin's lymphoma, sarcoma, renal cell carcinoma, and malignant melanoma. A childrens cancer group study

Background. Recombinant human Interleukin‐2 (IL‐2) has been effective at inducing measurable antitumor responses in adults with renal cell carcinoma and melanoma. It also is being tested as adjuvant therapy for patients with acute myeloid leukemia after autologous bone marrow transplantation.

Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report.

Purpose The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] ≥1,000/mm3 and platelet count ≥100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 &mgr;g/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. Patients and Methods From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 &mgr;g/kg per day or 10.0 &mgr;g/kg per day of G-CSF subcutaneously until recovery of ANC to ≥1,000/mm3. Results The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC ≥1,000/mm3 for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count ≤20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery ≥100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%–59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. Conclusion In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 &mgr;g/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.

Gallbladder dysfunction in diabetes mellitus

To further elucidate the mechanism of impaired gallbladder emptying in diabetics with and without neuropathy, gallbladder function was assessed by ultrasonography following a medium-chain triglyceride (lipomul, 1.5 mg/kg) infusion into the duodenum and compared to that during intravenous infusion of cholecystokinin in diabetic women. Results were compared with five healthy control women. Mean (±sd) maximal percent gallbladder volume in diabetics following lipomul was reduced to 49±8% and after intravenous cholecystokinin to 47±9%, which was less than those in controls, 21±9% and 24±6%, respectively, but not significantly different. Further analysis of gallbladder emptying to lipomul differentiated two subgroups of diabetics: one subgroup (N=5) had emptying comparable to controls (responders), while the other (N=5) had very modest emptying (nonresponders). Two of the patients in the latter group had normal gallbladder emptying during exogenous cholecystokinin and their response would be compatible with visceral neuropathy. Blood levels of cholecystokinin, measured by bioassay, following lipomul and exogenous cholecystokinin were similar in controls and diabetics. Presence of diabetic neuropathy did not correlate with impaired gallbladder emptying. Follow up at 6 and 12 months of the three nonresponder diabetics revealed that no gallstones had developed and that two of them became responders to exogenous cholecystokinin. We conclude that: (1) following lipomul, about 50% of diabetics in this study have impaired gallbladder emptying, which is not strictly correlated with diabetic neuropathy; (2) this was not due to abnormal cholecystokinin release; (3) in diabetic patients with impaired gallbladder emptying another abnormality may be present in the gallbladder; and (4) impaired gallbladder contraction may not lead to gallstone formation in one-year follow-up.

Clinical results of decompressivedermotomy-fasciotomy**

Seventy-three dermotomy-fasciotomies (DFs) wereperformed in 68 patients from 1986 to 1991. A database record was compiled on each patient. Variables included age, mode of injury, method of initial wound closure, and associated injuries. A multivariate stepwise logistic regression analysis was performed to determine which variables were associated with wound complications. Thirty-eight percent of patients who underwent DF developed wound complications. One hundred percent of those patients with postoperative arterial or graft thrombosis developed wound complications (P DF is frequently necessary in the treatment of patients with compartment syndrome but is associated with significant morbidity. This study suggests that closure of DF wounds utilizing skin graft allows for continued osteofascial decompression while concomitantly minimizing invasive sepsis.

Correspondence of In Vitro and In Vivo Fluconazole Dose-Response Curves for Cryptococcus neoformans

ABSTRACT We conducted in vitro experiments to evaluate the susceptibility of a clinical isolate of Cryptococcus neoformans to a wide range of concentrations of fluconazole. In vitro susceptibility was tested using broth macrodilution methods modified to provide a numeric count of viable organisms. The association between the quantitative in vitro response and fluconazole drug concentrations was estimated using local nonparametric regression. Regression analysis was used to assess the correspondence between the in vitro fluconazole concentration-response curve and the murine dose-response curve observed in our previously reported murine model. The regression model was then used to predict the murine response. There was a strong correspondence between in vitro measures of response to fluconazole alone and the previously reported biologic effects seen in the mouse. In vitro antifungal drug susceptibility testing can reliably predict the murine response to fluconazole.

Comparison of melphalan with cyclophosphamide, methotrexate, and 5-fluorouracil in patients with ovarian cancer.

Melphalan (L‐PAM) was compared to (C) cyclophosphamide, (M) methotrexate, and (F) 5‐fluorouracil (CMF) in 413 patients with advanced ovarian carcinoma. L‐PAM was given 3.5 mg/m2 twice daily for 5 days every 5 weeks. CMF doses were: C, 400 mg/m2; M, 15 mg/m2; and F, 400 mg/m2 IV on days 1 and 8 every 28 days. Three hundred seventy‐five patients have been analyzed (L‐PAM, 190; CMF, 185). One hundred fifty‐three patients (41%) had measurable disease, 109 (29%) had evaluable disease, and 113 (30%) had nonmeasurable, nonevaluable disease. Response rates for patients with measurable and evaluable disease combined were similar: L‐PAM, 32/130 (24%) (15% complete response); CMF, 47/132 (35%) (18% complete response). Patients with Stage IV measurable disease had a greater response rate to CMF, 22/52 (42%) versus L‐PAM, 6/39 (15%). Survival and time to treatment failure were similar for both treatment regimens. Survival was improved in responders. Medians are: complete response, 28.1 months; partial response, 12.3 months; and no response, 6.7 months. Disease stage, performance status and age were identified as important prognostic variables for both survival and time to treatment failure.