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Breast cancer resistance protein (BCRP) is a novel member of the adenosine triphosphate-binding cassette superfamily of transport proteins. Transfection and enforced expression of BCRP in drug-sensitive cells confer resistance to mitoxantrone, doxorubicin, daunorubicin, and topotecan. We studied blast cells from 21 acute leukemia patients (20 acute myeloid leukemia, 1 acute lymphocytic leukemia) for the expression of BCRP mRNA using a quantitative reverse-transcription polymerase chain reaction assay. BCRP mRNA expression varied more than 1000-fold among the samples tested, with low or barely detectable expression in half of the samples. Seven samples (33%) had relatively high expression of BCRP mRNA. High expression of BCRP did not correlate strongly with high expression of P-glycoprotein, suggesting that BCRP may cause resistance to certain antileukemic drugs in P-glycoprotein-negative cases. High expression of BCRP mRNA is sufficiently frequent in AML to warrant more extensive investigations to determine the relation of disease subtype and treatment outcome to BCRP expression and function.

The intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor to three patients with leukemia who were receiving marrow aplasia-inducing chemotherapy resulted in the development of wide-spread erythematous macules and papules. The course of the eruption paralleled the time of infusion of the granulocyte-macrophage colony-stimulating factor. Skin biopsy specimens taken from two of the eruptions displayed characteristic changes consisting of a variable mixture of granulocytes and lymphocytes, increased number and size of dermal macrophages, mild to moderate epidermal exocytosis, intercellular edema, and rare dyskeratotic keratinocytes. Immunophenotypic analysis of one specimen was notable for keratinocyte intercellular adhesion molecule-1 expression. Administration of the recombinant human cytokine in pharmacologic doses is postulated to induce changes in the immunologic status of the skin, resulting in the expression of a cutaneous eruption.

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor- risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4–21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

The authors examined 117 consecutive patients with acute leukemia within a few days of diagnosis. Sixty-six patients had acute nonlymphocytic leukemia, and 51 had acute lymphocytic leukemia. Forty-two percent of the patients had abnormal ocular findings related to leukemia. The authors found an association between the presence of intraretinal hemorrhages and thrombocytopenia for all patients. In addition, patients with acute lymphocytic leukemia and intraretinal hemorrhages had lower hematocrit levels than did those without such hemorrhage. The presence of anemia was related to the findings of white-centered hemorrhages in patients with acute nonlymphocytic leukemia. The presence of cotton-wool spots was not associated with hematologic parameters. Intraretinal hemorrhages, white-centered hemorrhages, and cotton-wool spots were all found more frequently in adults than in children.

Over 80 percent of patients with invasive pulmonary aspergillosis (IPA) undergoing intensive antileukemic chemotherapy in a recent two-year period survived the pulmonary infection as a result of early diagnosis and aggressive therapy with high-dose amphotericin B and 5-fluorocytosine. CT played an important role in establishing the early diagnosis of IPA and affected management. Since our original communication describing the CT findings of IPA, we have added ten new cases, each subsequently substantiated by lung biopsy (two), autopsy (two), and/or positive cultures of sputum or extrapulmonary sites (seven). The CT halo sign, or zone of lower attenuation surrounding a pulmonary mass, was present in eight of nine patients with early CT scans obtained during bone marrow aplasia. Characteristic CT progression from multiple fluffy masses to cavitation or air crescent formation suggested IPA in five of seven patients with serial CT scans. CT directly affected patient management in seven of ten cases. Scan findings were one criterion for increasing to high-dose amphotericin B or for adding 5-fluorocytosine. CT characteristics of healing IPA lesions were similar to resolving pulmonary infarcts and were used to monitor disease activity in patients on long-term amphotericin B and prior to retreatment chemotherapy.

Eighteen patients referred to The Johns Hopkins Oncology Center for treatment of acute myelocytic leukemia during a 2-year period had pretreatment wbc counts greater than 50,000/microliter. Despite immediate admission, aggressive supportive care, and rapid institution of chemotherapy, six patients died from complications of the high wbc count at presentation. The patients who died had significantly higher initial wbc counts, lower platelet counts, and lower arterial oxygen saturation; they were older, more likely to be female, and more likely to have abnormal serum urea nitrogen than the 12 patients who survived. Five of the six patients who died had experienced a delay of greater than 48 hours from diagnosis to referral, and only one of the 12 patients who survived was not promptly referred for treatment at the time of diagnosis (P = 0.004). A mathematical model, the logit of the fraction of the initial wbc count versus the logarithm of time after starting therapy, was used to describe the response of the wbc count to chemotherapy. This logit analysis reduced the data for individual patients to a linear function, permitting statistical description of the population as a whole. This statistical description makes possible the comparison of different approaches to lowering the wbc count in such patients and the correlation of rate of response of wbc count with the probability of achieving remission and with duration of remission.

Several previous reports have suggested an association between human histocompatibility antigens (HLA) and survival in acute myelocytic leukemia (AML). The authors have retrospectively analyzed the records of 104 consecutive newly diagnosed patients with AML treated on the Leukemia Service of the Johns Hopkins Oncology Center from March 1978 through May 1982 who had HLA typing performed to further evaluate this point. The authors have been unable to demonstrate a statistically significant association of HLA phenotype with the ability to achieve a complete response (CR), length of CR, survival of the total group of treated patients, or survival of only those patients achieving a CR (P less than 0.05). The available evidence does not strongly support a significant influence of HLA on survival in AML.

Macular and papular eruptions are ascribed to various causes, often drug-related hypersensitivity or toxicity. We observed patients with cutaneous eruptions during hospital admissions for induction or augmentation chemotherapy in the treatment of leukemia. In 10 of 14 patients, macular and papular eruptions occurred in a strikingly similar pattern, at the earliest recovery of peripheral lymphocytes, after chemotherapy-induced nadir of the leukocyte count. A concomitant sharp, transient rise in temperature accompanied the eruption of lymphocyte recovery. Skin biopsy specimens were obtained from 8 of these 10 patients and showed a superficial, perivascular mononuclear cell infiltrate. Immunohistochemical analysis of the cellular infiltrate was performed. The rash of lymphocyte recovery may be due to the actual return of immunocompetent lymphocytes to the peripheral circulation and skin after the chemotherapy-induced nadir of the leukocyte count. These observations suggest that macular and papular eruptions relate to specific immunologic events.

Thirteen cases of Listeria monocytogenes infection occurred at the Johns Hopkins Oncology Center over a 10-year period, representing 0.09% of all admissions. These cases principally occurred in patients with underlying hematologic of lymphoreticular malignancy, but in all patients other causes of immune suppression were also present. Corticosteroids were the most frequent exogenous cause of immune suppression. Bacteremia was detected more frequently than meningitis and in contrast to earlier reports, bacteriologic cure was achieved in 12 of 13 patients. Therapeutic success appeared to be related to early institution of effective antimicrobial agents. Despite eradication of infection, seven of the patients were dead within three months from progression of their underlying disease. The overall survival rate of cancer patients with listeriosis is therefore a function of the underlying malignancy and not the infection.

Twenty-three patients with small cell carcinoma of the lung (15 with limited disease and eight with extensive disease) were randomized into one of two induction schedules of high-dose cyclophosphamide (CY), 60 mg/kg iv, given either on Days 1 and 2 or on Days 1 and 8. Following the high-dose CY, patients were treated with a sequence of three monthly courses of COMB (CY, 800 mg/m2; vincristine [Oncovin], 1.4 mg/m2; methotrexate, 20 mg/m2; and BCNU, 60 mg/m2) alternating with high-dose CY. The overall response rate to the high-dose CY was 70% with 17% being complete responses (CRs). COMB produced no additional responses. There was no significant difference in response rate with either high-dose CY schedule. There was no unexpected morbidity associated with the intensive regiment despite marked myelosuppression. The high-dose CY administered on Days 1 and 8 appeared less toxic than that given on Days 1 and 2. Laboratory studies demonstrated that small cell carcinoma cells respond to drug-induced humoral stimulation in vitro; and that tumor proliferation in vivo temporally coincides with increased serum stimulatory activity. This study demonstrates that high-dose CY is a safe and effective induction therapy for small cell carcinoma of the lung although the low CR rate obtained is disappointing.

Taxol, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered to adults with refractory leukemias as a 24-h i.v. infusion in a Phase I study. The primary objectives were to determine the maximum tolerated dose of taxol administered on this schedule to patients with acute leukemias and describe the nonhematological toxicities which became dose limiting. The starting dose, 200 mg/m2, was based on the maximum tolerated dose in solid tumor trials, in which myelosuppression precluded dose escalation. Seventeen patients received 28 evaluable courses at 200, 250, 315, and 390 mg/m2. Severe mucositis limited further dose escalation. Other nonhematological effects included peripheral neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, diarrhea, and an acute pulmonary reaction that was presumptively due to taxol's Cremophor vehicle. Mean peak taxol plasma concentrations at all dose levels were in the range of concentrations that were previously demonstrated to induce microtubule bundles, a morphological effect associated with cytotoxicity, in leukemia cells in vitro. Pretreatment blasts from 12 patients were incubated with taxol ex vivo. Taxol-induced microtubule bundles were apparent in the blasts of eight patients who also had cytoreduction of tumor, and sensitivity to bundle formation was related to the magnitude of antitumor activity. In contrast, taxol did not induce microtubule bundles ex vivo in the blasts of the other four total nonresponders. Based on this study, the maximum tolerated doses and recommended Phase II doses for taxol, limited by nonhematological toxicity and administered as a 24-h i.v. infusion to patients with refractory leukemias, are 390 and 315 mg/m2. Phase II trials at these myelosuppressive doses are required to determine taxol's activity in the treatment of leukemias. In addition, further evaluation of microtubule bundle formation ex vivo in Phase II studies is necessary to determine the ultimate utility of this assay in assessing tumor sensitivity to taxol.

In order to evaluate bacterial factors which might predispose to P. aeruginosa colonization or bacteremia in the granulocytopenic patient, 132 isolates recovered from 44 oncology patients were evaluated for antigenic serotype, iron correctable sensitivity to pooled human serum, antibiotic susceptibility, production of lecithinase, elastase, protease, gelatinase, pyocyanin and pyoverdin. Similarly, potential host factors, primarily total iron binding capacity, were evaluated in a subpopulation of acute leukemia patients composed of 13 control patients without P. aeruginosa cultured during their hospital course, 11 colonization only patients and 15 P. aeruginosa bacteremia patients. No significant differences were observed between strains recovered from bacteremia vs. colonization patients for extracellular enzyme activity, pigment production, serum sensitivity and antigenic serotype. Significant differences were observed between bacteremia and colonizing strains for antibiotic susceptibility to ticarcillin, 40% vs. 76% (P less than 0.002); piperacillin, 44% vs. 86% (P less than 0.006); and cefsulodin, 60% vs. 90% (P less than 0.02). Of the host factors evaluated in the acute leukemia patients, significant differences were observed between the TIBC nadir of control patients and both colonization patients (P less than 0.0002) and bacteremia patients (P less than 0.0004). P. aeruginosa bacteremia was associated with the temporal occurrence of TIBC nadir and the detection of the organism. These data suggest a possible role for beta-lactam antibiotic resistance and host iron binding capacity as determinants and possible predictors of P. aeruginosa sepsis in the granulocytopenic patient.