Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis.

We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).

Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

PURPOSE: To compare complete response rates, time to failure, survival, and toxicity for patients with intermediate-grade non-Hodgkin's lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) versus those treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B), in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG). PATIENTS AND METHODS: Between October 1986 and June 1991, 304 patients were randomized, of whom 236 were eligible for analysis. Eligibility criteria included diffuse small cleaved-cell, diffuse mixed small- and large-cell, follicular large-cell, diffuse large-cell, and large-cell immunoblastic, stages I bulky or II to IV. RESULTS: There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. The rate of death of MACOP-B patients relative to CHOP patients was estimated to be 0.91 (P = .64) when stratified by prognostic group. There were no significant differences between the two regimens in any of the prognostic subgroups. Toxicity was significantly more severe with MACOP-B, particularly cutaneous toxicity, stomatitis, and gastrointestinal ulceration. The average relative dose-intensity (RDI) of MACOP-B was 0.91 and of CHOP was 0.90, indicating good dose delivery in this multicenter group setting. CONCLUSION: CHOP chemotherapy produced results equivalent to those of MACOP-B in patients with intermediate-grade NHL and with significantly fewer toxic complications. Despite relatively poor results in some patient subgroups, CHOP remains the standard chemotherapy for this disease, against which all new regimens should be compared.

Failure of intensive chemotherapy in poor prognosis non-Hodgkin's lymphoma.

In an attempt to improve response and survival rates in patients with non-Hodgkin's lymphoma, a relatively intense six drug regimen MATCOP was developed comprising four-weekly cycles of methotrexate (100 mg/m2, IV, day 8), Adriamycin (30 mg/m2, IV, days 1,2), teniposide (75 mg/m2, IV, day 1), cyclophosphamide (300 mg/m2, po, days one to five), Oncovin (1.4 mg/m2, IV: maximum 2 mg, days 8, 15) and prednisolone (100 mg, po, days one to five). A randomised trial was conducted comparing MATCOP with the standard CHOP regimen, comprising three-weekly cycles of cyclophosphamide (750 mg/m2, IV, day 1), Adriamycin (50 mg/m2, IV, day 1), Oncovin (1.4 mg/m2 IV: maximum 2 mg, day 1) and prednisolone (100 mg, po, days two to six). Eighty patients with large cell lymphoma, diffuse mixed small cleaved and large cell lymphoma or diffuse small cleaved cell lymphoma were randomised, 47 to MATCOP and 33 to CHOP. MATCOP patients experienced increased granulocytopenia, thrombocytopenia (p less than 0.0001), mucositis (p = 0.002) and infections (p = 0.01) compared to CHOP patients. Complete response rates were similar: 66% for MATCOP patients and 61% for CHOP patients. There were no apparent differences in the time to relapse for patients achieving CR, the time to treatment failure or the overall survival time. Thus despite an increase in toxicity, the more intense regimen MATCOP failed to confer any therapeutic benefit compared with the standard CHOP regimen. Survival was not influenced but toxicity was increased by dose intensification.

Idiopathic sudden hearing loss and disturbance of iron metabolism. A clinical survey of 426 cases.

The role of disturbances of the iron metabolism (DIM) in idiopathic sudden hearing loss (ISHL) was investigated in 426 patients with ISHL who received iron therapy, anti-DIM medication, vitamins, and a combined regimen in a randomized study which was stratified by stages and groups. Low concentrations of haemoglobin, serum iron, serum ferritin, and red cell basic ferritin as well as abnormal circadian variations in the serum iron level were observed. The results were significantly better in patients receiving iron therapy than in those receiving anti-DIM medication, vitamins, and the combined regimen. Hearing improvement was achieved in 53.26% of the patients whose treatment started later than 3 months after the onset of the disease. The clinical association of DIM and ISHL is discussed.

Infradiaphragmatic Hodgkin's disease, long term follow-up of a rare presentation.

Hodgkin's disease limited to the infradiaphragmatic region was seen in 30 of 306 (9.8%) of all Stage I and II patients referred to the Peter MacCallum Cancer Institute between 1968 and 1980. The male:female ratio was 2.3:1 with median age of 43.5 years at presentation. Of the seven patients with clinical stage (CS) IA-IIA disease who had staging laparotomy and splenectomy only one CSIIA patient had splenic involvement. The patients were staged as pathological stage (PS) IA 2, PSIIA 5, CSIA 4, CSIIA 10, CSIIB 9. Primary treatment was by radiation in 24 patients, combination chemotherapy in five and surgical excision in one. Twenty-five patients achieved complete response. Relapse free survival (RFS) at five and ten years was 59% and the five and ten-year survival was 75% and 67% respectively. On univariate analysis the significant prognostic factors for RFS and survival were stage, constitutional symptoms and presence of bulky disease. Using Cox regression analysis the only significant variable for RFS and survival was bulky disease (p = 0.01, 0.02). A treatment policy for patients with infradiaphragmatic Hodgkin's disease is recommended.

Semi-continuous microcarrier culture of rCHO cells secreting HBsAg by feeding microcarriers.

On the basis of culturing rCHO cells semi-continuously with a constant concentration of microcarriers, cell yield and HBsAg expression were increased by feeding microcarriers, step by step, to provide a surface for cells to grow. A process of culturing rCHO cells semi-continuously to produce HBsAg by feeding microcarriers was established, in which the maximum microcarrier concentration was defined. The foundation has been laid for culturing rCHO cells continuously to reach high cell yield and high HBsAg expression.

Trisomy 4 in acute nonlymphocytic leukemia. An Australian case.

We report a case of acute nonlymphocytic leukemia, type M4 according to the FAB classification, whose cytogenetics showed trisomy 4 and multiple double minute chromosomes. The patient gave no history of exposure to toxic or carcinogenic substances.

Nitrogen mustard, vincristine, procarbazine, and prednisolone for relapse after radiation in Hodgkin's disease. An analysis of long-term follow-up.

One hundred and sixty-one patients who were treated with nitrogen mustard, vincristine, procarbazine, and prednisolone (MOPP) chemotherapy for Hodgkin's disease have been observed for a median of 10.2 years. Eighty-two percent of those patients received MOPP after relapse from previous irradiation. The complete response (CR) rate was 71%. For the 116 patients achieving CR the relapse-free survival at 5 years was 83% and at 10 years, 79%. The overall survival was 72% at 5 years and 64% at 10 years. In a stepwise logistic regression analysis the most important clinical factors influencing response were B symptoms at presentation (fever greater than 38 degrees C, night sweats, weight loss greater than 10% of body weight), histologic subtype, and lung or pleural involvement. Patients who received MOPP as first-line therapy had a significantly worse response rate than those who received MOPP upon relapse after radiotherapy. This difference is reduced when adjustments are made for the presence of the above prognostic factors. A Cox regression analysis showed that Stage IV at presentation and lymphocyte-depleted histology were the most important factors indicating reduced survival. Patients who achieved a CR to MOPP had a significantly improved survival. Of the 65 patients who had died at the time of the analysis of this series, 46 died of progressive Hodgkin's disease. All four patients who developed secondary acute nonlymphocytic leukemia had received radiation as well as MOPP.

Nocardia infection in splenectomized patients: case reports and a review of the literature.

Opportunistic infections are increasingly becoming a problem in cancer patients amongst whom infection with Nocardia species is particularly difficult to detect due to the capricious natural history of the disease. Three cases of Nocardia infection in patients who had undergone splenectomy for haematological malignancy are presented. These cases illustrate the diverse mode of presentation, the natural history and the difficulties in early and accurate diagnosis of Nocardia infection. Despite the difficulties in arriving at the correct diagnosis, these cases highlight the importance of early institution of appropriate antibiotic therapy. Antibiotics should be given in adequate doses to control the initial infection and be maintained for a prolonged period to prevent relapses.

Diagnosis of granulocytic sarcoma facilitated by monoclonal antibodies.

A 36 year old woman presented with a nasopharyngeal tumour which was diagnosed and treated as diffuse large cell lymphoma. Twelve mth later the patient developed acute myeloid leukemia. At this stage, the original biopsies were reviewed and considered in retrospect to be granulocytic sarcoma on the basis of staining for chloracetate esterase and lysozyme. She achieved and maintained marrow and peripheral blood remission with chemotherapy, but developed several cutaneous nodules and 2 breast lumps. One breast lump was excised and was found, by the use of monoclonal antibodies, to carry myeloid markers. Thus monoclonal antibodies provided additional confirmatory evidence for the diagnosis of granulocytic sarcoma.

DNA ploidy patterns and cytokinetics of non-Hodgkin's lymphoma.

Flow cytometry studies for cellular DNA analysis were performed in 115 cases of non-Hodgkin's lymphoma, 53 of which had not received any prior chemotherapy or radiotherapy. DNA content was measured in ethanol fixed cells stained with chromomycin A3. According to the criteria of the International Working Formulation there were 43 low grade, 58 intermediate grade, and eight high grade lymphomas; six cases were in the miscellaneous group. Seventy seven (67%) had only diploid DNA content. Thirty eight (33%) showed DNA aneuploidy; 20 of these had been previously treated with chemotherapy or radiotherapy, or both. DNA aneuploidy was seen as hyperdiploidy in all cases except one, and it varied from slightly hyperdiploid to tetraploid. The incidence of aneuploidy increased significantly with increasing histological grade (p = 0.0002) and was not related to previous treatment. The low, intermediate, and high grade lymphomas had 14% (six of 43), 47% (27 of 58), and 62.5% (five of eight) cases, respectively, that showed DNA aneuploidy. The percentage of cells in S phase increased significantly with a higher histological grade (p less than 0.0001). The median S fraction in the low, intermediate, and high grade lymphomas was 1.0 (0.5 to 10)% 4 (0.4 to 35)%, and 27 (4.6-56)%, respectively. There is a significant correlation between histological grade and S fraction and the presence or absence of aneuploidy. There is heterogeneity, however, within both histological grade and a histological subtype.

Vincristine neurotoxicity enhanced in combination chemotherapy including both teniposide and vincristine.

A high incidence of severe peripheral neuropathy occurred during the pilot study of a new regimen for the treatment of non-Hodgkin's lymphoma. The clinically observed incidence and severity of vincristine-induced peripheral neuropathy was considerably enhanced by the sequential use of vincristine and teniposide in this combination chemotherapy.

Pathological rupture of the spleen in transforming non-Hodgkin's lymphoma.

Two patients with an initial diagnosis of a poorly differentiated lymphocytic lymphoma suffered a pathological rupture of the spleen in association with the histological transformation of the disease to a large cell lymphoma and the development of a leukaemic phase. The value of computerized tomographic scanning of the upper abdomen in confirming the diagnosis of splenic rupture is demonstrated.

The phenotype of mantle zone lymphoma studied by monoclonal antibodies.

The clinical, pathological and immunological features of a case of mantle zone lymphoma are described. The patient presented at the age of 16 with a history of painless enlargement of the inguinal lymph nodes, biopsy of which revealed a nodular small cell lymphoma. During the course of 11 yr he was treated with total nodal irradiation, splenectomy and combination chemotherapy at different times. A recent lymph node biopsy reviewed along with the previous node biopsies was diagnosed as mantle zone lymphoma. At this stage, the immunological studies showed that the neoplastic lymphoid cells had characteristic markers of mantle zone lymphocytes. He is asymptomatic with mild generalized lymphadenopathy 11 yr after the initial diagnosis. This case illustrates the diagnostic and therapeutic problems which may be encountered. Detailed immunological marker studies with an extended panel of monoclonal antibodies are described.

Vincristine neurotoxicity in Charcot-Marie-Tooth syndrome.

The case of a patient with Charcot-Marie-Tooth syndrome and diffuse large-cell lymphoma, in whom a severe generalized weakness developed after the intravenous administration of vincristine (2 mg) during combination chemotherapy, is reported. Spontaneous resolution of the severe weakness occurred when teniposide was substituted for vincristine in the chemotherapy regimen.