amphotericin-b and Lymphoma

Talaromyces marneffei infection is an important opportunistic infection associated with acquired immune deficiency syndrome (AIDS). However, it is unusual in patients with non-AIDS and other non-immunosuppressed conditions. We report a case of delayed diagnosis of disseminated T. marneffei infection in non-AIDS, non-immunosuppressive and non-endemic conditions.. Early diagnosis in HIV-negative patients who are otherwise not immunosuppressed and endemic poses a serious challenge. T. marneffei infection is an FDG-avid nonmalignant condition that may lead to false-positive FDG PET/CT scans. Nevertheless, integrated FDG PET/CT is necessary in patients with fever of unknown origin in the early period to perform earlier biopsy for histopathology and culture in highly avid sites and to avoid delays in diagnosis and treatment.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; China; Delayed Diagnosis; Diagnosis, Differential; Fatal Outcome; Fever; High-Throughput Nucleotide Sequencing; HIV; Humans; Liver Failure, Acute; Lymphoma; Male; Mycoses; Positron Emission Tomography Computed Tomography; Talaromyces; Tomography, X-Ray Computed; Young Adult

Cryptococcosis is an opportunistic invasive fungal infection that is well described and easily recognised when it occurs as meningitis in HIV-infected persons. Malignancy and its treatment may also confer a higher risk of infection with Cryptococcus neoformans, but this association has not been as well described. A case of cryptococcosis in a cancer patient is presented, and all cases of coincident C. neoformans infection and malignancy in adults published in the literature in English between 1970 and 2014 are reviewed. Data from these cases were aggregated in order to describe the demographics, type of malignancy, site of infection, clinical manifestations, treatment and outcomes of cryptococcosis in patients with cancer. Haematologic malignancies accounted for 82% of cases, with lymphomas over-represented compared to US population data (66% vs. 53% respectively). Cryptococcosis was reported rarely in patients with solid tumours. Haematologic malignancy patients were more likely to have central nervous system (P < 0.001) or disseminated disease (P < 0.001), receive Amphotericin B as part of initial therapy (P = 0.023), and had higher reported mortality rates than those with solid tumours (P = 0.222). Providers should have heightened awareness of the possibility of cryptococcosis in patients with haematologic malignancy presenting with infection.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Female; Hematologic Neoplasms; Humans; Lymphoma; Meningitis, Cryptococcal; Middle Aged; Neoplasms; Opportunistic Infections

Invasive fungal sinusitis is becoming increasingly common in patients undergoing BMT. This study was undertaken to evaluate the incidence, presenting symptoms, diagnosis procedures, treatment and outcome of invasive fungal sinusitis. The study population comprised 423 consecutive BMT patients at Hadassah University Hospital from January 1986 to August 1992. Eleven patients (2.6%) developed invasive fungal sinusitis, 8 had underlying hematologic malignancies and 3 severe aplastic anemia (SAA). Median interval between BMT and fungal sinusitis was 22.5 days (range 2-106 days). Eight of 11 patients had protracted neutropenia (median 8 days with median neutrophil count at the time of fungal sinusitis diagnosis of 0.25 x 10(9)/l). Four patients developed GVHD before fungal sinusitis was diagnosed. Presenting symptoms were fever (100%), orbital swelling (63%), facial pain (54%) and nasal congestion (36%). In 8 patients Aspergillus species were isolated (A. flavus in 7, A. quadrilineatus in 1); in 1 patient Candida albicans was isolated and in the other 2 fungal elements were detected histologically (Fusarium and Mucor, respectively). Six of the patients underwent surgical debridement at diagnosis. Three received granulocyte transfusions. All patients received systemic amphotericin B (7 conventional and 4 amphotericin B colloidal dispersion (ABCD)). Only 2 of the 11 patients responded completely to therapy with a follow-up of 15 months. It appears that invasive fungal sinusitis is a potentially fatal complication in immunocompromised patients post-BMT. Current treatment approaches are largely ineffective and new methods of management of this serious problem are needed.

Topics: Adolescent; Adult; Amphotericin B; Anemia, Aplastic; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Debridement; Drainage; Female; Follow-Up Studies; Graft vs Host Disease; Granulocytes; Humans; Immunocompromised Host; Incidence; Infant; Leukemia; Leukocyte Transfusion; Lymphoma; Male; Middle Aged; Mitosporic Fungi; Mycoses; Neutropenia; Sinusitis; Survival Rate; Treatment Outcome

The term mucormycosis encompasses a distinctive group of infections caused by fungi belonging to genera within the taxonomic order Mucorales, usually Rhizopus, Absidia, Mortierella, and Mucor. These fungi are widespread in nature, subsisting on decaying vegetation and diverse organic materials. Although the fungi and spores of Mucorales show minimal intrinsic pathogenicity toward normal persons, they can initiate aggressive and fulminant infections under certain clinical conditions. Ketoacidotic diabetics are predisposed to rhinocerebral mucormycosis, whereas patients with leukemia or lymphoma are susceptible to pulmonary or disseminated infections. These infections, which often result in devastating long-term sequelae for surviving patients, pose difficult diagnostic and therapeutic challenges.

Topics: Amphotericin B; Dermatomycoses; Diabetic Ketoacidosis; Facial Dermatoses; Female; Gastrointestinal Diseases; Humans; Leukemia; Lung Diseases, Fungal; Lymphoma; Male; Mucorales; Mucormycosis

Topics: Acute Disease; Adrenal Cortex Hormones; Amphotericin B; Aspergillosis; Blood Transfusion; Candidiasis; Cryptococcosis; Drug Therapy, Combination; Flucytosine; Hodgkin Disease; Humans; Iron; Leukemia; Leukemia, Lymphoid; Lymphoma; Mucor; Multiple Myeloma; Mycoses; Neutropenia; Rhizopus

Topics: Amphotericin B; Ampicillin; Antifungal Agents; Bacterial Infections; Blood Transfusion; Bone Marrow Transplantation; Carbenicillin; Cephalothin; Diagnosis, Differential; Fever; Gentamicins; Humans; Infections; Leukemia; Leukocytes; Lymphoma; Methicillin; Mycoses; Patient Isolators; Penicillin Resistance; Pneumonia, Pneumocystis; Polymyxins; Sepsis; Toxoplasmosis; Virus Diseases

Topics: Adult; Amphotericin B; Candidiasis; Female; Gastrointestinal Diseases; Histoplasmosis; Humans; Infant; Leukemia; Lymphoma; Male; Mucormycosis; Mycoses; Nystatin

Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT.. We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater.. A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug.. High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Topics: Administration, Oral; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Leukemia; Lipids; Lymphoma; Male; Middle Aged; Mycoses; Prospective Studies; Risk; Tacrolimus; Time Factors; Transplantation, Homologous; Triazoles

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).

Topics: Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Bacteremia; Candidiasis, Oral; Double-Blind Method; Drug Therapy, Combination; Fever; Fluconazole; Humans; Incidence; Infusions, Intravenous; Leukemia; Lymphoma; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

To determine the value of aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis (IPA), we initiated a prospective randomized multicenter trial. The scheduled intent-to-treat interim analysis included 115 patients (30%) with prolonged neutropenia after chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia/high-grade non-Hodgkin's lymphoma, or solid tumors undergoing autologous stem cell transplantation. Sixty-five patients had been randomized to receive prophylactic aerosol amphotericin B inhalations at a dose of 10 mg twice daily (group A); for the remaining 50 patients no aerosol amphotericin B prophylaxis was used (group B). No serious side effects from amphotericin B inhalations occurred, but coughing (54%), bad taste (51%), and nausea (37%) caused early cessation of aerosol amphotericin B prophylaxis in 23% (15/65) of courses. In group A, the incidence of proven, probably, or possible IPA was 5% (3/65) as compared with 12% (6/50) in group B (p > 0.05). Microbiologically documented bacterial pneumonias were observed in 5/65 (8%) patients in group A and in 1/50 (2%) patients in group B (p > 0.05). Thus, no reduction in incidence of IPA from use of prophylactic aerosol amphotericin B inhalations was found in this interim analysis. As there were no serious side effects from aerosol amphotericin B prophylaxis, accrual in the study will continue for a total of 380 patients.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Female; Humans; Leukemia; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Neutropenia

Our previous experiences with liposomal amphotericin have suggested that it is an effective antifungal agent in neutropaenic patients with relatively few toxicity problems compared with conventional amphotericin B. This interim report presents early data from a single-centre, prospective randomised study with AmBisome. The study was designed to compare the early initiation of AmBisome in febrile neutropaenic patients (with haematological malignancy) with its later use, and to examine the efficacy and toxicity of different doses of this antifungal agent. Our experiences from the first 137 patients recruited (n = 200) are discussed, in addition to some of the difficulties that have arisen during the study.

Topics: Amphotericin B; Ceftazidime; Fever; Humans; Leukemia; Lymphoma; Neutropenia; Prospective Studies

Patients with haematological malignancies requiring an antifungal therapy were randomly assigned to receive amphotericin B diluted in either 5% dextrose or in fat emulsion (Intralipid). Twenty-one patients were included in each group. Mean duration of amphotericin B therapy was 8.4 days in the dextrose group and 12.8 days in the Intralipid group. Amphotericin B infusion induced chills in 16 of 21 patients in the dextrose group and in 5 of 21 in the Intralipid group (P = 0.0008). Serum creatinine increased > 75% from baseline in ten patients in the dextrose group compared with only two in the Intralipid group (P = 0.007). A > or = 50% decrease of creatinine clearance was observed in 14 of 21 patients in the dextrose group compared with seven of 21 patients in the Intralipid group (P = 0.025). No difference was found between the two groups with regard to potassium and sodium requirement. Among patients who did not receive magnesium before antifungal therapy, magnesium supplementation was required more frequently in the dextrose group (8/12 vs 2/11; P = 0.02). Concomitant amikacin dosage reduction was more frequent in the dextrose group due to nephrotoxicity (7/19 vs 2/20; P = 0.045). A similar difference in vancomycin dosage reduction was observed between the two groups (12/20 vs 5/19; P = 0.03).

Topics: Adult; Aged; Amphotericin B; Fat Emulsions, Intravenous; Female; Glucose; Humans; Kidney; Leukemia; Lymphoma; Male; Middle Aged

The prophylactic and therapeutic effects of the oral administration of amphotericin B (AMPH) to patients with deep mycosis associated with hematologic diseases were evaluated in an investigation including determination of serum concentrations of the antibiotic. Prophylactic effects were examined in 111 subjects, and the efficacy rates averaged 83.8% at daily doses from 1,200 to 4,800 mg. The efficacy was significantly higher at a dose of 2,400 mg/day than at a dose of 1,200 mg/day (P less than 0.05). The efficacy rate tended to be higher when the length of administration period was 1 month or more. The percentage of the number of days of fever by neutrophil count was significantly less at a daily dose of 2,400 mg than at 1,200 mg in patients with neutrophil count of 1,000 cells/mm3 or less (P less than 0.001). The safety was evaluated in 131 subjects, and adverse effects were found in only 2 cases of nausea for an incidence rate of 1.5%. Therapeutic effects were studied in 12 cases, and efficacy rates averaged 58.3% at daily doses from 2,400 to 7,200 mg. Adverse effects consisted of 1 case of diarrhea among 15 subjects who were evaluated for the safety for an incidence rate of 6.7%. The serum concentrations of the antibiotic were examined in 60 of the prophylactic and therapeutic subjects. Average concentrations of AMPH at 4 hours after the first daily dose of 1,200, 2,400 and 4,800 mg were 0.040, 0.053 and 0.078 micrograms/ml, respectively. Concentrations gradually increased thereafter and reached averages of 0.089, 0.090 and 0.132 micrograms/ml, respectively, for the 3 dose levels on the 7th day. These results indicated that there were no serious adverse effects and serum concentrations were above the Candida MIC values at daily prophylactic and therapeutic doses of 1,200 to 7,200 mg of AMPH. Based on these findings, this drug can be expected to show prophylactic and therapeutic effects with safety in cases of deep mycosis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amphotericin B; Drug Evaluation; Female; Hematologic Diseases; Humans; Leukemia; Lymphoma; Male; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Mycoses

Autopsy examinations were conducted in 72 patients with hematologic malignant neoplasms who received antibacterial therapy before their deaths. These patients were participants in a large double-blind study designed to assess the efficacy of oral amphotericin B in decreasing the incidence of candidal infection. The patients received either 50 mg of amphotericin B orally four times a day, or they received a matching placebo. Eight of 33 patients (24%) who had received placebo and two of 39 (5%) who had received amphotericin had histopathologic evidence of disseminated candidiasis. We conclude that in these patients with hematologic malignant neoplasms who received antibiotics within two weeks of death, the concomitant oral administration of amphotericin was effective in decreasing the incidence of systemic candidal infections, indicating that the gastrointestinal tract serves as a portal of entry for Candida albicans.

Topics: Administration, Oral; Adult; Aged; Amphotericin B; Autopsy; Candidiasis; Clinical Trials as Topic; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged

Mucormycosis is a conditionally pathogenic fungal disease with high morbidity that mainly affects patients with decreased immunity. Diagnosis relies on the histopathological examination of microorganisms with the typical structure of mucormycetes in tissues and subsequent confirmation

Topics: Amphotericin B; Anti-Bacterial Agents; High-Throughput Nucleotide Sequencing; Humans; Lymphoma; Metagenomics; Mucormycosis

Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients.. We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI.. Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner.. The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Drug Interactions; Female; Humans; Leukemia, Myeloid, Acute; Lymphoma; Male; Middle Aged; Multiple Myeloma; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Surveys and Questionnaires; Vancomycin

Macrophages in the tumor microenvironment play a critical role in tumorigenesis and anti-cancer drug resistance. Burkitt's lymphoma (BL) is a B-cell non-Hodgkin's lymphoma with dense macrophage infiltration. However, the role for macrophages in BL remains largely unknown.. B7-H1, a transmembrane glycoprotein in the B7 family, suppresses T cell activation and proliferation and induces the apoptosis of activated T cells. The expression of B7-H1 in BL clinical tissues was determined by streptavidin-peroxidase immunohistochemistry. The mutual regulation between macrophages and BL Raji cells was investigated in a co-culture system. The cell proliferation and cell cycle distribution of Raji cells were determined using BrdU staining coupled with flow cytometry. CD163, CD204 and B7-H1 expression was assessed by flow cytometry and Western blot. Cell invasion was analyzed by Transwell assay. The expression of cytokines was detected by quantitative RT-PCR. Immunofluorescence and allogeneic T-cell proliferation assays were used to compare the expression of B7-H1, p-STAT6, or p-STAT3 and CD3+ T cell proliferation treated with or without amphotericin B.. B7-H1 was highly expressed in tumor infiltration macrophages in most clinical BL tissues. In vitro, Raji cells synthesized IL-4, IL-6, IL-10 and IL-13 to induce CD163, CD204 and B7-H1 expression in co-cultured macrophages, which in turn promoted Raji cell proliferation and invasion. Interestingly, antifungal agent amphotericin B not only inhibited STAT6 phosphorylation to suppress the M2 polarization of macrophages, but also promoted CD3+ T cell proliferation by regulating B7-H1 protein expression in macrophages.. Amphotericin B might represent a novel immunotherapeutic approach to treat patients with BL.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-H1 Antigen; Biomarkers; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lymphocyte Activation; Lymphoma; Macrophages; Middle Aged; Phagocytosis; STAT6 Transcription Factor; T-Lymphocytes; Tumor Microenvironment; Young Adult

Paecilomyces sp. are emerging pathogens in immunocompromised patients. We report here a case of Paecilomyces variotii fungemia, cured with amphotericin and anidulafungin, illustrating difficulties of early diagnosis and therapeutic choice in such rare fungal infection.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Echinocandins; Fungemia; Hepatic Insufficiency; Humans; Liver Transplantation; Lymphoma; Male; Middle Aged; Paecilomyces

Recently, geographic variations in resistance to agents commonly used in the treatment of cryptococcosis have been reported. Therefore, the antifungal susceptibilities of 31 clinical isolates of Cryptococcus neoformans, collected in Serbia during 10-year period, were investigated. Strains were isolated from cerebrospinal fluid (n=28) and blood (n=3), from patients with AIDS (n=26), lymphoma (n=4) and kidney transplant recipient (n=1). The minimal inhibitory concentrations (MICs) of amphotericin B, 5-fluorocytosine, fluconazole and itraconazole were determined by the E-test(®) method. The isolates were highly susceptible to amphotericin B (100% susceptibility at MIC<0.5 μg/mL) and 5-fluorocytosine (87.1% susceptibility at MIC ≤ 4 μg/mL). Geometric mean MIC of amphotericin B and 5-fluorocytosine were 0.102 μg/mL and 0.396 μg/mL, respectively. Fluconazole exhibited the lowest activity in vitro (48.4% susceptibility at MIC ≤ 8 μg/mL) with a significant resistance rate. The activity of itraconazole was also decreased (48.4% susceptibility at MIC ≤ 0.25 μg/mL). The geometric mean MIC of fluconazole stood at 15.14 μg/mL and of itraconazole was 0.144 μg/mL. Cross-resistance among azoles was not common (3.2%), but the parallel increase in fluconazole and itraconazole MIC has been observed (P<0.01). The low rate of susceptibility to fluconazole stresses the need for active antifungal surveillance of C. neoformans and of the corresponding data from different geographic regions.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cerebrospinal Fluid; Cross Infection; Cryptococcosis; Cryptococcus neoformans; Drug Resistance, Multiple, Fungal; Fluconazole; Flucytosine; Fungemia; Humans; Itraconazole; Kidney Transplantation; Lymphoma; Meningitis, Cryptococcal; Microbial Sensitivity Tests; Postoperative Complications; Serbia

A retrospective study was performed to evaluate the efficacy and safety of liposomal amphotericin B (L-AMB) in a total of 32 cases who were among patients hospitalized at the Fourth Department of Internal Medicine, Sapooro Medical University from December 2006 to April 2008. Primary diagnoses were hematologic diseases in 87.5% of subjects. The most common hematologic diseases included acute myelogenous leukemia in 50% of the subjects, followed by malignant lymphoma in 12.5% of the subjects. The mean administration period was 14.2 +/- 12.9 days, and the mean cumulative dose was 1,786 +/- 2,181 mg. L-AMB improved 21 of 29 cases (72.4%) with some fungal infections or fever-associated neutropenia. Adverse events occurred in 9 cases to a slight degree, in 7 cases to a moderate degree, and in no case to a severe degree. Hypokalemia and hypercreatininemia were seen in 7 cases (21.9%) and 4 cases (12.5%), respectively, but these adverse reactions were so mild that the treatment did not need to be discontinued. Any adverse reactions for which treatment administration was discontinued were confirmed to have disappeared at the end of the study. These results support the efficacy and safety of L-AMB in accordance with previous foreign reports. It was noteworthy that early use of L-AMB prior to established diagnosis sometimes better therapeutic outcomes. It was also suggested that L-AMB could be safely administered while controlling electrolyte balance, such as serum potassium concentration, with sufficient fluid replacement, including physiological saline infusion. There are limitations in the use of the conventional form of amphotericin B because of its renal toxicity and other reasons. However, L-AMB had fewer side effects, so the agent was considered useful for the treatment of hematologic disease patients who either had mycosis or carried a risk for fungal infection.

Topics: Amphotericin B; Female; Humans; Leukemia, Myeloid, Acute; Liposomes; Lymphoma; Male; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Immunocompromised Host; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Muscle Neoplasms; Prednisolone; Psoas Muscles; Pyrimidines; Treatment Outcome; Triazoles; Vincristine; Voriconazole

We describe a 9-yr-old boy who received the highest cumulative dose so far reported of liposomal amphotericin B. The patient underwent an allogeneic bone marrow transplantation (BMT) for adrenoleucodystrophy, after a conditioning regimen with busulfan, thiothepa and cyclophosphamide. Rabbit antithymoglobulin, cyclosporin and prednisone were used as prophylaxis against graft vs. host disease (GVHD). Post-transplant Epstein-Bar-virus-related lymphoma was diagnosed on day +68 and was treated with donor-derived lymphocytes. The patient developed a severe form of GVHD, and a progressive worsening of his neurological status because of progression of his underlying disease. Death from septic shock occurred 23 months after BMT. During prolonged hospitalization, 19,750 mg of liposomal amphotericin B, about 1000 mg/kg, were given for prophylactic or empirical therapeutic purposes without significant nephrotoxicity. This case suggests that liposomal amphotericin B is safe and well-tolerated even if is administered for long periods and a cumulative dose fivefold greater than the nephrotoxic threshold of amphotericin B deoxycholate is achieved.

Topics: Adrenoleukodystrophy; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Candidiasis; Child; Creatinine; Disease Progression; Epstein-Barr Virus Infections; Fatal Outcome; Graft vs Host Disease; Humans; Kidney; Kidney Diseases; Liposomes; Lymphoma; Male; Pseudomonas Infections; Shock, Septic; T-Lymphocytes, Cytotoxic; Transplantation Conditioning

A 66-year-old woman with malignant lymphoma became neutropenic during chemotherapy and developed cryptococcemia. After amphotericin B had been commenced, she developed significant hypokalemia and polyuria, though her renal function remained stable. The laboratory findings showed no evidence of renal tubular acidosis. With vigorous water and potassium replacement, amphotericin B had been continued until the cumulative dose reached 2.5 g. After the cessation of amphotericin B, the hypokalemia and polyuria resolved promptly. Based on theses findings, she was diagnosed as nephrogenic diabetes insipidus with hypokalemia and without renal tubular acidosis due to amphotericin B. This complication is usually reversible, and vigorous water and potassium replacement may allow completion of treatment by amphotericin B, though careful monitoring of body water balance and renal function is of importance.

Topics: Aged; Amphotericin B; Antifungal Agents; Antigens, Fungal; Antimetabolites, Antineoplastic; Bacteremia; Cryptococcosis; Cryptococcus neoformans; Diabetes Insipidus, Nephrogenic; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lymphoma; Mercaptopurine; Tomography, X-Ray Computed

The clinical relevance of mold isolated from blood cultures, even in severely immunosuppressed allogeneic hematopoietic stem cell transplantation (HSCT) recipients, remains uncertain. The authors hypothesized that isolation of non-Candida fungi from blood cultures in patients undergoing high-risk HSCT would have clinical significance.. The authors reviewed the records of 73 allogeneic HSCT recipients between January 1, 1993 and January 1, 2001 in whom fungal species were isolated from blood cultures.. Fifty-two episodes of non-Candida fungemia occurred in 48 patients (66%) after a median of 10 days (range, 2-341) after transplantation. All 48 patients had indwelling intravascular catheters, and 23 patients (48%) had profound neutropenia. Thirty-five of 48 patients had received partially matched, related donor stem cell grafts (19 patients had 3-antigen-mismatched grafts); 35 patients had undergone T-cell depleted transplantation and 9 patients were receiving treatment for acute graft-versus-host disease. In 5 of 48 patients (10%), death was attributed to fungemia that occurred 8-11 days after the initial fungal blood culture was obtained; all 5 patients were age > 30 years. No deaths occurred in the younger age group (n = 22 patients; P = 0.05). In the 24 patients who did not receive systemic antifungal therapy, 4 deaths (17%) were attributed to infections with Penicillium (n = 2 patients), Epicoccum (n = 1 patient), or Penicillium plus Cladosporium species (n = 1 patient). Of the 24 patients who received amphotericin B, only 1 patient (4%) died as a result of a probable hematogenous Aspergillus species infection; this difference in outcome, however, was not significant (P = 0.2).. Most of the non-Candida fungal blood culture isolates in recipients of high-risk, mismatched donor transplantation were clinically nonsignificant. However, because these low-virulence saprophytes occasionally may cause life-threatening disease, a reevaluation of the existing diagnostic paradigm is needed so that clinically significant fungemia may be differentiated from pseudofungemia.

Topics: Adolescent; Adult; Amphotericin B; Aspergillus; Child; Child, Preschool; Cladosporium; Culture Techniques; Female; Fungemia; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lymphoma; Male; Middle Aged; Penicillium; Retrospective Studies; Risk Factors; Transplantation, Homologous; Treatment Outcome

The aim of this study was to evaluate the relevance of in vitro antifungal susceptibility to clinical response in neutropenic patients with invasive oral aspergillosis.. Nine isolates of Aspergillus species were obtained from invasive oral infections in 9 patients with hematologic malignancies and tested for their in vitro susceptibility to amphotericin B, fluconazole, miconazole, 5-fluorocytosine, and itraconazole. Minimal inhibitory concentration values of the 5 drugs were obtained for each fungus through use of a microdilution broth method. The patients were treated with intravenous amphotericin B (30-50 mg/day) in combination with oral 5-fluorocytosine (3000-6000 mg/day) and/or oral itraconazole (200 mg/day).. Amphotericin B and itraconazole were found to be very active, with minimal inhibitory concentration values of 0.861 and 0.194 microg/mL, respectively. Miconazole and 5-fluorocytosine showed minimal inhibitory concentration values of 1.72 and 3.56 microg/mL, respectively. On the other hand, fluconazole FCZ showed low activity, with a minimal inhibitory concentration value in excess of 64.0 microg/mL. During neutropenia, combined antifungal chemotherapy stabilized oral aspergillosis and prevented the spread of oral lesions in 8 patients in whom neutrophil counts eventually recovered.. The results imply that in vitro susceptibility testing may serve as an informative parameter with respect to the efficacy of these antifungals in the treatment of invasive oral aspergillosis, inducing fungal stasis until the neutrophils recover.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Aspergillus; Drug Combinations; Drug Evaluation; Female; Fluconazole; Flucytosine; Humans; Immunocompromised Host; Itraconazole; Leukemia; Lymphoma; Male; Miconazole; Microbial Sensitivity Tests; Middle Aged; Mouth Diseases; Neutropenia

We report two cases of invasive pulmonary aspergillosis due to Aspergillus flavus in one patient who with chronic nephritis and to A. fumigatus in another with malignant lymphoma. After receiving intravenous liposomal amphotericin B therapy for 31 and 35 days, respectively, the patients were cured and did not experience any severe adverse effects.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Drug Carriers; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Liposomes; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Radiography

Conventional amphotericin B (Amph-B) is the drug of choice for treating systemic fungal infections. Recently, a new formulation has become available, encapsulated in liposomes (Amph-lip). This new form of administration was developed in order to lower the acute side effects and to offer the possibility of administering high doses of amphotericin B. Experience with Amph-lip is limited, especially in children. We treated four children with documented systemic fungal infections with Amph-lip and administered it empirically to 12 children. Fifteen of these 16 children were severely granulocytopenic oncologic patients. One 3-month-old baby suffered from systemic candidiasis. Amph-lip was preferred to conventional Amph-B in children with organ dysfunction developing as a consequence of conventional chemotherapy or bone marrow transplantation, after failure of conventional Amph-B to improve a fungal infection, and after adverse drug reactions had occurred. The daily doses of Amph-lip ranged from 1 to 6 mg/kg (median 3 mg/kg), the cumulative doses from 13 to 311 mg/kg (median 75 mg/kg). Acute adverse reactions or organ function abnormalities attributable to Amph-lip did not occur in 402 administrations. Amph-lip has proven to be well tolerated by children in terms of acute toxicity and in the long term. Although large cumulative doses were given, organ function abnormalities attributable to Amph-lip doses were not detected in any of ten long-term survivors over a median observation time of 36 months (range 30-44 months). Amph-lip appears to be a promising alternative antifungal treatment, especially for patients with impaired organ function, when high doses of amphotericin B are necessary.

Topics: Adolescent; Agranulocytosis; Amphotericin B; Bone Marrow Transplantation; Child; Child, Preschool; Drug Carriers; Hematologic Diseases; Humans; Immunocompromised Host; Infant; Leukemia; Liposomes; Lymphoma; Mycoses; Time Factors; Treatment Outcome

The use of oral itraconazole (200 mg daily) plus nasal amphotericin B (10 mg daily) for prophylaxis of invasive aspergillosis was evaluated in 164 patients with hematological malignancies at risk due to presence of neutropenia and/or steroid therapy. This prophylactic regimen was evaluated for a period of two years. Two hundred and ninety patients with similar characteristics who were observed over the three-year period prior to the introduction of prophylaxis served as historical control group. Environmental surveillance during the study period showed constant contamination of the air with Aspergillus. Prophylaxis significantly reduced the incidence of proven invasive aspergillosis from 12/290 to 0/164 (p = 0.004), and reduced the mortality rate from 8/290 to 0/164. The incidence of proven plus probable aspergillosis amounted to 34/290 in the control group and 8/164 in the study group (p = 0.01); the mortality rates were 11/290 (3.7%) and 2/164 (1.2%) respectively. All nasal cultures in the study group were negative for Aspergillus. The prophylactic regimen was well tolerated. Larger studies assessing each agent alone and in combination are necessary to confirm these observations.

Topics: Administration, Intranasal; Administration, Oral; Adult; Air Microbiology; Amphotericin B; Aspergillosis; Aspergillus; Humans; Itraconazole; Leukemia; Lymphoma; Pilot Projects

In patients with leukemia or lymphoma, the role of preventive oral hygiene in reducing infectious periodontal complications during aggressive chemotherapy is well documented. However, the effectiveness of these measures in preventing further dental or periodontal degradation remains to be demonstrated. 34 hospitalized patients with malignant heamatological diseases were observed. During chemotherapy, tooth brushing was replaced by 3 daily mouth-rinses with 0.2% chlorhexidine digluconate. The periodontal status of these patients, appears unchanged after 12 months. This suggests that the prophylactic measures do prevent a measurable periodontal degradation, even in the presence of pre-existing periodontal disease.

Topics: Acyclovir; Amphotericin B; Ceftazidime; Chlorhexidine; Dental Plaque Index; Fluconazole; Humans; Immunosuppression Therapy; Ketoconazole; Leukemia; Lymphoma; Miconazole; Norfloxacin; Periodontal Diseases; Periodontal Index; Tooth Loss; Vancomycin

A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48-72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973-1981) to 4% (6 of 153 patients; 1982-1986, P less than 0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973-1981) to 4% (2 of 50 patients; 1982-1986, P less than 0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.

Topics: Adult; Aged; Agranulocytosis; Amphotericin B; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukemia; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies

Nine patients with hematologic malignancies developed fungal infections, predominantly involving the liver and spleen. Eight patients had biopsy-documented progressive candidiasis and one had an unclassified fungus. The patients were treated with liposomal-amphotericin B (L-AmpB) after their fungal infection progressed during treatment with standard intravenous (IV) AmpB (Fungizone; E. R. Squibb & Son, Princeton, NJ) and/or other antifungals. Eight patients (88.8%) were cured of their fungal infection, and one showed improvement after treatment. Minor acute toxicity and no chronic toxicity were associated with the administration of L-AmpB. L-AmpB is a safe and effective therapeutic method for treating fungal infections that have invaded the liver and spleen even when they are refractory to conventional anti-fungal therapy.

Topics: Adolescent; Adult; Amphotericin B; Candidiasis; Child, Preschool; Female; Humans; Leukemia; Liposomes; Liver Diseases; Lymphoma; Male; Middle Aged; Splenic Diseases

Disseminated fungal disease, predominantly involving liver and spleen, developed in eight patients with hematologic malignancies. Because the patients failed to respond to standard antifungal drugs, they were treated with liposomal amphotericin B (L AmpB). Before therapy began, the diagnosis was confirmed histologically and the patients underwent abdominal computed tomography (CT), which indicated hepatosplenomegaly with or without multiple microabscesses in the liver and spleen. After each course of treatment with L AmpB, patients underwent CT, followed by either open or CT-guided percutaneous aspiration biopsy of the liver. Post-treatment CT showed partial regression of lesions in six patients and persistence in two. In all patients a liver biopsy confirmed that the lesions noted after treatment were due to granulomas or focal areas of fibrosis compatible with healing. Thus, the persistence of multiple defects on enhanced scans in two patients was not an indication of persistent abscesses. Clinical response was an additional important factor. Close clinical and pathologic correlation in addition to CT scanning are required in the follow-up of hepatosplenic fungal infections.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Biopsy; Candidiasis; Child; Female; Humans; Leukemia; Liposomes; Liver; Liver Diseases; Lymphoma; Male; Middle Aged; Splenic Diseases; Tomography, X-Ray Computed

Twelve patients with hematologic malignancies complicated by fungal infections were treated with liposomal amphotericin B (L-AmpB). Nine patients were granulocytopenic; the three additional patients with normal granulocyte counts were immunosuppressed. All patients had biopsy findings or cultural evidence of the progression of their fungal infection while being treated with conventional amphotericin B. Doses of 0.8-1.0 mg/kg of L-AmpB were administered intravenously every 24-72 hr. Three patients had a complete remission, five had a partial remission, and four showed no improvements. A total of 161 doses of L-AmpB were administered. Fever and chills occurred on seven occasions. No hematologic or blood chemistry abnormalities related to L-AmpB treatment were observed.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Candidiasis; Female; Histoplasmosis; Humans; Leukemia; Liposomes; Lymphoma; Male; Middle Aged; Mucormycosis; Mycoses; Neoplasms; Sarcoma, Kaposi

Two hundred thirty-five fungal infections occurred in patients with malignant diseases over a four-year period. One hundred eighty-eight were due to Candida species and Torulopsis glabrata and are reviewed herein. The frequency was highest in patients with acute leukemia (11.9 per 100 registrations) with a frequency of 0.8 per 100 registrations in all cancer patients at this institution. Three or more predisposing factors were present in more than 50 percent of the cases; antecedent myelosuppression, chemotherapy, and antibiotic therapy were most common. Blood cultures were positive in only 35 percent of patients with disseminated candidiasis. Twenty-nine of 55 patients (53 percent) had candidemia without identifiable organ infection recovered. Eleven were given no systemic antifungal therapy and recurrence of infection was documented in two patients. Only six (4.5 percent) of 133 patients with proved deep organ infections recovered. Respiratory failure was the clinical cause of death in 62 percent of patients. Clinical features, cultures, and serologic tests were usually of no assistance in establishing the diagnosis early in the course of the infection.

Topics: Acute Disease; Amphotericin B; Bacterial Infections; Bacteriological Techniques; Candida; Candidiasis; Cytomegalovirus Infections; Humans; Ketoconazole; Leukemia; Lymphoma; Miconazole; Mycoses; Neoplasms; Neutropenia

Between July 1973 and June 1981 systemic fungal infections were found in 27 of 270 autopsies of patients with hematologic malignancies: in 16 aspergillosis, in 6 candidiasis, in one aspergillosis and candidiasis, and in 4 mucormycosis. The frequency increased from 6% during the first 6 years to 25% during the last 2 years (p = 0.025). Fever despite antibiotics and new pulmonary infiltrates were the major symptoms. In only 6 of 16 patients did microbiological findings support the clinically suspected diagnosis. Systemic fungal infections were the principal cause of death in 12 patients. Because of the difficulty of establishing the diagnosis, empiric antimycotic therapy should be started promptly on clinical suspicion in patients with neutropenia and fever despite antibiotics.

Topics: Amphotericin B; Aspergillosis; Candidiasis; Humans; Leukemia; Lymphoma; Mucormycosis; Mycoses; Myeloproliferative Disorders; Retrospective Studies

Amphotericin B has a significant cytostatic effect on lymphadenosis cells of mice NK/LY. In a concentration of 6 units/ml it inhibits an increase in total nucleic acids by 50 per cent. Such cytostatic effect of amphotericin B combines with the effect of carminomycin and adriamycin. In concentrations having no cytostatic effect amphotericin B does not enhance the action of adriamycin and carminomycin on tumor cells.

Topics: Amphotericin B; Animals; Carubicin; Cells, Cultured; Daunorubicin; Doxorubicin; Drug Evaluation, Preclinical; Drug Synergism; In Vitro Techniques; Lymphoma; Mice; Neoplasms, Experimental

Topics: Acute Disease; Administration, Oral; Adult; Amphotericin B; Female; Hematologic Diseases; Humans; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Mycoses

Fungal infections are increasing in frequency, especially among patients with haematological malignancies. The fungi which cause most of the infections in cancer patients are Candida spp. and Aspergillus spp. These fungi seldom infect individuals with normal host defence mechanisms. Many factors predispose patients to fungal infection, including neutropenia, lymphopenia, gastro-intestinal ulceration, intravenous catheters and adrenal corticosteroid therapy. Candida spp. cause 5 major types of infection: dermatitis, thrush, gastro-intestinal, primary organ and disseminated infection. Aspergillus spp. and Phycomycetes cause pulmonary, disseminated or rhino-cerebral infection. Cryptococcus neoformans usually causes meningitis but may cause pneumonia or disseminated infection. The diagnosis of fungal infection is often made only at postmortem examination, because it is difficult to isolate the aetiological agent from sites of infection. Amphotericin B remains the mainstay of antifungal therapy, but is seldom effective in the patient with compromised host defences. Successful management of these infections in the future will depend upon improvement in diagnostic capabilities as well as the introduction of more effective and less toxic antifungal agents.

Topics: Amphotericin B; Aspergillosis; Candidiasis; Humans; Leukemia; Lymphoma; Mycoses; Neoplasms; Nocardia Infections

Aspergillus infections in patients with cancer are difficult to diagnose, and such diagnoses are frequently made at necropsy. Earlier therapy has been proposed to provide better response. We reviewed 17 consecutive patients with documented aspergillosis to determine the impact of earlier diagnosis and prompt treatment with amphotericin B. Sixteen had hematologic malignancies, and all had marked granulocytopenia. Six were diagnosed and treated within 96 h of the appearance of infiltrates. Three of these six had complete resolution of all signs and symptoms of aspergillus infection. The other three had a partial response to therapy despite continued granulocytopenia. All 11 patients in whom antifungal therapy was either delayed (six) or not given (five) for at least 2 weeks after the infiltrate was present diet with progressive aspergillosis aggressive diagnostic methods to establish the diagnosis of aspergillosis are warranted so that antifungal therapy can be started early, which may then be successful in resolving these potentially fatal infections.

Topics: Agranulocytosis; Amphotericin B; Aspergillosis; Humans; Lymphoma; Neoplasms; Time Factors

Three patients seen recently at Wilford Hall USAF Medical Center emphasize the point that coccidioidomycosis may resemble lymphoma because of persistence of adenopathy on the chest roentgenogram after the initial infiltrate has resolved. Such a clinical picture strongly indicates dissemination and is probably sufficient reason to initiate therapy.

Topics: Adult; Amphotericin B; Coccidioidomycosis; Diagnosis, Differential; Humans; Lymphatic Diseases; Lymphoma; Male; Middle Aged; Radiography

Pulmonary aspergillosis in patients with leukemia or lymphoma is usually a fatal infection. However, difficulty in obtaining a premortem diagnosis has often prevented an adequate trial of anti-fungal chemotherapy. In this report, nine cases of aspergillus pneumonia in patients with hematologic malignancy were diagnosed during a one-year period. Five of nine patients had a premortem diagnosis (56%) and eight of nine (89%) received a premortem trial of amphotericin B. Two of nine patients survived infection, including one patient with prolonged neutropenia. Better diagnostic methods and wider use of antifungal chemotherapy may improve prognosis for aspergillus infection in patients with hematologic malignancy.

Topics: Amphotericin B; Aspergillosis; Humans; Immunosuppression Therapy; Leukemia; Lymphoma; Pneumonia

Topics: Adolescent; Adult; Aged; Amphotericin B; Amyloidosis; Blastomycosis; Carcinoma; Child; Diabetes Complications; Female; Histoplasmosis; Humans; Lymphoma; Male; Middle Aged; Spheroplasts

Adoptive immunotherapy in the form of a transient graft of mismatched DBA/2 BM + LN cells was used in combination with several chemoradiotherapy regimens to treat AKR mice bearing advanced SLL. Leukemic mice treated in this manner had a significant prolongation of their MST and significantly higher survival rates 60 and 90 days posttreatment than corresponding control groups. Syngeneic- or allogeneic-matched cells did not provide substantial GVL effect. An inverse relationship that influenced survival was observed between the radiation dose and the dose of GVL effector cells used to treat leukemic AKR mice in the treatment model. Recurrence leukemia remains a major problem.

Topics: Amphotericin B; Animals; Bone Marrow Cells; Bone Marrow Transplantation; Cyclophosphamide; Graft vs Host Reaction; Leukemia, Experimental; Lymph Nodes; Lymphocyte Culture Test, Mixed; Lymphoma; Mice; Mice, Inbred AKR; Mice, Inbred DBA; Nitroso Compounds; Radiation Chimera; Time Factors; Transplantation, Homologous

Topics: Amphotericin B; Animals; Bone Marrow Cells; Bone Marrow Transplantation; Cyclophosphamide; Immunotherapy; Leukemia, Experimental; Lymph Nodes; Lymphoma; Mice; Mice, Inbred AKR; Mice, Inbred Strains; Neoplasms, Experimental; Transplantation, Homologous

Topics: Adult; Aged; Amphotericin B; Aspergillosis; Female; Humans; Lung Diseases, Fungal; Lymphoma; Male; Pneumonia

The cellular effects of three nitrosourea derivatives were investigated on a human lymphoma cell line. The three drugs show similar threshold-type dose-response survival curves on asynchronous cells treated for 1 hr. Longer incubation periods result in rapid biological degradation for 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, whereas, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, remains cytotoxic after about 24 hr. Important differences were noted with respect to cell cycle dependency. The 1,3-bis(2-chloroethyl)-1-nitrosourea was more effective in early S and in G2 phase, whereas both 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea were more effective in early S. 1,3-bis(2-chlrorethyl)-1-nitrosourea exerted a considerable degree of killing in G1. Cells were unable to recover from priming damage induced by all 3 nitrosourea derivatives. No synergistic effects were observed in combination with vitamin A.

Topics: Amphotericin B; Carmustine; Cell Line; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Lomustine; Lymphoma; Neoplasms, Experimental; Nitrosourea Compounds; Semustine; Time Factors; Vitamin A

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.

Topics: Amphotericin B; Animals; Cyclophosphamide; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Leukemia; Lymphoma; Mice; Mice, Inbred AKR; Nitrosourea Compounds