Feasibility and Safety of a Combined Metabolic Strategy in Glioblastoma Multiforme: A Prospective Case Series.

Background: Glioblastoma multiforme (GBM) may be susceptible to metabolic strategies such as fasting and ketogenic diets, which lower blood glucose and elevate ketones. Combining these two strategies may be an ideal approach for sustaining a potentially therapeutic glucose ketone index (GKI). In this prospective case series, we observed whether a combined metabolic strategy was feasible, safe, and capable of sustaining a GKI <6 in patients with GBM. Methods: We provided recommendations and guidelines to 10 GBM patients at various stages of tumour progression and treatment that enabled them to complete a 5-7-day fast every 1-2 months combined with a modified ketogenic diet during the intervening weeks. Patients monitored their blood glucose and ketone levels and body weight. Adverse effects were assessed. Results: Patients completed a mean of 161 ± 74 days of the combined metabolic strategy, with 34 ± 18 (21%) days of prolonged fasting (mean fast duration: 6.0 ± 1.4 days) and 127 ± 59 (79%) days on the ketogenic diet. The mean GKI for all 10 patients was 3.22 (1.28 during the fasts, 5.10 during the ketogenic diet). Body weight decreased by 8.4 ± 6.9 kg (11.2% decrease in baseline weight). The most common adverse effects attributed to the fasts and ketogenic diet were fatigue, irritability, and feeling lightheaded. The metabolic strategy did not interfere with standard oncological treatments. Conclusion: This is the first study to observe the feasibility and safety of repeated, prolonged fasting combined with a modified ketogenic diet in patients with GBM. Using minimal support, patients maintained the combined metabolic strategy for 5-6 months while sustaining a potentially therapeutic mean GKI of 3.22. Weight loss was considerable. Adverse effects attributed to the metabolic strategy were mild, and it did not interfere with standard oncological treatments. Study Registration: This study is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12620001310954. The study was registered on 4 December 2020.

The use of ketoconazole in the treatment of blastomycosis.

We retrospectively reviewed our experience using ketoconazole in the therapy of blastomycosis. Over the course of 30 months, blastomycosis was diagnosed in 11 patients. Their clinical presentations ranged from the asymptomatic pulmonary nodule to the adult respiratory distress syndrome. Six of 8 patients treated with ketoconazole completed a 6-month course of 400 mg daily. Seventeen to 40 months after completion of therapy, the patients who had completed 6 months of therapy were well. Ketoconazole should play a major role in the therapy of blastomycosis because of its efficacy and because its administrative costs are lower than those of amphotericin B. It can be recommended for patients who have been symptomatic for longer than 3 wk and are not improving and for those who undergo resection of an asymptomatic pulmonary nodule. Amphotericin B remains the drug of choice in patients with life-threatening illness who require ventilatory assistance, have developed renal failure, or have central nervous system involvement. Severely immunocompromised patients with disseminated disease should also be treated with amphotericin B. Patients treated with ketoconazole should have close medical follow-up.

In vitro tumor necrosis factor induction assay for analysis of febrile toxicity associated with amphotericin B preparations.

Amphotericin B can stimulate macrophages to produce tumor necrosis factor alpha (TNF alpha), one of the inflammatory mediators that may be responsible for the febrile toxicity associated with drug administration. The purpose of this study was to compare the in vitro TNF-inducing activity of one recalled lot of an amphotericin B preparation which was associated with more frequent febrile reactions in patients with a preparation not associated with a greater incidence of febrile reaction. We found that the former preparation induced significantly more TNF than the latter preparation, and the in vitro data correlated with the results of rabbit pyrogen testing. The in vitro TNF induction assay may serve as a screening tool for the selection of the least pyrogenic lots of amphotericin B preparation.

Detection of a Trichosporon beigelii antigen cross-reactive with Cryptococcus neoformans capsular polysaccharide in serum from a patient with disseminated Trichosporon infection.

Latex beads coated with anti-Cryptococcus neoformans antibody were agglutinated by serum from a bone marrow transplant recipient having a disseminated infection caused by Trichosporon beigelii. The cryptococcal latex agglutination titer in the serum of the patient rose to 1:2,560 by the time of his death. Necropsy confirmed the disseminated Trichosporon infection and absence of C. neoformans. Cell wall extracts of the isolate of the patient and two additional strains of T. beigelii agglutinated anti-Cryptococcus-coated latex beads. The antigen in the serum of the patient and in the extracts responsible for the agglutination was not destroyed by proteolytic enzymes or heat. A single antigen reactive with rabbit anti-Trichosporon serum could be identified in the serum of the patient and the cell wall extracts by rocket immunoelectrophoresis and crossed immunoelectrophoresis. Rocket immunoelectrophoresis and indirect fluorescent-antibody staining demonstrated that anti-Trichosporon antibody recognized the capsular polysaccharide of C. neoformans.

Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome.

BACKGROUND AND METHODS: Few cases of overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome have been reported. We describe 10 patients with this condition who were treated at one center in Wisconsin. RESULTS: All 10 patients presented with fever, cough, and dyspnea; radiographic evidence of diffuse pulmonary infiltrates; and marked impairment of oxygenation. The mean alveolar-arterial oxygen gradient was 616 mm Hg. Six of the patients had no underlying disease associated with altered immunity, and two had no recent exposure to environmental reservoirs of Blastomyces dermatitidis. In all 10 patients, large numbers of broad-based budding yeasts were seen on microscopical examination of tracheal secretions. All patients were treated with intravenous amphotericin B (0.7 to 1.0 mg per kilogram per day). Of the five survivors, four received full doses of amphotericin B in the first 24 hours, and four required mechanical ventilatory support for 7 to 151 days. Long-term follow-up of three survivors showed good recovery of pulmonary function. CONCLUSIONS: Overwhelming infection with B. dermatitidis can cause diffuse pneumonitis and the adult respiratory distress syndrome, even in immunocompetent hosts. With prompt diagnosis by microscopical examination of tracheal secretions, intensive therapy with amphotericin B, and ventilatory support, good recovery of pulmonary function is possible.

Treatment of murine candidosis and cryptococcosis with a unilamellar liposomal amphotericin B formulation (AmBisome).

This investigation examined the therapeutic efficacy of AmBisome, a unilamellar (55-75 nm) liposome amphotericin B preparation with a murine LD50 by the intravenous route of greater than 175 mg/kg amphotericin B. Both fungal burden and survival were used to evaluate the drug's efficacy against murine candidosis and cryptococcosis. Single and multiple dose intravenous treatment with AmBisome (2.5, 5.0 and 10.0 mg/kg) reduced the colony forming units/mg kidney in candida-infected mice by 99% and improved survival by at least 40% relative to untreated control mice. Repeated intravenous dosing of candida-infected mice with equivalent amounts (0.75 mg/kg) of conventional amphotericin B (Fungizone) or AmBisome showed comparable reduction of yeasts in the kidneys. When mice were infected systemically with Cryptococcus neoformans, all but one of the 30 mice given AmBisome (5.0, 7.5 or 10.0 mg/kg) survived until the experiment was terminated 35 days after infection. Liver and spleen cultures from AmBisome-treated mice were negative for fungal growth. All the mice given conventional amphotericin B intraperitoneally at 4.5 mg/kg survived and cleared the infection from the livers although some of the mice had infected spleens. The percentage of cultured brains free of cryptococcus was 89% following treatment with 10.0 mg/kg AmBisome, and 80% with 4.5 mg/kg conventional drug. These preclinical studies of systemic candidosis and cryptococcosis demonstrate comparable efficacy of AmBisome and conventional amphotericin B at low doses and improved efficacy with AmBisome at doses higher than can be safely administered of the conventional drug.