ß-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus.

Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog ß-d-N4-hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable in vitro anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 µM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection.

Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model.

BACKGROUND: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. METHODS: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2. FINDINGS: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants. INTERPRETATION: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses. FUNDING: Funding bodies are described in the Acknowledgments section.

Utility of whole brain radiation therapy for leptomeningeal carcinomatosis.

BACKGROUND: Although whole brain radiation therapy (WBRT) is commonly used as first-line treatment for leptomeningeal carcinomatosis, the prognosis is uncertain despite treatment. Moreover, the benefit of WBRT for leptomeningeal carcinomatosis has not been adequately evaluated. Therefore, this study aimed to clarify the utility of WBRT for leptomeningeal carcinomatosis. METHODS: Consecutive patients who received WBRT for leptomeningeal carcinomatosis or brain metastasis from solid tumors between January 2008 and July 2017 were retrospectively evaluated. The overall survival, symptom relief, and adverse events were compared between patients with leptomeningeal carcinomatosis and those with brain metastasis after WBRT. RESULTS: Of the 277 treated patients, 204 patients (22 with leptomeningeal carcinomatosis and 182 with brain metastasis) were included in the study. The median overall survival was 440 days (95% confidence interval [CI] 0-931 days) for patients with leptomeningeal carcinomatosis and 322 days (95% CI 196-448 days) for those with brain metastasis (p = 0.972 on the log-rank test). On evaluating the overall survival of patients with leptomeningeal carcinomatosis, the prognostic factors of performance status 0-1, no extracranial metastasis, and no symptoms at the time of WBRT showed a significant survival advantage on univariate analysis. Among patients with leptomeningeal carcinomatosis, those with headache and nausea often showed improvement while those with depressed levels of consciousness and seizures did not. On comparing all-grade adverse events, vomiting and seizures were more frequent in patients with leptomeningeal carcinomatosis than in those with brain metastasis. CONCLUSIONS: WBRT was generally well tolerated and effective for treating patients with leptomeningeal carcinomatosis.

Efficacy of prophylactic irradiation to the contralateral testis for patients with advanced-stage primary testicular lymphoma: an analysis of outcomes at a single institution.

BACKGROUND: Primary testicular lymphoma (PTL) is a rare, extranodal lymphoma that often relapses in the contralateral testis. We evaluated outcomes in patients with any stage of PTL who had received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) with rituximab chemotherapy and prophylactic radiotherapy to the contralateral testis. METHODS: We retrospectively identified 15 patients (median age 66 years; range 39-81) diagnosed with diffuse large B-cell PTL in the period 2000-2014. Characteristics and outcomes of these cases were evaluated. RESULTS: All patients received initial orchiectomy followed by CHOP with or without rituximab. Thirteen patients received prophylactic irradiation to the contralateral testis. During follow-up (median 67 months; range 8-190), one patient died of PTL, three died of other disease, and nine were free from relapse. For stage I-II disease, 5-year progression-free and overall survival rates were 80 and 100%, respectively. For stage III-IV PTL, 5-year progression-free and overall survival rates were 50 and 72%, respectively. Notably, no patient developed contralateral testicular involvement after prophylactic irradiation. CONCLUSIONS: The observed outcomes suggest that the combination of (i) CHOP plus rituximab and (ii) radiotherapy for local recurrence prophylaxis is promising for both stage I-II and stage III-IV PTL.

Long-term outcome of hypofractionated radiotherapy to the whole breast of Japanese women after breast-conserving surgery.

BACKGROUND: In Japan, there are still no reports of long-term outcome for hypofractionated radiotherapy to the whole breast after breast-conserving surgery (BCS). We report our institution's results from evaluation of the efficacy and safety of hypofractionated radiotherapy for Japanese women. METHODS: Data in the medical records of 327 patients were retrospectively reviewed. The patients were treated with hypofractionated radiotherapy between January 2003 and December 2006 at the Kawasaki Medical School Hospital and were followed for more than 3 years. The median age was 54 years old (the age range was 28-80 years). The whole breast was irradiated with a total dose of 42.56 Gy/16 fx with boost irradiation to positive margins. Adjuvant therapy consisted of chemotherapy and/or hormone therapy and was administered to 300 patients, based on their stage or pathological findings. RESULTS: Follow-up periods ranged from 21 to 92 months; the median follow-up period was 60 months. At 5-year follow-up, overall survival, cause-specific survival, relapse-free survival, and local control were 96.0, 97.5, 95.3, and 99.7% respectively. Grade 2 radiation pneumonitis occurred in five patients. Grade 2 radiation dermatitis occurred in 17 patients. Severe late complications were not observed. CONCLUSIONS: In our study, hypofractionated radiotherapy led to good results without severe toxicity. We believe hypofractionated radiotherapy after BCS is safe and efficient treatment for Japanese women.