Norimitsu Kadowaki

Severe fever with thrombocytopenia syndrome (SFTS) is a disease caused by SFTS virus (SFTSV), an RNA virus, and endemic to Asia. The case fatality rate in Japan is estimated to be approximately 27%. Currently, no efficacious drugs are available. Favipiravir (FPV) has the potential to treat SFTS. However, no quantitative studies comparing FPV with conventional treatments have been conducted in the country. We conducted an open-label, interventional study in which patients with SFTS were administered FPV 1800 mg twice on the first day, followed by 800 mg twice daily for nine days. Additionally, we performed a retrospective observational study on patients with SFTS who received the best supportive care (BSC) without FPV treatment by collecting medical data from individuals at the same institutions. Patients aged 20–85 years were recruited, and blood samples were collected on Days 0 (pre-dose), 1, 3, 6, 9, 14, and 27 in the interventional study. Outcomes and laboratory parameters were compared by 1:1 matching using propensity score (PS). Thirty and 78 patients were enrolled in the FPV and the BSC groups, respectively. Twenty-three pairs were identified by PS matching. The risk ratio of fatality for the FPV group compared to the BSC group reduced to 0.500 after matching. Ferritin levels associated with hemophagocytosis severity were significantly different between the FPV and BSC groups on Days 3 to 9 after matching. No concerning serious adverse events were observed in the FPV group. This interventional study has been registered with the Japan Registry of Clinical Trials as jRCT2080223816 .

Objectives: Despite advancements in molecular-targeted therapies and immune checkpoint inhibitors, the survival rate of patients with advanced lung cancer remains unsatisfactory. Therefore, new and effective treatment strategies are urgently needed. Both mesenchymal-epithelial transition (MET) inhibitors and oncolytic viruses exhibit immunomodulatory properties along with direct antitumor effects. Materials and Methods: The antitumor effects of a combination therapy using MDRVV, a modified vaccinia virus for oncolytic virus therapy, and tepotinib, a MET inhibitor, were evaluated in vitro and in vivo using lung cancer models. Results: The combination therapy demonstrated additive cytotoxic effects on various lung cancer cell lines in vitro and significantly suppressed tumor growth in an immunocompetent mouse model. MDRVV triggered immunogenic cell death, evidenced by the release of adenosine triphosphate (ATP) and high-mobility group box-1 (HMGB-1). Additionally, the combination therapy enhanced CD4+ and CD+ T-cell infiltration more effectively than either agent alone. MDRVV exhibited antitumor effects not only in the inoculated tumors but also in distant tumors, with the most pronounced effect observed when combined with tepotinib. Conclusions: These findings suggest that combining a MET inhibitor with oncolytic vaccinia virus represents a promising and effective strategy for improving lung cancer treatment by targeting both tumor cells and the tumor microenvironment.

Background/Objectives: Immune checkpoint inhibitors (ICIs) cause interstitial lung diseases (ILDs) as a type of immune-related adverse event (irAE). The characteristics of ICI-ILD are diverse. The objective of this study is to investigate the clinical features of ICI-ILD, with particular emphasis on insidiously progressive ICI-ILD. Methods: We retrospectively analyzed 232 patients with advanced lung cancer who were treated with ICIs (including combination therapy with cytotoxic agents). Results: IrAEs were observed in 85 patients (36.6%). The most frequent irAE was ICI-ILD (41 patients, 17.7% of all patients). The occurrence of ICI-ILD was associated with a significantly better response compared to the non-irAE group (response rates: 88% vs. 33%), longer progression-free survival (PFS) (median: 17.5 vs. 3.0 months), and longer overall survival (median: 52.6 vs. 16.6 months), respectively. However, six patients died from ICI-ILD, which could be divided into two patterns: early-onset ICI-ILD in three patients (median PFS: 1.2 months), and insidiously progressive ICI-ILD in three patients. In the latter type, ICI-ILD developed unnoticed, progressed insidiously, and led to respiratory failure (median PFS: 7.2 months). The non-organizing pneumonia pattern and a weak response to corticosteroid therapy were also common findings. On average, six cycles of ICI treatment were administered between the time when ICI-ILD became retrospectively recognizable and the discontinuation of ICI treatment. During this period, C-reactive protein levels and the extent of ILD involvement gradually increased. Conclusions: Insidiously progressive ICI-ILD can lead to fatal outcomes. Early discontinuation of ICIs upon recognition of this type of ICI-ILD may improve patient outcomes.

Purpose: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). Methods: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. Results: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. Conclusion: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

We aimed to determine the association between disease activity during pregnancy and pregnancy outcomes of women with polymyositis and dermatomyositis (PM/DM). Patients with PM/DM who were managed from pregnancy to delivery at Kagawa University Hospital from March 2006 to May 2021 were enrolled. Clinical data were retrospectively analyzed to evaluate the association between disease activity during pregnancy and pregnancy outcomes. Eight pregnancies in 5 women with PM/DM were analyzed. The mean age at conception was 28.3 ± 3.8 years, and mean disease duration was 6.3 ± 3.2 years. Four patients required an increased glucocorticoid dosage because of worsening disease activity (sustained elevation of creatine phosphokinase [CPK] concentration). Two patients who continuously received immunosuppressive drugs from conception to delivery showed no increase in disease activity and did not need increased glucocorticoid dosages. The pregnancy outcomes were 1 spontaneous abortion and 7 live births. The mean gestation length was 35.3 ± 5.2 weeks, and mean birthweight was 2297.7 ± 1041.4 g. Five adverse pregnancy outcomes (APOs) occurred (2 preterm births and 4 low birthweights); most of these cases had sustained elevation of CPK concentration and increased glucocorticoid dosages. No APOs occurred in the 2 patients who received continuous immunosuppressive medication. Continued use of pregnancy-compatible medications and control of disease activity with lower glucocorticoid dosages in pregnancies with PM/DM may be important to achieve good pregnancy outcomes.

Background: Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. Case presentation: We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens—nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient’s peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. Conclusions: We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.