Development of Acute Adult T-cell Leukemia Following PD-1 Blockade Therapy for Lung Cancer

Immune checkpoint inhibitors (ICIs) are widely used for the treatment of various cancers. However, paradoxical exacerbation of neoplasms, referred to as “hyperprogressive disease,” has been reported in a proportion of patients treated with anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) blockade. We herein report a case of acute adult T-cell leukemia (ATL) that developed shortly after the administration of nivolumab, a PD-1 inhibitor, to treat non-small-cell lung cancer. There were no signs of ATL before the administration of nivolumab, and seropositivity for human T-cell leukemia virus type-1 (HTLV-1) was confirmed after the development of acute ATL. We speculate that nivolumab likely contributed to the development of acute ATL.     

Empagliflozin is associated with lower risk of cardiovascular events and all‐cause mortality in routine care in East Asia: Results from the EMPRISE study

Aims/IntroductionThe EMPA‐REG OUTCOME® trial demonstrated benefits of empagliflozin, a sodium‐glucose cotransporter‐2 inhibitor (SGLT2i), on cardiovascular, renal outcomes and all‐cause mortality in patients with type 2 diabetes and established cardiovascular disease. The EMPRISE study program evaluates how these effects translate in a broad population of patients with type 2 diabetes in routine clinical care across countries.Materials and MethodsThe study included patients ≥18 years with type 2 diabetes initiating empagliflozin or any dipeptidyl peptidase‐4 inhibitors (DPP‐4i) from large administrative databases in Japan, South Korea, and Taiwan. Propensity score‐matched (1:1) ‘as‐treated’ analyses comparing the risk of cardiovascular outcomes and all‐cause mortality between empagliflozin and DPP‐4i use were performed in each country. Pooled hazard ratios (pHR) with 95% confidence intervals (CI) were computed using random effects meta‐analysis models comparing both empagliflozin and SGLT2i with DPP‐4i use, respectively. Intention‐to‐treat and subgroup analyses in patients with/without cardiovascular disease and in patients receiving 10 mg empagliflozin were performed.ResultsThe study included 28,712 and 70,233 matched patient pairs for empagliflozin/DPP‐4i and SGLT2i/DPP‐4i analyses, respectively. The risk of composite outcomes including (i) hospitalization for heart failure (HHF) and all‐cause mortality was lower with empagliflozin (pHR 0.76, 95% CI 0.67–0.86) and SGLT2i (0.71, 0.65–0.77); (ii) combined myocardial infarction, stroke, and all‐cause mortality was also lower with empagliflozin (0.74, 0.61–0.88) and SGLT2i (0.69, 0.60–0.78) compared to DPP‐4i. The intention‐to‐treat and three subgroup analyses were consistent with results of the main analyses.ConclusionsThe results suggest that both empagliflozin and SGLT2i compared with DPP‐4i are associated with a lower risk of cardiovascular events and all‐cause mortality in routine clinical care in East Asia.     

Different Clinical Courses of Nephronophthisis in Dizygotic Twins

Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.     

Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.     

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy

The effect of radiotherapy during immunotherapy on immune-related adverse events (irAEs) is not fully understood. We herein report a 74-year-old woman diagnosed with lung adenocarcinoma with programmed death ligand 1 expression ≥50% and treated with pembrolizumab. She developed fatal immune thrombocytopenia associated with pembrolizumab immediately following radiotherapy. A flow cytometry analysis of peripheral blood detected an increased expression of programmed death-1 (PD-1) and Ki-67 in CD4^＋ and CD8^＋ T cells after radiotherapy, compared with pre-irradiation measurements. This case suggests that radiotherapy may evoke irAEs during treatment with anti-PD-1 antibodies, which physicians should consider when using radiotherapy in patients treated with these drugs.     

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916^T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.     

Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index

Aims/IntroductionMany East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in ''super‐aged'' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups.Materials and MethodsData were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m²). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed.ResultsIn this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups.ConclusionsIn this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile.     

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples

ObjectivePrecursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.MethodsWe analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease.Results TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer.ConclusionThe sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.