Comparison of the efficacy of first­/second­generation EGFR­tyrosine kinase inhibitors and osimertinib for EGFR­mutant lung cancer with negative or low PD­L1 expression.

In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with negative or low programmed death ligand-1 (PD-L1) expression, the acquisition rate of the T790M mutation is higher after treatment with first-/second-generation EGFR-tyrosine kinase inhibitors (TKIs) and the progression-free survival (PFS) is longer in patients treated with osimertinib. The present study compared the clinical course after the initiation of each EGFR-TKI monotherapy in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. Data of patients with EGFR-mutant NSCLC with negative or low PD-L1 expression who were treated with EGFR-TKI monotherapy were retrieved and retrospectively analyzed. Between June 2013 and November 2023, 26 and 29 patients were treated with first-/second-generation EGFR-TKIs and osimertinib, respectively. The PFS time was longer in patients treated with osimertinib (median, 22.5 months) than in those treated with first-/second-generation EGFR-TKIs (median, 12.9 months). However, the EGFR-TKI treatment duration, defined as the PFS for osimertinib, or the sum of the PFS for first-/second-generation EGFR-TKIs and sequential osimertinib therapy after the acquisition of the T790M mutation, was similar between patients treated with first-/second-generation EGFR-TKIs (median, 23.0 months) and osimertinib (median, 22.5 months). The Cox proportional hazard model suggested that there was no significant difference in the EGFR-TKI treatment duration between patients treated with first-/second-generation EGFR-TKIs and patients treated with osimertinib (hazard ratio, 1.31, 95% CI, 0.55-3.13). In conclusion, first-/second-generation EGFR-TKIs and osimertinib were associated with a similar EGFR-TKI treatment duration in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. The findings suggested that both treatments are promising for this population.

Immune Checkpoint Inhibitor Therapy for Patients With Non-small Cell Lung Cancer Ineligible for Platinum Doublet Chemotherapy.

BACKGROUND/AIM: Combined therapy with immune checkpoint inhibitors plus platinum doublet chemotherapy has a survival advantage over platinum doublet chemotherapy in patients with non-small cell lung cancer. However, a variety of factors make it difficult to administer treatment with platinum doublet chemotherapy in many patients in clinical practice and there are few reports on the efficacy and safety of first-line treatments with immune checkpoint inhibitors for patients who are ineligible for platinum doublet chemotherapy. This observational study aimed to evaluate the efficacy and safety of first-line immune checkpoint inhibitor therapy for this population. PATIENTS AND METHODS: We retrospectively assessed the survival and adverse events from the initiation of first-line immune checkpoint inhibitor therapy, including pembrolizumab or nivolumab plus ipilimumab in patients with non-small cell lung cancer who were ineligible for platinum doublet chemotherapy. RESULTS: Data from 48 patients were analyzed. Seventeen patients showed a performance status (PS) of ≥2 while 16 and 15 patients were considered ineligible for platinum doublet chemotherapy because of age and comorbidities, respectively. The median (95% confidential interval, CI) progression-free survival (PFS) and overall survival (OS) of the 48 patients were 7.1 (1.7-13.7) and 31.7 (8.8-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 30.8% (18.2%-47.2%) and 50.7% (33.7%-67.7%), respectively. In patients with a PS of ≥2, the median (95% CI) PFS and OS were 1.6 (1.2-not estimated) and 5.5 (2.3-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 34.3% (15.8%-59.2%) and 45.3% (22.2%-70.7%), respectively. CONCLUSION: Patients with non-small cell lung cancer and a PS of 0-1 who were ineligible for platinum doublet chemotherapy had favorable outcome after the initiation of ICI therapy, and even in patients with a PS of ≥2, they achieved high two-year PFS and OS rates.

A Case Report of Anti-TIF1-γAntibody-Positive Dermatomyositis Concomitant with Small Cell Neuroendocrine Carcinoma of the Urinary Bladder.

Small cell neuroendocrine carcinoma is rare among urinary bladder cancer types, and to date, there are no case reports of concurrent antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis. We describe the case of a 69-year-old Japanese man who presented with elevated creatine kinase levels and haematuria on medical examination. Approximately one month later, he developed dysphagia. Laryngoscopy confirmed laryngeal dysfunction. He also presented with muscle weakness and a skin rash. Magnetic resonance imaging of the upper extremities suggested bilateral brachial muscle myositis. He was diagnosed as having dermatomyositis and was later found to be positive for antitranscriptional intermediary factor 1-γ antibody. Computed tomography revealed an intravesical space-occupying lesion and right iliac lymphadenopathy, suggesting urinary bladder cancer. The patient was admitted to our hospital for treatment. Urinary bladder biopsy confirmed small cell neuroendocrine carcinoma because tumour cells were positive for synaptophysin, CD56, and chromogranin A. Thus, the patient was diagnosed as having an antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis concomitant with urinary bladder small cell neuroendocrine carcinoma. The patient was treated with glucocorticoid and intravenous immune globulin therapy for dermatomyositis. Radiotherapy was selected for the carcinoma. Although muscle weakness and skin symptoms improved with treatment, dysphagia persisted. Furthermore, expression of the transcriptional intermediary factor 1-γ protein in tumour cells was also confirmed by immunohistochemistry, but the significance is unknown. It should be noted that antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis can occur concomitantly with such a rare malignancy.

Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice.

OBJECTIVE: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. METHODS: High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. RESULTS: The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. CONCLUSIONS: Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.

Peripheral CD4 memory T cells predict the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer.

Immune checkpoint inhibitors have significantly improved the prognosis in patients with non-small cell lung cancer, compared with cytotoxic agents. However, the prediction of treatment response is often difficult, even after assessing the tumor programmed death-ligand 1 expression. We conducted this observational study to analyze the association between the differentiation of peripheral CD4 + T cells and the efficacy of immune checkpoint inhibitor therapy. We enrolled patients who were diagnosed with non-small cell lung cancer and received immune checkpoint inhibitor therapy between 2020 and 2022. Blood samples were collected at the start of immune checkpoint inhibitor therapy, and the expressions of PD-1, CCR7, and CD45RA in peripheral CD4 + T cells were analyzed by flow cytometry. The association between the findings of flow cytometry and survival after the initiation of the immune checkpoint inhibitor therapy was evaluated. Forty patients with non-small cell lung cancer were enrolled. The Cox proportional hazards model showed that an increased proportion of CD45RA-CD4 + T cells was associated with a reduced risk of progression after adjustment for performance status, tumor programmed death-ligand 1 expression level, mutation status of the epidermal growth factor receptor gene, and combined therapy with cytotoxic agents. The present study showed that the proportion of peripheral CD45RA- CD4 + T cells was associated with progression-free survival after the initiation of immune checkpoint inhibitor therapy, independent of several clinical factors.

An autopsy case of anti-MDA5 antibody-positive amyopathic dermatomyositis with an initial manifestation of panniculitis on the left upper arm.

A 53-year-old man was presented with refractory panniculitis on the left upper arm that had persisted for 10 months. The patient was diagnosed with lupus profundus, wherein oral glucocorticoid therapy was initiated. Four months prior, ulceration was observed in the same area. Dapson was administered instead, scarring the ulcer but enlarging the panniculitis. Five weeks earlier, he developed a fever, productive cough, and dyspnoea. Three weeks earlier, a skin rash was observed on the forehead, left auricle posterior to the neck, and extensor aspect of the left elbow. Chest computed tomography showed pneumonia in the right lung, after which the patient's dyspnoea worsened. The patient was admitted and diagnosed with anti-MDA5 antibody-positive amyopathic dermatomyositis (ADM) based on skin findings, hyperferritinaemia, and rapidly progressive diffuse lung shadows. Glucocorticoid pulse therapy, intravenous cyclophosphamide, and tacrolimus were initiated, and later, plasma exchange therapy was combined. However, his condition worsened and required management with extracorporeal membrane oxygenation. The patient expired on day 28 after hospitalisation. An autopsy revealed hyalinising to fibrotic stages of diffuse alveolar damage. Strong expression of myxovirus resistance protein A was observed in three skin biopsy specimens from the time of initial onset, consistent with ADM. Anti-MDA5 antibody-positive ADM not only manifests typical cutaneous symptoms, but also rarely occurs with localised panniculitis, such as in the present case. In patients with panniculitis of unknown aetiology, the possibility of initial symptoms of ADM should be included in the differential diagnosis.

Association Between the Severity of Immune-related Adverse Events and the Prognosis in Patients With Non-small Cell Lung Cancer Receiving Treatment With Immune Checkpoint Inhibitors.

BACKGROUND/AIM: Among patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI), survival is reported to be longer in those experiencing immune-related adverse events (irAEs). We evaluated the progression-free survival (PFS) in the absence of further treatment after ICI therapy was discontinued because of the emergence of irAEs in patients with NSCLC. PATIENTS AND METHODS: Data from patients with NSCLC in whom ICI therapy was discontinued because of the development of irAEs were retrospectively analyzed. The primary endpoint was the PFS from the last day of administration of ICIs, in the absence of any further treatment. RESULTS: A total of 162 patients with NSCLC received treatment with ICIs between January 2016 and December 2021. Among them, ICI therapy was discontinued in 33 patients because of the appearance of irAEs. The median (95% confidence interval) PFS in the absence of any treatment after the last administration of ICIs was 7.2 (4.2-12.3) months. According to the Common Terminology Criteria for Adverse Events, the Cox proportional hazards model was used to identify the severity of irAEs, which were determined to be significantly associated with the PFS in the absence of any further treatment after the last administration of ICI therapy. CONCLUSION: Although the present study showed that the PFS in patients with NSCLC was relatively long in the absence of any further treatment after the last administration of ICIs, the PFS was associated with the severity of the irAEs, and some patients showed early disease progression or death.

Associations of immune checkpoint inhibitor therapy efficacy with clinical parameters and tumor­infiltrating CD68­positive cell counts in patients with EGFR­mutant non­small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has been less effective in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations than in patients with EGFR wild-type NSCLC. This retrospective study was conducted to investigate the associations of clinical parameters with the efficacy of ICI therapy in patients with EGFR-mutant NSCLC. Clinical information was retrieved from the medical charts, and immunohistochemical analysis was performed in some cases to determine the tumor-infiltrating CD68-positive cell count. Data from 46 patients were included in the analysis. The median (95% confidence interval) progression-free survival and overall survival from the initiation of ICI therapy was 1.4 months (1.0-1.7 months) and 6.4 months (3.9-19.0 months), respectively. Analysis using a Cox proportional hazards model revealed that tumor programmed death-ligand 1 expression was associated with the overall survival of patients with EGFR-mutant NSCLC after ICI treatment. The tumor-infiltrating CD68-positive cell count was evaluated in 11 patients. Comparison using the log-rank test revealed that the progression-free survival time after ICI treatment was longer in the patients with lower tumor-infiltrating CD68-positive cell counts than those with higher tumor-infiltrating CD68-positive cell counts. The present analysis demonstrated that PD-L1 expression and the tumor-infiltrating CD68-positive cell count may be associated with the efficacy of ICI therapy in patients with NSCLC harboring EGFR mutations.

Efficacy of immune checkpoint inhibitor therapy in patients with pulmonary sarcomatoid carcinoma in clinical practice.

OBJECTIVE: Studies have suggested the potential efficacy of immune checkpoint inhibitors (ICIs) for pulmonary sarcomatoid carcinoma. This multicenter observational study was conducted to evaluate the efficacy of systemic ICI therapy and chemoradiation followed by durvalumab therapy for pulmonary sarcomatoid carcinoma. METHODS: We analyzed the data of patients with pulmonary sarcomatoid carcinoma who received systemic ICI therapy or chemoradiation followed by durvalumab therapy between 2016 and 2022. RESULTS: In this study, data of a total of 22 patients who received systemic ICI therapy and four patients who received chemoradiation followed by durvalumab therapy were analyzed. In the patients who received systemic ICI therapy, the median progression-free survival after initiation of therapy was 9.6 months, and the overall survival did not reach the median. The 1-year progression-free survival rate and overall survival rate were estimated to be 45.5% and 50.1%, respectively. Although the log-rank test revealed no significant association between the tumor expression level of programmed death ligand-1 (tumor proportion score evaluated using 22C3 antibody: ≥50% vs. <50%) and the survival duration, the majority of patients showing long-term survival showed a tumor proportion score of ≥50%. Of four patients treated with chemoradiation followed by durvalumab therapy, two patients showed an overall survival of ≥30 months, whereas the remaining two patients died within 12 months. CONCLUSION: The progression-free survival of patients who received systemic ICI therapy was 9.6 months, suggesting that ICI therapy might be effective in patients with pulmonary sarcomatoid carcinoma.

The gut microbiome: a core regulator of metabolism.

The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains comprising more than 1000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70-90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.

Depletion of CD206+ M2-like macrophages induces fibro-adipogenic progenitors activation and muscle regeneration.

Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206+ M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206+ M2-like macrophages or deletion of CD206+ M2-like macrophages-specific TGF-ß1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206+ M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206+ M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-ß signaling. Here we show that CD206+ M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells.

Perioperative C-peptide index is associated with the status of diabetes management after pancreatectomy.

AIMS/INTRODUCTION: This study aimed to identify the clinical factors affecting postoperative residual pancreatic ß-cell function, as assessed by the C-peptide index (CPI), and to investigate the association between perioperative CPI and the status of diabetes management after pancreatectomy. MATERIALS AND METHODS: The associations between perioperative CPI and clinical background, including surgical procedures of pancreatectomy, were analyzed in 47 patients who underwent pancreatectomy, and were assessed for pre-and postoperative CPI. The association between perioperative CPI and glycemic control after pancreatectomy was investigated. RESULTS: The low postoperative CPI group (CPI <0.7) had longer duration of diabetes (17.5 ± 14.5 vs 5.5 ± 11.0 years, P = 0.004), a higher percentage of sulfonylurea users (41.7 vs 8.7%, P = 0.003) and a greater number of drug categories used for diabetes treatment (1.9 ± 1.1 vs 0.8 ± 0.8, P <0.001) than did the high postoperative CPI group. Postoperative CPI was higher (1.4 ± 1.2 vs 0.7 ± 0.6, P = 0.039) in patients with low glycosylated hemoglobin (<7.0%) at 6 months after pancreatectomy; preoperative (2.0 ± 1.5 vs 0.7 ± 0.5, P = 0.012) and postoperative CPI (2.5 ± 1.4 vs 1.4 ± 1.1, P = 0.020) were higher in non-insulin users than in insulin users at 6 months after surgery. CONCLUSIONS: The duration of diabetes and preoperative diabetes treatment were associated with residual pancreatic ß-cell function after pancreatectomy. Furthermore, perioperative ß-cell function as assessed by CPI was associated with diabetes management status after pancreatectomy.

Association of Tumor PD-L1 Expression With Time on Treatment Using EGFR-TKIs in Patients With EGFR-Mutant Non-small Cell Lung Cancer.

BACKGROUND/AIM: The association between tumor PD-L1 expression and the rate of acquisition of the T790M mutation during treatment with first-/second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a matter of study. This retrospective study was conducted to evaluate the association of tumor PD-L1 expression with the time on treatment under EGFR-TKIs in patients with EGFR-mutant non-small cell lung cancer (NSCLC), treated with first-/second-generation EGFR-TKIs. PATIENTS AND METHODS: We conducted a retrospective review of the medical charts of patients with EGFR-mutant NSCLC treated with first- /second-generation EGFR-TKIs. Time on treatment with EGFR-TKIs was defined as the sum of progression-free survival period (PFS) from the start of treatment with first- /second-generation EGFR-TKIs and the PFS from the start of osimertinib treatment after acquisition of the T790M mutation. Tumor PD-L1 expression was evaluated using the 22C3 antibody. RESULTS: Data of a total of 49 patients were analyzed, including 20 patients with negative tumor PD-L1 expression (tumor proportion score <1%) and 29 patients with positive tumor PD-L1 expression (tumor proportion score ≥1%). In the negative tumor PD-L1 expression group, the T790M mutation was detected in 12 (75%) of the 16 patients. In the positive tumor PD-L1 expression group, the T790M mutation was detected 6 (31.6%) out of the 19 patients in whom it was tested. The median (95% confidence interval) time on treatment with EGFR-TKIs was 21.7 (12.9-24.8) months and 12.3 (5.6-22.2) months in the negative and positive tumor PD-L1 expression groups, respectively. Analysis using a Cox proportional hazards model identified performance status and presence/absence of tumor PD-L1 expression as significantly associated with the time on treatment with EGFR-TKIs. CONCLUSION: EGFR-mutant NSCLC patients with negative tumor PD-L1 expression showed a higher rate of acquisition of the T790M mutation and implementation rate of osimertinib therapy, leading to a longer time on treatment with EGFR-TKI.

Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial.

BACKGROUND: Semaglutide 2·4 mg once weekly has been investigated for weight management in global populations. Differences exist between Asian and non-Asian populations in terms of body composition and definitions of obesity. In the Semaglutide Treatment Effect in People with obesity (STEP) 6 trial, we assessed the effect of semaglutide versus placebo for weight management in adults from east Asia with obesity, with or without type 2 diabetes. METHODS: This randomised, double-blind, double-dummy, placebo-controlled, phase 3a superiority trial was done at 28 outpatient clinics in Japan and South Korea. Eligible participants were adults (aged ≥18 years in South Korea; ≥20 years in Japan) with a BMI of at least 27·0 kg/m2 with two or more weight-related comorbidities or a BMI of 35·0 kg/m2 or more with one or more weight-related comorbidity (one comorbidity had to be either hypertension, dyslipidaemia, or, in Japan only, type 2 diabetes) who had at least one self-reported unsuccessful dietary attempt to lose bodyweight. Participants were randomly assigned (4:1:2:1) to once-weekly subcutaneous semaglutide 2·4 mg or matching placebo, or semaglutide 1·7 mg or matching placebo, plus lifestyle recommendations for 68 weeks. Data for the placebo groups were pooled in statistical analyses. The primary endpoints were percentage change in bodyweight from baseline at week 68 and the proportion of participants who had achieved a reduction of at least 5% of baseline bodyweight at week 68. Change in abdominal visceral fat area was assessed as a supportive secondary endpoint using computed tomography scanning in a subset of participants. Efficacy outcomes were assessed in the full analysis set, which included all randomly assigned participants according to the intention-to-treat principle. Safety was assessed in all participants who received at least one dose of the study drug. This trial was registered with ClinicalTrials.gov, NCT03811574. FINDINGS: Between Jan 21, 2019 and June 4, 2019, 437 participants were screened, of whom 401 were randomly assigned to semaglutide 2·4 mg (n=199), semaglutide 1·7 mg (n=101), or placebo (n=101) and included in the intention-to-treat analysis. Estimated mean change in bodyweight from baseline to week 68 was -13·2% (SEM 0·5) in the semaglutide 2·4 mg group and -9·6% (0·8) in the semaglutide 1·7 mg group versus -2·1% (0·8) in the placebo group (estimated treatment difference [ETD] -11·1 percentage points [95% CI -12·9 to -9·2] for semaglutide 2·4 mg vs placebo; -7·5 percentage points [95% CI -9·6 to -5·4] for semaglutide 1·7 mg vs placebo; both p<0·0001). At week 68, a larger proportion of participants had achieved a 5% or higher reduction in baseline bodyweight in the semaglutide 2·4 mg group (160 [83%] of 193 participants) and semaglutide 1·7 mg group (71 [72%] of 98 participants) than in the placebo group (21 [21%] of 100 participants); odds ratio [OR] 21·7 [95% CI 11·3 to 41·9] for semaglutide 2·4 mg vs placebo; OR 11·1 [95% CI 5·5 to 22·2] for semaglutide 1·7 mg vs placebo; both p<0·0001). Abdominal visceral fat area was reduced by 40·0% (SEM 2·6) among participants in the semaglutide 2·4 mg group and 22·2% (3·7) among participants in the semaglutide 1·7 mg group versus 6·9% (3·8) in the placebo group (ETD -33·2% [95% CI -42·1 to -24·2] for semaglutide 2·4 mg vs placebo; -15·3% [95% CI -25·6 to -4·9] for semaglutide 1·7 mg vs placebo). 171 (86%) of 199 participants in the semaglutide 2·4 mg group, 82 (82%) of 100 participants in the semaglutide 1·7 mg group, and 80 (79%) of 101 participants in the placebo group reported adverse events. Gastrointestinal disorders, which were mostly mild to moderate, were reported in 118 (59%) of 199 participants in the semaglutide 2·4 mg group, 64 (64%) of 100 participants in the semaglutide 1·7 mg group, and 30 (30%) of 101 participants in the placebo group. Adverse events leading to trial product discontinuation occurred in five (3%) of 199 participants in the semaglutide 2·4 mg group, three (3%) of 100 participants in the semaglutide 1·7 mg group, and one (1%) of 101 participants in the placebo group. INTERPRETATION: Adults from east Asia with obesity, with or without type 2 diabetes, given semaglutide 2·4 mg once a week had superior and clinically meaningful reductions in bodyweight, and greater reductions in abdominal visceral fat area compared with placebo, representing a promising treatment option for weight management in this population. FUNDING: Novo Nordisk. TRANSLATIONS: For the Korean and Japanese translations of the abstract see Supplementary Materials section.

Astaxanthin, a Marine Carotenoid, Maintains the Tolerance and Integrity of Adipose Tissue and Contributes to Its Healthy Functions.

Recently, obesity-induced insulin resistance, type 2 diabetes, and cardiovascular disease have become major social problems. We have previously shown that Astaxanthin (AX), which is a natural antioxidant, significantly ameliorates obesity-induced glucose intolerance and insulin resistance. It is well known that AX is a strong lipophilic antioxidant and has been shown to be beneficial for acute inflammation. However, the actual effects of AX on chronic inflammation in adipose tissue (AT) remain unclear. To observe the effects of AX on AT functions in obese mice, we fed six-week-old male C57BL/6J on high-fat-diet (HFD) supplemented with or without 0.02% of AX for 24 weeks. We determined the effect of AX at 10 and 24 weeks of HFD with or without AX on various parameters including insulin sensitivity, glucose tolerance, inflammation, and mitochondrial function in AT. We found that AX significantly reduced oxidative stress and macrophage infiltration into AT, as well as maintaining healthy AT function. Furthermore, AX prevented pathological AT remodeling probably caused by hypoxia in AT. Collectively, AX treatment exerted anti-inflammatory effects via its antioxidant activity in AT, maintained the vascular structure of AT and preserved the stem cells and progenitor's niche, and enhanced anti-inflammatory hypoxia induction factor-2α-dominant hypoxic response. Through these mechanisms of action, it prevented the pathological remodeling of AT and maintained its integrity.

A Case of Granulomatosis with Polyangiitis with Various Breast Lesions as the Initial Symptoms: A Case-Based Review.

A 44-year-old woman presenting with pus-like discharge from the nipples visited our hospital for scleritis. Subcutaneous induration and ulceration were found on her breast. She was diagnosed with granulomatosis with polyangiitis (GPA) considering scleritis, sinusitis, cutaneous granuloma formation, and antiproteinase 3-antineutrophil cytoplasmic antibodies and was successfully treated with glucocorticoids. Fifteen months later, she developed pulmonary consolidation and a right breast nodule. Biopsies of the breast nodule showed granulomatous vasculitis, and she was treated with rituximab. While breast involvement in GPA is rare, unilateral breast mass is a typical clinical feature; thus, GPA should be considered in such cases.

TCR function analysis using a novel system reveals the multiple unconventional tumor-reactive T cells in human breast cancer-infiltrating lymphocytes.

Tumor-infiltrating lymphocytes (TILs) are a potent source for obtaining tumor-reactive T cell receptors (TCRs). Although comprehensive methods to analyze the TCR repertoire in TILs have been reported, the evaluation system for TCR-reactivity to endogenously expressed antigen in tumor cells remains laborious and time consuming. Consequently, very limited numbers of TCRs in TILs have been analyzed for their reactivity to tumor cells. In this study, we developed an efficient evaluation system for TCR function designated c-FIT (comprehensive functional investigation of TCRs) to analyze TCR reactivity. The c-FIT system enabled us to analyze up to 90 TCRs for their reactivity to tumor cells by a single assay within a month. Using c-FIT, we analyzed 70 TCRs of CD8+ TILs derived from two breast cancer patients and obtained 23 TCRs that reacted to tumor cells. Surprisingly, although two TCRs were HLA class I-restricted, the remaining 21 TCRs were non-HLA-restricted. Thus, c-FIT can be applied for monitoring multiple conventional and unconventional antigen-specific killer T cells in TILs, leading to the development of new designs for more effective T-cell-based immunotherapies.

Case Series of Pleomorphic Carcinoma of the Lung Treated With Immune Checkpoint Inhibitors.

AIM: We report, herein, three cases of pleomorphic carcinoma of the lung treated with immune checkpoint inhibitors. Case 1: A 73-year-old man was diagnosed as having pleomorphic carcinoma of the lung and treated with pembrolizumab alone. However, he showed no response and died 4 months after the initiation of the treatment. Case 2: A 66-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on a combination regimen of pembrolizumab plus carboplatin plus nab-paclitaxel, and a remarkable response was observed. Case 3: A 49-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on pembrolizumab monotherapy as second-line treatment. Eleven months after the treatment initiation, computed tomography revealed the decrease of tumor diameter. CONCLUSION: Immune checkpoint inhibitor therapy is expected to improve the prognosis of patients with pleomorphic carcinoma of the lung.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodium-glucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥ 90, 60 to < 90, 45 to < 60, and < 45) and two subgroups (≥ 60 and < 60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to < 90 or ≥ 90 mL/min/1.73 m2. Bodyweight and HbA1c decreased in all subgroups, the latter by - 0.91% to - 0.40% (P < 0.05 vs. baseline). eGFR increased in the 45 to < 60 mL/min/1.73 m2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥ 90 and 60 to < 90 mL/min/1.73 m2 subgroups (- 8.27 ± 13.73 and - 1.22 ± 10.34 mL/min/1.73 m2; P < 0.001), but not to < 60 mL/min/1.73 m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue.

Meflin (Islr) expression has gained attention as a marker for mesenchymal stem cells, but its function remains largely unexplored. Here, we report the generation of Meflin-CreERT2 mice with CreERT2 inserted under the Meflin gene promoter to label Meflin-expressing cells genetically, thereby enabling their lineages to be traced. We found that in adult mice, Meflin-expressing lineage cells were present in adipose tissue stroma and had differentiated into mature adipocytes. These cells constituted Crown-like structures in the adipose tissue of mice after high-fat diet loading. Cold stimulation led to the differentiation of Meflin-expressing lineage cells into beige adipocytes. Thus, the Meflin-CreERT2 mouse line is a useful new tool for visualizing and tracking the lineage of Meflin-expressing cells.