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INTRODUCTION We evaluated the efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia (AAD) in Japanese patients. METHODS This was a phase 2/3 multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Patients with AAD were randomized to receive brexpiprazole 1 mg/day or 2 mg/day, or placebo (3:4:4) for 10 weeks. RESULTS For the primary endpoint (change in Cohen‐Mansfield Agitation Inventory [CMAI] total score from baseline to Week 10), both brexpiprazole 1 mg and 2 mg groups demonstrated statistically significant improvement versus placebo (2 mg: least squares [LS] mean difference –7.2 [95% confidence interval (CI): –10.0 to –4.3], p‐value < 0.0001, 1 mg: LS mean difference –3.7 [95% CI: –6.8 to –0.7], p‐value = 0.0175). The incidences of treatment‐emergent adverse events reported in the brexpiprazole 1 mg, 2 mg, and placebo groups were 76.8%, 84.6%, and 73.8%, respectively. DISCUSSION Brexpiprazole 1 mg/day and 2 mg/day for 10 weeks was efficacious and well tolerated. Highlights Brexpiprazole treatment for 10 weeks improved agitation in Alzheimer's dementia. The efficacy of brexpiprazole 1 mg/day has been confirmed for the first time. The incidence of adverse events was higher compared to the previous studies. Both brexpiprazole 1 mg/day and 2 mg/day were generally well tolerated.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a molecularly targeted cancer phototherapy that is based on injecting a conjugate of a silicon‐phthalocyanine derivative, IRdye 700DX (IR700), and a monoclonal antibody that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light results in the rapid and highly selective immunogenic cell death of targeted cancer cells. Because many cancers grow in bones through which light does not penetrate well, the goal of this study was to determine if NIR‐PIT can effectively treat cancers in bone. A bovine rib was used as a bone sample. Because the sample’s NIR light transmittance was shown to be approximately 4.52% in preliminary tests, it was hypothesized that a maximum radiation dosage of 128 and 1500 J/cm2 would be sufficient to induce cell death in in vitro target cells and in vivo mouse tumor models, respectively. Cell viability was measured through bioluminescence studies comparing relative luciferase activity, as well as a cytotoxicity assay. In the in vitro model, tumor cell viability was significantly decreased after 64 and 128 J/cm2 NIR light irradiation through the bone. An in vivo mouse tumor model also showed that 1500 J/cm2 NIR light irradiation through the bone significantly reduced tumor viability at both 24 and 48 hours posttreatment compared to the control group (P = .026 and .040 respectively). Therefore, despite limitations in light transmission, NIR‐PIT nevertheless is capable of effectively treating cancers within bone. Tumors were successfully treated through a bovine bone sample.

Most patients with non‐small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR‐TKI), and their sensitivities to various EGFR‐TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR‐TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3‐L858R), L861Q (Ba/F3‐L861Q) or S768I (Ba/F3‐S768I) mutations were created and their drug sensitivities to various EGFR‐TKI were examined. Both the Ba/F3‐L861Q and Ba/F3‐S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3‐L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3‐L858R cell line. The Ba/F3‐L861Q cell line was similarly sensitive and the Ba/F3‐S768I cell line was less sensitive to osimertinib, compared with the Ba/F3‐L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations. In this study, we focused on the EGFR L861Q and S768I mutations and investigated the in vitro sensitivities of cells carrying these mutations to various EGFR‐tyrosine kinase inhibitors (TKIs). Non‐small cell lung cancer (NSCLC) harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib but not to erlotinib, and NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib but not to erlotinib or osimertinib. Afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.

Background Acute pyelonephritis (APN) with obstructive uropathy often causes sepsis. Recently, sepsis was redefined using the sequential organ failure assessment (SOFA) score, based on the new Sepsis-3 criteria. We investigated predictors for sepsis using this new definition in patients with obstructive APN associated with upper urinary tract calculi. Methods We retrospectively evaluated patients who were admitted to our hospital for treatment of obstructive APN associated with upper urinary tract calculi. Blood and urine samples were collected before treatment of obstructive APN. Treatment included adequate antimicrobial therapy and emergency drainage to decompress the renal collecting system. We diagnosed sepsis using the new Sepsis-3 definition. We assessed predictors for sepsis by multivariate logistic regression analysis. Results Sixty-one patients were included in this study. Overall, all patients underwent emergency drainage, and 11 (18.0%) patients showed sepsis. There were no significant differences in performance status or comorbidities between sepsis and non-sepsis groups. Platelet count and serum albumin level were significantly lower in the sepsis group than in the non-sepsis group ( p  = 0.001 and p  = 0.016, respectively). Procalcitonin (PCT) and presepsin (PSEP) levels were significantly higher in the sepsis group than in the non-sepsis group ( p  < 0.001 and p  < 0.001, respectively). Multivariate analysis showed that PCT elevation (OR = 13.12, p  = 0.024) and PSEP elevation (OR = 13.13, p  = 0.044) were independent predictors for sepsis. Conclusions Elevation of PCT and PSEP levels before treatment might predict the development of sepsis in patients with obstructive APN.

Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non‐small cell lung cancer. We have now applied next‐generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG‐positive LSCC cell lines in association with attenuation of the FGFR1–ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. The angiokinase inhibitor nintedanib is a potential targeted agent for lung squamous cell carcinoma (LSCC) positive for genetic alterations affecting FGFR genes. We screened 75 LSCC specimens for FGFR alterations by next‐generation sequencing and thereby identified various such genetic changes including copy number gain, mutations, and a fusion in 15 of the 75 (20.0%) cases. Among the patients with relapse after surgery, the presence of FGFR alterations was associated with a significantly shorter overall survival.

Although the albumin-to-globulin ratio (AGR) is a promising biomarker, no study has investigated its prognostic significance for advanced urothelial carcinoma (UC). This study conformed to the REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria. We retrospectively reviewed 176 patients with advanced UC treated with pembrolizumab between 2018 and 2020. We evaluated the associations between pretreatment clinicopathological variables, including the AGR and performance status (PS), with progression-free survival, cancer-specific survival, and overall survival. The Cox proportional hazards model was used for univariate and multivariable analyses. The AGR was dichotomized as < 0.95 and ≥ 0.95 based on receiver operating characteristic curve analysis. After excluding 26 cases with missing data from the total of 176 cases, 109 (73%) patients experienced disease progression, 75 (50%) died from UC, and 6 (4%) died of other causes (median survival = 12 months). Multivariate analyses identified PS ≥ 2 and pretreatment AGR < 0.95 as independent poor prognostic factors for all endpoints. Furthermore, a prognostic risk model incorporating these two variables achieved a relatively high concordance index for all endpoints. This is the first report to evaluate the significance of AGR in advanced UC. Pretreatment AGR < 0.95 may serve as a prognostic marker for advanced UC treated with pembrolizumab.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is diagnosed when hepatic steatosis is proven by imaging and one of the five cardiometabolic criteria is present. The relationship between MASLD and body composition components has recently received increased research attention. However, the five cardiometabolic criteria do not include components of body composition. This study aimed to identify significant body composition factors associated with MASLD in patients undergoing health checkups. Methods: This study included a cohort of 6599 examinees who participated in a health check-up conducted between 2022 and 2023, and their data were prospectively analyzed. The inclusion criteria were undergoing abdominal ultrasonography, alcohol consumption <30 g/day for males or <20 g/day for females, and one of the five cardiometabolic criteria. Results: Finally, 3864 examinees were enrolled. In total, 1133 (51.8%) males and 454 (27.1%) females had MASLD. Sarcopenia was present in only 0.62% of males and 0.66% of females with MASLD. The MASLD group had significantly lower skeletal muscle mass/weight (SMM/WT) values than the non-MASLD group. Multivariate analysis revealed that SMM/WT was independently associated with MASLD. Conclusions: SMM/WT was significantly associated with MASLD. Therefore, muscle mass assessment using SMM/WT may be a potential marker for diagnosing MASLD.

Lung cancer is the leading cause of cancer-related mortality worldwide [1, 2]. The epidermal growth factor receptor (EGFR) is recognized as an important molecular target in cancer therapy, and somatic activating mutations of the EGFR gene (EGFR mutations) are known as one of the oncogenic driver mutations in non small cell lung cancer (NSCLC). NSCLCs with EGFR mutations are associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) [3]. Gefitinib and erlotinib are first-generation (1G) reversible EGFR-TKIs that are highly effective against NSCLC carrying common activating EGFR mutations (exon 19 deletion or exon 21 L858R) [4-8]. Although most patients respond dramatically to such treatments, the majority eventually experience disease progression [9]. Many studies have revealed several resistance mechanisms and candidates, including the secondary EGFR mutation T790 M [10] and other uncommon mutations (L747S [11], D761Y [12], and T854A [13]), MET amplification [14], HER2 amplification [15], PTEN down-regulation [16], high-level HGF expression [17], epithelial-mesenchymal transition [18], and conversion to small cell lung cancer [19] (for review, see [20, 21]). Afatinib, a second-generation (2G) irreversible EGFR-TKI, also exhibits a marked efficacy against NSCLC carrying EGFR mutations, similar to the effects of gefitinib and erlotinib [19, 22]. In addition, afatinib can be effective against uncommon EGFR mutations [23, 24] for which 1G-TKIs are less effective [25, 26]. Apparently, not all EGFR mutations are created equal; thus, different EGFR mutations may have different sensitivities to various EGFR-TKIs [27]. The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Approximately 50% of cases with acquired resistance to EGFR-TKI therapy carry this T790 M mutation in the kinase domain of EGFR as well as an EGFR-activating mutation [28-30]. Several recent studies have demonstrated that third-generation (3G) irreversible EGFR-TKIs, which are mutant-selective inhibitors, can overcome T790 M-mediated resistance [31-34]. These findings suggest that different EGFR mutations have different sensitivities to EGFR-TKIs. Although uncommon, there have been several reports showing that other secondary mutations (L747S [11], D761Y [12], and T854A [13]) induce resistance to 1G-TKIs. The anticancer activities of 2G- or 3G-TKIs against these uncommon secondary mutations, however, remain unclear. In the present study, the anticancer activities of various EGFR-TKIs (1G, 2G, or 3G) against uncommon secondary EGFR mutations were investigated in vitro using the murine Ba/F3 cell system. The Ba/F3 cell system is a murine pro-B cell line that is dependent on interleukin-3 (IL-3) for its survival and growth and is a well-validated and widely used cell system. The ability of Ba/F3 cells transfected with a mutated version of the gene to proliferate in the absence of IL-3 indicates an oncogenic ability [35, 36].

Introduction Testicular germ cell tumors with somatic‐type malignancy, wherein teratomas transform into sarcomas, is drug resistant and has a poor prognosis. Case presentation A 43‐year‐old man presented with a left testicular tumor, multiple pulmonary metastases, and mediastinal and para‐aortic lymph node metastases. The testicular tumors were diagnosed as germ cell tumors. After bleomycin, etoposide, and cisplatin chemotherapy; right upper lobectomy for the pulmonary metastasis; and paclitaxel, ifosfamide, and cisplatin chemotherapy, rapidly progressing mediastinal lymph node metastasis was observed. It was resected at another specialized center owing to the challenging surgical approach. The histopathological diagnosis of the resected tumor was a teratoma with somatic‐type malignancy (rhabdomyosarcoma). Subsequently, left hilar lymph node metastasectomy and left upper lobectomy were performed for the pulmonary metastases. The patient survived for more than 8 years after initial treatment. Conclusion Surgery, although challenging, may yield long‐term survival for patients with testicular germ cell tumors with sarcomatous transformation.