Incidence of nausea/vomiting following propofol sedation with adaptive servo-ventilation for atrial fibrillation ablation.

Background: Postoperative nausea and vomiting (PONV) following atrial fibrillation (AF) ablation can cause considerable distress. Aim: Continuous intravenous propofol sedation with adaptive servo-ventilation (ASV) with or without an analgesic, pentazocine, during AF ablation was studied in 272 consecutive patients with paroxysmal, persistent, and long-standing persistent AF. The study objectives were to determine the incidence of PONV after AF ablation and to assess the predictive value of factors for PONV using the area under the receiver operating characteristic curve (AUC). Results: The present sedation maneuver was successfully accomplished with a low incidence of hypotension and without discontinuation of ablation or switching to general anesthesia, while maintaining an acceptable procedural time (102 ± 32 min). The incidence of PONV was 5.5% (15/272). Nausea occurred in nine patients after an average of 4.6 ± 3.5 h (range: 2-12 h) postablation, and vomiting with nausea occurred in six patients after an average of 4.5 ± 3.1 h (range: 1-9 h) postablation. The postablation interval did not differ significantly between the occurrence of nausea and nausea accompanied by vomiting. AUCs based on various factors, including the Apfel score, ranged from 0.55 to 0.67, indicating low accuracy in predicting PONV occurrence. Conclusions: The incidence of PONV after propofol sedation with ASV was the lowest (5.5%) reported to date. Scoring systems, which included the Apfel score, were ineffective in predicting PONV. The low PONV incidence in addition to the efficacy of propofol sedation with ASV revealed the adequacy of this regimen for AF ablation.

Microbiota-derived acetylcholine can promote gut motility in Drosophila melanogaster.

The gut microbiota is crucial for intestinal health, including gastrointestinal (GI) motility. How commensal bacterial species influence GI motility has not been fully elucidated. A major factor of GI motility is the gut contraction promoting the propulsive movement of orally ingested materials. Here, we developed a method to monitor and quantify gut contractions in living Drosophila melanogaster larvae. We found that the culture medium of an isolated strain Lactiplantibacillus plantarum Lsi promoted gut contraction in vivo, which was not observed in Leuconostoc sp. Leui nor Acetobacter persici Ai culture medium. To identify bacteria-derived metabolites, we performed metabolome analysis of the culture media by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of the 66 metabolites detected, we found that some metabolites changed in a species-specific manner. Among them, acetylcholine was specifically produced by L. plantarum. Feeding exogenous acetylcholine increased the frequency of gut contractions, which was blocked by D-tubocurarine, an inhibitor of nicotinic acetylcholine receptors. In this study, we propose a mechanism by which the gut microbiota influences Drosophila gut motility. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma-Factor analysis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. METHODS: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. RESULTS: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. CONCLUSION: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

Survival Impact of Second-Line Immune Checkpoint Inhibitors in Older Patients With Advanced Squamous-Cell NSCLC: Post Hoc Analysis of the CAPITAL Study.

Introduction: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS). Methods: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status. Results: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p = 0.032); no such differences were observed in the nab-PC arm. Conclusions: We found that second-line ICI treatment seemed to have a little impact on OS.

Clinical benefit of platinum doublet combination therapy in older adults with advanced non-small cell lung cancer: A prospective multicenter study by the National Hospital Organization in Japan.

BACKGROUND: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. METHODS: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453). DISCUSSION: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy.

Predicting systemic therapy toxicity in older adult patients with advanced non-small cell lung cancer: A prospective multicenter study of National Hospital Organization in Japan.

INTRODUCTION: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients. MATERIALS AND METHODS: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%). DISCUSSION: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.

Updated Analysis of NEJ009: Gefitinib-Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated EGFR.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized, open-label, phase III NEJ009 study, gefitinib plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with gefitinib-alone in patients with untreated non-small-cell lung cancer harboring mutations in epidermal growth factor receptor. Herein, we report the updated survival outcome and long-term tolerability. Patients were randomly assigned to gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May 22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95% CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was 38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to 1.06; P = .127). The OS in both groups was similar for the overall patient population. No severe adverse events occurred since the first report. This updated analysis revealed that the GCP regimen improved PFS and PFS2 with an acceptable safety profile compared with gefitinib-alone. GCP is more efficient than gefitinib monotherapy as a first-line treatment for non-small-cell lung cancer with epidermal growth factor receptor mutations.

[Measurement as a Personal Dose Equivalent of X-ray Room Scattered Dose in ERCP Inspection].

PURPOSE: In the revised Regulation on Prevention of Ionizing Radiation Hazards (April 2020), the equivalent dose limit for the lens of the eye was lowered to "100 mSv in 5 years and 50 mSv in 1 year." It is necessary to reduce occupational exposure in the healthcare sector. The purpose of this study was to facilitate comparison with the equivalent dose limit in an endoscopic retrograde cholangiopancreatography (ERCP) examination by measuring the scattered dose in an X-ray room as an individual dose equivalent. METHODS: The scattered dose was measured by dosimeters positioned in a grid pattern in the X-ray room. The dose rate was measured with and without the use of a protective cloth (0.25 mm Pb equivalent) suspended around the X-ray tube extending to the patient. The dose reduction rate of the material was evaluated during the simulated ERCP. RESULTS: The maximum dose rate at the position of the surgeon performing an ERCP inspection in the standing position was 2.9 mSv/h (3 mm dose equivalent rate) at 150 cm from the ground. The number of ERCP examinations to comply with the equivalent dose limit of the equivalent dose of the lens of the eye without the protective cloth was 28 per year. CONCLUSION: The results of this study suggest that individual dose equivalent measurements in the X-ray clinic may facilitate comparison with the equivalent dose limit.

Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life. METHODS: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47). INTERPRETATION: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression. FUNDING: Chugai Pharmaceutical.

Pharmacokinetic and pharmacogenomic analysis of low-dose afatinib treatment in elderly patients with EGFR mutation-positive non-small cell lung cancer.

PURPOSE: An increasing number of advanced non-small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters. PATIENTS AND METHODS: The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and ß of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs. RESULTS: The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed. CONCLUSIONS: An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.

First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002).

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer.

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).

BACKGROUND: A cisplatin plus irinotecan (CPT-11) regimen is used for patients with extensive disease small cell lung cancer (ED-SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open-label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded to induction therapy. METHODS: Patients with histologically- or cytologically-confirmed ED-SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT-11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT-11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1-3) every three weeks. RESULTS: A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT-11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6-11.8), and the median overall survival was 20.1 months (95% CI: 13.7-not reached). No statistically significant difference in progression-free survival (PFS) were noted between patients treated with CPT-11 and those treated with AMR. There were no treatment-related deaths in this study. CONCLUSIONS: Maintenance therapy with CPT-11 or AMR after induction therapy might be effective in some patients.

Prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer: comparison of diagnostic performances of dedicated breast PET, whole-body PET, and dynamic contrast-enhanced MRI.

PURPOSE: To compare the diagnostic performance of ring-type dedicated breast PET (dbPET), whole-body PET (WBPET), and DCE-MRI for predicting pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 29 women with histologically proven breast cancer on needle biopsy between July 2016 and July 2019 (age: mean 55 years; range 35-78). Patients underwent WBPET followed by ring-type dbPET and DCE-MRI pre- and post-NAC for preoperative evaluation. pCR was defined as an invasive tumor that disappeared in the breast. Standardized uptake values corrected for lean body mass (SULpeak) were calculated for dbPET and WBPET scans. Maximum tumor length was measured in DCE-MRI images. Reduction rates were calculated for quantitative evaluation. Two radiologists independently evaluated the qualitative findings. Reduction rates and qualitative findings were compared between the pCR (n = 7) and non-pCR (n = 22) groups for each modality. Differences in quantitative and qualitative data between the two groups were analyzed statistically. RESULTS: Significant differences were observed in the reduction rates of dbPET and DCE-MRI (P = 0.01 and 0.03, respectively) between the two groups. Univariate and multiple logistic regression analyses revealed that SULpeak reduction rates in WBPET and dbPET (P = 0.02 and P = 0.01, respectively) and in dbPET (odds ratio, 16.00; 95% CI 1.57-162.10; P = 0.01) were significant indicators associated with pCR, respectively. No between-group differences were observed in qualitative findings in the three modalities. CONCLUSION: SULpeak reduction rate of dbPET > 82% was an independent indicator associated with pCR after NAC in breast cancer.

Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2.

Reduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.

Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using 125I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004).

OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Randomized phase II trial of carboplatin + nab-paclitaxel versus cisplatin + gemcitabine for chemotherapy-naïve squamous cell carcinoma: North Japan lung cancer study group 1302.

BACKGROUND: A subset analysis of the CA031 trial showed significant improvement in the overall response rate after administration of carboplatin plus weekly albumin-bound paclitaxel compared to carboplatin plus paclitaxel for squamous cell carcinoma of the lung (SQ). We conducted this phase II study to compare carboplatin plus weekly albumin-bound paclitaxel (CnP) to cisplatin plus gemcitabine (CG), a standard regimen for SQ. METHODS: Chemotherapy-naïve patients with SQ were randomly assigned to receive cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks or carboplatin (area under the curve: 6 mg/mL/min) on day 1 plus nab-paclitaxel (75 mg/m2) on days 1, 8, and 15 every 3 weeks. The primary endpoint was overall response rate. The secondary endpoints were progression-free survival, overall survival, disease control rate, and toxicity. RESULTS: Between June 2013 and October 2018, 71 patients were enrolled and assigned to either the CG arm (n = 35) or the CnP arm (n = 36) of the study. The overall response rate was 43% [95% confidence interval (CI) 27.3-58.5] in the CG arm and 47% (95% CI 31.7-62.7) in the CnP arm. Although drug combination efficacies did not differ, there were differences in toxicity: hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) were found mostly in the CG arm, whereas anemia and sensory neuropathy were more common in the CnP arm. CONCLUSIONS: CnP had similar response as CG despite being a carboplatin-based regimen and toxicities differed between arms. Regarding ORR, CnP was comparable to CG for SQ.

Prognostic factors for patients with metastatic or recurrent thymic carcinoma receiving palliative-intent chemotherapy.

BACKGROUND: Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database. PATIENTS AND METHODS: Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival. RESULTS: Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P =  0.047), and hypoalbuminemia (P =  0.0021) were identified as prognostic factors in a multivariate analysis. CONCLUSION: The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.

Detection of somatic TP53 mutation in surgically resected small-cell lung cancer by targeted exome sequencing: association with longer relapse-free survival.

OBJECTIVES: Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. PATIENTS AND METHODS: We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). RESULTS: We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86-30.79] in a mutation-positive group vs 10.39 months (6.96-13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29-0.89, p = 0.019) but not overall survival (OS). CONCLUSION: These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC.