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Aim We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan Patients and methods The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group). Results A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively). Conclusion POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients’ quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001−3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p

Background Eribulin is a chemotherapeutic drug that prolongs overall survival (OS) in patients with HER2-negative metastatic breast cancer (MBC), mainly in third-line or later chemotherapy (ChT) [1]. However, health-related quality of life (HRQOL) and efficacy in patients who receive eribulin as first- or second-line therapy is not well known. In contrast, S-1, an oral 5-fluorouracil derivative, shows similar OS to taxanes as first-line ChT and better HRQOL, based on a large phase III trial conducted in Japan [2]. Here, we compared the effect on HRQOL and efficacy of eribulin and S-1 in MBC patients in a first- or second-line ChT setting. Methods We planned an open-label, multicenter, randomized controlled phase III study at 50 hospitals in Japan. We enrolled patients with HER2-negative MBC who had no or one previous ChT for MBC regardless of prior administration of anthracyclines and taxanes. Patients were randomly assigned (1:1) to either eribulin (1.4 mg/m² administered on days 1 and 8 of a 21-day) or S-1 (40–60 mg twice daily for 14 consecutive days, followed by a 7-day break). Randomization was stratified by institution, age, treatment line, hormone receptor status, and time from surgery to recurrence. HRQOL assessment was conducted using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 questions (QLQ-C30) every six weeks until week 24, and then every nine weeks until week 42 after baseline assessment. The primary outcome measure was the global health status (GHS) score of EORTC QLQ-C30, with a prespecified non-inferiority margin of 10% for a difference in the proportion of patients experiencing deterioration at one year. Clinically meaningful deterioration was defined as a ≥ 10-point decrease from baseline GHS score or death. Secondary outcomes were OS, progression-free survival (PFS), and adverse events. We estimated that the study needed 330 patients to obtain 80% power for non-inferiority. This trial was registered with the University Hospital Medical Information Network, Japan (protocol ID 000021398). Results Between June 2016 and October 2019, 302 patients were enrolled, with 152 assigned to eribulin and 148 to S-1. The full analysis set for HRQOL assessment included 134 and 136 patients, while that for efficacy consisted of 141 and 144 patients, respectively. Overall compliance with the questionnaire was 85.6 %. Among the full analysis set for efficacy, 28 (19.9%) and 31 (21.5%) cases were triple negative, respectively. Eribulin and S-1 were administered as first-line ChT in 99 (70.2%) and 101 (70.1%) patients, respectively. Risk difference of GHS deterioration through one year for the eribulin versus S1 group was -0.66% (95% CI -12.47 to 11.16; P non-inferiority =0.077). Median time to first deterioration in GHS score was 5.64 months (95% CI 3.51–8.00) and 5.28 months (95% CI 3.28-7.80) (HR 1.07 [95% CI 0.79–1.45]; P =0.667); median OS was 35.0 months (95% CI 27.2-41.0) and 27.8 months (95% CI 24.6-33.5) (HR 0.69 [95% CI 0.50-0.95]; P=0.023); and median PFS was 6.07 months (95% CI 5.48-7.80) and 6.66 months (95% CI 5.48-7.77), respectively (HR 0.90 [95% CI 0.68-1.18]; P=0.427). No previously unrecognized adverse events were observed. Conclusions We found a marginal non-inferiority in HRQOL for eribulin, albeit that the difference was not statistically significant owing to the smaller than planned sample size. Time to first clinically meaningful deterioration was almost identical between the two arms, whereas OS was significantly extended with eribulin. These findings indicate that eribulin in first- or second-line ChT is acceptable as a standard regimen in this patient population. [1] Lancet 2011; 377: 914–23 [2] Lancet Oncol 2016; 17: 90–98 Citation Format: Yuichiro Kikawa, Kosuke Kashiwabara, Naruto Taira, Tsuguo Iwatani, Kojiro Shimozuma, Shoichiro Ohtani, Tetsuhiro Yoshinami, Junichiro Watanabe, Masahiro Kashiwaba, Ken-ichi Watanabe, Masahiro Kitada, Koichi Sakaguchi, Yuko Tanabe, Tomohiko Aihara, Hirofumi Mukai, Masato Takahashi. Eribulin versus S-1 as first- or second- line chemotherapy to assess Health-related Quality of Life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomized controlled trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-03-01.

We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy.This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population.High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002).These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Despite the widespread use of peripheral intravenous catheters, unscheduled catheter failure before completion of treatment occurs frequently. If a large vein is selected, catheter failures may be prevented despite administering a highly irritant drug. In this study, we attempted to use a catheter that can be placed in a large upper arm vein. The new catheter was 88 mm long but had no guidewire to reduce contamination risk. This study aimed to evaluate the safety of the first-in-human trial for the new catheter with the administration of highly irritant drugs. This study was conducted at a university hospital in Tokyo, Japan. Eight Japanese adults were hospitalized adults with planned administration of non-cancer drugs with high irritant potential using a peripheral catheter. A trained nurse catheterized with the new catheter in the upper arm using ultrasonography. The catheterization site was monitored by staff and a research nurse once every 24 hours for up to 7 days. No adverse events or catheter failure occurred and the catheter placement success rate was 100%. In two patients, a temporary occlusion alarm of the infusion pump occurred, possibly due to the flexion of the catheter base. The new peripheral intravenous catheter did not interrupt medical treatments as is common after placement, but safety administered the irritant drugs. However, because this catheter may be easily affected by the contraction of the muscle at the fixation position, the position and method of catheter fixation in the upper arm need to be carefully considered.

Arteriovenous malformations (AVMs) of the diencephalon (DC) and brainstem (BS) are difficult to treat. Stereotactic radiosurgery (SRS) is a reasonable option; however, an optimal radiosurgical dose needs to be established to optimize long-term outcomes.To evaluate dose-dependent long-term outcomes of SRS for DC/BS-AVMs.We retrospectively analyzed the long-term outcomes of 118 patients who had SRS-treated DC/BS-AVMs. The outcomes included post-SRS hemorrhage, AVM obliteration, neurological outcomes, and disease-specific survival. According to margin doses, the patients were classified into low (18 Gy), medium (18-20 Gy), and high (20 Gy) dose groups.SRS reduced the annual hemorrhage rate from 8.6% to 1.6% before obliteration and 0.0% after obliteration. The cumulative hemorrhage rate in the low dose group was likely to be higher than that in the other groups ( P = .113). The cumulative obliteration rates in the entire cohort were 74% and 83% at 5 and 10 years, respectively, and were significantly lower in the low dose group than in the other groups (vs medium dose: P = .027, vs high dose: P = .016). Multivariate analyses demonstrated that low dose SRS was significantly associated with worse obliteration rates (hazard ratio 0.18, 95% CI 0.04-0.79; P = .023).SRS with a margin dose of 18 to 20 Gy for DC/BS-AVMs may be optimal, providing a higher obliteration rate and lower risk of post-SRS hemorrhage than lower dose SRS. Dose reduction to18 Gy should only be optional when higher doses are intolerable.

There are two types of pressure injuries: self-load-related pressure injuries (PIs) and medical device-related pressure injuries (MDRPIs), but the differences in risk factors between PIs and MDRPIs have not yet been clarified. If risk factors for PIs and MDRPIs differ, preventive interventions should take this into account. This is a prospective cohort study aimed to determine the cumulative incidence of PIs and MDRPIs in critically ill patients and to identify corresponding risk factors. The study included 1418 patients who were admitted to the critical care medical center of a single university hospital in Tokyo, Japan, between 1 December 2019 and 31 August 2020. The Kaplan-Meier method was used to calculate the cumulative incidence of PIs and MDRPIs. Furthermore, the Cox proportional hazards model was used to analyse the predictors in both the PI and MDRPI incidence and non-incidence groups. Predictors were based on data from the 0th disease day. The cumulative incidence of PIs and MDRPIs was 4.6/1000 person-days and 3.6/1000 person-days, respectively. Multivariate analysis using the Cox proportional hazards model showed that common risk factors for the occurrence of PIs and MDRPIs were possession of PI on admission, higher blood lactate, blood purification therapy, and positional restriction. The risk factors for PIs only were diabetes mellitus, septic shock, and a lower serum albumin level, while the risk factors for MDRPIs only were the D-dimer level and extracorporeal membranous oxygenation treatment. Therefore, prophylactic interventions need to consider these different risk factors.

Background The safety of intraperitoneally administrated paclitaxel (ip PTX) was demonstrated in the phase I trial of ip PTX combined with conventional systemic chemotherapy for colorectal cancer with peritoneal carcinomatosis. Moreover, the median survival time was 29.3 months, which was longer than that observed in previous studies. Here, we planned the phase II trial of ip PTX: the iPac-02 trial.Methods This multicenter, open-label, single assignment interventional clinical study includes patients with colorectal cancer with unresectable peritoneal carcinomatosis. FOLFOX-bevacizumab or CAPOX-bevacizumab is administered concomitantly as systemic chemotherapy. PTX 20 mg/m2 is administered weekly through the peritoneal access port in addition to these conventional systemic chemotherapies. The response rate is the primary endpoint. Progression-free survival, overall survival, peritoneal cancer index improvement rate, rate of negative peritoneal lavage cytology, safety, and response rate to peritoneal metastases are the secondary endpoints. A total of 38 patients are included in the study. In the interim analysis, the study will continue to the second stage if at least 4 of the first 14 patients respond to the study treatment. The study has been registered at the Japan Registry of Clinical Trials (jRCT2031220110).

Objectives The double-blind, parallel-group comparison, investigators initiated phase II clinical trial of IDEC-C2B8 (Rituximab) in patients with Systemic sclerosis (DesiReS) trial showed that rituximab is effective in treating skin sclerosis in SSc. However, which patient groups are likely to benefit from rituximab is unknown. Methods We performed post-hoc analysis of prospective data from 54 patients who received rituximab or placebo in the DesiReS trial. Twenty-seven baseline factors were used to investigate subpopulations with different magnitudes of rituximab effect on modified Rodnan skin score (mRSS) change at 24 weeks. Based on a machine-learning algorithm called the causal tree, we explored the combination of predictors needed to identify subpopulations that would respond to rituximab and have good treatment outcomes. Results Three factors were identified as branches of the decision tree: peripheral blood CD19-positive cell counts’, ‘mRSS’, and ‘serum surfactant protein D (SP-D) levels’. It was only in the subpopulation of patients with CD19-positive cell counts of Conclusion SSc patients who have high CD19-positive cell counts and high mRSS are expected to have greater improvement in mRSS with rituximab. When the patients with high CD19-positive cell counts show low mRSS, serum SP-D levels may modify the treatment effect. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT04274257 and UMIN-CTR; https://center6.umin.ac.jp, UMIN000030139.

To evaluate the efficacy and safety of nafamostat combined with favipiravir for coronavirus disease 2019.We conducted a multicenter, randomized, single-blind, placebo-controlled parallel assignment study in hospitalized patients with mild-to-moderate coronavirus disease 2019 pneumonia. Patients were randomly assigned to receive favipiravir alone (n=24) or nafamostat with favipiravir (n=21). Outcomes included changes in the WHO Clinical Progression Scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpOThere was no significant difference in changes in the Clinical Progression Scale between nafamostat with favipiravir and favipiravir alone groups (median, -0·444 vs. -0·150, respectively; least-squares mean difference, -0·294; p=0·364). Time to improvement in body temperature was significantly shorter in the combination group (5·0 days; 95% CI, 4·0-7·0) than in the favipiravir group (9·0 days; 95% CI, 7·0-18·0; p=0·009). Changes in SpOAlthough our study showed no differences in clinical progression, earlier defervescence and recovery of SpOThis study was registered in the Japan Registry of Clinical Trials (identifier: jRCTs031200026) and WHO's International Clinical Trial Registry Platform (identifier: JPRN-jRCTs031200026).

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent Todai OncoPanel as part of Advanced Medical Care B with approval by the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were performed in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those thirty transcripts, six had treatment implications and four had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

This study aimed to determine whether the prognosis of small-cell lung cancer (SCLC) patients with malignant central airway obstruction (MCAO) who receive chemotherapy without undergoing transbronchial intervention (TBI) is not inferior to that of SCLC patients without MCAO.We compared overall survival (OS) from the time of SCLC diagnosis between stage III or IV SCLC patients with MCAO (MCAO group, n=22) and those without MCAO (non-MCAO group, n=88). MCAO is generally defined as50% obstruction of the trachea or mainstem bronchi.The median interval from the time of SCLC diagnosis until the initiation of anticancer therapy and the median number of chemotherapy regimens were 6 days and 2 regimens, respectively, in the MCAO group and 15 days and 2 regimens in the non-MCAO group. During the median follow-up period of 11.7 months after SCLC diagnosis, 95% of the patients in the MCAO group and 85% of the patients in the non-MCAO group died. No difference in the median OS (11.9 months vs. 12.4 months, p=0.455) was seen between the MCAO group and the non-MCAO group. A multivariate analysis showed that the presence of MCAO was not associated with an increased risk of death in SCLC patients who received chemotherapy (p=0.664).The prognosis of SCLC patients with MCAO who receive chemotherapy without undergoing TBI is not inferior to that of SCLC patients without MCAO.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

Background EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR‐TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified. Methods Patients with NSCLC who progressed after treatment with EGFR‐TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas®), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next‐generation sequencing (NGS) of ctDNA was performed with Guardant360®. Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed. Results Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation. Conclusions NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M., A retrospective analysis of comprehensive next‐generation sequencing (NGS) of ctDNA in a multi‐center, prospective observational cohort study conducted to examine the efficacy of liquid biopsy as a predictive marker for third generation treatment with the EGFR tyrosine kinase inhibitor (EGFR‐TKI), osimertinib is reported in this paper. We demonstrated that the number of genomic alterations was significantly higher in non‐responders than in responders to osimertinib, suggesting that plasma NGS could be a better method for predicting osimertinib efficacy in patients with advanced NSCLC.

Aim Clinical evidence on cardiovascular health metrics of couples, as defined by the American Heart Association (AHA), remains to be scarce. This study aims to explore the correlation of the AHA-defined cardiovascular health metrics within couples using a nationwide epidemiological database. Methods We examined the modified cardiovascular health metrics among 87,160 heterosexual couples using the health claims database from the Japan Medical Data Center. The ideal cardiovascular health metrics is comprised of (1) nonsmoking, (2) body mass index ＜25 kg/m2, (3) physical activity at goal, (4) untreated blood pressure ＜120/80 mm Hg, (5) untreated fasting glucose ＜100 mg/dL, and (6) untreated total cholesterol ＜200 mg/dL. Results A correlation was noted on the ideal modified cardiovascular health metrics between couples. The prevalence of meeting ≥ 5 ideal components in the female partners increased from 32 % in the male partners meeting 0-1 ideal component to 56 % in those meeting 6 ideal components. The same trend has been observed in all generations (20-39 years, 40-49 years, 50-59 years, ≥ 60 years). The association between couples is found to be better in terms of smoking status, blood pressure, and fasting glucose level. Conclusion There was an intracouple correlation of the ideal modified cardiovascular health metrics, suggesting the importance of couple-based intervention to improve cardiovascular health status.

To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P

Background Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC., Highlights • Nab-Paclitaxel at 260 mg/m2 is used to treat metastatic breast cancer (MBC). • Nab-Paclitaxel frequently causes severe neuropathy or myalgia. • A reduced nab-paclitaxel dose of 180 mg/m2 q3w was effective and had less toxicities. • Therapeutic indices of reduced doses were increased compared to the standard dose.

Background Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6Rβ, sCD163, sIL-6Rα, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m2/year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

Transbronchial microwave ablation (MWA) can be performed safely in patients with malignant central airway obstruction (MCAO), under moderate sedation and a high fraction of inspired oxygen.We retrospectively evaluated the difference in the overall survival (OS) after transbronchial interventions (TBIs) between MCAO patients with endoluminal or mixed-type obstruction who were treated by MWA (MWA group, n=34) and those with extraluminal obstruction who were treated by stent placement (STP) (STP group, n=27).The OS was longer in the MWA group than in the STP group (10.2 months vs. 4.5 months, p=0.001). A significant difference in the OS between the two groups was observed in the patients who received post-TBI anticancer therapy (27.2 months vs. 6.0 months, p=0.002). The OS tended to be longer in the MWA group than in the STP group, among the patients who received best supportive care alone (3.8 months vs. 1.8 months, p=0.068). Nine patients (26%) of the MWA group underwent additional MWA when tumor regrowth into the airway lumen was noted (median of TBI sessions, 3). Multivariate analysis identified the adoption of MWA as the initial treatment procedure to be independently associated with a reduced risk of death in patients with MCAO (hazard ratio=0.473, p=0.031).Adoption of MWA as the initial treatment procedure is beneficial in MCAO patients with endoluminal or mixed-type obstruction, regardless of whether patients receive post-TBI anticancer therapy or not.

Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups