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Background: Cachexia is a poor prognostic factor in many advanced cancers. Cachexia diagnostic criteria of the European Palliative Care Research Collaboration (EPCRC) may underestimate cachexia in Asians; therefore, new criteria have been proposed by the Asian Working Group for Cachexia (AWGC). We compared both criteria to determine differences in diagnostic rates and their association with lung cancer prognosis., Patients and Methods: This single-center, retrospective cohort study considered lung cancer outpatients receiving chemotherapy. Survival was analyzed using Kaplan-Meier curves and log-rank tests. The association between cachexia diagnosis and prognosis was examined for each set of criteria using a Cox proportional hazards model. C-statistic analysis was performed to compare the discriminative power for prognosis., Results: Among the 106 participants analyzed (median age, 75 [71-79] years; 75 males [70.8%]; 91 [85.9%] with performance status [PS] 0-1), 58 (54.7%) and 77 (72.6%) cachexia cases were diagnosed using the EPCRC and AWGC criteria, respectively. The latter encompassed all but one patient diagnosed using the EPCRC criteria. Patients with cachexia had a significantly poorer prognosis according to both criteria (EPCRC, p = 0.002; AWGC, p = 0.001). Both criteria had almost equal discriminative power for prognosis (EPCRC, C-statistic = 0.658; AWGC, C-statistic = 0.658). CRP in the AWGC criteria was most strongly related to prognosis., Conclusions: Cachexia was an independent poor prognostic factor in lung cancer patients receiving chemotherapy under the AWGC and EPCRC criteria, both of which had similar prognostic discriminatory power. Among CRP, anorexia, and grip strength, elevated CRP may be the most prognostically relevant parameter in the AWGC criteria., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Introduction: Extensive small cell lung cancer (ES-SCLC) are currently managed using first-line chemotherapy options, including atezolizumab (Atezo) plus etoposide and carboplatin (CE) or durvalumab (Durva) plus etoposide with either cisplatin (PE) or carboplatin (CE). However, a definitive distinction in therapeutic effects between Atezo and Durva in these regimens remains unestablished., Methods: We analyzed data from 100 patients diagnosed with ES-SCLC who received immune checkpoint inhibitors (ICIs) as first-line chemotherapy. Among them, 70 were administered Atezo + CE, 12 received Durva + PE, and 18 received Durva + CE. We assessed the efficacy of the two ICIs across various factors., Results: The progression-free survival (PFS) and overall survival (OS) did not significantly differ between Atezo + CE and Durva + CE/PE as first-line chemotherapy treatments for SCLC. We observed no significant differences in age, sex, performance status (PS), liver metastasis, bone metastasis, or platinum-based agent usage between the treatment cohorts. However, a marked improvement in PFS and OS was observed in the solitary patient with brain metastasis treated with Atezo + CE., Conclusion: The primary distinction between these treatments was observed in the management of patients with brain metastasis. The literature lacks comparative studies on the effects of first-line ICI treatment on the central nervous system, rendering our findings significant in clinical practice. Despite the retrospective nature of this study and the potential for various biases, we recommend the preferential use of Atezo + CE in patients with brain metastasis to potentially enhance prognosis., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non-small-cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression between 1% and 49%., Materials and Methods: We conducted a retrospective study of patients with NSCLC who were treated with chemotherapy or chemoimmunotherapy between March 2016 and May 2023. The patients had histologically confirmed NSCLC, stage III-IV or postoperative recurrence, TTF-1 measurements, and PD-L1 expression levels between 1% and 49%. Clinical data were analyzed to evaluate the effect of TTF-1 expression on treatment efficacy., Results: This study included 283 of 624 patients. TTF-1-positive patients showed longer progression-free survival (PFS) and overall survival (OS) (PFS: 6.4 months [95% confidence interval (CI): 5.0-9.4] vs 4.1 months [95% CI: 2.7-6.1], p=0.03, OS: 17.9 months [95% CI: 15.2-28.1] vs 9.4 months [95% CI: 6.3-17.0], p<0.01) in the chemotherapy cohorts (n=93). In the chemoimmunotherapy cohort (n=190), there was no significant difference in PFS and OS between TTF-1-positive and negative groups (PFS: 7.6 months [95% CI: 6.4-11.0] vs 6.0 months [95% CI: 3.6-12.6], p=0.59, OS: 25.0 months [95% CI: 18.0-49.2] vs 21.3 months [95% CI: 9.8-28.8], p=0.09)., Conclusion: In patients with NSCLC with PD-L1 expression between 1% and 49%, TTF-1 expression was a predictor of chemotherapeutic, but not chemoimmunotherapeutic, efficacy.

A simple method for determining the anaerobic threshold in patients with heart failure (HF) is needed. This prospective clinical trial (LacS-001) aimed to investigate the safety of a sweat lactate-monitoring sensor and the correlation between lactate threshold in sweat (sLT) and ventilatory threshold (VT). To this end, we recruited 50 patients with HF and New York Heart Association functional classification I-II (mean age: 63.5 years, interquartile range: 58.0-72.0). Incremental exercise tests were conducted while monitoring sweat lactate levels using our sensor. sLT was defined as the first steep increase in lactate levels from baseline. Primary outcome measures were a correlation coefficient of ≥ 0.6 between sLT and VT, similarities as assessed by the Bland-Altman analysis, and standard deviation of the difference within 15 W. A correlation coefficient of 0.651 (95% confidence interval, 0.391-0.815) was achieved in 32/50 cases. The difference between sLT and VT was -4.9 ± 15.0 W. No comparative error was noted in the Bland-Altman plot. No device-related adverse events were reported among the registered patients. Our sweat lactate sensor is safe and accurate for detecting VT in patients with HF in clinical settings, thereby offering valuable additional information for treatment., (© 2024. The Author(s).)

Early and accurate cancer diagnosis is crucial for improving patient survival rates. Luminescent nanoparticles have emerged as a promising tool in fluorescence bioimaging for cancer diagnosis. To enhance diagnostic accuracy, ligands promoting endocytosis into cancer cells are commonly incorporated onto nanoparticle surfaces. Folic acid (FA) is one such ligand, known to specifically bind to folate receptors (FR) overexpressed in various cancer cells such as cervical and ovarian carcinoma. Therefore, surface modification of luminescent nanoparticles with FA can enhance both luminescence efficiency and diagnostic accuracy. In this study, luminescent europium-doped hydroxyapatite (EuHAp) nanocrystals were prepared via hydrothermal method and subsequently modified with (3-Aminopropyl)triethoxysilane (APTES) followed by FA to target FR-positive human cervical adenocarcinoma cell line (HeLa) cells. The sequential grafting of APTES and then FA formed a robust covalent linkage between the nanocrystals and FA. Rod-shaped FA-modified EuHAp nanocrystals, approximately 100 nm in size, exhibited emission peaks at 589, 615, and 650 nm upon excitation at 397 nm. Despite a reduction in photoluminescence intensity following FA modification, fluorescence microscopy revealed a remarkable 120-fold increase in intensity compared to unmodified EuHAp, attributed to the enhanced uptake of FA-modified EuHAp. Additionally, confocal microscope observations confirmed the specificity and the internalization of FA-modified EuHAp nanocrystals in HeLa cells. In conclusion, the modification of EuHAp nanocrystals with FA presents a promising strategy to enhance the diagnostic potential of cancer bioimaging probes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development., Methods: This retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs., Results: Our study included 181 patients (median age: 82 years, range: 80-94), mostly men (73%), with a performance status of 0-1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/μL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118., Conclusion: IO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed., (© 2024. The Author(s).)

Cardiac involvement of eosinophilic granulomatosis with polyangiitis is a rare but life-threatening complication. We present a case of eosinophilic granulomatosis with polyangiitis with moderately impaired ventricular function forming a ventricular thrombus. Pathological assessment of endomyocardial biopsy specimen revealed aggregated eosinophils in the subendocardium, suggesting ventricular endothelial damage leading to thrombus formation., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Objective: Cancer cachexia constitutes a poor prognostic factor in patients with lung cancer. However, the factors associated with cancer cachexia remain unclear. This study aimed to identify factors that influence cancer cachexia in patients with lung cancer., Methods: In this retrospective observational study conducted at the Kansai Medical University, 76 patients with lung cancer were evaluated for physical function, nutritional status (Mini Nutritional Assessment-Short Form) and physical activity (International Physical Activity Questionnaire-Short Form) at the first visit to the rehabilitation outpatient clinic. The patients were divided into cachexia and noncachexia groups. The log-rank tests and Cox proportional hazards model were used to investigate the relationship between cachexia and prognosis. To examine the factors that influence cachexia, multivariate regression analysis with significant (P < 0.05) variables in the univariate logistic regression analysis was performed. Spearman's correlation analysis was performed to investigate the association between International Physical Activity Questionnaire-Short Form and performance status., Results: Overall, 42 patients (55.2%) had cachexia associated with survival time since their first visit to the outpatient rehabilitation clinic, even after confounders adjustment (hazard ratio: 3.24, 95% confidence interval: 1.12-9.45, P = 0.031). In the multivariate analysis, Mini Nutritional Assessment-Short Form (odds ratio: 20.34, 95% confidence interval: 4.18-99.02, P < 0.001) and International Physical Activity Questionnaire-Short Form (odds ratio: 4.63, 95% confidence interval: 1.20-17.89, P = 0.026) were identified as independent factors for cachexia. There was no correlation between International Physical Activity Questionnaire-Short Form and performance status (r = 0.155, P = 0.181)., Conclusion: Malnutrition and low physical activity were associated with cachexia in patients with lung cancer. The International Physical Activity Questionnaire-Short Form may be a useful indicator of physical activity in cachexia. Regularly assessing these factors and identifying suitable interventions for cachexia remain challenges to be addressed in the future., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects., Methods and Analysis: In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint., Ethics and Dissemination: The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses., Trial Registration Number: UMIN000045229., Competing Interests: Competing interests: Dr Shiraishi reports consulting fee from Otsuka Pharmaceutical and lecture fees from Otsuka Pharmaceutical, Novartis, AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheime, and Bayer.Dr. Ikemura reports an unrestricted research grant from Bristol Myer Squibb.Dr Kohsaka received an unrestricted research grant from Novartis and honoraria from Pfizer Japan. The remaining authors have no conflict of interest to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cancer theranostics combines therapeutic and diagnostic capabilities into a single system to treat cancer efficiently. Biocompatible nanomaterials can be engineered to exhibit cancer theranostic functions, for instance radiosensitization and photoluminescence. In this study, trivalent Bi and Eu ions were co-substituted into the lattice of hydroxyapatite (Bi(III):Eu(III) HAp) to develop a cancer theranostic nanocrystal. Bi provides radiosensitization capabilities while Eu imparts photoluminescence properties. To complement the radiotherapeutic function, l-buthionine sulfoximine (l-BSO) was adsorbed onto the nanocrystal surface. l-BSO inhibits the biosynthesis of cellular antioxidants, which can enhance radiosensitization effects. The Bi(III):Eu(III) HAp nanocrystals were prepared via a hydrothermal method. Structural and compositional analyses showed that both Bi and Eu ions were substituted into the HAp lattice. l-BSO was adsorbed onto the surface via electrostatic interactions between the charged carboxyl and amino groups of l-BSO and the surface ions of the nanocrystals. The adsorption followed the Langmuir isotherm model, implying a homogeneous monolayer adsorption. The l-BSO adsorbed Bi(III):Eu(III) HAp nanocrystals were found to have negligible cytotoxicity except the setting with l-BSO adsorbed amounts of 0.44 μmol/m 2 . This l-BSO amount was found to be high enough to elicit cytotoxicity due to l-BSO being released and causing excessive antioxidant depletion. Gamma ray irradiation clearly activated the cytotoxicity of the samples and increased the cell death rate, confirming radiosensitization abilities. At a constant amount of nanocrystals, the cell death rate increases with l-BSO concentration. This indicates that l-BSO can enhance the radiosensitization effect of the Bi(III):Eu(III) HAp nanocrystals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO 2 ) kinetics at the onset of exercise. This factor is called the VO 2 time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO 2 time constant has not been elucidated. Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO 2 time constant during cardiopulmonary exercise testing. The VO 2 time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO 2 time constant/FFMI value. Results Patients with a low VO 2 time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO 2 time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO 2 time constant/FFMI. Conclusion An increased abnormal cardiac mitochondria ratio might be associated with a high VO 2 time constant/FFMI value in patients with NICM.

Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (<75 years) groups. Herein, 85 patients received nal-IRI+5-FU/LV, with 32 assigned to the elderly group. Patient characteristics in the elderly and non-elderly groups were as follows: age: 78.5 (75-88)/71 (48-74), male: 17/32 (53%/60%), performance status (ECOG) 0:9/20 (28%/38%), nal-IRI+5-FU/LV in second line: 23/24 (72%/45%), respectively. A significantly high number of elderly patients exhibited aggravated kidney and hepatic functions. Median overall survival (OS) and progression-free survival (PFS) in the elderly group vs. non-elderly group were 9.4 months vs. 9.9 months (hazard ratio (HR) 1.51, 95% confidence interval (CI) 0.85-2.67, p = 0.16) and 3.4 months vs. 3.7 months (HR 1.41, 95% CI 0.86-2.32, p = 0.17). Both groups exhibited a similar incidence of efficacy and adverse events. There were no significant differences in OS and PFS between groups. We analyzed the C-reactive protein/albumin ratio (CAR) and neutrophil/lymphocyte ratio (NLR) as indicators that could determine eligibility for nal-IRI+5-FU/LV. The median CAR and NLR scores in the ineligible group were 1.17 and 4.23 ( p < 0.001 and p = 0.018, respectively). Elderly patients with worse CAR and NLR score could be deemed ineligible for nal-IRI+5-FU/LV.

Background: Atrial fibrillation (AF) ablation is performed under deep sedation, which may cause inspiration-induced negative left atrial pressure (INLAP) associated with deep inspiration. INLAP could be the cause of periprocedural complications., Methods: We retrospectively enrolled 381 patients with AF (mean age, 63.9 ± 10.8 years; 76 women; 216 cases of paroxysmal AF) who underwent CA under deep sedation using an adaptive servo ventilator (ASV). Patients whose LAP was not obtained were excluded. INLAP was defined as <0 mmHg of mean LAP during inspiration immediately after the transseptal puncture. The primary and secondary endpoints were the presence of INLAP and the incidence of periprocedural complications., Results: Among 381 patients, INLAP was observed in 133 (34.9%). Patients with INLAP had higher CHA 2 DS 2 -Vasc scores (2.3 ± 1.5 vs. 2.1 ± 1.6) and 3% oxygen desaturation indexes (median 18.6 (interquartile range 11.2-31.1) vs. 15.7 (8.1-25.3)), and higher prevalence of diabetes mellitus (23.3 vs. 13.3%) than patients without INLAP. Air embolism occurred in four patients with INLAP (3.0 vs. 0.0%)., Conclusion: INLAP is not rare in patients undergoing CA for AF under deep sedation with ASV. Much attention should be paid to the possibility of air embolism in patients with INLAP.

Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed., (© 2023. The Author(s).)