Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy.

BACKGROUND: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge. METHODS: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed. RESULTS: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17. CONCLUSION: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

Real-World Efficacy and Safety of Durvalumab Administration Following Chemoradiotherapy in Elderly Patients With Unresectable Locally Advanced Nonsmall Cell Lung Cancer: A Multicenter, Retrospective Study.

BACKGROUND: The PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients. PATIENTS AND METHODS: We reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients. RESULTS: The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups. CONCLUSIONS: The real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above.

Comparison of Anorectal Function and Quality of Life Measures in Patients Following Intersphincteric Resection and Lower Anterior Resection.

This study explored postoperative outcomes for patients with lower rectal cancer who underwent low anterior resection (LAR) or intersphincteric resection (ISR). A total of 49 patients (33 LAR, 16 ISR) were followed using anorectal manometry and quality of life (QOL) questionnaires over a year, pre- and post surgery. The primary aim of this study is to clarify differences in anal manometry, sphincter function, fecal incontinence, and QOL between the two surgical arms. The secondary aim was to identify indicators suitable for assessing relationships between anorectal manometry measurements, fecal incontinence, and QOL. Anorectal manometry elements (AMEs), such as atmospheric maximum mean squeeze pressure (aMSP), maximum tolerable volume (MTV), and incremental maximum mean squeeze pressure (iMSP), showed no significant differences during the observation period. However, maximum resting pressure (MRP), high-pressure zone length (HPZ), and threshold volume (TV) were significantly worse in the ISR group. Fecal incontinence, measured by Wexner and Kirwan scores, was significantly better in the LAR group. We observed no differences in SF36 between the two groups. Multi-correlation analysis revealed positive and negative correlations among these factors, with inverse correlations between anorectal manometry measurements and incontinence assessments decreasing post-surgery. We found no correlation between SF36 and anorectal manometry at any time. The findings indicate that surgical technique affects postoperative anal function, fecal incontinence, and SF36. However, combined assessment methods should be used with caution when deriving relationships between anal function and SF36.

Oncological similarities between large type 3 and type 4 tumors in patients with resectable gastric cancer: a propensity score-matched analysis of a multi-institutional dataset.

BACKGROUND: Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue. METHODS: In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences. RESULTS: Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.14-2.74). However, among the large type 3 tumors, a remarkable difference in prognosis was observed between the differentiated and undifferentiated histological types. A comparison was made between large type 3 with undifferentiated phenotype and type 4, each with 39 patients after propensity score matching. Outcomes in both groups were similar in terms of overall survival (HR 1.28; 95% CI 0.73-2.25) and relapse-free survival (HR 1.34; 95% CI 0.80-2.27). No statistically significant differences were observed in the incidence of peritoneal recurrence (35.9% vs. 46.1%, P = 0.36) and lymph node recurrence (25.6% vs. 12.8%, P = 0.15). CONCLUSIONS: Large type 3 tumors with undifferentiated phenotype and type 4 tumors were oncologically similar. This subgroup could be considered as a new entity for future clinical trials.

Efficacy of timing­dependent infusion of nivolumab in patients with advanced gastric cancer.

Although an association exists between the timing of immune checkpoint inhibitor (ICI) administration and therapeutic efficacy in several types of cancer, to the best of our knowledge, no reports exist regarding this relationship in gastric cancer (GC). The present study aimed to evaluate the optimal timing of ICI (nivolumab) administration in patients with advanced GC. A total of 58 consecutive patients with advanced GC who received nivolumab monotherapy after ≥2 chemotherapy regimens were retrospectively evaluated. These patients were divided into two groups according to the median time of nivolumab administration: i) Early-timing and (ii) late-timing groups, and the efficacy was assessed in both groups. The early-timing group had significantly longer overall survival (OS) than the late-timing group [median OS 8.2 months; 95% confidence interval (CI), 4.2-12.9 vs. median OS 5.4 months; 95% CI, 3.6-6.1]. Moreover, patients in the early-timing group had significantly longer progression-free survival (PFS) than those in the late-timing group (median PFS 2.6 months; 95% CI, 1.3-3.9 months vs. median PFS 1.6 months; 95% CI, 0.9-2.1 months). Furthermore, univariate analysis showed that early timing, immune-related adverse events and nonsteroidal anti-inflammatory drug administration were associated with longer OS and PFS. Cutoff Finder analysis revealed that the optimal timing of nivolumab administration for achieving better outcomes was before 12:06 p.m. Nivolumab administration in the morning, especially before 12:06 p.m., had a better clinical impact on patients with advanced GC.

Prognostic Significance of Plasma Neutrophil Extracellular Trap Levels in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185). The clinical significances of NET levels before/after treatment and posttreatment changes were statistically evaluated. As a result, multivariate Cox analysis showed that high NET levels before treatment were statistically significant predictors of unfavorable overall survival (OS; p < 0.001, HR 1.702, 95% CI 1.356-2.137) and progression-free survival (PFS; p < 0.001, HR 1.566, 95% CI 1.323-1.855). The Kaplan-Meier curves showed significant separation between the high- and low-NET groups in OS (p = 0.002) and PFS (p < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS (p < 0.001) and PFS (p < 0.001) by multivariate Cox analysis. Notably, the pretreatment NET levels were significantly correlated with the plasma levels of NET-related inflammatory cytokines, such as IL-6 and IL-8, and with NET-related gene expression and immune-suppressive profile in peripheral blood mononuclear cells. Our findings suggest that NETs released from activated neutrophils might reduce the clinical efficacy of ICIs in patients with NSCLC.

Enlarged Perivascular Spaces Are Independently Associated with High Pulse Wave Velocity: A Cross-Sectional Study.

Background: Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer's disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. Objective: To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. Methods: We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia (BG)-EPVS or centrum semiovale (CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. Results: We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02-1.38], 1.09 [1.01-1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01-1.12, p = 0.006). Conclusions: Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment.

Treatment Outcomes in Patients with Conjunctival Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma.

Purpose: To report the outcomes of different therapies in patients with conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. Patients and Methods: This retrospective study included patients diagnosed with conjunctival MALT lymphoma between August 2000 and April 2022. Patients were classified into three groups according to their treatment: an observation group, a radiation therapy (RT) group, and a rituximab group (rituximab with or without chemotherapy). We analyzed overall survival (OS), overall, local, and systemic relapse-free survival (RFS), and adverse events after treatment. Results: This study included 15 patients (22 eyes). The 10-year OS was 100%. The 2-, 5-, and 10-year overall RFS rates were 80.1%, 41.2%, and 41.2% in all patients, respectively. The 2- and 5-year local RFS rates in the observation group were 100% and 0%, respectively. The 2-, 5-, and 10-year local RFS rates were 87%, 87%, and 87% in the RT group and 83%, 67%, and 67% in the rituximab group, respectively. The 2- and 5-year systemic RFS rates in the observation group were both 100%, and the 2-, 5-, and 10-year systemic RFS rates were 92%, 55%, and 55% in the RT group, and 100%, 60%, and 60% in the rituximab group, respectively. After RT, 53.3% of the eyes developed cataracts and 75% of these were treated with cataract surgery. In addition, 53.3% of the eyes developed dry eyes and were treated with eye drops. Rituximab with or without chemotherapy resulted in some systemic adverse events, but these improved following symptomatic therapies. Conclusion: RT resulted in good local control of conjunctival MALT lymphoma; however, systemic relapse may occur during long-term follow-up. Local and/or systemic relapse may also occur during long-term follow-up in patients treated by observation or rituximab with or without chemotherapy. Patients with conjunctival MALT lymphoma should be followed-up carefully for as long as possible after treatment.

Effects of sarcopenia on changes in prevalence of patients with depressive mood during hospitalization in geriatric rehabilitation.

Background: The effect of sarcopenia on depressive mood during geriatric rehabilitation remains unclear. This study investigated the potential influence of sarcopenia on depressive mood among geriatric patients in a rehabilitation setting. Methods: This observational cohort study enrolled 204 patients aged ≥65 years (mean: 78.8±7.6 years, 45.1% women) admitted to a rehabilitation unit between April 2020 and July 2021. Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment (AWGS2019) criteria, which include low handgrip strength and muscle mass. Depressive mood was defined as a 15-item Geriatric Depression Scale score of ≥6 points. We applied logistic regression models to examine the influence of sarcopenia on depressive mood at discharge. Results: We observed sarcopenia in 58.3% of patients. The logistic regression model showed that sarcopenia negatively influenced depressive mood at discharge (odds ratio, 5.460; 95% confidence interval, 2.344-13.415). Of the 68 patients without depressive mood at admission, those with sarcopenia (n=31) had a significantly higher incidence of depressive mood at discharge compared with patients without sarcopenia (n=37) (41.9% vs. 16.2%, p=0.037). Conclusion: Sarcopenia at admission negatively affected depressive mood at discharge from geriatric rehabilitation. Thus, early and routine assessment of sarcopenia is vital for patients undergoing geriatric rehabilitation.

Feeding Assistance Skill Score: development and verification of reliability and validity.

PURPOSE: Feeding assistance should be safe and improve the assisted individual's ability to feed, yet objective tools for evaluating these skills are lacking. This study focuses on developing a tool for assessing feeding assistance skills. METHODS: A group consisting of 25 experts employed the Delphi method to achieve a consensus on the essential items necessary for assessing feeding assistance skills. Subsequently, a draft score using a three-point scale was developed. To test the reliability of the draft scores, a group of 20 patients and 20 nurses was matched to record a meal assistance scene, which were independently evaluated by three raters. We computed the AC1 statistic to assess both intra- and inter-rater reliability, and further examined correlations between the Feeding Assistance Skill Score (FASS) scores and outcome items to verify validity. RESULTS: Initially, an 18-item draft score was generated using the Delphi method. Subsequently, seven items were omitted from the intra- or inter-rater reliability analysis. Furthermore, after discussion, researchers removed one item that assessed food cognition, because the agreement score between the two items was 91%. Finally, the 10-item FASS was developed, showing a correlation with dietary intake upon validation. CONCLUSIONS: We successfully developed a scoring system for peer evaluation of feeding assistance skills. Future studies should aim to validate the FASS. The implementation of the FASS aims to assess the effectiveness of feeding assistance training and care quality, potentially improving safety and satisfaction for those receiving feeding assistance.