Efficacy and safety of sintilimab in combination with chemotherapy for recurrent extensive-stage small cell lung cancer: a real-world retrospective study.

Background: Immune checkpoint inhibitors (ICIs) no longer are approved for second-line or later treatment of extensive-stage small cell lung cancer (ES-SCLC), and have not been studied in combination with chemotherapy. Exploring the efficacy and safety of second-line or later immunotherapy for ES-SCLC is an urgent clinical question that needs to be addressed, and combination therapies are an important research direction. This study intended to investigate the efficacy and safety of the sintilimab in combination with chemotherapy as a second-line and beyond treatment option for ES-SCLC. Methods: Medical records of patients who received treatment with sintilimab in combination with chemotherapy or chemotherapy alone as a second-line or beyond therapy were retrospectively analyzed. The study evaluated efficacy and safety. Indicators of efficacy included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety indicators included adverse events (AEs). Results: This cohort comprised of 46 patients: 24 in the sintilimab combination chemotherapy group and 22 in the chemotherapy group. Chemotherapy received by both groups was either albumin-bound paclitaxel or irinotecan. Compared with the chemotherapy group, the sintilimab combination chemotherapy group had higher ORR and DCR (ORR: 37.5% vs. 9.1%, P=0.04; DCR: 75.0% vs. 40.9%, P=0.04), and significantly prolonged PFS and OS [median PFS (mPFS): 5.07 vs. 2.45 months, P=0.006; median OS (mOS): 14.43 vs. 10.34 months, P=0.009]. Also, there was no significant increase in the incidence of AEs in the sintilimab combination chemotherapy group, which was well tolerated by patients. Conclusions: Sintilimab in combination with chemotherapy is superior to single-agent chemotherapeutic treatment as second-line or later therapy in ES-SCLC patients who have not received prior immunotherapy. These results need to be confirmed in future clinical trials.

Prevalence and Risk Factors for Occupational Voice Disorders in Nepalese Teachers: A Cross-Sectional Study.

Introduction Teachers are a high-risk group for the development of vocal dysfunction, as they use voice extensively in their profession. Objective To know the prevalence and risk factors associated with voice strain in teachers. Methods A cross-sectional study was conducted among schoolteachers in Chitwan, Nepal. The Voice Handicap Index questionnaire was used as a survey tool. Result A total of 315 teachers were enrolled in the study. The mean age of the participants was of 36.7 years. Teachers from public schools, primary grade classes, > 50 pupils in the classroom, > 24 hours of classes per week, dust in class, and recurrent tonsil problems were associated with various degrees of vocal handicap. Conclusion There is a high prevalence of voice disorder among teachers. A holistic approach, which includes teacher education regarding voice care during their work and management of their voice handicap by taking into consideration different risk factors, must be adopted.

Analysis of Circulating Tumor DNA Predicts Outcomes of Short Course Consolidation Immunotherapy in Unresectable Stage III Non-Small Cell Lung Cancer.

INTRODUCTION: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiotherapy (CRT) followed by one year of checkpoint inhibitor (CPI) therapy. However, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of unresectable locally advanced NSCLC patients treated on a phase 2 trial of short course consolidation immunotherapy after CRT, with the goal of testing if ctDNA may be able to identify patients who do not require a full year of treatment. PATIENTS AND METHODS: Plasma samples for ctDNA analysis were collected from patients on the BTCRC LUN 16-081 trial after completion of CRT, prior to C2D1 of CPI (i.e. 1 month after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using CAPP-Seq. Levels of ctDNA at each time point were correlated with clinical outcomes. RESULTS: Detection of ctDNA predicted significantly inferior progression-free survival (PFS) after completion of CRT (24-month 29% vs 65%, P = 0.0048), prior to C2D1 of CPI (24-month 0% vs 72%, P < 0.0001) and at the end of CPI (24-month 15% vs 67%, P = 0.0011). Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 72% vs 0%, P < 0.0001). Progression of disease occurred within <12 months of starting CPI in all patients with increasing ctDNA levels at C2D1. CONCLUSION: Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment.

Dissecting the MUC5AC/ANXA2 signaling axis: implications for brain metastasis in lung adenocarcinoma.

Non-small cell lung carcinoma (NSCLC) exhibits a heightened propensity for brain metastasis, posing a significant clinical challenge. Mucin 5ac (MUC5AC) plays a pivotal role in the development of lung adenocarcinoma (LUAD); however, its role in causing brain metastases remains unknown. In this study, we aimed to investigate the contribution of MUC5AC to brain metastasis in patients with LUAD utilizing various brain metastasis models. Our findings revealed a substantial increase in the MUC5AC level in LUAD brain metastases (LUAD-BrM) samples and brain-tropic cell lines compared to primary samples or parental control cell lines. Intriguingly, depletion of MUC5AC in brain-tropic cells led to significant reductions in intracranial metastasis and tumor growth, and improved survival following intracardiac injection, in contrast to the observations in the control groups. Proteomic analysis revealed that mechanistically, MUC5AC depletion resulted in decreased expression of metastasis-associated molecules. There were increases in epithelial-to-mesenchymal transition, tumor invasiveness, and metastasis phenotypes in tumors with high MUC5AC expression. Furthermore, immunoprecipitation and proteomic analysis revealed a novel interaction of MUC5AC with Annexin A2 (ANXA2), which activated downstream matrix metalloproteases and facilitated extracellular matrix degradation to promote metastasis. Disrupting MUC5AC-ANXA2 signaling with a peptide inhibitor effectively abrogated the metastatic process. Additionally, treatment of tumor cells with an astrocyte-conditioned medium or the chemokine CCL2 resulted in upregulation of MUC5AC expression and enhanced brain colonization. In summary, our study demonstrates that the MUC5AC/ANXA2 signaling axis promotes brain metastasis, suggesting a potential therapeutic paradigm for LUAD patients with high MUC5AC expression.

A cross-sectional survey of patient attitudes towards telemedicine in head and neck surgical oncology.

OBJECTIVE: To investigate patient attitudes towards desire for and barriers to utilizing telemedicine visits for head and neck oncology care. METHODS: This is a retrospective analysis of data from cross-sectional survey responses collected via prospectively administered questionnaire to 616 adult patients during their clinical visit to a tertiary care head and neck surgical oncology clinic. Responses to questions investigating interest in telemedicine and potential barriers were collated with patient demographics, measures of rurality, and insurance status. Interest in telemedicine appointments was the assessed primary outcome. RESULTS: Of 616 survey respondents, 315 (51 %) indicated interest in telemedicine visits. Limitations in access to technology (17.5 %) and lack of reliable internet connection (13.14 %) were identified as key barriers to telemedicine use. Lack of interest in telemedicine was associated with older age (OR 0.97 [95%CI 0.96-0.98]), governmental insurance (0.43 [0.31-0.60]) and, retired work status (0.48 [0.33-0.69]). Women (1.43 [1.04-1.97]) and patients who reported access to compatible electronic devices (41.05 [14.88-113.20]) and reliable internet connection (20.94 [8.34-52.60]) were more likely to be interested in telemedicine appointments. Respondents also indicated preference for a "hands on" examination over telemedicine appointments. CONCLUSION: Nearly 1 in 2 patients evaluated in a tertiary care head and neck surgical oncology clinic expressed reticence regarding telemedicine for clinical visits. Limited access to technology platforms and unreliable internet remain key concerns for these patients. Understanding the needs and attitudes of specific patient populations may be important for organizations pivoting to telemedicine platforms to ensure equity in healthcare access. LEVEL OF EVIDENCE: Retrospective analysis of prospectively collected cross-sectional survey.

Quality of Life and Depression Symptoms After Therapy De-Escalation in HPV+ Oropharyngeal Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Despite interest in therapy de-escalation for survivors of human papillomavirus-mediated oropharyngeal squamous cell carcinoma (HPV-positive OPSCC), the association of de-escalated therapy with patient-reported quality of life (QoL) outcomes and burden of depressive symptoms remains unclear. Objective: To identify associations between clinicopathologic and therapeutic variables with patient-reported QoL outcomes and depression symptom burden in patients with HPV-positive OPSCC, who were enrolled in a therapy de-escalation trial. Design, Setting, and Participants: In this nonrandomized controlled, open-label, curative-intent therapy de-escalation clinical trial in adults with stage I, II, and III HPV-positive OPSCC, patients were recruited from a high-volume head and neck oncology practice. Main Outcomes and Measures: The main outcomes of this study included quantitative, patient-reported QoL and depression symptoms per well-validated inventories. Patient-reported QoL was based on Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) scores (range, 0-148; lower score indicates inferior QoL). Patient-reported depression-related symptom burden was based on Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) scores (range, 0-27; a higher score indicates a higher burden of depression symptoms). Baseline clinicopathologic and treatment variables were paired with FACT-HN and QIDS-SR scores at baseline, 3, 6, 12, 24, and 36 months. Linear mixed-effect models with a random intercept were used for each participant and fixed effects for other measures. Regression coefficients are reported with 95% CIs. Results: A total of 95 patients were followed up for a median (IQR) of 2.2 (1.6-3.2) years. Of these, 93 patients (98%) were male with a mean (SD) age of 60.5 (8.2) years. Overall, 54 participants (57%) had a history of current or former smoking, 47 (50%) underwent curative-intent surgery (with or without adjuvant therapy), and 48 (50%) underwent primary radiotherapy (with or without chemotherapy). The median (IQR) radiotherapy dose was 60 (60-70) Gy. Five deaths and 2 recurrence events were observed (mean [SD] recurrence interval, 1.4 [1.5] years). A higher radiotherapy dose was the only modifiable factor associated with inferior patient-reported QoL (lower FACT-HN) (coefficient, -0.66 [95% CI, -1.09 to -0.23]) and greater burden of depression-related symptoms (higher QIDS-SR) (coefficient, 0.11 [95% CI, 0.04-0.19]). With the 70-Gy dose as reference, improvements in FACT-HN and QIDS-SR scores were identified when patients received 51 to 60 Gy (coefficient, 12.75 [95% CI, 4.58-20.92] and -2.17 [-3.49 to -0.85], respectively) and 50 Gy or lower (coefficient, 15.03 [4.36-25.69] and -2.80 [-4.55 to -1.04]). Conclusions and Relevance: In this nonrandomized controlled, open-label, curative-intent therapy de-escalation trial, a higher radiotherapy dose was associated with inferior patient-reported QoL and a greater burden of depression-related symptoms. This suggests opportunities for improved QoL outcomes and reduced depression symptom burden with a reduction in radiotherapy dose. Trial Registration: ClinicalTrials.gov Identifier: NCT04638465.

Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.

Disparities in Thyroid Cancer Diagnosis Based on Residence and Distance From Medical Facility.

Context: Rural-urban disparities have been reported in cancer care, but data are sparse on the effect of geography and location of residence on access to care in thyroid cancer. Objective: To identify impact of rural or urban residence and distance from treatment center on thyroid cancer stage at diagnosis. Methods: We evaluated 800 adults with differentiated thyroid cancer in the iCaRe2 bioinformatics/biospecimen registry at the Fred and Pamela Buffett Cancer Center. Participants were categorized into early and late stage using AJCC staging, and residence/distance from treating facility was categorized as short (≤ 12.5 miles), intermediate (> 12.5 to < 50 miles) or long (≥ 50 miles). Multivariable logistic regression was used to identify factors associated with late-stage diagnosis. Results: Overall, 71% lived in an urban area and 29% lived in a rural area. Distance from home to the treating facility was short for 224 (28%), intermediate for 231 (28.8%), and long for 345 (43.1%). All 224 (100%) short, 226 (97.8%) intermediate, and 120 (34.7%) long distances were for urban patients; in contrast, among rural patients, 5 (2.16%) lived intermediate and 225 (65.2%) lived long distances from treatment (P < .0001). Using eighth edition AJCC staging, the odds ratio of late stage at diagnosis for rural participants ≥ 55 years was 2.56 (95% CI, 1.08-6.14) (P = .03), and for those living ≥ 50 miles was 4.65 (95% CI, 1.28-16.93) (P = .0075). Results were similar using seventh edition AJCC staging. Conclusion: Older age at diagnosis, living in rural areas, and residing farther from the treatment center are all independently associated with late stage at diagnosis of thyroid cancer.

Effect of Yoga-based breathing practices on depression, anxiety, stress, and fear of COVID-19 positive hospitalized patients: A randomized controlled trial.

BACKGROUND: COVID-19 infection has an impact on the mental state of patients and requires attention to mental health care. OBJECTIVE: The aim of this study is to assess the effect of Yoga-based breathing practices on the mental state of patients with COVID-19. MATERIAL AND METHODS: A randomized controlled trial was conducted with63 patients (male=46) who were RT-PCR positive for COVID-19 and hospitalized with asymptomatic (RT-PCR positive but no symptoms), mild (febrile, body ache, pharyngitis, nonproductive cough), and moderate (SpO2< 92%) symptoms assigned in the yoga (n=32) and control group (n=31). The study was conducted at Atharva Multispecialty Hospital and Research Center, North India. The yoga group received Yoga-based breathing practices twice a day for ten days in addition to conventional care, and the control group was advised not to do the practice. The Depression Anxiety and Stress scale (DASS-21) and fear of COVID-19 were assessed at baseline and after 10 days. Repeated measures ANOVA with Bonferroni correction was used to assess between and within subjects' effects. RESULTS: The experimental group had better scores for depression, anxiety, stress, total DASS scores, and fear of COVID-19 (p<0.001) when compared with the control group. Within the group, analyses demonstrated improved scores in all domains in the yoga group (p<0.001) by the end of the intervention. In contrast, the control group improved only in stress scores (p=0.002), total DASS scores (p=0.012), and fear of COVID-19 (p=0.039). There are no adverse effects seen with Yoga-based breathing practices in these patients. CONCLUSION: Yoga-based breathing practices have been found to have positive impact on mental health among COVID-19-positive patients during hospitalization. TRIAL REGISTRY NUMBER CTRI: CTRI/2022/03/041071 Clinical Trials-Registry in India.

Effect of Yoga in Industrial Workers with Chronic Venous Insufficiency: A Randomized Controlled Trial.

Background and objective: Prolonged standing is one of the significant contributors to chronic venous insufficiency (CVI) in industry workers. Yoga is proven to be an effective therapy in treating occupational hazards. The current study aimed to investigate the effect of yoga on CVI among industry workers. Methodology: Male workers (n = 100) from machinery manufacturing industries in Bangalore meeting the inclusion and exclusion criteria were recruited for the study. The yoga group received a specifically designed yoga module for 6 days a week for 12 weeks, and the control group was offered lifestyle suggestions. Plasma homocysteine was used as the primary outcome variable, whereas Venous Clinical Severity Score, ankle brachial pressure index (ABPI), ankle and calf circumference, CVI questionnaire, and Chalder fatigue scale were assessed as secondary variables at baseline and the end of 12 weeks of intervention. Results: Eighty-eight participants (yoga = 43, control = 45) completed the study. A one-way analysis of covariates (ANCOVA) was used to determine the significant differences between groups in the post-values. A significant difference was found between groups in plasma homocysteine (partial eta squared = 0.34, p < 0.001). All variables, except for ABPI, calf circumference, and ankle circumference, had shown statistically significant differences between the yoga and control groups after 12 weeks of intervention, with moderate to high effect sizes. There were no significant adverse events associated with the intervention. Conclusions: Yoga practices can reduce the symptoms of CVI along with vascular inflammation as indicated by reduced plasma homocysteine. Overall, yoga practices are found to be safe and efficacious for managing CVI. IEC Reference Number: RES/IEC-SVYASA/184/2021 Trial Registration Number (If Clinical Trial): CTRI/2021/02/030944.

Durvalumab Outcomes in Stage III Non-small Cell Lung Cancer: A Single-institution Study.

BACKGROUND/AIM: The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy (CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution. PATIENTS AND METHODS: We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR). RESULTS: We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR. CONCLUSION: Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.

Phase I/II study to evaluate consolidative hypofractionated radiation therapy for boosting the residual primary disease in combination with durvalumab after definitive chemoradiation therapy for stage III non-small cell lung cancer (NSCLC): study protocol for a prospective trial.

Background: Recent advancements in the management of non-small cell lung cancer (NSCLC) have confirmed the utility of adding adjuvant immunotherapy to concurrent chemoradiotherapy in stage III disease but intrathoracic progression remains at high rate. Additional studies have sought to investigate the synergistic relationship of immunotherapy and radiation therapy (RT). The goal of this study is to evaluate the safety and efficacy of combining consolidative hypofractionated radiation therapy (hfRT) using stereotactic body radiotherapy (SBRT) technique for boosting the residual primary lung cancer with adjuvant anti-programmed death-ligand 1 (PD-L1) therapy concurrently after completion of definitive chemoradiation therapy (dCRT) in the rates of tumor control locoregionally and distantly. Methods: Eligible subjects with stage III NSCLC must have gross residual tumor that is smaller than 5.0 cm in maximal dimension following dCRT. Consolidative hfRT will be delivered 1 to 2 months after finishing dCRT and concurrently with adjuvant anti-PD-L1 therapy using durvalumab. Consolidative hfRT will start from 6.5 Gy ×2 fractions and dose escalate to 10 Gy ×2 fractions in a 3+3 design. At the final determined consolidative hfRT dose level, a total of 32 subjects with pathologically documented stage III NSCLC treated with two or more cycles of platinum-based doublet chemotherapy concurrently with RT will be enrolled for data analyses. Discussion: We hypothesize that the use of consolidative hfRT directed to the residual primary lung tumor in combination with adjuvant anti-PD-L1 therapy will provide additional immunostimulation and therefore improved locoregional and distant control when compared to either modality used independently. Registration: Clinicaltrials.gov: NCT04748419.

A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy.

PURPOSE: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). RESULTS: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. CONCLUSIONS: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting. See related commentary by Wu and Luke, p. 9.

Surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non-small cell lung cancer.

OBJECTIVE: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains unknown. We aimed to determine operative complexity and perioperative outcomes associated with neoadjuvant chemotherapy and nivolumab with or without ipilimumab. METHODS: A total of 44 patients with stage IB (≥4 cm) to IIIA non-small cell lung cancer were treated on sequential platform arms of the NEOSTAR trial. A total of 22 patients were treated with nivolumab + chemotherapy, and 22 patients were treated with ipilimumab + nivolumab + chemotherapy. The safety of surgical resection after neoadjuvant therapy was estimated using 30-day complication rates. Operative reports and surgeons' narratives were evaluated to determine procedural complexity and operative conduct. RESULTS: All 22 of 22 patients (100%) treated with nivolumab + chemotherapy underwent surgical resection: 20 R0 (90.9%), 17 (77.3%) lobectomies, 1 wedge resection, 2 segmentectomies, and 2 pneumonectomies. The majority, 21 of 22 (95%), were performed by thoracotomy. A total of 13 of 22 (59.1%) were rated as challenging resections. A total of 4 of 22 patients (18.2%) experienced grade 3 or greater Clavien-Dindo complication. A total of 20 of 22 patients (90.9%) treated with ipilimumab + nivolumab + chemotherapy underwent surgical resection: 19 R0 (95%), 18 (90%) lobectomies, 1 pneumonectomy, and 1 segmentectomy. A total of 16 of 20 (80%) resections were performed via thoracotomy, 3 of 20 (15%) via robotics, and 1 of 20 (5%) via thoracoscopy. A total of 9 of 20 (45%) resections were considered challenging. A total of 4 of 20 patients (20%) experienced grade 3 or greater Clavien-Dindo complication. CONCLUSIONS: Surgical resections are feasible and safe, with high rates of R0 after neoadjuvant chemotherapy and nivolumab with or without ipilimumab. Overall, approximately half of cases (22/42, 52.3%) were considered to be more challenging than a standard lobectomy.

Exploring the Effect of Trataka (A Yogic Cleansing Technique) and Cold Eye Pack on Eye Strain During COVID-19 Pandemic: A Randomized Three-Arm Trial.

Objective: Computer vision syndrome is a major global public health concern affecting >60 million individuals globally. Yoga and naturopathy practices can reduce visual fatigue and strain. The present study attempted to explore the effect of trataka that is, a yogic cleansing technique and cold eye pack on visual strain and fatigue. Subjects: Three hundred volunteers from an IT company were recruited following inclusion and exclusion criteria. Intervention: The subjects were randomly distributed in three groups, that is, trataka, cold eye pack, and waitlist control group with an allocation ratio of 1:1:1. Outcome measure: Visual Fatigue Scale and Visual symptoms checklist (VSC) was administered at baseline and end of 2 weeks. Repeated measures analysis of variance (RM-ANOVA) with Bonferroni corrections was used to test the difference across the groups. Results: All the variables were similar at the baseline among the groups. Significant changes in the within-group analysis occurred in both the trataka and cold eye pack groups. The RM-ANOVA revealed significant differences in the VAS and VSC (p = 0.001) and the post hoc analysis suggested that there were significant differences in both the trataka and cold eye pack group when compared with the control group (p = 0.001); however, there was no differences between the trataka and cold eye pack group in both the scales (p = 1). Conclusions: The results of the present study suggest that a trataka and cold eye pack for 14 days improves self-rated visual strain and fatigue among IT professionals with computer vision syndrome. Clinical Trial registration number: CTRI/2020/11/029003.

Yoga for musculoskeletal pain, discomfort, perceived stress, and quality of sleep in industry workers: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Work-related musculoskeletal pain and discomfort are due to repetitive, unnatural, continuous movements and postures. Yoga therapy is beneficial for pain and disability in occupational settings. The current study aims to investigate the effect of yoga on musculoskeletal pain, stress, and sleep quality among industry workers. METHODOLOGY: The study was conducted as a parallel randomized controlled open-label trial. An allocation ratio of 1:1 was followed for randomization. A health survey was used to recruit 90 male workers in machinery manufacturing industries from Bengaluru. A specially designed yoga module was administered five days a week for eight weeks to yoga group. The waitlisted control group received lifestyle suggestions. Cornell Musculoskeletal Discomfort Questionnaire (CMDQ), Perceived Stress Scale (PSS), and Pittsburgh Sleep Quality Index (PSQI) were administered at baseline, at the fourth week and eighth weeks. Repeated Measures Analysis of Variance (RM-ANOVA) was conducted to elicit the group*time interactions. RESULTS: Ninety participants (Yoga = 45, Control = 45) with age 40.57 ± 6.85 were randomized. Significant interactions were found in CMDQ, VAS, PSS and PSQI scores. Further, between group comparison demonstrate significant difference between the groups at the end of 8 weeks for CMDQ, VAS and PSS scores. CONCLUSIONS: Yoga can be used to reduce musculoskeletal pain, discomfort, perceived stress and improve sleep quality among industry workers. TRIAL REGISTRATION NUMBER: CTRI/2022/03/040894.

Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors.

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

Designing and validation of Yoga module for workers with prolonged standing.

BACKGROUND: Prolonged standing is a part of several professions, which can have physical and psychosocial implications. Yoga as a mind-body therapy may be useful to prevent and manage such health issues. However, there is a lack of a standardized yoga module addressing the health issues of workers with prolonged standing. OBJECTIVES: Thus, the present study was undertaken to design and validate a specific yoga module for the target population. METHODS: A yoga module was prepared by reviewing yoga texts for the specific needs of the target population. This was validated for content validity for the experts on a Likert scale. 71 yoga experts validated the module. The content validity ratio (CVR) above 0.70 was considered to be valid. RESULTS: The validated yoga module consists of joint loosening and strengthening exercises, asana, pranayama and relaxation techniques. The average CVR for the module was found to be 0.80. CONCLUSION: The designed yoga module is found to be valid by the experts. The module needs to be assessed for feasibility and efficacy in the target population.

A retrospective analysis of immune checkpoint inhibitors in patients with preexisting organ dysfunction.

BACKGROUND: There are limited to no data regarding the use of immune checkpoint inhibitors (ICIs) in patients who have preexisting organ dysfunction because these patients are frequently excluded from clinical trials. The authors' objective was to evaluate the effects of ICIs in patients with chronic kidney disease (CKD), cirrhosis, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF). METHODS: Data were obtained retrospectively for patients older than 18 years with solid organ malignancies who received at least one dose of an ICI between January 1, 2015, and January 1, 2021, and had either CKD (n = 90), cirrhosis (n = 20), COPD (n = 142), or CHF (n = 82) before ICI initiation at the authors' institution. Descriptive statistics were used to summarize patient characteristics, treatment characteristics, immune-related adverse events (IrAEs), and outcomes. An independent samples t-test or the Wilcoxon rank-sum test was used to assess differences in continuous variables; the χ2 test or the Fisher exact test was used to assess differences in categorical variables between patients with and without IrAEs. Progression-free survival (PFS) was assessed using Kaplan-Meier curves, and the log-rank test was used to assess differences in PFS. RESULTS: In all four cohorts, there were no statistically significant differences in patient characteristics, treatment characteristics, or outcomes, such as the number of hospitalizations and PFS, among those who experienced IrAEs compared with those who did not. In the CKD cohort, patients with IrAEs were significantly less likely to die than those without IrAEs (52% vs. 81% [p = .009] for all patients; 53% vs. 83% [p = .008] for patients with stage II/III disease who received no definitive local treatment and patients with stage IV disease); this difference was not observed in the cirrhosis, COPD, or CHF cohorts. There was no statistically significant difference in the number of heart failure and COPD exacerbations during the receipt of ICIs in the CHF and COPD cohorts, respectively. The incidence and time to onset of IrAEs in this study appeared to be similar to those reported previously in clinical trials that excluded patients with significant comorbidities. CONCLUSIONS: The current results demonstrate that ICIs are well tolerated by patients who have preexisting organ dysfunction.