Relationships between prolonged physical and social isolation during the COVID-19 pandemic, reduced physical activity and disability in activities of daily living among people with advanced respiratory disease.

In people with advanced respiratory disease, we examined (i) the impact of COVID-19-related physical and social isolation on physical activity and (ii) relationships between time spent in isolation and disability in activities of daily living. Cross-sectional analysis was conducted in adults with advanced non-small cell lung cancer, chronic obstructive lung disease or interstitial lung disease. Measures included change in physical activity since physically and socially isolating (Likert scale) and disability (Barthel Index and Lawton-Brody IADL scale) or difficulty (World Health Organisation Disability Assessment Schedule-2.0) in daily activities. Multiple logistic regression was used to examine factors associated with disability in daily activities. 194/201 participants were isolating for a median [IQR] 5 [3-8]-month period, often leading to lower levels of physical activity at home (n = 94, 47%), and outside home (n = 129, 65%). 104 (52%) and 142 (71%) were not fully independent in basic and instrumental activities of daily living, respectively. 96% reported some degree of difficulty in undertaking daily activities. Prolonged physical and social isolation related to increased disability in basic (r = -0.28, p < 0.001) and instrumental (r = -0.24, p < 0.001) activities of daily living, and greater difficulty in daily activities (r = 0.22, p = 0.002). Each month spent in physical or social isolation was independently related to disability in basic activities of daily living (odds ratio [OR], 1.17 [95% CI: 1.03-1.33], p = 0.013). These findings suggest disability in daily activities is associated with prolonged physical or social isolation, which may present as difficulty in people who are fully independent. Post-isolation recovery and rehabilitation needs should be considered for all people deemed extremely clinically vulnerable.

In-situ hearing threshold estimation using Gaussian process classification.

One in six Americans suffers from hearing loss. While treatment with amplification is possible for many, the acceptance rate of hearing aids is low. Poor device fitting is one of the reasons. The hearing aid fitting starts with a detailed hearing assessment by a trained audiologist in a sound-controlled environment, using standard equipment. The hearing aid is adjusted step-by-step, following well-described procedures based on the audiogram. However, for many patients in rural settings, considerable travel time to a hearing center discourages them from receiving a hearing test and treatment. We hypothesize that hearing assessment with the patient's hearing aid can reliably substitute the hearing test in the clinic. Over-the-counter hearing aids could be programmed from a distance and fine-tuned by the hearing aid wearer. This study shows that a patient-controlled hearing assessment via a hearing aid in a non-clinical setting is not statistically different from an audiologist-controlled hearing assessment in a clinical setting. The differences in hearing obtained with our device and the Gaussian Process are within 3 dB of the standard audiogram. At 250 Hz, the sound delivery with the hearing aid used in this study added an additional reduction of sound level, which was not compensated.

Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer.

Background: STK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis. Methods: Forty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test. Results: In the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype. Conclusions: Our retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.

A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139.

INTRODUCTION: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC). PATIENTS AND METHODS: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects. The primary endpoint was progression-free survival (PFS). The positive PFS result was considered as PFS>6m (historical control). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) defined by complete response (CR) + partial response (PR) + stable disease (SD) ≥ 2 months, overall survival (OS), and safety. RESULTS: Thirty patients were enrolled from November 2018 to October 2020. The study was closed early due to 3 patient deaths, possibly related to treatment. Median age 64 (range 38-83); Men/Women 20/10; PD-L1 TPS < 1%/1-49%/ ≥ 50% (8/15/7). The median follow-up was 20.3 months ( 1-28.1). ORR 42.9% (95% CI, 24.5-62.8%), DCR 96.4% (95% CI, 81.7-99.9%). The median PFS and OS were 11.3m (5.5-14.9,P > .05) and 22.4m (22.4-NR), respectively. Four patients had G4 toxicity (anemia, febrile-neutropenia, severe neutropenia, sepsis), and 3 patients had G5 toxicity (thromboembolism, sepsis, colonic perforation). CONCLUSION: ABCPem was associated with increased PFS compared to historical controls but this difference did not meet the statistical significance. Three on-treatment deaths and 5 thromboembolic events prompted early closure.

Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study.

BACKGROUND: Tumor mutational burden (TMB) is a potential biomarker to predict tumor response to immuno-oncology agents in patients with metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC between 2012 and 2019 who had received comprehensive genomic profiling (CGP) and any NSCLC-related treatment at 9 U.S. cancer centers. Baseline characteristics and clinical outcomes were compared between patients with TMB <10 and TMB ≥10. RESULTS: Among the 667 patients with CGP results, most patients received CGP from Foundation Medicine (64%) or Caris (20%). Patients with TMB ≥10 (vs. TMB <10) were associated with a positive smoking history. TMB was associated with ALK (p = 0.01), EGFR (p < 0.01), and TP53 (p < 0.05) alterations. TMB >10 showed a significant association towards longer overall survival (OS) (HR: 0.43, 95% CI: 0.21-0.88, p = 0.02) and progression-free survival (PFS) (HR: 0.43, 95% CI: 0.21-0.85, p = 0.02) in patients treated with first-line immunotherapy and tested by Foundation Medicine or Caris at treatment initiation. CONCLUSIONS: TMB levels greater than or equal to 10 mut/Mb, when tested by Foundation Medicine or Caris at treatment initiation, were significantly associated with improved OS and PFS among patients treated with first-line immunotherapy-containing regimens. Additional prospective research is warranted to validate this biomarker along with PD-L1 expression.

Combining radiation therapy and immunotherapy for lung cancers: a narrative review.

Lung cancer remains the leading cause of cancer morbidity and mortality worldwide among both men and women. While surgical resection remains the standard of care for early stage NSCLC, chemoradiation has been a mainstay of treatment for locally advanced non-small-cell lung cancer (LA-NSCLC) patients for decades. Consolidation immunotherapy has improved survival in this subset of patients after conventional chemoradiation, and has emerged as the new standard. The synergy between immunotherapy and radiation, as well as ongoing research on the effects of radiation on the immune system, allows for the exploration of new avenues in the treatment of LA-NSCLC. In addition to the use of durvalumab as consolidative systemic therapy after concurrent chemoradiotherapy for Stage III NSCLC, other combination regimens have been shown to be effective in various disease stages in preclinical and clinical studies. These regimens include CTLA-4 and PD/PDL-1 checkpoint inhibitors combined with radiation treatment. While these combined regimens have demonstrated efficacy, they are not without toxicity, and require additional evaluation when combined with radiation. In this review, we have summarized the immunostimulatory and immunosuppressive effects of radiation therapy. We also evaluate the current evidence and ongoing research supporting the combination of radiotherapy and immunotherapy across early to LA-NSCLC.

Overexpression of excision repair cross-complementing 1 gene associates with higher risk of therapeutic failure after definitive chemoradiation for unresectable non-small cell lung cancer.

BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) is typically treated with concurrent chemoradiation (CRT). Excision Repair Cross-Complementing 1 (ERCC1) is a protein involved in DNA damage repair. The objective of this study was to assess whether higher tumoral ERCC1 expression would associate with worse clinical outcomes in NSCLC treated with CRT. METHODS: Twenty-five patients were included. Relative expression levels of messenger RNA (mRNA) for ERCC1 were measured with a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and expressed as scaled ERCC1 mRNA gene expression value. Patients were followed every 3 months with history, physical exam, and imaging to assess clinical outcomes. We evaluated the associations between ERCC1, as well as other prognostic variables including stage, age, gender, race, histology, RT dose, performance status, and progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method and Cox regression. RESULTS: Recursive partitioning analysis identified a GeneExp cutoff of 1.54. Higher ERCC1 expression was associated with worse PFS [hazard ratio (HR) =1.70, P=0.04] and trended towards worse OS (HR =1.53, P=0.11). Increasing tumor volume (HR =1.001, P=0.055), squamous cell (HR =7.86, P=0.008) and poorly differentiated histology (HR =5.25, P=0.06) also associated with worse OS. The cumulative incidence of local recurrence at 1 year trended higher with ERCC1 GeneExp ≥1.54 (78.1%) compared to ERCC1 GeneExp <1.54 (14.9%, P=0.08). Distant relapse at 1 year was 72% with tumor ERCC1 expression ≥1.54 and 52% with ERCC1 expression <1.54 (P=0.28). CONCLUSIONS: Higher ERCC1 expression by qRT-PCR appears to correlate with worse PFS in locally advanced NSCLC treated with CRT. However, the overall sample size of the population was small; thus, larger studies are warranted to integrate molecular biomarkers to identify patients who might benefit from treatment intensification.

Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications. METHODS: We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method. RESULTS: Median age at diagnosis was 70 years (range 55-85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile. CONCLUSION: Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.

Tumor volume reduction evaluated by cone beam computed tomography during stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND: We hypothesized that significant tumor volume reduction (TVR) occurs over the course of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC), and that TVR correlates with clinical outcomes. METHODS: We conducted a retrospective review of patients treated with SBRT for early stage NSCLC across two academic centers. For each patient, we contoured the tumor volume (TV) on cone beam computed tomography (CBCT) images obtained before each treatment fraction. We then calculated TVR based on the TV from the first and last days of treatment. We used log-rank tests to quantify differences in overall survival (OS), progression-free survival (PFS) and recurrence based on TVR. RESULTS: Data from 69 patients and a total of 73 treated tumors were analyzed. The median follow-up for survivors was 51.8 months (range, 6.9 to 80.0 months). The median TVR for the cohort was 10.1% (range, -5.7% to 43.5%). There was no significant difference in either OS (median 33.4 vs. 29.1 months, P=0.79) or PFS (median 26.3 vs. 12.3 months, P=0.43) for those with high TVRs (≥10.1%) vs. low TVRs (<10.1%), respectively. There was a trend toward superior 2-year PFS in the high TVR group (52.2% vs. 36.7%, P=0.062), but this effect diminished on longer follow-up (4-year PFS 31.9% vs. 26.7%, P=0.15). No associations were observed between TVR and local, regional or distant recurrence. CONCLUSIONS: We were not able to demonstrate that TVR is a reliable predictive imaging marker for stage I/II NSCLC treated with SBRT. Future studies with larger sample sizes are needed to clarify a potential relationship between TVR and early outcomes.

Development and Implementation of Maternity Dashboard in Regional Hospital for Quality Improvement at Ground Level: A Pilot Study.

OBJECTIVES: We sought to develop and implement a Maternity Dashboard to improve the quality of health care at the ground level. METHODS: We conducted a prospective, descriptive cross-sectional study, involving patients with high-risk pregnancies who had been referred to Nizwa Hospital, Oman. The selection of quality indicators was based on the prototype of clinical outcomes from the Royal College of Obstetricians and Gynecologists. The Maternity Dashboard team adapted local parameters and used preselected general parameters, based on clinical observations, to develop the dashboard. RESULTS: The issues posing a threat to Nizwa Hospital in becoming a world-class healthcare facility were: overbooked outpatient department, insufficient staff, and more junior doctors compared to senior doctors and consultants. Additionally, being pioneers, naturally, the dashboard development team faced difficulties while handling adverse situations. More time, guidance, and standardization of quality indicators are desirable. CONCLUSIONS: Following the approval for a Maternity Dashboard in Nizwa Hospital, the data compiled in an Excel sheet are transmitted manually every month for display on the dashboard in the delivery suite. It is intended to make data collected and dissemination completely automated in the future with the help of the Al-Shifa Healthcare Information System. Expansion of the idea of a Maternity Dashboard to other hospitals and specialties at the regional and tertiary level of the health care system in Oman and a comparison of the standard of health care provided between hospitals based on similar quality indicators would be the next milestone.

Synchronous Oligometastatic Non-small Cell Lung Cancer Managed With Curative-Intent Chemoradiation Therapy: Long-term Outcomes From a Single Institution.

PURPOSE: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. METHODS AND MATERIALS: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. RESULTS: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. CONCLUSIONS: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Dosimetric Predictors of Symptomatic Cardiac Events After Conventional-Dose Chemoradiation Therapy for Inoperable NSCLC.

INTRODUCTION: We hypothesized that higher cardiac doses correlates with clinically significant cardiotoxicity after standard-dose chemoradiation therapy (CRT) (∼60 Gy) for inoperable NSCLC. METHODS: We retrospectively reviewed the records of 140 patients with inoperable NSCLC treated with concurrent CRT from 2007 to 2015. Extracted data included baseline cardiac status, dosimetric parameters to the whole heart (WH) and cardiac substructures, and the development of post-CRT symptomatic cardiac events (acute coronary syndrome [ACS], arrhythmia, pericardial effusion, pericarditis, and congestive heart failure [CHF]). Competing risks analysis was used to estimate time to cardiac events. RESULTS: Median follow-up was 47.4 months. Median radiation therapy dose was 61.2 Gy (interquartile range, 60 to 66 Gy). Forty patients (28.6%) developed 47 symptomatic cardiac events at a median of 15.3 months to first event. On multivariate analysis, higher WH doses and baseline cardiac status were associated with an increased risk of symptomatic cardiac events. The 4-year cumulative incidence of symptomatic cardiac events was 48.6% versus 18.5% for mean WH dose ≥ 20 Gy versus < 20 Gy, respectively (p = 0.0002). Doses to the WH, ventricles, and left anterior descending artery were associated with ACS/CHF, whereas doses to the WH and atria were not associated with supraventricular arrhythmias. Symptomatic cardiac events (p = 0.0001) were independently associated with death. CONCLUSIONS: Incidental cardiac irradiation was associated with subsequent symptomatic cardiac events, particularly ACS/CHF, and symptomatic cardiac events were associated with inferior survival. These results support the minimization of cardiac doses among patients with inoperable NSCLC receiving standard-dose CRT.

Decision-to-Delivery Time Intervals in Emergency Caesarean Section Cases: Repeated cross-sectional study from Oman.

OBJECTIVES: In cases of fetal intolerance to labour, meeting the standard decision-to-delivery time interval (DDI) of ≤30 minutes is challenging. This study aimed to assess DDIs in emergency Caesarean section (CS) cases to identify factors causing DDI delays and the impact of a delayed DDI on perinatal outcomes. METHODS: This repeated cross-sectional study included all emergency CS procedures performed due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse at the Nizwa Hospital, Nizwa, Oman. Three audit cycles of three months each were conducted between April 2011 and June 2013, including an initial retrospective cycle and two prospective cycles following the implementation of improvement strategies to address factors causing DDI delays. Poor perinatal outcomes were defined as Apgar scores of <7 at five minutes, admission to the Special Care Baby Unit (SCBU) or a stillbirth. RESULTS: In the initial cycle, a DDI of ≤30 minutes was achieved in 23.8% of 84 cases in comparison to 44.6% of 83 cases in the second cycle. In the third cycle, 60.8% of 79 women had a DDI of ≤30 minutes (P <0.001). No significant differences in perinatal outcomes for cases with a DDI of ≤30 minutes versus 31-60 minutes were observed; however, a DDI of >60 minutes was significantly associated with poor neonatal outcomes in terms of increased SCBU admissions and low Apgar scores (P <0.001 each). Factors causing DDI delays included obtaining consent for the CS procedure, a lack of operating theatre availability and moving patients to the operating theatre. CONCLUSION: The identification of factors causing DDI delays may provide opportunities to improve perinatal outcomes.

Should electroconvulsive therapy be an early consideration for suicidal patients?

INTRODUCTION: This article describes a quality management project undertaken for the purpose of ensuring that the most appropriate patients were being selected for electroconvulsive therapy (ECT) at an 80-bed, state-operated, civil psychiatric facility for the seriously mentally ill. METHOD: Thirty mentally ill patients, including patients with comorbid substance abuse diagnoses, were treated with ECT. Pre-ECT and post-ECT scores on the 24-item Brief Psychiatric Rating Scale (BPRS-24) were compared with admission and discharge BPRS-24 scores of a control group treated with psychotropic medication. RESULTS: ECT-treated patients demonstrated greater improvement in BPRS scores during a shorter period than did non-ECT-treated patients. Furthermore, the greatest improvement was seen in the areas of depression and expressed suicidal intent. An unanticipated result was that patients with comorbid substance abuse diagnoses treated with ECT showed the most improvement in these areas. CONCLUSION: ECT was shown to be particularly useful in the treatment of suicidally inclined depressed patients, suggesting that ECT should be an early consideration for suicidal patients.

Peer review for residents.

OBJECTIVE: Accreditation Council of Graduate Medical Education (ACGME) currently requires experiences in administration for psychiatry residents. In response to this challenge, the authors created a peer review workshop. METHODS: The authors report on the design, implementation, and outcome of the peer review workshop for PGY-3 and PGY-4 psychiatry residents. RESULTS: Comparison of pre and post results of a 10-question test given to the resident group showed a statistically significant improvement. Moreover, it was noticed that the discussion among the residents rose to a new level of appreciation of administrative techniques and skills. The residents rated the workshop very favorably and unanimously recommended that the workshop be repeated on a yearly basis at the beginning of the academic year with the previous year's PGY-3s serving as mentors at each clinical site. CONCLUSION: The workshop process described has potential practical application for other psychiatry residency programs that are also attempting to respond to these ACGME challenges.