Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients.

Immune-related adverse events (IrAEs) of immune checkpoint inhibitors (ICIs) can be serious and unpredictable. We examine the incidence rate and risk factors for IrAEs in an Asian cohort of nonsmall cell lung cancer (NSCLC) patients treated with immunotherapy. Between June 2014 and August 2020, we retrospectively analysed IrAEs in NSCLC patients treated with anti-PD-1 or anti-PD-L1 inhibitors at the National University Cancer Institute, Singapore. A Poisson regression model was used to estimate the effect of risk factors on incidence rate of any grade IrAEs. One hundred and forty-one patients were enrolled. Median age was 63. Majority were male (67%) with Eastern Cooperative Oncology Group (ECOG) PS 0-1 (77%). More than half (56%) received pembrolizumab. Eleven percent harboured epidermal growth factor receptor (EGFR) mutation. Eighteen percent received concomitant chemotherapy. Median number of cycles was 4, and median duration of treatment was 2.1 months. IrAEs were seen in 71 (50.4%) patients, with an incidence rate of 99 events per 1000 person-months. Fatigue (25%), rash (10.5%) and pneumonitis (7.9%) were the most common IrAEs. Twenty out of 152 IrAEs (13.2%) were Grade 3 or higher in severity: most common being pneumonitis (5.3%), fatigue (3.3%) and transaminitis (1.3%). Multivariable analysis demonstrated that concomitant chemotherapy use, higher BMI and presence of EGFR mutation are significant predictors for IrAEs (P < .0001; P = .016; P = .007). Our findings can help guide risk stratification and monitoring of IrAEs among NSCLC patients on immunotherapy.

Impact of structured curriculum with simulation on bronchoscopy.

BACKGROUND AND OBJECTIVE: Simulation enhances a physician's competency in procedural skills by accelerating ascent of the learning curve. Training programmes are moving away from the Halstedian model of 'see one, do one, teach one', also referred as medical apprenticeship. We aimed to determine if a 3-month structured bronchoscopy curriculum that incorporated simulator training could improve bronchoscopy competency among pulmonary medicine trainees. METHODS: We prospectively recruited trainees from hospitals with accredited pulmonary medicine programmes. Trainees from hospitals (A, B and C) were assigned to control group (CG) where they received training by traditional apprenticeship while trainees from hospital D were assigned to intervention group (IG) where they underwent 3-month structured curriculum that incorporated training with the bronchoscopy simulator. Two patient bronchoscopy procedures per trainee were recorded on video and scored independently by two expert bronchoscopists using the modified Bronchoscopy Skills and Tasks Assessment Tool (BSTAT) forms. A 25 multiple choice questions (MCQ) test was administered to all participants at the end of 3 months. RESULTS: Eighteen trainees participated; 10 in CG and eight in IG with equal female:male ratio. Competency assessed by modified BSTAT and MCQ tests was variable and not driven by volume as IG performed fewer patient bronchoscopies but demonstrated better BSTAT, airway anaesthesia and MCQ scores. Bronchoscopy simulator training was the only factor that correlated with better BSTAT (r = 0.80), MCQ (r = 0.85) and airway anaesthesia scores (r = 0.83), and accelerated the learning curve of IG trainees. CONCLUSION: An intensive 3-month structured bronchoscopy curriculum that incorporated simulator training led to improved cognitive and technical skill performance as compared with apprenticeship training.

Four Patients with COVID-19 and Tuberculosis, Singapore, April-May 2020.

Coronavirus disease (COVID-19) and tuberculosis (TB) developed in 4 foreign workers living in dormitories in Singapore during April-May 2020. Clinical manifestations and atypical radiographic features of COVID-19 led to the diagnosis of TB through positive interferon-gamma release assay and culture results. During the COVID-19 pandemic, TB should not be overlooked.

Singapore tuberculosis (TB) clinical management guidelines 2024: A modified Delphi adaptation of international guidelines for drug-susceptible TB infection and pulmonary disease.

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). METHOD: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. RESULTS: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. CONCLUSIONS: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Diagnostic Yield and Safety of CP-EBUS-TBNA and RP-EBUS-TBLB under Moderate Sedation: A Single-Center Retrospective Audit.

Convex probe endobronchial ultrasound transbronchial needle aspirations (CP-EBUS-TBNAs) and radial probe endobronchial ultrasound transbronchial lung biopsies (RP-EBUS-TBLBs) can be performed under moderate sedation or general anesthesia. Moderate sedation is more convenient, however patient discomfort may result in inadequate tissue sampling. General anesthesia ensures better patient cooperation but requires more logistics and also carries sedation risks. We aim to describe the diagnostic yield and safety of CP-EBUS-TBNAs and RP-EBUS-TBLBs when performed under moderate sedation at our center. All patients who underwent CP-EBUS-TBNA and/or RP-EBUS-TBLB under moderate sedation, between January 2015 and May 2017, were reviewed. Primary outcomes were defined in regard to the diagnostic yield and safety profile. A total of 336 CP-EBUS-TBNAs and 190 RP-EBUS-TBLBs were performed between January 2015 and May 2017. The mean sedation doses used were 50 mcg of intravenous fentanyl and 2.5 mg of intravenous midazolam. The diagnostic yield of the CP-EBUS-TBNAs and RP-EBUS-TBLBs were 62.5% and 71.6%, respectively. Complication rates were low with: transient bleeding 11.9%, transient hypoxia 0.5%, and pneumothorax 0.1%. None required escalation of care, post procedure. Performing CP-EBUS-TBNAs and RP-EBUS-TBLBs under moderate sedation is safe and provides good diagnostic yield. These procedures should, therefore, be considered as first-line sampling techniques.

A systematic review and meta-analysis of the adequacy of endobronchial ultrasound transbronchial needle aspiration for next-generation sequencing in patients with non-small cell lung cancer.

OBJECTIVES: Next-generation sequencing (NGS) is able to identify targetable mutations to guide therapy and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) offers a potential route to routinely obtain specimens for analysis. However, the suitability of EBUS-TBNA samples for NGS remains uncertain. MATERIALS & METHODS: A search was conducted from inception till 28th August 2020. Pooled proportion of adequate EBUS-TBNA samples for NGS was obtained based on binomial distribution with Freeman-Tukey double-arcsine transformation. meta-analysis of means was conducted to determine mean weight of DNA extracted from EBUS-TBNA samples. meta-regression was performed to explore sources of heterogeneity. The random-effects model was used for all analyses to account for variation between studies. RESULTS: Twenty-one studies comprising 1,175 patients were included. The pooled proportion of adequate EBUS-TBNA samples for NGS (yield) was 86.5% (95%-CI: 80.9% to 91.4%). Pooled mean weight of DNA extracted from EBUS-TBNA samples was 868.7 ng (95%-CI: 446.3 ng to 1291.1 ng). However, considerable heterogeneity (I2 = 84.0%, 97.1%) was found. Meta-regression with a mixed-effects negative exponential model showed an increased proportion of adequate EBUS-TBNA samples for NGS as mean number of passes increases (ß = 0.495, 95%-CI 0.313 to 0.676, P < 0.001). Modelled yield rates were 77.3%, 86.2%, 91.6% and 94.9% at mean passes of 3, 4, 5 & 6 respectively. CONCLUSION: EBUS-TBNA was associated with a high yield for NGS and the success of EBUS-TBNA sampling for NGS was proportional to the number of passes.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Transitioning to Combined EBUS EUS-B FNA for Experienced EBUS Bronchoscopist.

Endobronchial ultrasound (EBUS) combined with trans-esophageal endoscopic ultrasound bronchoscope guided fine need aspirate (EUS-B FNA) of mediastinal lymph nodes is an established procedure for diagnosis. The main barrier to a combined EBUS EUS-B FNA approach is availability of trained and accredited pulmonologist who can perform procedure safely and confidently. To address this gap, we undertook a training program for experienced EBUS bronchoscopists to train, learn, and incorporate combined EBUS EUS-B FNA into their procedural practice. Thirty-two patients were selected based on CT and or PET findings. Four experienced bronchoscopists participated by reading through learning material, observing 5 cases before performing EUS-B FNA under direct supervision. Forty-one lymph nodes and 6 non-nodal lesions were sampled. EUSAT assessment was performed by supervisor. Learning curves were derived from assessment scores. We observed that learning curve tends to plateau when participant can perform 3 or more consecutive cases with EUSAT score above 50. There were no complications. Our experience suggests that there is relative ease in transition to combined EBUS EUS-B TBNA procedures for mediastinal lymphadenopathy and lung cancer diagnosis and staging for experienced bronchoscopist using a program which incorporates direct supervision, EUSAT assessment, and extension of EUS B FNA training into daily real-world practice.

Controversies in Sepsis Management-What is the Way Forward?

Sepsis is life-threatening and might potentially progress from dysregulation to severe organ dysfunction. It is recognised by the World Health Organisation as a global health priority. The mortality rate for sepsis has decreased in many countries, and this is credited to the earlier recognition and treatment of this complex syndrome. In 2002, the Surviving Sepsis Campaign was launched, and there have been several revisions to the sepsis recommendations therefrom. The latest sepsis guidelines focus on viral as well as bacterial infections, and advise that initiating resuscitation and management should take place within one hour from when sepsis is initially suspected. Numerous studies and guidelines pertaining to sepsis management have been published over the past 2 decades. The use of novel therapies and alternative adjunctive therapies has tremendous potential in sepsis management. Debates amongst intensivists exist with the creation of updated sepsis guidelines and advances in treatment. The present review article provides both a summary and recommendations based on the latest clinical evidence and controversies around sepsis management.

Perceptions of a night float system for intern doctors in an internal medicine program: an Asian perspective.

Long duty hours have been associated with significant medical errors, adverse events, and physician "burn-out". An innovative night float (NF) system has been implemented in our internal medicine program to reduce the negative effects of long duty hours associated with conventional full-call systems. However, concerns remain if this would result in inadequate training for interns. We developed a structured questionnaire to assess junior doctors' perceptions of the NF system compared to full calls, in areas of patient safety, medical training, and well-being. Ninety-seven (71%) of the 137 doctors polled responded. Ninety-one (94%) felt the NF system was superior to the full call system. A strong majority felt NF was beneficial for patient safety compared to full call (94% vs. 2%, p<0.001). The NF system was also perceived to reduce medical errors (94% vs. 2%, p<0.001) and reduce physician "burn-out" (95% vs. 5%, p<0.001). Beyond being a practical solution to duty-hour limitations, there was a significant perceived benefit of the NF system compared to the full call in terms of overall satisfaction, patient safety, reducing medical errors and physician "burn-out".

Vanished: Is This for Real?

Spontaneous regression (SR) of lung cancer is especially rare. We report a case of an early endobronchial squamous cell carcinoma that exhibited complete radiologic and pathologic SR soon after diagnosis. The patient was monitored radiologically and bronchoscopically at regular intervals and to date, the biopsy samples have been negative. Remarkably, SR has been maintained 6 years after diagnosis, without local recurrence or distant metastases. Many hypotheses abound to explain how complete SR was achieved and maintained despite the lack of treatment.

End-of-life care in the general wards of a Singaporean hospital: an Asian perspective.

BACKGROUND: Despite international differences in cultural perspectives on end-of-life issues, little is known of the care for the dying in the general wards of acute hospitals in Asia. METHODS: We performed a retrospective medical chart review of all 683 adult patients who died without intensive care unit (ICU) admission in our Singaporean hospital in 2007. We first evaluated the prevalence of do-not-resuscitate (DNR) orders and orders for or against life-sustaining therapies; second, if such orders were discussed with the patients and/or family members; and third, the actual treatments provided before death. RESULTS: There were DNR orders for 66.2% of patients and neither commitment for DNR nor cardiopulmonary resuscitation (CPR) for 28.1%. Orders to limit life-sustaining therapies, including ICU admission, intubation, and vasopressors/inotropes were infrequent. Only 6.2% of the alert and conversant patients with DNR orders were involved in discussions on these orders. In contrast, such discussions with their family members occurred 82.9% of the time. Interventions in the last 24 hours of life included CPR (9.4%), intubation (6.4%), vasopressors/inotropes (14.8%), tube feeding (24.7%), and antibiotics (44.9%). Analgesia was provided in 29.1% of patients. CONCLUSIONS: There was a lack of commitment by doctors on orders for DNR/CPR and to limit life-sustaining therapies, infrequent discussions with patients on end-of-life decisions, and excessive burdensome interventions with inadequate palliative care for the dying. These findings may reflect certain Asian cultural biases. More work is required to improve our quality of end-of-life care.

Implementation and experience of the first chief residency program in singapore.

BACKGROUND: Like their counterparts in many other nations, physicians in Singapore are tasked with providing care, conducting research, and teaching and providing leadership to junior doctors. In this paper, we describe our experience implementing the first chief residency program in Singapore. INITIATIVE: A pilot of a chief residency program was initiated in the Department of Medicine at National University Hospital in July 2008, with 1 chief resident (CR) and 2 associate CR positions. The pilot used the US model for CR training as the initial framework. CRs would assist in the orientation and integration of new residents, teach residents, promote camaraderie among residents, help resolve issues, function as a liaison to senior staff, and would be developed as potential health care leaders and physician role models. RESULTS: The CRs performed a host of administrative duties and initiated several improvements in the residency, including better practices for leave scheduling, call roster planning, and a night float system. CRs attended monthly meetings with division heads and participated in departmental strategic planning as well as professional development and leadership courses. The CR position was well regarded by the other residents, and this resulted in increased interest in identifying and addressing opportunities for improvement. The introduction of a chief residency also made the department a more attractive posting for residents and contributed to a significant increase in the number of applicants for residency rotations. CONCLUSIONS: A chief residency program can benefit residents' morale and a CR's development as a leader, and it can facilitate linkage between junior and senior hospital management that promotes active involvement in problem solving and clinical and education improvement. Support from hospital administrators and senior clinicians is essential, and mentoring and succession planning are important to ensure the program's continued success.