Perioperative management of sarcopenia in patients undergoing major surgeries in Singapore: a modified delphi consensus.

BACKGROUND: Ageing population is a worldwide phenomenon with correspondingly higher proportion of older patients being treated in the hospital setting. Sarcopenia, which increases with age, has serious negative implications on health, hospitalization and overall postoperative recovery. There is no mutual consensus on perioperative management of sarcopenia in surgical patients in Singapore. The purpose of this study is to create greater clarity pertaining to the recognition of sarcopenia, the application of assessment criteria of sarcopenia and perioperative management of surgical patients in Singapore. METHODS: A modified Delphi consensus consisting of a panel of experts from Singapore forming a multidisciplinary team, including surgeons, geriatricians, anesthesiologists, physiotherapists and dieticians. Eight recommendations were proposed by the steering committee. Literature search from MEDLINE, Embase and Scopus for articles up till June 2023 were performed to support recommendation statements. The expert panel voted on agreement to recommendation statements and graded the level of evidence supporting each statement through surveys to achieve consensus, set at 85% a priori. RESULTS: The panelists underwent two rounds of anonymized, independent voting before reaching consensus for all eight statements. After the first round, seven statements reached consensus, including the corresponding grading for level of evidence. The statement which did not achieve consensus was revised with supporting literature and after the second round of survey, all eight statements and level of evidence reached consensus, completing the Delphi process. These eight statements covered themes to (1) encourage the identification of sarcopenia, (2) guide pre-operative and (3) post-operative management of sarcopenia. CONCLUSION: With the varying approaches in perioperative management, poor understanding of and identification of sarcopenia can result in suboptimal management of sarcopenia in surgical patients. Given the abundance of evidence linking beneficial impact on recovery and post-operative complications with prudent management of sarcopenia, it is imperative and urgent to achieve awareness and consensus.

Head-to-head Comparison of the Diagnostic Accuracy of Prostate-specific Membrane Antigen Positron Emission Tomography and Conventional Imaging Modalities for Initial Staging of Intermediate- to High-risk Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Whether prostate-specific membrane antigen positron emission tomography (PSMA-PET) should replace conventional imaging modalities (CIM) for initial staging of intermediate-high risk prostate cancer (PCa) requires definitive evidence on their relative diagnostic abilities. OBJECTIVE: To perform head-to-head comparisons of PSMA-PET and CIM including multiparametric magnetic resonance imaging (mpMRI), computed tomography (CT) and bone scan (BS) for upfront staging of tumour, nodal, and bone metastasis. EVIDENCE ACQUISITION: A search of the PubMed, EMBASE, CENTRAL, and Scopus databases was conducted from inception to December 2021. Only studies in which patients underwent both PSMA-PET and CIM and imaging was referenced against histopathology or composite reference standards were included. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) checklist and its extension for comparative reviews (QUADAS-C). Pairwise comparisons of the sensitivity and specificity of PSMA-PET versus CIM were performed by adding imaging modality as a covariate to bivariate mixed-effects meta-regression models. The likelihood ratio test was applied to determine whether statistically significant differences existed. EVIDENCE SYNTHESIS: A total of 31 studies (2431 patients) were included. PSMA-PET/MRI was more sensitive than mpMRI for detection of extra-prostatic extension (78.7% versus 52.9%) and seminal vesicle invasion (66.7% versus 51.0%). For nodal staging, PSMA-PET was more sensitive and specific than mpMRI (73.7% versus 38.9%, 97.5% versus 82.6%) and CT (73.2% versus 38.5%, 97.8% versus 83.6%). For bone metastasis staging, PSMA-PET was more sensitive and specific than BS with or without single-photon emission computerised tomography (98.0% versus 73.0%, 96.2% versus 79.1%). A time interval between imaging modalities >1 month was identified as a source of heterogeneity across all nodal staging analyses. CONCLUSIONS: Direct comparisons revealed that PSMA-PET significantly outperforms CIM, which suggests that PSMA-PET should be used as a first-line approach for the initial staging of PCa. PATIENT SUMMARY: We reviewed direct comparisons of the ability of a scan method called PSMA-PET (prostate-specific membrane antigen positron emission tomography) and current imaging methods to detect the spread of prostate cancer outside the prostate gland. We found that PSMA-PET is more accurate for detection of the spread of prostate cancer to adjacent tissue, nearby lymph nodes, and bones.

Effectiveness of Immune Checkpoint Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma: A Meta-analysis Including Low PD-L1 Subgroups.

Importance: Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced esophageal squamous cell carcinoma in both first- and second-line settings. However, the benefit of ICIs in patients with low programmed death ligand 1 (PD-L1) expression remains unclear. Objective: To derive survival data for patient subgroups with low PD-L1 expression from clinical trials comparing ICIs with chemotherapy in esophageal squamous cell carcinoma and to perform a pooled analysis. Data Sources: Kaplan-Meier curves from the randomized clinical trials were extracted after a systematic search of Scopus, Embase, PubMed, and Web of Science from inception until October 1, 2021. Study Selection: Randomized clinical trials that investigated the effectiveness of anti-PD-1-based regimens for advanced esophageal squamous cell carcinoma and that reported overall survival (OS), progression-free survival, or duration of response were included in this meta-analysis. Data Extraction and Synthesis: Kaplan-Meier curves of all-comer populations, subgroups with high PD-L1, and those with low PD-L1 (when available) were extracted from published articles. A graphic reconstructive algorithm was used to calculate time-to-event outcomes from these curves. In studies with unreported curves for subgroups with low PD-L1 expression, KMSubtraction was used to impute survival data. KMSubtraction is a workflow to derive unreported subgroup survival data with from subgroups. An individual patient data pooled analysis including previously reported and newly imputed subgroups was conducted for trials with the same treatment line and PD-L1 scoring system. Data analysis was conducted from January 1, 2022, to June 30, 2022. Main Outcomes and Measures: Primary outcomes included Kaplan-Meier curves and hazard ratios (HRs) for OS for subgroups with low PD-L1 expression. Secondary outcomes included progression-free survival and duration of response. Results: The randomized clinical trials CheckMate-648, ESCORT-1st, KEYNOTE-590, ORIENT-15, KEYNOTE-181, ESCORT, RATIONALE-302, ATTRACTION-3, and ORIENT-2 were included, totaling 4752 patients. In the pooled analysis of first-line trials that evaluated a tumor proportion score (CheckMate-648 and ESCORT-1st), no significant benefit in OS was observed with immunochemotherapy compared with chemotherapy in the subgroup of patients who had a tumor proportion score lower than 1% (HR, 0.91; 95% CI, 0.74-1.12; P = .38) compared with chemotherapy. In the pooled analysis of first-line trials that evaluated combined positive score (KEYNOTE-590 and ORIENT-15), there was a significant but modest OS benefit for immunochemotherapy compared with chemotherapy in the subgroup with a combined positive score lower than 10 (HR, 0.77; 95% CI, 0.62-0.94; P = .01). Conclusions and Relevance: Findings suggest a lack of survival benefit of ICI-based regimens in the first-line setting compared with chemotherapy alone in the subgroup with a tumor proportion score lower than 1%.

Association of obstructive sleep apnea with thyroid cancer incidence: a systematic review and meta-analysis.

PURPOSE: Obstructive sleep apnea (OSA) is a postulated carcinogen based on epidemiological associations with all-cancer incidence and non-thyroid biological models. However, associations with thyroid carcinoma are unclear. METHODS: We included observational/randomized studies of associations of OSA with thyroid carcinoma incidence/mortality in adults, from four databases. Random-effects meta-analyses and the population attributable fraction (PAF; from published global OSA prevalence estimates) were computed. RESULTS: We included four observational studies (N = 2,839,325), all with moderate/low risk of bias. OSA diagnosis was associated with twofold incidence of thyroid carcinoma (pooled HR 2.32, 95% CI 1.35-3.98, I2 = 95%), after multi-adjustment for demographics, BMI, smoking, alcohol, and comorbidities. Subgroup analysis of studies with at least 5 years of follow-up showed a stronger association of OSA with thyroid cancer incidence (pooled HR 3.27, 95% CI 2.80-3.82, I2 = 0%). Up to 14.5% (95% CI 4.29-27.6%) of incident thyroid carcinomas globally may be associated with OSA. Thyroid carcinoma mortality data was unavailable. CONCLUSIONS: OSA is associated with higher thyroid carcinoma incidence, though this does not prove causation. Biological/clinical studies should investigate OSA severity in relation to thyroid carcinoma progression and mortality, stratified by tumor histology.

The Association of Obstructive Sleep Apnea With Breast Cancer Incidence and Mortality: A Systematic Review and Meta-analysis.

PURPOSE: Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship. METHODS: We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted meta-analysis and performed pre-specified subgroup analyses. RESULTS: We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03-1.80; N = 6, I² = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98-1.87; N = 5, I² = 96%) and 1.57 (95% CI, 1.14-2.18; N = 4; I² = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA. CONCLUSION: This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression.

Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis.

STUDY OBJECTIVES: Biological models suggest that obstructive sleep apnea (OSA) is potentially carcinogenic. We aimed to clarify the inconsistent epidemiological literature by considering various traditional and novel OSA severity indices. METHODS: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for observational or randomized studies of associations of OSA, measured by diagnostic codes or any index, each with all-cancer incidence or mortality in adults, compared with participants with no/mild OSA. Two reviewers independently selected studies, extracted data, and evaluated study bias using the Newcastle-Ottawa scale and quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). We performed inverse variance-weighted, random-effects meta-analyses and sensitivity analyses. RESULTS: We included 20 observational studies (5,340,965 participants), all with moderate/low bias, from 1,698 records. Based on T90 (sleep duration with oxygen saturation < 90%), patients with OSA who had moderate (T90 > 1.2%, hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.07-1.54) and severe nocturnal hypoxemia (T90 > 12%, HR = 1.43, 95% CI = 1.16-1.76) experienced 30%-40% higher pooled all-cancer risk than normoxemic patients, after multiple adjustment for covariates including obesity. Furthermore, severe nocturnal hypoxemia nearly tripled all-cancer mortality (HR = 2.66, 95% CI = 1.21-5.85). Patients with apnea-hypopnea index-defined severe OSA, but not moderate OSA, had higher all-cancer risk (HR = 1.18, 95% CI = 1.03-1.35) but similar all-cancer mortality as patients without OSA. An OSA diagnosis was not associated with all-cancer risk. Evidence quality ranged from low to moderate. Insufficient evidence was available on the oxygen desaturation index, lowest/median saturation, and arousal index. CONCLUSIONS: In patients with OSA, nocturnal hypoxemia is independently associated with all-cancer risk and mortality. Future studies should explore if risk differs by cancer type, and whether cancer screening and OSA treatment are beneficial. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=220836; Identifier: CRD42021220836. CITATION: Tan BKJ, Teo YH, Tan NKW, et al. Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis. J Clin Sleep Med. 2022;18(5):1427-1440.

Obstructive Sleep Apnea and Lung Cancer: A Systematic Review and Meta-Analysis.

Rationale: In 2020, lung cancer was the leading cause of cancer deaths and the most common cancer in men. Although obstructive sleep apnea (OSA) has been postulated to be carcinogenic, epidemiological studies are inconclusive. Objectives: To investigate the associations between OSA and the incidence and mortality of lung cancer. Methods: Four electronic databases (PubMed, Embase, Cochrane Library, and Scopus) were searched from inception until 6 June 2021 for randomized controlled trials and observational studies examining the association between sleep apnea and incident lung cancer. Two reviewers selected studies, extracted data, graded the risk of bias using the Newcastle-Ottawa scale and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Random-effects models were used to meta-analyze the maximally covariate-adjusted associations. Results: Seven studies were included in our systematic review, among which four were suitable for meta-analysis, comprising a combined cohort of 4,885,518 patients. Risk of bias was low to moderate. OSA was associated with a higher incidence of lung cancer (hazard ratio, 1.25; 95% confidence interval, 1.02-1.53), with substantial heterogeneity (I2 = 97%). Heterogeneity was eliminated, with a stable pooled effect size, when including the three studies with at least 5 years of median follow-up (hazard ratio, 1.32; 95% confidence interval, 1.27-1.37; I2 = 0%). Conclusions: In this meta-analysis of 4,885,518 patients from four observational studies, patients with OSA had an approximately 30% higher risk of lung cancer compared with those without OSA. We suggest more clinical studies with longer follow-up as well as biological models of lung cancer be performed to further elucidate this relationship.

Low Programmed Death-Ligand 1-Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma.

PURPOSE: The US Food and Drug Administration has granted regulatory approval for the use of nivolumab-an immune checkpoint inhibitor (ICI)-in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1-expressing tumors remains unclear. MATERIALS AND METHODS: This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved. RESULTS: CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P < .001). CONCLUSION: Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1-expressing GEAC tumors.

Obstructive sleep apnea and the incidence and mortality of gastrointestinal cancers: a systematic review and meta-analysis of 5,120,837 participants.

Background: Emerging evidence has shown higher overall cancer incidence in patients with obstructive sleep apnea. Gastrointestinal cancers, including esophageal, stomach, liver, pancreas, and colorectal cancers account for 26% of incident cancers. However, the link between gastrointestinal cancers and obstructive sleep apnea is still unclear. We performed a systematic review and meta-analysis (registered PROSPERO CRD42021220836) to investigate the association between obstructive sleep apnea and incidence of gastrointestinal cancer. Methods: We searched four electronic databases (PubMed, Embase, Cochrane Library, Scopus) and included studies published from inception till 15th November 2020 reporting the association of obstructive sleep apnea with gastrointestinal cancer incidence. Extracted data was meta-analyzed in a random-effects model. Results: A total of seven studies were included, forming a combined cohort of 5,120,837 patients. Studies which adjusted for demographics and comorbidities were included in meta-analysis. Among four studies with 7-11 years of median follow-up, patients with obstructive sleep apnea experienced increased incidence of colorectal cancer (HR 1.70, 95% CI: 1.48-1.96, I2=22%). Pancreatic cancer incidence was nominally increased in three studies (HR 1.36, 95% CI: 0.88-2.09, I2=96), though this was not statistically significant. There was no association between obstructive sleep apnea and liver cancer incidence among three studies (HR 0.99, 95% CI: 0.81-1.22, I2=84). However, the lack of a statistically significant relationship between obstructive sleep apnea and pancreatic cancer in our meta-analysis does not necessarily imply the true absence of an association. Conclusions: An increased risk of colorectal cancer was seen in patients with obstructive sleep apnea among studies with long-term follow-up. Further research is required to explore the utility of incorporating obstructive sleep apnea screening into colorectal cancer screening guidelines to identify high-risk individuals and to confirm a possible association of obstructive sleep apnea with pancreatic cancer. PROSPERO Registration: CRD42021220836.

The association of obstructive sleep apnea with melanoma incidence and mortality: a meta-analysis of 5,276,451 patients.

BACKGROUND: Melanoma is the most aggressive and lethal form of skin cancer. While emerging in-vivo evidence suggests that intermittent hypoxia, a hallmark feature of obstructive sleep apnea (OSA), may induce melanoma tumorigenesis, the epidemiological association between OSA and melanoma has been inconsistent. METHODS: We performed a literature search of PubMed, Embase, Scopus and Cochrane Library from inception until 6 June 2021. Two reviewers independently selected randomized trials or observational studies that reported the association of OSA with melanoma incidence or mortality in adults, in comparison to participants with no OSA. Two reviewers independently extracted relevant data and assessed the quality of evidence using the GRADE framework and the Newcastle-Ottawa Scale (NOS). We pooled data using an inverse variance-weighted meta-analysis and ran pre-specified subgrourp analyses. RESULTS: The meta-analysis included six studies out of 1897 records, comprising a combined cohort of 5,276,451 patients. All studies were adjusted for covariates, with majority of studies adjusting for age (N=5) and sex (N = 4). Compared to those without OSA, patients with OSA had 71% higher pooled hazards of melanoma (HR = 1.71; 95% CI: 1.08-2.69, I2 = 99%). Subgroup analyses for studies with (1) median follow-up duration of at least five years, (2) prospective study design, (3) adjustment for obesity yielded HRs of 1.88 (95%CI:1.32-2.67, N = 5), 1.11 (95%CI:0.77-1.60, N = 2) and 1.52 (95%CI:0.75-3.08, N = 3) respectively. One study investigating the relationship between OSA and melanoma mortality detected no association. There were insufficient studies to assess publication bias. CONCLUSIONS: Meta-analysis of mainly retrospective observational studies, with significant heterogeneity, suggests increased melanoma incidence in OSA patients. Future studies should prospectively explore the differential risk of melanoma for varying OSA severity, and whether timely OSA treatment may mitigate this risk.

A Systematic Review and Meta-Analysis of the Effectiveness of Neuroprotectants for Paclitaxel-Induced Peripheral Neuropathy.

BACKGROUND: Paclitaxel-induced peripheral neuropathy (PIPN) is a disabling side effect of paclitaxel with few effective preventive strategies. We aim to determine the efficacy of pharmacological and non-pharmacological neuroprotective interventions in preventing PIPN incidence. METHODS: Biomedical literature databases were searched from years 2000 to 2021 for trials comparing neuroprotective interventions and control. Meta-analysis was performed using the random-effects model. The primary outcome was the incidence of PIPN. RESULTS: Of 24 relevant controlled trials, 14 were eligible for meta-analysis. Pooled results from seven non-pharmacological trials were associated with a statistically significant 48% relative reduction of PIPN risk with low heterogeneity. Conversely, pooled results from six pharmacological trials were associated with a significant 20% relative reduction of PIPN risk with moderate heterogeneity. Both pharmacological and non-pharmacological approaches appear effective in reducing PIPN incidence in the treatment arm compared to control (pooled RR < 1). CONCLUSION: Current evidence suggests that both interventions may reduce PIPN risk. Non-pharmacological interventions appear more effective than pharmacological interventions.

Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment.

Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.