Neoadjuvant immunotherapy improves outcomes for resectable gastroesophageal junction cancer: A systematic review and meta-analysis.

BACKGROUND: In recent years, neoadjuvant immunotherapy (NAIT) has developed rapidly in patients with gastroesophageal junction cancer (GEJC). The suggested neoadjuvant treatment regimens for patients with GEJC may vary in light of the efficacy and safety results. METHODS: A search of the Cochrane Library, PubMed, Embase, and Web of Science was completed to locate studies examining the safety and effectiveness of NAIT for resectable GEJC. We analyzed the effect sizes (ES) and 95% confidence intervals (CI) in addition to subgroups and heterogeneity. Meta-analyses were performed using Stata BE17 software. RESULTS: For these meta-analyses, 753 patients were chosen from 21 studies. The effectiveness of NAIT was assessed using the pathological complete response (pCR), major pathological response (MPR), and nodal downstage to ypN0 rate. The MPR, pCR, and nodal downstage to ypN0 rate values in NAIT were noticeably higher (MPR: ES = 0.45; 95% CI: 0.36-0.54; pCR: ES = 0.26; 95% CI: 0.21-0.32; nodal downstage to ypN0 rate: ES = 0.60; 95% CI: 0.48-0.72) than those of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) (MPR < 30%; pCR: ES = 3%-17%; nodal downstage to ypN0 rate: ES = 21%-29%). Safety was assessed using the treatment-related adverse events (trAEs) incidence rate, surgical delay rate, surgical complications incidence rate, and surgical resection rate. In conclusion, the incidence of trAEs, incidence of surgical complications, and surgical delay rate had ES values of 0.66, 0.48, and 0.09, respectively. These rates were comparable to those from nCT or nCRT (95% CI: 0.60-0.70; 0.15-0.51; and 0, respectively). The reported resection rates of 85%-95% with nCT or nCRT were comparable to the mean surgical resection rate of 90%. CONCLUSION: NAIT is an effective treatment for resectable GEJC; additionally, the level of NAIT toxicity is acceptable. The long-term effects of NAIT require further study.

Correlation of Neutrophil-Lymphocyte and Albumin-Globulin Ratios With Outcomes in Patients With Breast Cancer Undergoing Neoadjuvant Chemotherapy or Upfront Surgery.

PURPOSE: Higher neutrophil-lymphocyte ratio (NLRs) indicate a pro-inflammatory state and are associated with poor survival. Conversely, higher albumin-globulin ratio (AGRs) may be associated with improved prognosis. We aimed to investigate the association between NLR and AGR and prognosis and survival in patients with breast cancer. METHODS: This retrospective study included all patients with stage I-III breast cancer between 2011 and 2017 in Singapore General Hospital and National Cancer Center Singapore. Multivariate logistic regression analysis of NLR, AGR, age, stage, grade, and subtype was performed. Survival data between groups were compared using Cox regression analysis and log-rank tests. RESULTS: A total of 1,188 patients were included, of whom 323 received neoadjuvant chemotherapy (NACT) and 865 underwent upfront surgery. In patients who underwent NACT, a higher AGR was significantly associated with a higher pCR rate (cut-off > 1.28; odds ratio [OR], 2.03; 95% confidence interval [CI], 1.13-3.74; p = 0.020), better DFS (cut off > 1.55; hazard ratio [HR], 0.37; 95% CI, 0.16-0.85; p = 0.019), and better CSS (cut off > 1.46; HR, 0.39; 95% CI, 0.17-0.92; p = 0.031). Higher NLR was significantly associated with worse DFS (cut off > 4.09; HR, 1.77; 95% CI, 1.07-2.91; p = 0.026) and worse CSS (cut off > 4.09; HR, 1.98; 95% CI, 1.11-3.53; p = 0.021). In patients who underwent upfront surgery, higher AGR correlated with significantly better OS (cut off > 1.17; HR, 0.54; 95% CI, 0.36-0.82; p = 0.004) and higher NLR correlated with worse OS (cut off > 2.38; HR, 1.63; 95% CI, 1.09-2.44; p = 0.018). CONCLUSION: NLR and AGR are useful in predicting the response to NACT as well as prognosis of patients with breast cancer. Further studies are needed to explore their value in clinical decision making.

ENABLE-SG (Educate, Nurture, Advise, Before Life Ends for Singapore) as a proactive palliative care model: protocol for a hybrid type 1 effectiveness-implementation randomized wait-list controlled trial.

BACKGROUND: Specialist palliative care is often provided late in the patient's disease trajectory in response to uncontrolled symptoms. Shifting from this reactionary illness-stress paradigm to a proactive health-wellness approach, the ENABLE (Educate, Nurture, Advise, Before Life Ends) telehealth model aims to enhance the coping, stress and symptom management, self-care, and advance care planning skills of patients with advanced cancers and their caregivers. The ENABLE model has been culturally adapted to Singapore (ENABLE-SG) and pilot-tested. A hybrid type 1 effectiveness-implementation design will be used to evaluate the effectiveness of ENABLE-SG while collecting real-world implementation data. METHODS: This single-centre, assessor-blind, wait-list (immediately vs. 6 months) randomized controlled trial will recruit 300 adult patients within 60 days of an advanced cancer diagnosis and their family caregivers from the National Cancer Centre of Singapore. ENABLE-SG comprises structured psychoeducational sessions with a telehealth coach, covering essential topics of early palliative care. Participants will be assessed at baseline and every 3 months until patient's death, 12 months (caregivers), or end of study (patients). The primary outcome is patient quality of life 6 months after baseline. Secondary patient-reported outcomes include mood, coping, palliative care concerns, and health status. Secondary caregiver-reported outcomes include caregiver quality of life, mood, coping, and care satisfaction. Mixed-effects regression modelling for repeated measurements will be used. To assess the effectiveness of ENABLE-SG versus usual care, patient and caregiver outcomes at 6 months will be compared. To compare earlier versus delayed ENABLE-SG, patient and caregiver outcomes at 12 months will be compared. Within the hybrid type 1 effectiveness-implementation design, implementation outcomes will be evaluated in both the early and delayed groups. Acceptability, adoption, appropriateness, and feasibility will be assessed using a feedback survey and semi-structured interviews with a purposive sample of patients, caregivers, and healthcare providers. Transcribed interviews will be analysed thematically. Other implementation outcomes of penetration, fidelity, and cost will be assessed using records of study-related processes and summarized using descriptive statistics. A cost-effectiveness analysis will also be conducted. DISCUSSION: This study will assess both effectiveness and implementation of ENABLE-SG. Insights into implementation processes can facilitate model expansion and upscaling. TRIAL REGISTRATION: Registered prospectively on ClinicalTrials.gov, NCT06044441. Registered on 21/09/2023.

Can an Integrated Palliative and Oncology Co-rounding Model Reduce Aggressive Care at the End of Life? Secondary Analysis of an Open-label Stepped-wedge Cluster-randomized Trial.

BACKGROUND: Clinical trial evidence on the effect of palliative care models in reducing aggressive end-of-life care is inconclusive. We previously reported on an integrated inpatient palliative care and medical oncology co-rounding model that significantly reduced hospital bed-days and postulate additional effect on reducing care aggressiveness. OBJECTIVES: To compare the effect of a co-rounding model vs usual care in reducing receipt of aggressive treatment at end-of-life. METHODS: Secondary analysis of an open-label stepped-wedge cluster-randomized trial comparing two integrated palliative care models within the inpatient oncology setting. The co-rounding model involved pooling specialist palliative care and oncology into one team with daily review of admission issues, while usual care constituted discretionary specialist palliative care referrals by the oncology team. We compared odds of receiving aggressive care at end-of-life: acute healthcare utilization in last 30 days of life, death in hospital, and cancer treatment in last 14 days of life between patients in two trial arms. RESULTS: 2145 patients were included in the analysis, and 1803 patients died by 4th April 2021. Median overall survival was 4.90 (4.07 - 5.72) months in co-rounding and 3.75 (3.22 - 4.21) months in usual care, with no difference in survival (P = .12). We found no significant differences between both models with respect to receipt of aggressive care at end-of-life. (Odds Ratio .67 - 1.27; all P > .05). CONCLUSION: The co-rounding model within an inpatient setting did not reduce aggressiveness of care at end-of-life. This could be due in part to the overall focus on resolving episodic admission issues.

Spider venom-derived peptide JZTX-14 prevents migration and invasion of breast cancer cells via inhibition of sodium channels.

Nav1.5 channel is crucial for the proliferation and migration of breast cancer cells. In this study, we investigated the anticancer effect of JZTX-14, a natural peptide considered an effective antagonist of Nav1.5. First, we successfully isolated and purified the 31 amino acid peptide JZTX-14 containing three pairs of disulfide bonds from spider venom and synthesised JZTX-14 by solid phase synthesis. We then predicted their physiochemical properties and structures in the peptide database. Further, we investigated the effects of natural and synthetic JZTX-14 on the proliferation and migration of MDA-MB-231 breast cancer cells via modulation of sodium current through the Nav1.5 channel. The results showed that both synthetic and natural JZTX-14 inhibited Nav1.5 currents, indicating the successful synthesis of JZTX-14. However, JZTX-14 did not affect MDA-MB-231 cell proliferation but inhibited its migration. Transcriptome analysis revealed that JZTX-14 downregulated S100A4 and FBXO2 and upregulated SERPINB2 in MDA-MB-231 cells. Western blot analysis demonstrated an increased level of the epithelial marker, E-cadherin, and decreased levels of the mesenchymal markers, N-cadherin and vimentin, and matrix metalloproteinase (MMP2), indicating the possible underlying mechanism of the inhibition of MDA-MB-231 cell migration by JZTX-14. This study provides a new target for inhibiting breast cancer metastasis and identifies a potent natural peptide for treating Triple-negative breast cancer.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.

AIM: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. METHODS: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. RESULTS: 455 patients were included (267 EGFR-mutated, EGFR-M+; 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. CONCLUSION: PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

Modern-era radiotherapy and ischaemic heart disease-related mortality outcomes in Asian breast-cancer patients.

Introduction: Left-sided breast-cancer patients treated with adjuvant radiotherapy (RT) before the 1990s were associated with increased risk of cardiac mortality. Modern RT techniques have since improved, resulting in lower radiation doses to the heart. However, concerns regarding cardiac toxicity remain. In a retrospective cohort study, we compare the ischaemic heart disease (IHD)-related mortality of left-sided versus right-sided breast-cancer patients. We present the results of the cardiac mortality and all-cause mortality risk of Asian breast-cancer survivors treated with RT in Singapore. Material and methods: A total of 14,419 Asian women from a single institution were treated for breast cancer from 2000 to 2016. A systematic mortality follow-up was conducted until December 2015. The effect of breast cancer laterality on IHD-related mortality and on overall mortality was investigated. Mean heart doses were recorded for patients from 2010-2016. Results: In the irradiated group (n = 9556), we found no difference in IHD-related mortality or overall mortality when comparing the left- and right-sided breast cancers. The hazard ratio of cardiac mortality for left-sided versus right-sided RT was 0.94 (95% CI: 0.64-1.38). The hazard ratio for all-cause mortality was 1.03 (95% CI: 0.94-1.13). Conclusions: Our study of Asian cancer patients did not reveal a significant increase in the risk of IHD-related mortality or overall mortality comparing left- vs. right-sided breast cancers in modern-era RT.

Efficacy of targeted therapies for oncogene-driven lung cancer in early single-arm versus late phase randomized clinical trials: A comparative analysis.

There is an expanding number of approved targeted therapies for oncogene-driven lung cancer and many emerging therapies with promising efficacy data. Regulatory approvals are increasingly based on early phase trials (often single-arm phase II trials), in which the primary endpoint is objective response rate (ORR) or progression-free survival (PFS). Efficacy outcomes from early phase trials may not always correlate with those observed in later-phase randomized trials. In the precision oncology era with effective targeted therapies however, there are arguments for greater confidence in the efficacy outcomes from non-randomized single-arm trials. Nevertheless, there remain numerous challenges in understanding and interpreting efficacy outcomes for novel targeted therapies in trials that may have dose finding and safety as the primary objective and lack a standard-of-care control arm. Therefore, we sought to review the efficacy outcomes in early versus late phase clinical trials for approved targeted therapies in lung cancer - to better understand the interpretation of preliminary measures of clinical benefit. Nine pairs of early and late phase trials were identified, according to line of therapy for six targeted therapies in lung cancer (afatinib, ceritinib, crizotinib, dacomitinib, lorlatinib and osimertinib). Key efficacy outcomes, including ORR, PFS and overall survival (OS) were compared. Importantly, we found that in oncogene-driven lung cancer, early phase trial outcomes have historically been consistent with subsequent late phase trials. This suggests efficacy outcomes from early phase trials of targeted therapies in lung cancer may translate reliably to larger randomized trials. This has many potential implications for drug development in lung cancer, with regards to regulatory approvals and the design and conduct of clinical trials.

KDM6A Depletion in Breast Epithelial Cells Leads to Reduced Sensitivity to Anticancer Agents and Increased TGFß Activity.

KDM6A, an X chromosome-linked histone lysine demethylase, was reported to be frequently mutated in many tumor types including breast and bladder cancer. However, the functional role of KDM6A is not fully understood. Using MCF10A as a model of non-tumorigenic epithelial breast cells, we found that silencing KDM6A promoted cell migration and transformation demonstrated by the formation of tumor-like acini in three-dimensional culture. KDM6A loss reduced the sensitivity of MCF10A cells to therapeutic agents commonly used to treat patients with triple-negative breast cancer and also induced TGFß extracellular secretion leading to suppressed expression of cytotoxic genes in normal human CD8+ T cells in vitro. Interestingly, when cells were treated with TGFß, de novo synthesis of KDM6A protein was suppressed while TGFB1 transcription was enhanced, indicating a TGFß/KDM6A-negative regulatory axis. Furthermore, both KDM6A deficiency and TGFß treatment promoted disorganized acinar structures in three-dimensional culture, as well as transcriptional profiles associated with epithelial-to-mesenchymal transition and metastasis, suggesting KDM6A depletion and TGFß drive tumor progression. IMPLICATIONS: Our study provides the preclinical rationale for evaluating KDM6A and TGFß in breast tumor samples as predictors for response to chemo and immunotherapy, informing personalized therapy based on these findings.

Clinical Characteristics and Outcomes in Advanced KRAS-Mutated NSCLC: A Multicenter Collaboration in Asia (ATORG-005).

INTRODUCTION: Whereas interpatient heterogeneity in clinical characteristics and treatment outcomes of NSCLC harboring a KRAS mutation is recognized, the characterization of these patients in Asia has been limited. METHODS: A multicenter, retrospective cohort study was conducted in eight academic centers across Asia. Patients diagnosed with advanced NSCLC harboring a KRAS mutation and who had received at least one line of anticancer therapy between January 2014 and December 2018 were included. Modified time to next treatment (TTNT) was adopted as a proxy for progression-free survival. RESULTS: A total of 216 patients were analyzed. The median age at diagnosis of advanced NSCLC was 63.3 years, 70.8% were men and 89.8% had adenocarcinoma. KRAS G12D was the most common subtype (25.5%), followed by G12C (24.5%), and G12V (19.4%) The proportion of current or former smokers was 65.7% in the overall population, with 86.8% in G12C and 58.9% in non-G12C subgroups. For all treatments combined for the total population, the first-line duration of therapy, modified TTNT, and TTNT were 4.5 (95% confidence interval: 3.4-5.9), 6.2 (4.9-8.8), and 9.5 (7.1-11.4) months, respectively. The median overall survival for the total population was 10.3 (6.9-12.4) months and was prolonged in patients ever treated with immunotherapy (14.6 [8.6-19.1] versus 7.0 [5.9-10.6] mo, hazard ratio = 0.54, p < 0.001), with left truncation to account for the time of KRAS testing. CONCLUSIONS: Whereas treatment outcomes with conventional anticancer therapy are reasonable and immunotherapy looks promising, the unmet need remains high for patients with KRAS-mutated NSCLC in Asia, underscoring the need for novel therapeutic approaches.

ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells.

Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. In order to further investigate the role of this splice factor in RNA splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not in human cells contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to accurately model ZRSR2-mutant MDS in mice.

Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined. Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. Design, Setting, and Participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. Exposures: Adjuvant treatment was administered per investigator's discretion. Main Outcomes and Measures: The main outcome was 2-year disease-free survival (DFS). Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. Conclusions and Relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

Comparing the effect of a consult model versus an integrated palliative care and medical oncology co-rounding model on health care utilization in an acute hospital - an open-label stepped-wedge cluster-randomized trial.

BACKGROUND: The benefit of specialist palliative care for cancer inpatients is established, but the best method to deliver specialist palliative care is unknown. AIM: To compare a consult model versus a co-rounding model; both provide the same content of specialist palliative care to individual patients but differ in the level of integration between palliative care and oncology clinicians. DESIGN: An open-label, cluster-randomized trial with stepped-wedge design. The primary outcome was hospital length of stay; secondary outcomes were 30-day readmissions and access to specialist palliative care. ClinicalTrials.gov number NCT03330509. SETTING/PARTICIPANTS: Cancer patients admitted to the oncology inpatient service of an acute hospital in Singapore. RESULTS: A total of 5681 admissions from December 2017 to July 2019 were included, of which 5295 involved stage 3-4 cancer and 1221 received specialist palliative care review. Admissions in the co-rounding model had a shorter hospital length of stay than those in the consult model by 0.70 days (95%CI -0.04 to 1.45, p = 0.065) for all admissions. In the sub-group of stage 3-4 cancer patients, the length of stay was 0.85 days shorter (95%CI 0.05-1.65, p = 0.038). In the sub-group of admissions that received specialist palliative care review, the length of stay was 2.62 days shorter (95%CI 0.63-4.61, p = 0.010). Hospital readmission within 30 days (OR1.03, 95%CI 0.79-1.35, p = 0.822) and access to specialist palliative care (OR1.19, 95%CI 0.90-1.58, p = 0.215) were similar between the consult and co-rounding models. CONCLUSIONS: The co-rounding model was associated with a shorter hospital length of stay. Readmissions within 30 days and access to specialist palliative care were similar.

A comparative analysis between low-dose-rate brachytherapy and external beam radiation therapy for low- and intermediate-risk prostate cancer in Asian men.

OBJECTIVE: To report the long-term clinical outcomes of low-risk (LR) and intermediate-risk (IR) prostate cancer patients treated with low-dose-rate brachytherapy (LDR-BT) and external beam radiation therapy (EBRT). PATIENTS AND METHODS: Men with biopsy-proven low- and intermediate-risk prostate cancer received EBRT and LDR-BT in an Asian academic center from 2000 to 2019 were reviewed. Kaplan-Meier survival analysis was performed to compare biochemical failure-free survival (bFFS) and overall survival (OS) between LDR and EBRT in the low- and intermediate-risk cohorts. RESULTS: 642 patients (521 EBRT and 121 LDR-BT) with low- and intermediate-risk prostate cancer were included for analysis. In the intermediate-risk group, 5- and 10-year bFFS was 96%, 89% and 86%, 61% for LDR-BT and EBRT, respectively. LDR-BT was associated with a statistically significant improvement of bFFS in the intermediate-risk cohort (HR 2.7, p = 0.02). In the low-risk cohort, no difference of bFFS was found between LDR-BT and EBRT (HR 1.9, p = 0.08). Hormone therapy was more common in EBRT than LDR-BT for intermediate-risk group (71% versus 44%, p < 0.05). Prostate cancer-specific mortality was low in both EBRT (1%) and LDR-BT (2%) cohorts. No significant difference in OS was found between LDR-BT and EBRT in low- and intermediate-risk group (HR 2.1, p = 0.2 and HR = 1.7, p = 0.3). CONCLUSION: In our retrospective study, LDR-BT is associated with superior bFFS compared with EBRT in Asian men with intermediate-risk prostate cancer.

Effects of housing value and medical subsidy on treatment and outcomes of breast cancer patients in Singapore: A retrospective cohort study.

BACKGROUND: Socioeconomic status (SES) is likely to affect survival in breast cancer patients. Housing value is a reasonable surrogate for SES in Singapore where most residents own their own homes, which could be public (subsidised) or private housing. We evaluated effects of housing value and enhanced medical subsidies on patients' presentation, treatment choices, compliance and survival in a setting of good access to healthcare. METHODS: A retrospective analysis of breast cancer patients treated in a tertiary hospital cluster from 2000 to 2016 was performed. Individual-level Housing value Index (HI) was derived from each patient's address and then grouped into 3 tiers: HI(high)(minimal subsidy), HI(med)(medium subsidy) and HI(low)(high subsidy). Cox regression was performed to evaluate the associations between overall survival (OS) and cancer-specific survival (CSS) with HI and various factors. FINDINGS: We studied a multiracial cohort of 15,532 Stage 0-IV breast cancer patients. Median age was 53.7 years and median follow-up was 7.7 years. Patients with lower HI presented with more advanced disease and had lower treatment compliance. On multivariable analysis, compared to HI(high) patients, HI(med) patients had decreased OS (HR=1.14, 95% CI 1.05-1.23) and CSS (HR=1.15, 95% CI 1.03-1.27), and HI(low) patients demonstrated reduced OS (HR=1.16, 95% CI 1.01-1.33). Ten-year non-cancer mortality was higher in lower HI-strata. Enhanced medical subsidy approximately halved treatment noncompliance rates but its receipt was not an independent prognostic factor for survival. INTERPRETATION: Despite good healthcare access, lower-HI patients have poorer survival from both cancer and non-cancer causes, possibly due to delayed health-seeking and poorer treatment compliance. Enhanced subsidies may mitigate socioeconomic disadvantages. FUNDING: None.

Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis.

BACKGROUND: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs. METHODS: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019. The platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR), and the lymphocyte-monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan-Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters. RESULTS: The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4-7), high postoperative NLR (days 8-21), and high postoperative PLR (days 22-56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57-90) and low postoperative LMR (days 8-21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC. CONCLUSIONS: The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.

Understanding the Psychological Impact of COVID-19 Pandemic on Patients With Cancer, Their Caregivers, and Health Care Workers in Singapore.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact, and Singapore has seen 33,000 confirmed cases. Patients with cancer, their caregivers, and health care workers (HCWs) need to balance the challenges associated with COVID-19 while ensuring that cancer care is not compromised. This study aimed to evaluate the psychological effect of COVID-19 on these groups and the prevalence of burnout among HCWs. METHODS: A cross-sectional survey of patients, caregivers, and HCWs at the National Cancer Centre Singapore was performed over 17 days during the lockdown. The Generalized Anxiety Disorder-7 and Maslach Burnout Inventory were used to assess for anxiety and burnout, respectively. Self-reported fears related to COVID-19 were collected. RESULTS: A total of 624 patients, 408 caregivers, and 421 HCWs participated in the study, with a response rate of 84%, 88%, and 92% respectively. Sixty-six percent of patients, 72.8% of caregivers, and 41.6% of HCWs reported a high level of fear from COVID-19. The top concern of patients was the wide community spread of COVID-19. Caregivers were primarily worried about patients dying alone. HCWs were most worried about the relatively mild symptoms of COVID-19. The prevalence of anxiety was 19.1%, 22.5%, and 14.0% for patients, caregivers, and HCWs, respectively. Patients who were nongraduates and married, and caregivers who were married were more anxious. The prevalence of burnout in HCWs was 43.5%, with more anxious and fearful HCWs reporting higher burnout rates. CONCLUSION: Fears and anxiety related to COVID-19 are high. Burnout among HCWs is similar to rates reported prepandemic. An individualized approach to target the specific fears of each group will be crucial to maintain the well-being of these vulnerable groups and prevent burnout of HCWs.

Exploring MRI based radiomics analysis of intratumoral spatial heterogeneity in locally advanced nasopharyngeal carcinoma treated with intensity modulated radiotherapy.

BACKGROUND: We hypothesized that spatial heterogeneity exists between recurrent and non-recurrent regions within a tumor. The aim of this study was to determine if there is a difference between radiomics features derived from recurrent versus non recurrent regions within the tumor based on pre-treatment MRI. METHODS: A total of 14 T4NxM0 NPC patients with histologically proven "in field" recurrence in the post nasal space following curative intent IMRT were included in this study. Pretreatment MRI were co-registered with MRI at the time of recurrence for the delineation of gross tumor volume at diagnosis(GTV) and at recurrence(GTVr). A total of 7 histogram features and 40 texture features were computed from the recurrent(GTVr) and non-recurrent region(GTV-GTVr). Paired t-tests and Wilcoxon signed-rank tests were carried out on the 47 quantified radiomics features. RESULTS: A total of 7 features were significantly different between recurrent and non-recurrent regions. Other than the variance from intensity-based histogram, the remaining six significant features were either from the gray-level size zone matrix (GLSZM) or the neighbourhood gray-tone difference matrix (NGTDM). CONCLUSIONS: The radiomic features extracted from pre-treatment MRI can potentially reflect the difference between recurrent and non-recurrent regions within a tumor and has a potential role in pre-treatment identification of intra-tumoral radio-resistance for selective dose escalation.