Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. METHODS: Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. RESULTS: Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Effectiveness of a self-determination theory-based smoking cessation intervention plus instant messaging via mobile application for smokers with cancer: Protocol for a pragmatic randomized controlled trial.

BACKGROUND AND AIMS: Despite evidence that patients living with cancer who continue to smoke after diagnosis are at higher risk for all-cause mortality and reduced treatment efficacy, many cancer patients continue to smoke. This protocol is for a study to test the effectiveness of a self-determination theory-based intervention (quit immediately or progressively) plus instant messaging (WhatsApp or WeChat) to help smokers with cancer to quit smoking. DESIGN: This will be a multi-centre, two-arm (1:1), single-blind, pragmatic, individually randomized controlled trial. SETTING: Taking part will be specialist outpatient clinics in five major hospitals in different location-based clusters in Hong Kong. PARTICIPANTS: The sample will include 1448 Chinese smokers living with cancer attending medical follow-ups at outpatient clinics. INTERVENTIONS: The intervention group will receive brief advice (approximately 5-8 minutes) from research nurses in the outpatient clinics and then be invited to choose their own quit schedules (immediate or progressive). During the first 6-month follow-up period they will receive instant messaging with smoking cessation advice once per week for the first 3 months, and thereafter approximately once per month. They will also receive four videos, and those opting to quit progressively will receive a smoking reduction leaflet. The control group will also receive brief advice but be advised to quit immediately, and instant messaging with general health advice during the first 6-month follow-up period using the same schedule as the intervention group. Participants in both groups will receive smoking cessation leaflets. MEASUREMENTS: The primary outcome is biochemically validated smoking abstinence at 6 months, as confirmed by saliva cotinine level and carbon monoxide level in expired air. Secondary outcomes include biochemically validated smoking abstinence at 12 months, self-reported 7-day point prevalence of smoking abstinence at 6 and 12 months, self-reported ≥ 50% reduction of cigarette consumption at 6 and 12 months and quality of life at 6 and 12 months. All time-points for outcomes measures are set after randomization. COMMENTS: The results could inform research, policymaking and health-care professionals regarding smoking cessation for patients living with cancer, and therefore have important implications for clinical practice and health enhancement.

NTRK gene fusion testing and management in lung cancer.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients.

Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology.

Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide. However, its incidence, mortality, and characteristics are not uniform across all regions worldwide. Understanding the factors contributing to this diversity is crucial in a prevalent disease where most cases are diagnosed in advanced stages. Hence, prevention and early diagnosis emerge as the most efficient strategies to enhance outcomes. In Western societies, tobacco consumption constitutes the primary risk factor for lung cancer, accounting for up to 90% of cases. In other geographic locations, different significant factors play a fundamental role in disease development, such as individual genetic predisposition, or exposure to other carcinogens such as radon gas, environmental pollution, occupational exposures, or specific infectious diseases. Comprehensive clinical and molecular characterization of lung cancer in recent decades has enabled us to distinguish different subtypes of lung cancer with distinct phenotypes, genotypes, immunogenicity, treatment responses, and survival rates. The ultimate goal is to prevent and individualize lung cancer management in each community and improve patient outcomes.

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer.

OBJECTIVES: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for âˆ¼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. MATERIALS AND METHODS: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. RESULTS: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. CONCLUSION: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

Can ChatGPT Provide Quality Information on Integrative Oncology? A Brief Report.

This short report evaluated the accuracy and quality of information provided by ChatGPT regarding the use of complementary and integrative medicine for cancer. Using the QUality Evaluation Scoring Tool, a panel of 12 reviewers assessed ChatGPT's responses to 8 questions. The study found that ChatGPT provided moderate-quality responses that were relatively unbiased and not misleading. However, the chatbot's inability to reference specific scientific studies was a significant limitation. Patients with cancer should not rely on ChatGPT for clinical advice until further systematic validation. Future studies should examine how patients perceive ChatGPT's information and its impact on communication with health care professionals.

Association between potential supplement-drug interactions and liver diseases in patients with cancer: A large prospective cohort study.

BACKGROUND & AIMS: The concurrent use of herbal and dietary supplements and conventional drugs can lead to interactions in patients with cancer, of which hepatotoxicity is one of the most concerning sequelae. This study examined the potential supplement-drug interactions involving the hepatic system, and their associations with documented liver diseases, among patients with cancer in a large population-based cohort in the UK Biobank. METHODS: Participants diagnosed with cancer and had completed supplement-use assessment after diagnosis were included. Potentially interacting supplement-drug combinations that involved CYP enzymes or increased the risk of hepatotoxicity were identified from four tertiary databases. Liver diseases were identified using ICD-codes K70-77. Log-binomial regression was used to investigate the associations between potentially-interacting supplement-drug combinations and liver diseases documented (1) at any time, and (2) confined to only after the time of supplement-use assessment, adjusting for age, sex and pre-existing comorbidities. RESULTS: This analysis included 30,239 participants (mean age = 60.0 years; 61.9% female). Over half (n = 17,698, 58.5%) reported the use of supplements after cancer diagnoses. Among supplements users, 36.9% (n = 6537/17,698) were on supplement-drug combinations with interacting potential involving the hepatic system. Patients taking supplements and drugs who had hepatic comorbidities were more likely to take potentially interacting pairs (adjusted risk ratio = 1.14, 95% CI = 1.06-1.23, p < 0.001). However, no significant association was observed between the use of these combinations and subsequent liver diseases (all p > 0.05). CONCLUSION: Approximately one-third of the participants who had cancer and were supplement users had a risk of potential supplement-drug interactions that contribute to adverse liver effect. Healthcare professionals should communicate with patients with cancer, especially those with pre-existing liver diseases, about supplement use and proactively assess the clinical significance of potential interactions.

First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.

BACKGROUND: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study. METHODS: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment. RESULTS: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported. CONCLUSIONS: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study).

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44-3.12) years. The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

The impact of the multi-disciplinary molecular tumour board and integrative next generation sequencing on clinical outcomes in advanced solid tumours.

Background: The integration of next-generation sequencing (NGS) comprehensive gene profiling (CGP) into clinical practice is playing an increasingly important role in oncology. Therefore, the HKU-HKSH Multi-disciplinary Molecular Tumour Board (MTB) was established to advance precision oncology in Hong Kong. A multicenter retrospective study investigated the feasibility of the HKU-HKSH MTB in determining genome-guided therapy for treatment-refractory solid cancers in Hong Kong. Methods: Patients who were presented at the HKU-HKSH MTB between August 2018 and June 2022 were included in this study. The primary study endpoints were the proportion of patients who receive MTB-guided therapy based on genomic analysis and overall survival (OS). Secondary endpoints included the proportion of patients with actionable genomic alterations, objective response rate (ORR), and disease control rate (DCR). The Kaplan-Meier method was used in the survival analyses, and hazard ratios were calculated using univariate Cox regression. Findings: 122 patients were reviewed at the HKU-HKSH MTB, and 63% (n = 77) adopted treatment per the MTB recommendations. These patients achieved a significantly longer median OS than those who did not receive MTB-guided therapy (12.7 months vs. 5.2 months, P = 0.0073). Their ORR and DCR were 29% and 65%, respectively. Interpretation: Our study demonstrated that among patients with heavily pre-treated advanced solid cancers, MTB-guided treatment could positively impact survival outcomes, thus illustrating the applicability of NGS CGPs in real-world clinical practice. Funding: The study was supported by the Li Shu Pui Medical Foundation. Dr Aya El Helali was supported by the Li Shu Pui Medical Foundation Fellowship grant from the Li Shu Pui Medical Foundation. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

The use of traditional, complementary and integrative medicine in Chinese adolescent and young adult patients with cancer: A multicenter cross-sectional study.

PURPOSE: Adolescent and young adult (AYA) patients with cancer often experience unique physical and psychosocial complications. They may turn to traditional, complementary and integrative medicines (TCIM) to address these concerns. To examine the pattern of TCIM use among AYA patients with cancer and explored their preferences regarding TCIM education. METHODS: Between August 2021 and December 2022, 246 patients diagnosed with cancer between 15 and 39 years old were recruited from hospitals in Hong Kong. They completed a structured questionnaire on TCIM use, symptom burden, psychological status and preference on education content. Multivariable logistic regression was used to identify predictors of TCIM use, adjusting for age and sex. RESULTS: Overall, 60.2% reported TCIM use, most commonly vitamins (24.0%) and Chinese herbal medicine (22.0%). The most common reasons for using TCIM were to improve general health (70.9%) and manage chronic symptoms (33.1%). Among patients on active treatment, TCIM users tend to report higher anxiety symptoms (aOR = 1.13, 95% CI = 1.02-1.27). TCIM users who were post-treatment were more likely to have chronic comorbidities (aOR = 3.54, 95% CI = 1.29-11.5). AYA patients indicated that they would like TCIM information to address specific needs, particularly fatigue (53.7%) and psychological problems (54.1%). CONCLUSIONS: The use of TCIM is common among AYA patients with cancer, especially among patients with high symptom burdens. A tailored education programme should be provided based on patients' preferences and needs. Healthcare professionals including oncologists and oncology nurses should communicate with AYA patients about TCIM use and address their needs by making evidence-based referrals/recommendations based on treatment status and symptom burden.

Consensus Statements on Precision Oncology in the China Greater Bay Area.

BACKGROUND: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. METHODS: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. RESULTS: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. CONCLUSION: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

The Use of Traditional, Complementary, and Integrative Medicine in Cancer: Data-Mining Study of 1 Million Web-Based Posts From Health Forums and Social Media Platforms.

BACKGROUND: Patients with cancer are increasingly using forums and social media platforms to access health information and share their experiences, particularly in the use of traditional, complementary, and integrative medicine (TCIM). Despite the popularity of TCIM among patients with cancer, few related studies have used data from these web-based sources to explore the use of TCIM among patients with cancer. OBJECTIVE: This study leveraged multiple forums and social media platforms to explore patients' use, interest, and perception of TCIM for cancer care. METHODS: Posts (in English) related to TCIM were collected from Facebook, Twitter, Reddit, and 16 health forums from inception until February 2022. Both manual assessments and natural language processing were performed. Descriptive analyses were performed to explore the most commonly discussed TCIM modalities for each symptom and cancer type. Sentiment analyses were performed to measure the polarity of each post or comment, and themes were identified from posts with positive and negative sentiments. TCIM modalities that are emerging or recommended in the guidelines were identified a priori. Exploratory topic-modeling analyses with latent Dirichlet allocation were conducted to investigate the patients' perceptions of these modalities. RESULTS: Among the 1,620,755 posts available, cancer-related symptoms, such as pain (10/10, 100% cancer types), anxiety and depression (9/10, 90%), and poor sleep (9/10, 90%), were commonly discussed. Cannabis was among the most frequently discussed TCIM modalities for pain in 7 (70%) out of 10 cancer types, as well as nausea and vomiting, loss of appetite, anxiety and depression, and poor sleep. A total of 7 positive and 7 negative themes were also identified. The positive themes included TCIM, making symptoms manageable, and reducing the need for medication and their side effects. The belief that TCIM and conventional treatments were not mutually exclusive and intolerance to conventional treatment may facilitate TCIM use. Conversely, TCIM was viewed as leading to patients' refusal of conventional treatment or delays in diagnosis and treatment. Doctors' ignorance regarding TCIM and the lack of information provided about TCIM may be barriers to its use. Exploratory analyses showed that TCIM recommendations were well discussed among patients; however, these modalities were also used for many other indications. Other notable topics included concerns about the legalization of cannabis, acupressure techniques, and positive experiences of meditation. CONCLUSIONS: Using machine learning techniques, social media and health forums provide a valuable resource for patient-generated data regarding the pattern of use and patients' perceptions of TCIM. Such information will help clarify patients' needs and concerns and provide directions for research on integrating TCIM into cancer care. Our results also suggest that effective communication about TCIM should be achieved and that doctors should be more open-minded to actively discuss TCIM use with their patients.

Associations between Lifestyle Factors and Neurocognitive Impairment among Chinese Adolescent and Young Adult (AYA) Survivors of Sarcoma.

BACKGROUND: The effect of lifestyle on neurocognitive impairment among cancer survivors remain an understudied area. This study explored the association between lifestyle factors and neurocognitive outcomes (specifically, attention, memory, processing speed and cognitive flexibility) in AYA survivors (aged 15-39 years) of sarcoma. METHODS: This study recruited 116 AYA survivors (age 28.2 (SD = 8.2) years), who were diagnosed with osteosarcoma (49%) or soft-tissue sarcoma (51%) at age 13.3 (SD = 7.2) years. The neurocognitive battery included measures of attention, memory, motor-processing speed, and cognitive flexibility. Survivors reported health-damaging practices, which included: physical inactivity, smoking, alcohol intake, inadequate sleep (<7 h of actual sleep/day), sleep-related fatigue (Multidimensional Fatigue Scale) and long working hours (>9 h/day). General linear modeling was conducted to examine the association between lifestyle factors and neurocognitive outcomes, adjusting for age at diagnosis, sex, education attainment and clinical/treatment variables. RESULTS: At 14.9 (SD = 7.6) years post-diagnosis, survivors demonstrated impairment in attentiveness (4.3-13.0%), processing speed (34.5%) and cognitive flexibility (18.1%). Nearly half (45.7%) had developed a chronic health condition (CHC). Low physical activity (estimate = -0.97, p = 0.003) and sleep-related fatigue (estimate = -0.08, p = 0.005) were associated with inattention. Survivors who worked >9 h/day (n = 15) demonstrated worse attention (estimate = 5.42, p = 0.023) and cognitive flexibility (estimate = 5.22, p = 0.005) than survivors who worked ≤9 h/day (n = 66). Interaction analysis (CHCs*physical activity) showed that survivors who developed CHCs and reported low physical activity had worse attention (p = 0.032) and cognitive-flexibility (p = 0.019) scores than other subgroups. CONCLUSION: Treatment-related CHCs, coupled with continued physical inactivity, may exacerbate inattention and executive dysfunction among survivors. Long working hours and sleep-related fatigue are associated with worse functioning; this finding should be validated with prospective assessment of work-related stressors and objective sleep measures.

Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors.

Importance: New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing. Objective: To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing. Design, Setting, and Participants: This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022. Exposures: The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks. Main Outcomes and Measures: The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries. Results: In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient. Conclusions and Relevance: This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

EJSO educational Special issue from the TARPSWG - Standard medical treatment and new options in retroperitoneal sarcoma.

Retroperitoneal soft tissue sarcomas mainly consist histologically of liposarcomas and leiomyosarcomas. For the liposarcoma subgroup, the local relapse rate seems to determine patients' overall prognosis. In contrast, leiomyosarcoma patients are challenged by the development of metastatic disease; therefore, effective systemic therapies are the cornerstone to improve patients' outcome. No doubt, the limited number of active regimens currently available makes the treatment of patients with locally advanced and/or metastatic disease challenging and results in the overall poor prognosis of this population. In this European Journal of Surgical Oncology Educational Special Issue from the Transatlantic Australasian RetroPeritoneal Sarcoma Working Group (TARPSWG), we aim to summarize state-of-the-art systemic treatments for patients with retroperitoneal sarcomas with a focus on the locally advanced and metastatic disease setting including conventional standard chemotherapies as well as new innovative treatment approaches in order to identify current unmet medical needs guiding the sarcoma community to initiate appropriate translational research projects and design innovative clinical trials.