Abstract To summarise the prognostic value of patient‐reported outcomes (PROs) in advanced gastro‐oesophageal (GO) cancer. We systematically searched multiple databases using search terms related to advanced GO cancer, PRO and prognosis. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers independently screened articles and extracted data on study design, survival and associations between PROs and survival, in both univariable and multivariable analyses. QUIPS was used for quality assessment. From 3004 studies screened, seven studies were eligible, comprising PRO data from 2761 of 3408 (81%) participants. Median survival times ranged from 4.5 to 9.5 months. Among participants with oesophageal squamous cell carcinoma (SCC), physical functioning, social functioning and fatigue (QLQ‐C30) were associated with overall survival (OS) in one univariable analysis. Among three studies of participants with adenocarcinoma, univariable analyses revealed associations between OS and global quality of life (QOL), physical functioning, role functioning and social functioning; two studies showed association with pain. There was an association between emotional functioning, fatigue, lack of mobility, lack of self‐care, appetite loss/anorexia and OS in one study. One multivariable analysis among participants with oesophageal SCC showed physical and social functioning was associated with OS. Among participants with adenocarcinoma, multivariable analyses showed associations between OS and physical functioning/lack of mobility, appetite loss/anorexia (three studies), global QOL, role functioning/lack of self‐care, pain (two studies) and social functioning (one study). Physical functioning, role functioning, social functioning, pain, anorexia and global QOL were associated with OS in advanced GO cancer.
Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.
251 Background: To summarise the prognostic value of PROs in advanced GO cancer. Methods: We searched multiple databases using search terms developed with medical librarians. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers screened articles and extracted data on study design, survival, univariable and multivariable relationships between PROs and prognosis. QUAL-SYST was used for quality assessment. Discrepancies were resolved by a third reviewer. Results: Of 3002 abstracts, seven studies were included: four pooled analyses of randomised controlled trials (RCTs), two RCTs and one cohort study. Five received QUAL-SYST scores >65%. Total 3,408 patients and 2,761(81%) with PRO data. Median survival ranged from 4.5 to 9.5 months. In one univariable analysis for oesophageal squamous cell cancer (SCC), physical functioning and fatigue measured by QLQ-C30 had prognostic significance. For adenocarcinoma, physical functioning, global QOL, role functioning, emotional functioning (QLQ-C30) were significant in three studies. Pain was significant in three studies (QLQ-C30 n=2, EQ-5D-3L n=1). Fatigue (QLQ-C30) was significant in two studies. Appetite loss (QLQ-C30) was significant in two studies. In multivariable analyses for oesophageal SCC (QLQ-C30) physical and social functioning had prognostic significance. In adenocarcinoma, physical functioning, role functioning, appetite loss, global QOL, social functioning and pain showed prognostic significance (Table). One study showed adenocarcinoma patients with lower anorexia (FAACT-A/CS scores of >37) lived longer (19.3 months) than patients with low scores ≤37 (6.7 months). Conclusions: Baseline PROs for multiple functional domains, symptoms (pain, appetite loss) and overall QOL have prognostic significance in advanced GO cancer. Further research is needed to establish clear levels of the relationship which could assist in communication with patients about prognosis, and stratification for clinical trials.[Table: see text]
The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. LSTA1, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumour-specific drug delivery. In the phase Ib setting, LSTA1 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated. This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of LSTA1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 and LSTA1 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of LSTA1/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of LSTA1 warrants further evaluation.
Advances in genomics have enabled anticancer therapies to be tailored to target specific genomic alterations. Single-arm trials (SATs), including those incorporated within umbrella, basket, and platform trials, are widely adopted when it is not feasible to conduct randomized controlled trials in rare biomarker-defined subpopulations. External controls (ECs), defined as control arm data derived outside the clinical trial, have gained renewed interest as a strategy to supplement evidence generated from SATs to allow comparative analysis. There are increasing examples demonstrating the application of EC in precision oncology trials. The prospective application of EC in conducting comparative studies is associated with distinct methodological challenges, the specific considerations for EC use in biomarker-defined subpopulations have not been adequately discussed, and a formal framework is yet to be established. In this review, we present a framework for conducting a prospective comparative analysis using EC. Key steps are (1) defining the purpose of using EC to address the study question, (2) determining if the external data are fit for purpose, (3) developing a transparent study protocol and a statistical analysis plan, and (iv) interpreting results and drawing conclusions on the basis of a prespecified hypothesis. We specify the considerations required for the biomarker-defined subpopulations, which include (1) specifying the comparator and biomarker status of the comparator group, (2) defining lines of treatment, (3) assessment of the biomarker testing panels used, and (4) assessment of cohort stratification in tumor-agnostic studies. We further discuss novel clinical trial designs and statistical techniques leveraging EC to propose future directions to advance evidence generation and facilitate drug development in precision oncology.
The use of immune checkpoint inhibitors (ICIs) against programmed cell death protein -1 (PD-1), its ligand (PD-L1) and cytotoxic T- lymphocyte associated protein 4 (CTLA4) have been increasing. Immune induced myocarditis, myositis and myasthenia gravis are rare but potentially severe complications from these agents. Here we report 3 cases of ICI induced myocarditis, myositis, myasthenia gravis and transaminitis as a cluster, and highlights early diagnosis, prompt initiation of steroid sparing immunosuppressive therapy and multidisciplinary management.
Methods
Three patients received anti-PD-1 ICIs developed cardiac, neuromuscular complications and transaminitis within 4 weeks after initiation. Clinical data were retrospectively reviewed from medical records.
Results
All patients had elevated cardiac enzymes, developed complete heart block and underwent coronary catheterisation and pacemaker insertion. All patients developed myositis and myasthenia gravis (table 1) and were managed by multi-disciplinary team involving oncology, cardiology and neurology. Single-fibre electromyography was performed to confirm presence of myositis. One of three patients had positive acetylcholinesterase antibody, anti- muscle specific kinase antibody was negative in all cases. All patients developed grade 2–3 transaminitis with normal bilirubin. All patients received high-dose steroids. Steroid sparing therapy including intravenous immunoglobulin and mycophenolate mofetil were used early in 2 cases and was associated with rapid recovery of toxicities.
Conclusions
ICI induced myocarditis can be associated with myositis, myasthenia gravis and transaminitis. A high index of suspicion, comprehensive investigations and early involvement of multi-disciplinary teams are key to early accurate diagnosis. In steroid refractory cases, we propose early initiation of steroid sparing immunosuppressive therapy after 3 days.
Consent
Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development.
Abundant, indirect epidemiological evidence indicates that influenza contributes to all-cause mortality and cardiovascular hospitalisations with studies showing increases in acute myocardial infarction (AMI) and death during the influenza season.To investigate whether influenza is a significant and unrecognised underlying precipitant of AMI.Case-control study.Tertiary referral hospital in Sydney, Australia, during 2008 to 2010.Cases were inpatients with AMI and controls were outpatients without AMI at a hospital in Sydney, Australia.Primary outcome was laboratory evidence of influenza. Secondary outcome was baseline self-reported acute respiratory tract infection.Of 559 participants, 34/275 (12.4%) cases and 19/284 (6.7%) controls had influenza (OR 1.97, 95% CI 1.09 to 3.54); half were vaccinated. None were recognised as having influenza during their clinical encounter. After adjustment, influenza infection was no longer a significant predictor of recent AMI. However, influenza vaccination was significantly protective (OR 0.55, 95% CI 0.35 to 0.85), with a vaccine effectiveness of 45% (95% CI 15% to 65%).Recent influenza infection was an unrecognised comorbidity in almost 10% of hospital patients. Influenza did not predict AMI, but vaccination was significantly protective but underused. The potential population health impact of influenza vaccination, particularly in the age group 50-64 years, who are at risk for AMI but not targeted for vaccination, should be further explored. Our data should inform vaccination policy and cardiologists should be aware of missed opportunities to vaccinate individuals with ischaemic heart disease against influenza.
We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical-, and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles.
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