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Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI. A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017-2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type. Mean event rate for general irAE occurrence across any grade was 40.0% (37.3-42.7%) and high grade was 19.7% (15.8-23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 30.5% (28.1-32.9%), 45.7% (29.6-61.7%) for ICI combination therapy, and 30.0% (25.3-34.6%) for both ICI monotherapy and combination therapy. This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade.

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2 LMW ) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2 LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS + /CD206 + TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment. Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy. 

Immune checkpoint inhibitors have been approved in the USA for tumours exhibiting mismatch repair deficiency (dMMR), microsatellite instability (MSI), or high tumour mutational burden (TMB), with regulatory and reimbursement applications in multiple other countries underway. As the estimated budget impacts of future reimbursements depend on the size of the potential target population, we performed a scoping review and meta-analysis of the prevalence of these pan-tumour biomarkers in different cancers. We systematically searched Medline/Embase and included studies reporting the prevalence of dMMR/MSI/high TMB in solid tumours published 01/01/2018–31/01/2021. Meta-analyses were performed separately for the pan-cancer prevalence of each biomarker, and by cancer type and stage where possible. The searches identified 3890 papers, with 433 prevalence estimates for 32 different cancer types from 201 studies included in meta-analyses. The pooled overall prevalence of dMMR, MSI and high TMB (≥ 10 mutations/Mb) in pan-cancer studies was 2.9%, 2.7% and 14.0%, respectively. The prevalence profiles of dMMR/MSI and high TMB differed across cancer types. For example, endometrial, colorectal, small bowel and gastric cancers showed high prevalence of both dMMR and MSI (range: 8.7–26.8% and 8.5–21.9%, respectively) and high TMB (range: 8.5–43.0%), while cervical, esophageal, bladder/urothelial, lung and skin cancers showed low prevalence of dMMR and MSI (< 5%), but high prevalence of high TMB (range: 23.7–52.6%). For other cancer types, prevalence of all three biomarkers was generally low (< 5%). This structured review of dMMR/MSI/high TMB prevalence across cancers and for specific cancer types and stages provide timely evidence to inform budget impact forecasts in health technology assessments for drug approvals based on these pan-tumour biomarkers.

NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist . Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03–0.70%, with higher rates found in RNA-based assays . In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.

Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs . However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus ( Hh ), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh , Alpk1 −/− macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge. The Hiccs locus has been associated with susceptibility to colitis in mice. Here the authors identify a Hiccs locus gene encoding Alpha kinase 1 as a potent regulator of intestinal inflammation via modulation of the IL-12/Th1 axis.

Background: Although several strategies for modelling competing events in discrete event simulation (DES) exist, a methodological gap for the event-specific probabilities and distributions (ESPD) approach when dealing with censored data remains. This study defines and illustrates the ESPD strategy for censored data. Methods: The ESPD approach assumes that events are generated through a two-step process. First, the type of event is selected according to some (unknown) mixture proportions. Next, the times of occurrence of the events are sampled from a corresponding survival distribution. Both of these steps can be modelled based on covariates. Performance was evaluated through a simulation study, considering sample size and levels of censoring. Additionally, an oncology-related case study was conducted to assess the ability to produce realistic results, and to demonstrate its implementation using both frequentist and Bayesian frameworks in R. Results: The simulation study showed good performance of the ESPD approach, with accuracy decreasing as sample sizes decreased and censoring levels increased. The average relative absolute error of the event probability (95%-confidence interval) ranged from 0.04 (0.00; 0.10) to 0.23 (0.01; 0.66) for 60% censoring and sample size 50, showing that increased censoring and decreased sample size resulted in lower accuracy. The approach yielded realistic results in the case study. Discussion: The ESPD approach can be used to model competing events in DES based on censored data. Further research is warranted to compare the approach to other modelling approaches for DES, and to evaluate its usefulness in estimating cumulative event incidences in a broader context.

Background The aim of this study is to develop a method we call “cost mining” to unravel cost variation and identify cost drivers by modelling integrated patient pathways from primary care to the palliative care setting. This approach fills an urgent need to quantify financial strains on healthcare systems, particularly for colorectal cancer, which is the most expensive cancer in Australia, and the second most expensive cancer globally. Methods We developed and published a customized algorithm that dynamically estimates and visualizes the mean, minimum, and total costs of care at the patient level, by aggregating activity-based healthcare system costs (e.g. DRGs) across integrated pathways. This extends traditional process mining approaches by making the resulting process maps actionable and informative and by displaying cost estimates. We demonstrate the method by constructing a unique dataset of colorectal cancer pathways in Victoria, Australia, using records of primary care, diagnosis, hospital admission and chemotherapy, medication, health system costs, and life events to create integrated colorectal cancer patient pathways from 2012 to 2020. Results Cost mining with the algorithm enabled exploration of costly integrated pathways, i.e. drilling down in high-cost pathways to discover cost drivers, for 4246 cases covering approx. 4 million care activities. Per-patient CRC pathway costs ranged from $10,379 AUD to $41,643 AUD, and varied significantly per cancer stage such that e.g. chemotherapy costs in one cancer stage are different to the same chemotherapy regimen in a different stage. Admitted episodes were most costly, representing 93.34% or $56.6 M AUD of the total healthcare system costs covered in the sample. Conclusions Cost mining can supplement other health economic methods by providing contextual, sequence and timing-related information depicting how patients flow through complex care pathways. This approach can also facilitate health economic studies informing decision-makers on where to target care improvement or to evaluate the consequences of new treatments or care delivery interventions. Through this study we provide an approach for hospitals and policymakers to leverage their health data infrastructure and to enable real time patient level cost mining.

BackgroundComplex genomic profiling (CGP) has transformed cancer treatment decision making, yet there is a lack of robust and quantifiable evidence for how utilisation of CGP improves patient outcomes.ObjectiveThis study evaluated cohort level clinical effectiveness of CGP to improve overall survival (OS) in real-world advanced cancer patients using a registry-based matched control population.Patients and methodsTwo cohorts of advanced and refractory cancer patients were seen in consecutive series for early phase trial enrolment consideration. The first cohort (CGP group) accessed tumour profiling via a research study; while the second cohort that followed was not profiled. Overall survival between cohorts was compared using Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores.ResultsWithin the CGP group, 25 (17.6%) patients received treatment informed by CGP results and this subgroup had significantly improved survival compared with CGP patients in whom results did not impact their treatment (unadjusted HR = 0.44, (0.22–0.88), p = 0.02). However, when comparing the entire CGP cohort with the No CGP cohort, no significant survival benefit was evident with adjusted median OS for CGP of 13.5 months (9.2–17.0) compared with 11.0 (9.2–17.4) for No CGP (adjusted HR = 0.92, (0.65–1.30), p = 0.63).ConclusionsThis study utilised real-world data to simulate a control arm and quantify the clinical effectiveness of genomic testing. The magnitude of survival benefit for patients who had CGP result-led treatments was insufficient to drive an overall survival gain for the entire tested population. Translation of CGP into clinics requires strategies to ensure higher rates of tested patients obtain clinical benefit to deliver on the value proposition of CGP in an advanced cancer population.

ObjectiveWe study how clinical and socioeconomic factors influence colorectal cancer (CRC) costs for patients and Medicare in Australia. The study seeks to extend the limited Australian literature on CRC costs by analysing comprehensive patient-level medical services and pharmaceutical cost data.Design, setting and participantsUsing the Victorian Cancer Registry, we identified all patients in Victoria who were diagnosed with CRC from 2010 to 2019 and extracted their linked 2010–2021 Medicare data. This data includes expenses from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule services. We examined variables such as disease stage, CRC type, molecular profile, metastasis status and demographics (eg, age, birth country, socioeconomic level via the SEIFA index, and native language). We applied descriptive and log-linear multivariate regression analyses to explore patient and Medicare costs related to CRC treatment.ResultsCosts significantly rise with advanced cancer stages, especially on medication costs. Patients’ average out-of-pocket (OOP) expenses are roughly $A441 per year. Key cost influencers are gender, age and socioeconomic status. On average, males incur 13.5% higher annual costs, a significantly larger OOP expense, than females. Compared with patients aged 50 or below, there is a 7.1% cost increase for individuals aged 50–70 and an 8.8% decrease post-70, likely reflecting less intensive treatment for the elderly. Socioeconomic factors show a clear gradient. Wealthier areas experience higher costs, especially among native English speakers. Costs also vary based on cancer’s anatomical location and specific genetic mutations.ConclusionThe research highlights that CRC treatment expenses for patients and Medicare differ considerably due to factors such as diagnostic stage, demographics, anatomical location of the tumour and mutations. These cost variations lead to concerns about healthcare equality and decision-making autonomy. Policymakers may need to focus on early detection, increased support for advanced-stage patients, gender-sensitive healthcare, and equitable access to treatment across different socioeconomic groups.

Background Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI. Methods A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017–2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type. Results Mean event rate for general irAE occurrence across any grade was 40.0% (37.3–42.7%) and high grade was 19.7% (15.8–23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 30.5% (28.1–32.9%), 45.7% (29.6–61.7%) for ICI combination therapy, and 30.0% (25.3–34.6%) for both ICI monotherapy and combination therapy. Conclusion This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade.