Experiences and perspectives of colorectal cancer survivors and general practitioners on the delivery of survivorship care in general practice: a mixed methods study.

BACKGROUND: Many colorectal cancer (CRC) survivors experience ongoing sequelae from their cancer treatment. Limited evidence exists regarding how CRC survivors and general practitioners (GPs) manage these sequelae in the community. This study aimed to explore the experiences and perspectives of CRC survivors and GPs on current approaches to monitoring and managing sequelae of CRC treatment. METHODS: We conducted a mixed-methods study using cross-sectional national surveys and qualitative interviews with CRC survivors and GPs to explore: (1) treatment sequelae experienced by CRC survivors, (2) how these were monitored and managed by general practitioners, and (3) suggestions to improve ongoing management of the treatment sequelae. Survey responses were reported descriptively. Qualitative data were thematically analysed using an interpretive descriptive approach. RESULTS: Seventy participants completed surveys: 51 CRC survivors and 19 GPs, and four interviews were conducted with GPs. CRC survivors experienced a range of treatment sequelae, but often did not discuss these with their GPs (experienced vs discussed: 86% vs 47% for fatigue/lack of energy, 78% vs 27% for psychological/emotional concern, 63% vs 22% for impaired sleep, 69% vs 29% for weight loss/gain, 59% vs 16% for sexual and intimacy concerns). GPs reported inadequate information transfer from cancer services and workload as major barriers to optimal care. CONCLUSIONS: System-level changes that facilitate adequate information transfer from cancer services to GPs upon CRC treatment completion, as well as addressing time constraint issues essential for comprehensive monitoring and management of CRC treatment sequelae, could enhance the care of CRC survivors in the community setting.

Should I Take Aspirin? (SITA): RCT of a decision aid for cancer chemoprevention.

Background Australian guidelines recommend that all people aged 50-70 years old consider taking low-dose aspirin to reduce the risk of colorectal cancer (CRC). Aim To determine the effect of a consultation with a researcher in general practice using a decision aid about taking low-dose aspirin to prevent CRC on informed decision-making and low-dose aspirin uptake compared to a general CRC prevention brochure. Design and Setting Individually randomised controlled trial in six general practices in Victoria, Australia, from October 2020 to March 2021. Method Patients aged 50-70 years attending a general practitioner (GP) were recruited consecutively. The intervention was a consultation using a decision aid to discuss taking aspirin to reduce CRC risk; control consultations discussed reducing CRC risk generally. The self-reported co-primary outcomes were informed choices about taking aspirin at one month and low-dose aspirin uptake at six months. Results 261 participants (86% of eligible patients) were randomised into trial arms (129 intervention, 132 control). 17.7% (20/113) of intervention and 7.6% (9/118) control participants reported making an informed choice at one month, an estimated 9.1% (95% CI 0.29% to 18.5) between-arm difference in proportions [odds ratio (OR) 2.47 (97.5% CI:0.94 to 6.52) p=0.074]. The proportions of individuals who reported using aspirin at six months were: 10.2% (12/118) intervention vs 13.8% (16/116) control (estimated between-arm difference: -4.0% (95% CI: -13.5 to 5.5); [OR= 0.68 (97.5% CI:0.27 to 1.70), p= 0.692]. Conclusion The decision aid improved informed decision-making; but has little effect on long-term regular use of aspirin to reduce CRC risk.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

Supportive care needs of adults living with a peripherally inserted central catheter (PICC) at home: a qualitative content analysis.

BACKGROUND: Peripherally inserted central catheters (PICCs) are common vascular access devices inserted for adults undergoing intravenous treatment in the community setting. Individuals with a PICC report challenges understanding information and adapting to the device both practically and psychologically at home. There is a lack of research investigating the supportive care needs of individuals with a PICC to inform nursing assessment and the provision of additional supports they may require to successfully adapt to life with a PICC. The aim of this study was to identify the supportive care needs of adults with cancer or infection living with a PICC at home. METHOD: Qualitative, semi-structured interviews were used to identify supportive care needs of adults living with a PICC at home. Participants were recruited from cancer and infectious diseases outpatient units. Two researchers independently analysed transcripts using content analysis. RESULTS: A total of 15 participants were interviewed (30-87 years old). There were 5 males and 10 females interviewed, 9 participants had a cancer diagnosis and most lived in a metropolitan area. Many participants lived with a partner/spouse at home and three participants had young children. Participants identified supportive care needs in the following eight categories (i (i) Adapting daily life (ii) Physical comfort (iii) Self-management (iv) Emotional impact (v) Information content (vi) Understanding information (vii) Healthcare resources and (viii) Social supports. CONCLUSIONS: Adults living with a PICC at home report a broad range of supportive care needs. In addition to practical and information needs, health consumers may also require support to accept living with a device inside their body and to assume responsibility for the PICC. These findings may provide nurses with a greater understanding of individual needs and guide the provision of appropriate supports.

SCORE: a randomised controlled trial evaluating shared care (general practitioner and oncologist) follow-up compared to usual oncologist follow-up for survivors of colorectal cancer.

Background: SCORE is the first randomised controlled trial (RCT) to examine shared oncologist and general practitioner (GP) follow-up for survivors of colorectal cancer (CRC). SCORE aimed to show that shared care (SC) was non-inferior to usual care (UC) on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months. Methods: The study recruited patients from five public hospitals in Melbourne, Australia between February 2017 and May 2021. Patients post curative intent treatment for stage I-III CRC underwent 1:1 randomisation to SC and UC. SC replaced two oncologist visits with GP visits and included a survivorship care plan and primary care management guidelines. Assessments were at baseline, 6 and 12 months. Difference between groups on GHQ-QoL to 12 months was estimated from a mixed model for repeated measures (MMRM), with a non-inferiority margin (NIM) of -10 points. Secondary endpoints included quality of life (QoL); patient perceptions of care; costs and clinical care processes (CEA tests, recurrences). Registration ACTRN12617000004369p. Findings: 150 consenting patients were randomised to SC (N = 74) or UC (N = 76); 11 GPs declined. The mean (SD) GHQ-QoL scores at 12 months were 72 (20.2) for SC versus 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 month and 12 month follow-up was 69 for SC and 73 for UC, mean difference -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. There was no clear evidence of differences on other QoL, unmet needs or satisfaction scales. At 12 months, the majority preferred SC (40/63; 63%) in the SC group, with equal preference for SC (22/62; 35%) and specialist care (22/62; 35%) in UC group. CEA completion was higher in SC. Recurrences similar between arms. Patients in SC on average incurred USD314 less in health costs versus UC patients. Interpretation: SC seems to be an appropriate and cost-effective model of follow-up for CRC survivors. Funding: Victorian Cancer Agency and Cancer Australia.

Colorectal cancer detection and treatment with engineered probiotics.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool. We also demonstrate specific colonization of EcN to solitary neoplastic lesions in an orthotopic murine model of CRC. We then exploit this neoplasia-homing property of EcN to develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate, and demonstrate that oral delivery of this strain results in significantly increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. We also assess EcN engineered to locally release immunotherapeutics at the neoplastic site. Oral delivery to mice bearing adenomas, reduced adenoma burden by ∻50%, with notable differences in the spatial distribution of T cell populations within diseased and healthy intestinal tissue, suggesting local induction of robust anti-tumor immunity. Together, these results support the use of EcN as an orally-delivered platform to detect disease and treat CRC through its production of screening and therapeutic molecules.

Community-based Intravenous Treatment and Central Venous Access Devices: A Scoping Review of the Consumer and Caregiver Experience, Information Preferences, and Supportive Care Needs.

PURPOSE: Map existing research and describe the consumer/caregiver experience of community-based intravenous treatment, central venous access devices (CVADs), supportive care needs, and information preferences. DESIGN: Scoping review. METHODS: Five databases (Joanna Briggs Institute, Cochrane library, Emcare, Embase, and Medline) were searched. Screening and data extraction were performed independently by two reviewers. FINDINGS: Forty-eight studies were included. CONCLUSIONS: Although community-based intravenous treatment and CVADs have a significant impact on consumers and caregivers, there is scant research on their supportive care needs and information preferences. CLINICAL EVIDENCE: Some consumers and caregivers may require additional support while undergoing community-based intravenous treatment.

The nature and impact of patient and public involvement in cancer prevention, screening and early detection research: A systematic review.

Patient and public involvement can produce high-quality, relevant research that better addresses the needs of patients and their families. This systematic review investigated the nature and impact of patient and public involvement in cancer prevention, screening and early detection research. Two patient representatives were involved as members of the review team. Databases (Medline, EMBASE, Emcare, Involve Evidence Library) were searched for English-language studies published 1995-March 2022. Titles/abstracts were screened by two reviewers independently. For eligible studies, data were extracted on study characteristics, patient and public involvement (who, when, how, and impact on research outcomes), and reporting quality using the Guidance for Reporting Involvement of Patients and the Public 2-Short Form. Of 4095 articles screened, 58 were eligible. Most research was from the United States (81%) and examined cancer screening or prevention (82%). Community members/organisations/public were the most involved (71%); fewer studies involved patients and/or carers (14%). Over half reported a high-level of involvement (i.e. partner and/or expert involvement), although this declined in later stages of the research cycle, e.g. data analysis. Common positive impacts included improved study design, research methods and recruitment, although most papers (62%) did not describe methods to determine impact. Reporting quality was sub-optimal, largely due to failure to consider challenges. This review found that high-level involvement of patients and the public in cancer prevention, screening and early detection research is feasible and has several advantages. However, improvements are needed to encourage involvement across the research cycle, and in evaluating and reporting its impact.

The SCRIPT trial: study protocol for a randomised controlled trial of a polygenic risk score to tailor colorectal cancer screening in primary care.

BACKGROUND: Polygenic risk scores (PRSs) can predict the risk of colorectal cancer (CRC) and target screening more precisely than current guidelines using age and family history alone. Primary care, as a far-reaching point of healthcare and routine provider of cancer screening and risk information, may be an ideal location for their widespread implementation. METHODS: This trial aims to determine whether the SCRIPT intervention results in more risk-appropriate CRC screening after 12 months in individuals attending general practice, compared with standard cancer risk reduction information. The SCRIPT intervention consists of a CRC PRS, tailored risk-specific screening recommendations and a risk report for participants and their GP, delivered in general practice. Patients aged between 45 and 70 inclusive, attending their GP, will be approached for participation. For those over 50, only those overdue for CRC screening will be eligible to participate. Two hundred and seventy-four participants will be randomised to the intervention or control arms, stratified by general practice, using a computer-generated allocation sequence. The primary outcome is risk-appropriate CRC screening after 12 months. For those in the intervention arm, risk-appropriate screening is defined using PRS-derived risk; for those in the control arm, it is defined using family history and national screening guidelines. Timing, type and results of the previous screening are considered in both arms. Objective health service data will capture screening behaviour. Secondary outcomes include cancer-specific worry, risk perception, predictors of CRC screening behaviour, screening intentions and health service use at 1, 6 and 12 months post-intervention delivery. DISCUSSION: This trial aims to determine whether a PRS-derived personalised CRC risk estimate delivered in primary care increases risk-appropriate CRC screening. A future population risk-stratified CRC screening programme could incorporate risk assessment within primary care while encouraging adherence to targeted screening recommendations. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12621000092897p. Registered on 1 February 2021.

Challenges and opportunities for using population health data to investigate cancer survivors' quality of life in Australia.

There is a recognised need for reported national data that inform health policy, health professions, and consumers about the wellbeing of Australians with cancer and other chronic conditions. International initiatives have demonstrated the viability and benefits of utilising population-based cancer registries to monitor the prevalence and trajectory of health-related quality of life (HRQOL) outcomes among people with cancer. Establishing a similar level of monitoring in Australia would require timely access to health data collected by publicly funded, population-based cancer registries, and the capacity to link this information across jurisdictions. Combining information from different sources via data linkage is an efficient and cost-effective way to maximise how data are used to inform population health and policy development. However, linking health datasets has historically been highly restricted, resource-intensive, and costly in Australia due to complex and outdated legislative requirements, duplicative approval processes, and differing policy frameworks in each state and territory. This has resulted in significant research waste due to underutilisation of existing data, duplication of research efforts and resources, and data not being translated into decision-making. Recognising these challenges, from 2015 to 2017 the Productivity Commission investigated options for improving data availability and use in Australia, considering factors such as privacy, security, and intellectual property. The inquiry report recommended significant reforms for Australian legislation, including the creation of a data sharing and release structure to improve access to data for research and policy development purposes. This paper discusses (1) opportunities in HRQOL research enabled by data linkage, (2) barriers to data access and use in Australia and the implications for waste in HRQOL research, and (3) proposed legislative reforms for improving data availability and use in Australia.

Consumer engagement in health care policy, research and services: A systematic review and meta-analysis of methods and effects.

To assess the effects of consumer engagement in health care policy, research and services. We updated a review published in 2006 and 2009 and revised the previous search strategies for key databases (The Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; PsycINFO; CINAHL; Web of Science) up to February 2020. Selection criteria included randomised controlled trials assessing consumer engagement in developing health care policy, research, or health services. The International Association for Public Participation, Spectrum of Public Participation was used to identify, describe, compare and analyse consumer engagement. Outcome measures were effects on people; effects on the policy/research/health care services; or process outcomes. We included 23 randomised controlled trials with a moderate or high risk of bias, involving 136,265 participants. Most consumer engagement strategies adopted a consultative approach during the development phase of interventions, targeted to health services. Based on four large cluster-randomised controlled trials, there is evidence that consumer engagement in the development and delivery of health services to enhance the care of pregnant women results in a reduction in neonatal, but not maternal, mortality. From other trials, there is evidence that involving consumers in developing patient information material results in material that is more relevant, readable and understandable for patients, and can improve knowledge. Mixed effects are reported of consumer-engagement on the development and/or implementation of health professional training. There is some evidence that using consumer interviewers instead of staff in satisfaction surveys can have a small influence on the results. There is some evidence that consumers may have a role in identifying a broader range of health care priorities that are complementary to those from professionals. There is some evidence that consumer engagement in monitoring and evaluating health services may impact perceptions of patient safety or quality of life. There is growing evidence from randomised controlled trials of the effects of consumer engagement on the relevance and positive outcomes of health policy, research and services. Health care consumers, providers, researchers and funders should continue to employ evidence-informed consumer engagement in their jurisdictions, with embedded evaluation. Systematic review registration: PROSPERO CRD42018102595.

An RCT of a decision aid to support informed choices about taking aspirin to prevent colorectal cancer and other chronic diseases: a study protocol for the SITA (Should I Take Aspirin?) trial.

BACKGROUND: Australian guidelines recommend that all people aged 50-70 years old actively consider taking daily low-dose aspirin (100-300 mg per day) for 2.5 to 5 years to reduce their risk of colorectal cancer (CRC). Despite the change of national CRC prevention guidelines, there has been no active implementation of the guidelines into clinical practice. We aim to test the efficacy of a health consultation and decision aid, using a novel expected frequency tree (EFT) to present the benefits and harms of low dose aspirin prior to a general practice consultation with patients aged 50-70 years, on informed decision-making and uptake of aspirin. METHODS: Approximately five to seven general practices in Victoria, Australia, will be recruited to participate. Patients 50-70 years old, attending an appointment with their general practitioner (GP) for any reason, will be invited to participate in the trial. Two hundred fifty-eight eligible participants will be randomly allocated 1:1 to intervention or active control arms using a computer-generated allocation sequence stratified by general practice, sex, and mode of trial delivery (face-to-face or teletrial). There are two co-primary outcomes: informed decision-making at 1-month post randomisation, measured by the Multi-dimensional Measure of Informed Choice (MMIC), and self-reported daily use of aspirin at 6 months. Secondary outcomes include decisional conflict at 1-month and other behavioural changes to reduce CRC risk at both time points. DISCUSSION: This trial will test the efficacy of novel methods for implementing national guidelines to support informed decision-making about taking aspirin in 50-70-year-olds to reduce the risk of CRC and other chronic diseases. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620001003965 . Registered on 10 October 2020.

Hemoglobin, Body Mass Index, and Age as Risk Factors for Paclitaxel- and Oxaliplatin-Induced Peripheral Neuropathy.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development. Objective: To identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin. Design, Setting, and Participants: This cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020. Exposures: Paclitaxel or oxaliplatin chemotherapy. Main Outcomes and Measures: CIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development. Results: The study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (ß = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (ß = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (ß = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (ß = -1.08; 95% CI, -1.76 to -0.16; P = .01). Conclusions and Relevance: The results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.

A core set of patient-reported outcomes for population-based cancer survivorship research: a consensus study.

PURPOSE: Core outcome sets aim to improve the consistency and quality of research by providing agreed-upon recommendations regarding what outcomes should be measured as a minimum for a population and setting. This study aimed to identify a core set of patient-reported outcomes (PROs) representing the most important issues impacting on cancer survivors' long-term health, functioning, and quality of life, to inform population-based research on cancer survivorship. METHODS: In phase I, a list of 46 outcomes was generated through focus groups (n = 5) with cancer survivors (n = 40) and a review of instruments for assessing quality of life in cancer survivorship. In phase II, 69 national experts in cancer survivorship practice, research, policy, and lived experience participated in a two-round Delphi survey to refine and prioritise the listed outcomes into a core outcome set. A consensus meeting was held with a sub-sample of participants to discuss and finalise the included outcomes. RESULTS: Twelve outcome domains were agreed upon for inclusion in the core outcome set: depression, anxiety, pain, fatigue, cognitive problems, fear of cancer recurrence or progression, functioning in everyday activities and roles, financial toxicity, coping with cancer, overall bother from side effects, overall quality of life, and overall health status. CONCLUSIONS: We established a core set of PROs to standardise assessment of cancer survivorship concerns at a population level. IMPLICATIONS FOR CANCER SURVIVORS: Adoption of the core outcome set will ensure that survivorship outcomes considered important by cancer survivors are assessed as a minimum in future studies. Furthermore, its routine use will optimise the comparability, quality, and usefulness of the data cancer survivors provide in population-based research.

Core outcome sets in cancer and their approaches to identifying and selecting patient-reported outcome measures: a systematic review.

OBJECTIVES: Issues arising from a lack of outcome standardisation in health research may be addressed by the use of core outcome sets (COS), which represent agreed-upon recommendations regarding what outcomes should be measured as a minimum in studies of a health condition. This review investigated the scope, outcomes, and development methods of consensus-based COS for cancer, and their approaches and criteria for selecting instruments to assess core patient-reported outcomes (PROs). METHODS: Studies that used a consensus-driven approach to develop a COS containing PROs, for use in research with cancer populations, were sought via MEDLINE, CINAHL, Embase, Cochrane Library, and grey literature. RESULTS: Seventeen studies met the inclusion criteria. Most COS (82%) were specific to a cancer type (prostate, esophageal, head and neck, pancreatic, breast, ovarian, lung, or colorectal) and not specific to an intervention or treatment (76%). Conducting a systematic review was the most common approach to identifying outcomes (88%) and administering a Delphi survey was the most common approach to prioritising outcomes (71%). The included COS contained 90 PROs, of which the most common were physical function, sexual (dys) function, pain, fatigue, and emotional function. Most studies (59%) did not address how to assess the core PROs included in a set, while 7 studies (41%) recommended specific instruments. Their approaches to instrument appraisal and selection varied. CONCLUSION: Efforts to standardise outcome assessment via the development of COS may be undermined by a lack of recommendations on how to measure core PROs. To optimise COS usefulness and adoption, valid and reliable instruments for the assessment of core PROs should be recommended with the aid of resources designed to facilitate this process.

Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.

PURPOSE: Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown. EXPERIMENTAL DESIGN: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. RESULTS: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. CONCLUSIONS: Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Development of a Core Set of Patient-Reported Outcomes for Population-Based Cancer Survivorship Research: Protocol for an Australian Consensus Study.

BACKGROUND: Core outcome sets seek to improve the consistency and quality of research by providing agreed-upon recommendations regarding what outcomes should be measured as a minimum for a population and setting. The problems arising from a lack of outcome standardization in population-based cancer survivorship research indicate the need for agreement on a core set of patient-reported outcomes (PROs) to enhance data quality, consistency, and comparability. OBJECTIVE: This study aims to identify a core set of PROs, representing the most important issues impacting on cancer survivors' long-term health, functioning and quality of life, to inform population-based research on cancer survivorship. METHODS: In Phase I, a list of all potentially important outcomes will be generated through focus group discussions with cancer survivors and a review of measures for assessing quality of life in cancer survivorship. The consolidated list will be advanced to Phase II, where a stakeholder consensus process will be conducted with national experts in cancer survivorship to refine and prioritize the outcomes into a core outcome set. The process will consist of a two-round Delphi survey and a consensus meeting. Cancer survivors, oncology health care professionals, and potential end users of the core outcome set with expertise in cancer survivorship research or policy will be invited to participate. In Phase III, recommended measures for assessment of the core outcome set will be selected with advice from experts on the assessment, analysis, and interpretation of PROs. RESULTS: As of April 2019, data collection for Phase I is complete and data analysis is underway. These data will inform the list of outcomes to be advanced into Phase II. Recruitment for Phase II will commence in June 2019, and it is anticipated that it will take 6 months to complete the three-step consensus process and identify a provisional core outcome set. The study results are expected to be published in early 2020. CONCLUSIONS: Expert consensus-driven recommendations on outcome measurement will facilitate the inclusion of survivorship outcomes considered important by cancer survivors and health professionals in future research. Adoption of the core outcome set will enable comparison and synthesis of evidence across studies and enhance the quality of PRO data collected in cancer survivorship research, particularly when applied to address macro-level questions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14544.

The burden of pancreatic cancer in Australia attributable to smoking.

OBJECTIVE: To estimate the burden of pancreatic cancer in Australia attributable to modifiable exposures, particularly smoking. DESIGN: Prospective pooled cohort study. SETTING, PARTICIPANTS: Seven prospective Australian study cohorts (total sample size, 365 084 adults); participant data linked to national registries to identify cases of pancreatic cancer and deaths. MAIN OUTCOME MEASURES: Associations between exposures and incidence of pancreatic cancer, estimated in a proportional hazards model, adjusted for age, sex, study, and other exposures; future burden of pancreatic cancer avoidable by changes in exposure estimated as population attributable fractions (PAFs) for whole population and for specific population subgroups with a method accounting for competing risk of death. RESULTS: There were 604 incident cases of pancreatic cancer during the first 10 years of follow-up. Current and recent smoking explained 21.7% (95% CI, 13.8-28.9%) and current smoking alone explained 15.3% (95% CI, 8.6-22.6%) of future pancreatic cancer burden. This proportion of the burden would be avoidable over 25 years were current smokers to quit and there were no new smokers. The burden attributable to current smoking is greater for men (23.9%; 95% CI, 13.3-33.3%) than for women (7.2%; 95% CI, -0.4% to 14.2%; P = 0.007) and for those under 65 (19.0%; 95% CI, 8.1-28.6%) than for older people (6.6%; 95% CI, 1.9-11.1%; P = 0.030). There were no independent relationships between body mass index or alcohol consumption and pancreatic cancer. CONCLUSIONS: Strategies that reduce the uptake of smoking and encourage current smokers to quit could substantially reduce the future incidence of pancreatic cancer in Australia, particularly among men.

Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.

OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. DESIGN: We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. RESULTS: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. CONCLUSION: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.