National trends in utilisation of glucose lowering medicines by older people with diabetes in long-term care facilities.

AIMS: To examine national trends in glucose lowering medicine (GLM) use among older people with diabetes in long-term care facilities (LTCFs) during 2009-2019. METHODS: A repeated cross-sectional study of individuals ≥65 years with diabetes in Australian LTCFs (n = 140,322) was conducted. Annual age-sex standardised prevalence of GLM use and number of defined daily doses (DDDs)/1000 resident-days were estimated. Multivariable Poisson or Negative binomial regression models were used to estimate adjusted rate ratios (aRRs) and 95 % confidence intervals (CIs). RESULTS: Prevalence of GLM use remained steady between 2009 (63.9%, 95 %CI 63.3-64.4) and 2019 (64.3%, 95 %CI 63.9-64.8) (aRR 1.00, 95 %CI 1.00-1.00). The percentage of residents receiving metformin increased from 36.0% (95 %CI 35.3-36.7) to 43.5% (95 %CI 42.9-44.1) (aRR 1.01, 95 %CI 1.01-1.01). Insulin use also increased from 21.5% (95 %CI 21.0-22.0) to 27.0% (95 %CI 26.5-27.5) (aRR 1.02, 95 %CI 1.02-1.02). Dipeptidyl peptidase-4 inhibitor use increased from 1.0% (95 %CI 0.9-1.1) to 21.1% (95 %CI 20.7-21.5) (aRR 1.24, 95 %CI 1.24-1.25), while sulfonylurea use decreased from 34.4% (95 %CI 33.8-35.1) to 19.3% (95 %CI 18.9-19.7) (aRR 0.93, 95 %CI 0.93-0.94). Similar trends were observed in DDDs/1000 resident days. CONCLUSIONS: The increasing use of insulin and ongoing use of sulfonylureas suggests a need to implement evidence-based strategies to optimise diabetes care in LTCFs.

Predictors of mortality shortly after entering a long-term care facility.

OBJECTIVE: Moving into a long-term care facility (LTCF) requires substantial personal, societal and financial investment. Identifying those at high risk of short-term mortality after LTCF entry can help with care planning and risk factor management. This study aimed to: (i) examine individual-, facility-, medication-, system- and healthcare-related predictors for 90-day mortality at entry into an LTCF and (ii) create risk profiles for this outcome. DESIGN: Retrospective cohort study using data from the Registry of Senior Australians. SUBJECTS: Individuals aged ≥ 65 years old with first-time permanent entry into an LTCF in three Australian states between 01 January 2013 and 31 December 2016. METHODS: A prediction model for 90-day mortality was developed using Cox regression with the purposeful variable selection approach. Individual-, medication-, system- and healthcare-related factors known at entry into an LTCF were examined as predictors. Harrell's C-index assessed the predictive ability of our risk models. RESULTS: 116,192 individuals who entered 1,967 facilities, of which 9.4% (N = 10,910) died within 90 days, were studied. We identified 51 predictors of mortality, five of which were effect modifiers. The strongest predictors included activities of daily living category (hazard ratio [HR] = 5.41, 95% confidence interval [CI] = 4.99-5.88 for high vs low), high level of complex health conditions (HR = 1.67, 95% CI = 1.58-1.77 for high vs low), several medication classes and male sex (HR = 1.59, 95% CI = 1.53-1.65). The model out-of-sample Harrell's C-index was 0.773. CONCLUSIONS: Our mortality prediction model, which includes several strongly associated factors, can moderately well identify individuals at high risk of mortality upon LTCF entry.

National Trends in Antidepressant Use in Australian Residential Aged Care Facilities (2006-2019).

OBJECTIVES: Antipsychotics have been the focus of reforms for improving the appropriateness of psychotropic medicine use in residential aged care facilities (RACFs). Comprehensive evaluation of antidepressant use in RACFs is required to inform policy and practice initiatives targeting psychotropic medicines. This study examined national trends in antidepressant use among older people living in RACFs from 2006 to 2019. DESIGN: National repeated cross-sectional study. SETTING AND PARTICIPANTS: Individuals aged 65 to 105 years who were permanent, long-term (≥100 days) residents of Australian RACFs between January 2006 and December 2019 were included. METHODS: Annual age- and sex-adjusted antidepressant prevalence rates and defined daily doses (DDDs) supplied per 1000 resident-days from 2006 to 2019 were determined. Age- and sex-adjusted prevalence rate ratios (aRRs) and 95% confidence intervals (CIs) were estimated using Poisson and negative binomial regression models. RESULTS: A total of 779,659 residents of 3371 RACFs were included (786,227,380 resident-days). Overall, antidepressant use increased from 46.1% (95% CI, 45.9-46.4) in 2006 to 58.5% (95% CI, 58.3-58.8) of residents in 2019 (aRR, 1.02; 95% CI, 1.02-1.02). Mirtazapine use increased from 8.4% (95% CI, 8.2-8.5) to 20.9% (95% CI, 20.7-21.1) from 2006 to 2019 (aRR, 1.07; 95% CI, 1.07-1.07). Antidepressant use increased from 350.3 (95% CI, 347.6-353.1) to 506.0 (95% CI, 502.8-509.3) DDDs/1000 resident-days (aRR, 1.03; 95% CI, 1.03-1.03), with mirtazapine utilization increasing by 6% annually (aRR, 1.06; 95% CI, 1.06-1.06). CONCLUSIONS AND IMPLICATIONS: This nationwide study identified a substantial increase in antidepressant use among residents of Australian RACFs, largely driven by mirtazapine. With nearly 3 in every 5 residents treated with an antidepressant in 2019, findings highlight potential off-label use and suggest that interventions to optimize care are urgently needed.

Historical Trends and Future Projections of Demand for Permanent Residential Aged Care for Older People in Australia, 2008-2052.

OBJECTIVES: To examine the historical trends and predict the future rates and total volumes of permanent residential aged care (PRAC) service utilization in Australia. DESIGN: A population-based repeated cross-sectional and projection study of non-indigenous older people (≥65 years) accessing PRAC in Australia was conducted. SETTING AND PARTICIPANTS: Publicly available aged care admissions from the Australian Institute of Health and Welfare and population estimates from the Australian Bureau of Statistics were used. METHODS: Historical incidence rates (per 1000 people), incidence rate ratios (IRRs) and 95% CIs of PRAC admission from 2008-2009 to 2020-2021 were estimated using negative binomial regression models. The future incidence and prediction intervals (PIs) of PRAC admission between 2021-2022 and 2051-2052 were projected using a generalized additive model-negative binomial regression. All estimates were adjusted or standardized by sex and age. RESULTS: Between 2008-2009 and 2020-2021, the adjusted admission to PRAC decreased (from 23.6/1000 people to 15.7/1000 people with an IRR = 0.97/year, 95% CI 0.97-0.98). The projected PRAC admission rate will decrease to 12.1/1000 (95%PI 10.8-13.3) by 2037-2038 and 9.0/1000 (95%PI 7.6-10.4) by 2051-2052. The projected volume of PRAC admission will be 73,988 (95%PI 65,960-81,425) at its highest point in 2037-2038 and 64,579 (95%PI 54,258-74,543) in 2051-2052. CONCLUSIONS AND IMPLICATIONS: The utilization of PRAC has decreased in the past decade, and a predicted decrease in PRAC use in future years is estimated. However, the volume of PRAC utilization will still increase for the next 15 years (until 2037-2038) due to our increasingly older population. These findings can inform service planning of PRAC access in Australia.

Trends in utilisation of ultrasound by older Australians (2010-2019).

BACKGROUND: Older people have increasingly complex healthcare needs, often requiring appropriate access to diagnostic imaging, an essential component of their health and disease management planning. Ultrasound is a safe imaging tool used to diagnose several conditions commonly experienced by older people such as deep vein thrombosis. PURPOSE: To evaluate the utilisation of major ultrasound services by Australians ≥ 65 years old between 2009- and 2019. METHODS: This population-based and yearly cross-sectional study of ultrasound utilisation per 1,000 Australians ≥ 65 years old was conducted using publicly available data sources. Overall, examination site and age- and sex-specific incidence rate (IR) of ultrasound per 1,000 people, adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using negative binomial regression models. RESULTS: Over the study period, the crude utilisation of ultrasound increased by 83% in older Australians. Most ultrasound examinations were conducted on extremities (39%) and the chest (21%), with 25% of all ultrasounds investigating the vascular system. More men than women use ultrasounds of the chest (184/1,000 vs 268/1,000 people), particularly echocardiograms (177/1,000 vs 261/1,000 people), and abdomen (88/1,000 vs 92/1,000 people), especially in those ≥ 85 years old. Hip and pelvic ultrasound were used more by women than men (212/1,000 vs 182/1,000 people). There were increases in vascular abdominal (IRR:1.07, 95%CI:1.06-1.08) and extremeties (IRR:1.06, 95%CI:1.05-1.07) ultrasounds over the study period, particularly in ≥ 75 years old men. CONCLUSIONS: Ultrasound is a common and increasingly used diagnostic tool for conditions commonly experienced by older Australians.

The Utilization and National Variation of Plain X-Ray Services by Australian Residents of Long-Term Care Facilities.

OBJECTIVES: To (1) estimate incidence, trends, and determinants of government-subsidized diagnostic radiography (ie, plain x-ray) services utilization by Australian long-term care facility (LTCF) residents between 2009 and 2016; (2) examine national variation in services used. DESIGN: A repeated cross-sectional study. SETTING AND PARTICIPANTS: Australian LTCF residents who were ≥65 years old. METHODS: Medicare Benefits Schedule subsidized plain x-rays employed for diagnosing fall-related injuries, pneumonia, heart failure, and acute abdomen or bowel obstruction were identified. Yearly sex- and age-standardized utilization rates were calculated. Poisson and negative binomial regression models were employed. Facility-level variation was examined graphically. Overall and examination site-specific analyses were conducted. RESULTS: A total of 521,497 LTCF episodes for 453,996 individuals living in 3018 LTCFs were examined. The median age was 84 years (interquartile range 79-88), 65% (n = 339,116) were women, and 53.9% (n = 281,297) had dementia. In addition, 34.5% (n = 179,811) of episodes had at least one x-ray service. Overall, there was a 12% increase in utilization between 2009 and 2016 (from 535/1000 in 2009 to 602/1000 person-years in 2016, incidence rate ratio=1.02, 95% confidence interval 1.02-1.02). Factors associated with x-ray use included being 80-89 years old, being a man, not having dementia, having multiple health conditions (4-6 or ≥7 compared to 0-3), being at a smaller facility (0-24 bed compared to 50-74), facility located in the Australian state of New South Wales, or in major cities (compared to regional areas). National variation in x-ray service use, with largest differences observed by state, was detected. CONCLUSIONS AND IMPLICATIONS: Plain x-ray service utilization by LTCF residents increased 12% between 2009 and 2016. Sex, age, dementia status, having multiple health conditions as well as facility size, and location were associated with plain x-ray use in LTCFs and use varied geographically. Differences in x-ray service utilization by residents highlight lack of consistent access and potential over- or underutilization.

Trends in utilisation of plain X-rays by older Australians (2010-2019).

BACKGROUND: Older Australians are major health service users and early diagnosis is key in the management of their health. Radiological services are an important component of diagnosis and disease management planning in older Australians, but their national utilisation of diagnostic services has never been investigated in Australia. PURPOSE: This study aims to evaluate the utilisation of major plain X-rays by Australians ≥ 65 years old. METHODS: A population-based epidemiological evaluation and yearly cross-sectional analyses of X-ray examinations per 1,000 Australians aged ≥ 65 years old between 2009 and 2019 were conducted using publicly available Medicare Benefits Schedule and Australian Bureau of Statistics data sources. Age and sex specific incidence rate (IR) of plain X-rays per 1,000 Australians, adjusted incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using a negative binomial regression model. RESULTS: During the study period, the Australian population over 65 years old increased by 39% while the crude plain X-ray utilisation by this population increased by 63%. Most X-rays were conducted on extremities or the chest. Men used chest radiography more than women, and particularly for lungs, where the incidence increased the most in those ≥ 85 years old. There was an increase in X-rays of extremities and the hip joint between 2009-10 and 2013-14 in people ≥ 85 years old. CONCLUSION: The utilisation of plain X-rays of the chest, the gastro-intestinal tract and extremities was high and has increased among older Australians between 2009-10 and 2018-19. Plain X-rays remain a commonly used diagnostic tool for conditions affecting the older population.

Hospitalisation for lower respiratory viral infections in older people in residential aged care facilities.

OBJECTIVE: To quantify incidence, trends and outcomes associated with lower respiratory viral infection (LRVI) hospitalisations in Australian residential aged care facilities (RACFs). METHODS: A population-based cohort study of residents in RACFs aged ≥65 years from New South Wales (NSW), South Australia (SA) and Victoria (VIC) using data from the Registry of Senior Australians (2013-2016) was conducted. Age- and sex-standardised monthly and yearly LRVI hospitalisation incidences were calculated, and time trends and risk factors were assessed. RESULTS: Of 268 657 residents included over the study period, 12% had ≥1 LRVI hospitalisation. Average annual incidence/1000 residents was 7.1 [6.9-7.2] in 2013, increasing to 7.8 [7.7-8.1] in 2016. Males, increasing co-morbidity, presence of CHF, respiratory disease and hypertension had a higher incidence of LRVI hospitalisation. In-hospital mortality was 14%. Within 30 days following discharge, 15% died and 8% were readmitted. CONCLUSIONS: Prior to COVID-19, incidence of hospitalisation for LRVI in Australia's residential aged care population was increasing and was associated with significant morbidity and mortality.

Predictors of hospitalisations and emergency department presentations shortly after entering a residential aged care facility in Australia: a retrospective cohort study.

OBJECTIVES: To: (1) examine the 90-day incidence of unplanned hospitalisation and emergency department (ED) presentations after residential aged care facility (RACF) entry, (2) examine individual-related, facility-related, medication-related, system-related and healthcare-related predictors of these outcomes and (3) create individual risk profiles. DESIGN: Retrospective cohort study using the Registry of Senior Australians. Fine-Gray models estimated subdistribution HRs and 95% CIs. Harrell's C-index assessed risk models' predictive ability. SETTING AND PARTICIPANTS: Individuals aged ≥65 years old entering a RACF as permanent residents in three Australian states between 1 January 2013 and 31 December 2016 (N=116 192 individuals in 1967 RACFs). PREDICTORS EXAMINED: Individual-related, facility-related, medication-related, system and healthcare-related predictors ascertained at assessments or within 90 days, 6 months or 1 year prior to RACF entry. OUTCOME MEASURES: 90-day unplanned hospitalisation and ED presentation post-RACF entry. RESULTS: The cohort median age was 85 years old (IQR 80-89), 62% (N=71 861) were women, and 50.5% (N=58 714) had dementia. The 90-day incidence of unplanned hospitalisations was 18.0% (N=20 919) and 22.6% (N=26 242) had ED presentations. There were 34 predictors of unplanned hospitalisations and 34 predictors of ED presentations identified, 27 common to both outcomes and 7 were unique to each. The hospitalisation and ED presentation models out-of-sample Harrell's C-index was 0.664 (95% CI 0.657 to 0.672) and 0.655 (95% CI 0.648 to 0.662), respectively. Some common predictors of high risk of unplanned hospitalisation and ED presentations included: being a man, age, delirium history, higher activity of daily living, behavioural and complex care needs, as well as history, number and recency of healthcare use (including hospital, general practitioners attendances), experience of a high sedative load and several medications. CONCLUSIONS: Within 90 days of RACF entry, 18.0% of individuals had unplanned hospitalisations and 22.6% had ED presentations. Several predictors, including modifiable factors, were identified at the time of care entry. This is an actionable period for targeting individuals at risk of hospitalisations.

Predictors of short-term hospitalization and emergency department presentations in aged care.

OBJECTIVES: To examine individual, medication, system, and healthcare related predictors of hospitalization and emergency department (ED) presentation within 90 days of entering the aged care sector, and to create risk-profiles associated with these outcomes. DESIGN AND SETTING: Retrospective population-based cohort study using data from the Registry of Senior Australians. PARTICIPANTS: Older people (aged 65 and older) with an aged care eligibility assessment in South Australia between January 1, 2013 and May 31, 2016 (N = 22,130). MEASUREMENTS: Primary outcomes were unplanned hospitalization and ED presentation within 90 days of assessment. Individual, medication, system, and healthcare related predictors of the outcomes at the time of assessment, within 90 days or 1-year prior. Fine-Gray models were used to calculate subdistribution hazard ratios (sHR) and 95% confidence intervals (CI). Harrell's C-index assessed predictive ability. RESULTS: Four thousand nine-hundred and six (22.2%) individuals were hospitalized and 5028 (22.7%) had an ED presentation within 90 days. Predictors of hospitalization included: being a man (hospitalization sHR = 1.33, 95% CI 1.26-1.42), ≥3 urgent after-hours attendances (hospitalization sHR = 1.21, 95% CI 1.06-1.39), increasing frailty index score (hospitalization sHR = 1.19, 95% CI 1.11-1.28), individuals using glucocorticoids (hospitalization sHR = 1.11, 95% CI 1.02-1.20), sulfonamides (hospitalization sHR = 1.18, 95% CI 1.10-1.27), trimethoprim antibiotics (hospitalization sHR = 1.15, 95% CI 1.03-1.29), unplanned hospitalizations 30 days prior (hospitalization sHR = 1.13, 95% CI 1.04-1.23), and ED presentations 1 year prior (hospitalization sHR = 1.07, 95% CI 1.04-1.10). Similar predictors and hazard estimates were also observed for ED presentations. The hospitalization models out-of-sample predictive ability (C-index = 0.653, 95% CI 0.635-0.670) and ED presentations (C-index = 0.647, 95% CI 0.630-0.663) were moderate. CONCLUSIONS: One in five individuals with aged care eligibility assessments had unplanned hospitalizations and/or ED presentation within 90 days with several predictors identified at the time of aged care eligibility assessment. This is an actionable period for targeting at-risk individuals to reduce hospitalizations.

Effect of Dementia on Outcomes After Surgically Treated Hip Fracture in Older Adults.

BACKGROUND: Hip fractures are associated with increased mortality and functional limitations. However, the effect that dementia has on these outcomes in individuals in aged care settings after fracture is not well established. This study examined the association of dementia with post-hip fracture mortality, permanent residential aged care entry, transition care use, and change in activities of daily living (ADL) needs. METHODS: A retrospective cohort study using data from the Registry of Senior Australians (2003-2015) was conducted. Individuals with a hip fracture while receiving aged care services were included. Associations of dementia with mortality, risks of transition and permanent care use, and ADL needs progression were estimated using multivariable Cox, Fine-Gray, and logistic regression methods, respectively. RESULTS: Of 4771 individuals evaluated, 76% were women, the median age was 86 years (IQR 82-90), and 71% already lived in permanent residential aged care at the time of fracture. Within two years of their hip fracture, 50.4% (95% CI 48.9%-51.8%) of individuals died, 16.2% (95% CI 14.2%-18.2%) entered a transition care program, 59.1% (95% CI 56.5%-61.7%) entered permanent residential aged care, and 32% had greater ADL needs. Dementia was associated with higher risk of two-year mortality (HR = 1.19, 95% CI 1.09-1.30), 90-day entry into permanent care (sHR = 1.96, 95% CI 1.60-2.38), and increased likelihood of ADL limitations (OR = 1.36, 95% CI 1.00-1.85). Minor differences were seen in transition care use by dementia status. CONCLUSION: Dementia is a strong risk factor for mortality after hip fractures in individuals in aged care settings and associated with a high risk of entry into permanent care. LEVEL OF EVIDENCE: Prognostic level III.

An integrated knowledge translation approach to address avoidable rehospitalisations and unplanned admissions for older people in South Australia: implementation and evaluation program plan.

BACKGROUND: Repeated admission to hospital can be stressful for older people and their families and puts additional pressure on the health care system. While there is some evidence about strategies to better integrate care, improve older patients' experiences at transitions of care, and reduce preventable hospital readmissions, implementing these strategies at scale is challenging. This program of research comprises multiple, complementary research activities with an overall goal of improving the care for older people after discharge from hospital. The program leverages existing large datasets and an established collaborative network of clinicians, consumers, academics, and aged care providers. METHODS: The program of research will take place in South Australia focusing on people aged 65 and over. Three inter-linked research activities will be the following: (1) analyse existing registry data to profile individuals at high risk of emergency department encounters and hospital admissions; (2) evaluate the cost-effectiveness of existing 'out-of-hospital' programs provided within the state; and (3) implement a state-wide quality improvement collaborative to tackle key interventions likely to improve older people's care at points of transitions. The research is underpinned by an integrated approach to knowledge translation, actively engaging a broad range of stakeholders to optimise the relevance and sustainability of the changes that are introduced. DISCUSSION: This project highlights the uniqueness and potential value of bringing together key stakeholders and using a multi-faceted approach (risk profiling; evaluation framework; implementation and evaluation) for improving health services. The program aims to develop a practical and scalable solution to a challenging health service problem for frail older people and service providers.

The effect of frailty on outcomes of surgically treated hip fractures in older people.

BACKGROUND: Hip fractures are associated with mortality, disability, and loss of independence in older adults. While several risk factors associated with poor outcomes following a hip fracture have been identified, the effect of frailty status prior to hip fracture is not well established. AIM: To examine the associations of frailty with mortality, change in activities of daily living (ADL) limitations, and transition to permanent residential aged care in older people following a hip fracture. METHODS: A retrospective cohort study was conducted on people aged 65 years and older with a surgically treated hip fracture between 2003 and 2015. Frailty was estimated using a cumulative deficit-based frailty index and categorized into quartiles. Cox multivariable regression, logistic regression, and Fine-Gray multivariable regression models estimated associations of frailty with mortality, ADL limitations, and entry into permanent residential aged care, respectively. Hazard ratios (HR), odds ratios (OR), subdistribution hazard ratios (SHR), and 95% confidence intervals (95%CI) are reported. RESULTS: Out of 4771 individuals with hip fractures, 75.6% were female and the median age was 86 (interquartile range 82-90) years old. The two-year survival of patients following hip fracture was 43.7% (95%CI 40.9-46.7%) in those in the highest quartile of frailty, compared to 54.4% (95%CI 51.8-57.2%) for those in the lowest quartile (HR = 1.25, 95%CI 1.11-1.41, p < 0.001). No associations between pre-fracture frailty and post-fracture ADL limitations were observed. Additionally, no association of frailty with transition to permanent residential aged care for patients living in the community (n = 1361) was observed (SHR = 0.98, 95%CI 0.81-1.18, p = 1.000). CONCLUSIONS: Older patients with the highest level of frailty had an increased risk of mortality after hip fracture. Consideration for appropriate clinical interventions, including fall and frailty prevention measures, may be appropriate for this identified group of vulnerable individuals.

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems.

Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early-stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer-specific (CSS) or recurrence-free survival (RFS). The US patient cohort-based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5-year OS, CSS and RFS prediction differences of -6.5% to -9.9%, -9.1% to -14.4% and - 3.8% to -6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient-based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort-based survival calculators for early-stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi-feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting.

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors.

ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human colorectal cancer xenografts. MACROD2 deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988-1005. ©2018 AACR.See related commentary by Jin and Burkard, p. 921This article is highlighted in the In This Issue feature, p. 899.