Measurement that matters: A systematic review and modified Delphi of multidisciplinary colorectal cancer quality indicators.

AIM: To develop a priority set of quality indicators (QIs) for use by colorectal cancer (CRC) multidisciplinary teams (MDTs). METHODS: The review search strategy was executed in four databases from 2009-August 2019. Two reviewers screened abstracts/manuscripts. Candidate QIs and characteristics were extracted using a tailored abstraction tool and assessed for scientific soundness. To prioritize candidate indicators, a modified Delphi consensus process was conducted. Consensus was sought over two rounds; (1) multidisciplinary expert workshops to identify relevance to Australian CRC MDTs, and (2) an online survey to prioritize QIs by clinical importance. RESULTS: A total of 93 unique QIs were extracted from 118 studies and categorized into domains of care within the CRC patient pathway. Approximately half the QIs involved more than one discipline (52.7%). One-third of QIs related to surgery of primary CRC (31.2%). QIs on supportive care (6%) and neoadjuvant therapy (6%) were limited. In the Delphi Round 1, workshop participants (n = 12) assessed 93 QIs and produced consensus on retaining 49 QIs including six new QIs. In Round 2, survey participants (n = 44) rated QIs and prioritized a final 26 QIs across all domains of care and disciplines with a concordance level > 80%. Participants represented all MDT disciplines, predominantly surgical (32%), radiation (23%) and medical (20%) oncology, and nursing (18%), across six Australian states, with an even spread of experience level. CONCLUSION: This study identified a large number of existing CRC QIs and prioritized the most clinically relevant QIs for use by Australian MDTs to measure and monitor their performance.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The use of intraperitoneal chemotherapy for advanced ovarian cancer - The experience of a tertiary referral centre.

BACKGROUND: Platinum-based chemotherapy is the backbone of the medical management of ovarian cancer. The dose, route and timing of treatment are ongoing areas of debate. Intraperitoneal (IP) chemotherapy is an alternative delivery method treatment to the conventional intravenous (IV) route for patients with epithelial ovarian cancer, with efficacy supported by Level 1 evidence. AIMS: To compare the outcomes and feasibility of IP to IV delivery of platinum-based chemotherapy in patients with advanced epithelial ovarian cancer. MATERIALS AND METHODS: In a single institution, patients receiving adjuvant chemotherapy (IP and IV) for Stages III and IV epithelial ovarian cancer over the period January 2006-December 2018 were identified through a prospectively maintained database. All patients with an IP port inserted were included. A control group of patients treated with IV chemotherapy was created using criteria identified during the study and in the randomised trials that tested IP chemotherapy. Assessments were made for relapse-free survival (RFS) and overall survival (OS) for each cohort. RESULTS: A total of 639 patients received adjuvant chemotherapy (73 IP and 566 IV) during the study period. Both the IP group and matched IV control group (65 patients) had a median RFS of 26 months. The median OS in the IP group was 63.9 months, and in the IV group was 57.2 months. At ten years, a significantly higher proportion of patients were alive in the IP group cohort (16% vs 3%, relative risk 5.5, 95% CI 1.29-24, P = 0.012). IP chemotherapy was well tolerated by our cohort. In the IP group, 73% had four or more IP cycles and 99% received six or more cycles of chemotherapy. CONCLUSIONS: Our cohort had a high rate of completion of IP chemotherapy with excellent rates of completion of six cycles of any treatment. The RFS and OS in the IP chemotherapy group were comparable to each other and reflected those in the published literature. A significantly higher proportion of patients in the IP cohort were alive at ten years than in the IV cohort.

Feasibility of Microlearning for Improving the Self-Efficacy of Cancer Patients Managing Side Effects of Chemotherapy.

Lung cancer patients have a high symptom burden that negatively affects their quality of life. Increasing patient self-efficacy to deal with treatment side effects can ameliorate their symptom burden. Education programs can help enhance patient self-efficacy by giving patients more control over their condition through increased disease literacy. This study aimed to evaluate the feasibility of microlearning for delivering lung cancer patients' information on side effects of chemotherapy. Secondary objectives of the program are to understand the acceptability of microlearning for delivery this type of education to lung cancer patients and the potential impact of microlearning on patient self-efficacy, knowledge and confidence managing side effects of chemotherapy. A mixed-methods prepost test (or quasi-experimental) study design was used to better enable patients to identify and manage the side effects of their condition and chemotherapy. Participants were patients diagnosed with stage II to stage IV lung cancer, who had a life expectancy of greater than 3 months and were aged 18 years or older. Multiple validated scales were used to assess patient self-efficacy pre- and post-intervention. The online program was evaluated using quantitative data of completion rates extracted from the online platform. Semi-structured interviews were used to explore the impact of the online program on perceived self-efficacy and quality of life. Twenty-three participants agreed to participate in the study and five agreed to complete a semi-structured interview. Participants found the content comprehensive, relevant and engaging. The program improved perceived disease literacy and helped participants develop coping strategies to manage side effects. Participants also found the platform easy to use and navigate. Additional courses and features were requested. Patients with a diagnosis of cancer receive a large amount of information about the side effects of chemotherapy and how to manage them. This information is often provided soon after diagnosis or upon commencement of therapy, which can be overwhelming for some patients. Microlearning, a method of online learning that spaces distributing of content over several weeks, may be a useful tool for supporting delivering of health information to this group of patients.

Qualitative study of international key informants' perspectives on the current and future state of healthcare quality measurement and feedback.

OBJECTIVES: The aim of this study is to explore the current and future state of quality measurement and feedback and identify factors influencing measurement feedback systems, including the barriers and enablers to their effective design, implementation, use and translation into quality improvement. DESIGN: This qualitative study used semistructured interviews with key informants. A deductive framework analysis was conducted to code transcripts to the Theoretical Domains Framework (TDF). An inductive analysis was used to produce subthemes and belief statements within each TDF domain. SETTING: All interviews were conducted by videoconference and audio-recorded. PARTICIPANTS: Key informants were purposively sampled experts in quality measurement and feedback, including clinical (n=5), government (n=5), research (n=4) and health service leaders (n=3) from Australia (n=7), the USA (n=4), the UK (n=2), Canada (n=2) and Sweden (n=2). RESULTS: A total of 17 key informants participated in the study. The interview length ranged from 48 to 66 min. 12 theoretical domains populated by 38 subthemes were identified as relevant to measurement feedback systems. The most populous domains included environmental context and resources, memory, attention and decision-making, and social influences. The most populous subthemes included 'quality improvement culture', 'financial and human resource support' and 'patient-centred measurement'. There were minimal conflicting beliefs outside of 'data quality and completeness'. Conflicting beliefs in these subthemes were predominantly between government and clinical leaders. CONCLUSIONS: Multiple factors were found to influence measurement feedback systems and future considerations are presented within this manuscript. The barriers and enablers that impact these systems are complex. While there are some clear modifiable factors in the design of measurement and feedback processes, influential factors described by key informants were largely socioenvironmental. Evidence-based design and implementation, coupled with a deeper understanding of the implementation context, may lead to enhanced quality measurement feedback systems and ultimately improved care delivery and patient outcomes.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

An investigation of the utility of the Australian Guide to the Diagnosis of Fetal Alcohol Spectrum Disorder in young children.

BACKGROUND: Early diagnosis of children with fetal alcohol spectrum disorder (FASD) assists in implementing critical early support. The challenge lies in having a diagnostic process that enables valid and reliable assessment of domains of functioning in young children, with the added complexity that many children will also have co-occurring exposure to childhood adversity that is likely to impact these domains. METHODS: The aim of this study was to test a diagnostic assessment of FASD in young children using the Australian Guide to the Diagnosis of FASD. Ninety-four children (aged 3 to 7 years) with confirmed or suspected prenatal alcohol exposure were referred to two specialist FASD clinics for assessment in Queensland, Australia. RESULTS: There was a significant risk profile with 68.1% (n = 64) children having had contact with child protection services, and most children living in kinship (n = 22, 27.7%) or foster (n = 36, 40.4%) care. Forty-one percent of the children were Indigenous Australians. The majority (64.9%, n = 61) of children met criteria for FASD, 30.9% were classified as "At Risk" for FASD (n = 29), and 4.3% received no FASD diagnosis (n = 4). Only 4 (4%) children were rated as severe for the brain domain. Over 60% of children (n = 58) had two or more comorbid diagnoses. Sensitivity analyses indicated that the removal of comorbid diagnoses in the Attention, Affect Regulation, or Adaptive Functioning domains resulted in a change in 7 of 47 cases (15%) to an "At Risk" designation. CONCLUSIONS: These results highlight the complexity of presentation and the extent of impairment in the sample. The use of comorbid diagnoses to substantiate a "severe" designation in specific neurodevelopmental domains raises the question of whether there were false-positive diagnoses. The complexity of determining causal relationships between exposure to PAE and early life adversity on developmental outcomes continues to be a challenge in this young population.

Mainstream genetic testing for high-grade ovarian, tubal and peritoneal cancers: A tertiary referral centre experience.

BACKGROUND: Fifteen percent of ovarian, tubal, and peritoneal (OTP) invasive epithelial cancers are linked to an underlying heritable pathogenic variant (PV) in the BRCA1/2 cancer susceptibility genes. Identifying a PV has management implications for an affected individual and relatives. Cancer team-facilitated genetic testing (mainstreaming) aims to provide equitable systematic access to genetic testing for appropriate patients. AIM: To evaluate a multi-disciplinary team (MDT)-led mainstream germline genetic testing program for OTP cancer at a tertiary referral centre. MATERIALS AND METHODS: We conducted a retrospective review of our MDT-led mainstream genetic testing program initiated in June 2017. We included all patients diagnosed with OTP cancer registered with the hospital gynaecological oncology MDT from program initiation to December 2020. Patients were considered eligible for testing if they were diagnosed with a high-grade epithelial OTP AND ≤70 years, OR if >70 with a first/second degree relative with breast and/or ovarian cancer OR Jewish ancestry. RESULTS: Of 205 women diagnosed with high-grade epithelial OTP cancer, 140 were eligible for mainstreaming. Eight-five percent were mainstreamed, with the gynae-oncologists facilitating 64.5% of tests. The overall PV detection rate in BRCA1/2 was 10.1% (BRCA1 n = 9, BRCA2 n = 3). The median turnaround time (TAT) was 44.5 days (range 16-118). All women with PV were referred to the Familial Cancer Service for further assessment and five (of six eligible; 83%) were subsequently treated with polyadenosine diphosphate ribose polymerase inhibitors. Cascade testing was undertaken in 75% of families with a mean of three relatives tested per proband. CONCLUSION: Mainstreamed genetic testing is feasible, with an acceptable TAT, ensuring adequate opportunity to inform treatment decisions. Tumour testing and inclusion of moderate-risk cancer predisposition genes in mainstreaming represent potential pathways that will require further exploration.

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma.

BACKGROUND: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. METHODS: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. RESULTS: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). CONCLUSIONS: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

The impact of posttraumatic stress disorder on the psychological distress, positivity, and well-being of Australian police officers.

OBJECTIVE: Police officers experience many traumatic events over the course of their career, often resulting in posttraumatic stress disorder (PTSD) and associated psychological distress. Studies have investigated the efficacy of interventions aimed at reducing symptoms of PTSD experienced by police officers, but lacking are studies investigating the impact of PTSD on positivity, a construct we define as a latent variable estimated using self-report measures of optimism, gratitude, self-compassion, and mindfulness. The present study carried out a path analysis of a model testing the hypothesis that PTSD would be associated with increased psychological distress and decreased positivity, both of which influence well-being. The model also evaluated associations between constructs that could be modified through interventions to increase well-being-associations between posttraumatic growth, social support, physical activity and psychological distress, positivity, and well-being. METHOD: Police officers (n = 506) completed an online survey that included self-report measures of the constructs included in the model being tested. RESULTS: The model tested produced fit indices of root mean square error of approximation (RMSEA) = .089; comparative fit index (CFI) = .960; Tucker-Lewis index (TLI) = .93; standardized root mean square residual (SRMR) = .041 and R² = .79. Results found that neither PTSD or psychological distress had a direct effect on well-being. Psychological distress indirectly influenced well-being by lowering levels of positivity, while positivity was associated with higher scores on the measure of well-being. CONCLUSIONS: The implication of the results is that interventions aimed at enhancing positivity could be expected to improve well-being in police officers and offering traditional therapies together with positivity enhancing therapies may have additional benefits over either alone. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Policies are Needed to Increase the Reach and Impact of Evidence-Based Parenting Supports: A Call for a Population-Based Approach to Supporting Parents, Children, and Families.

Parents can be essential change-agents in their children's lives. To support parents in their parenting role, a range of programs have been developed and evaluated. In this paper, we provide an overview of the evidence for the effectiveness of parenting interventions for parents and children across a range of outcomes, including child and adolescent mental and physical health, child and adolescent competencies and academic outcomes, parental skills and competencies, parental wellbeing and mental health, and prevention of child maltreatment and family violence. Although there is extensive research showing the effectiveness of evidence-based parenting programs, these are not yet widely available at a population level and many parents are unable to access support. We outline how to achieve increased reach of evidence-based parenting supports, highlighting the policy imperative to adequately support the use of these supports as a way to address high priority mental health, physical health, and social problems.

The Relationship Between Sensory Processing and Attachment Patterns: A Scoping Review.

Background. Clinicians and researchers have observed that sensory processing and attachment difficulties frequently co-occur; however, little is known about which sensory processing and attachment patterns are interrelated across populations. Purpose. To review evidence of empirical relationships between sensory processing and attachment patterns across the life span. Method. Using the Arksey and O'Malley framework, four databases were searched up to June 2021 for studies that investigated relationships between sensory processing and attachment patterns. Findings. Twenty-two studies met inclusion criteria: nine considered sensory and attachment patterns in children/adolescents and thirteen in adults. In children, sensory modulation was positively associated with attachment security. In adults, more extreme patterns of sensory modulation (e.g., higher sensory sensitivity) were generally associated with attachment insecurity. Implications. Findings indicate empirical relationships between sensory processing and attachment constructs in children and adults that warrant further investigation. Occupational therapists should consider both sensory processing and attachment patterns when planning interventions.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

A review of Australian Government funding of parenting intervention research.

OBJECTIVES: Parenting is central to children's optimal development and accounts for a substantial proportion of the variance in child outcomes, including up to 40% of child mental health. Parenting is also one of the most modifiable, proximal, and direct factors for preventing and treating a range of children's problems and enhancing wellbeing. To determine the effectiveness of new approaches to parenting intervention, and to evaluate how to optimise reach and uptake, sufficient funding must be allocated for high quality research. METHOD: We reviewed funding awarded by the National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) for parenting intervention research during 2011-2020. RESULTS: Parenting intervention research received 0.25% of the NHMRC and ARC research budgets. CONCLUSIONS: There is a substantial mismatch between the funding of parenting intervention research and the impact of improved parenting on short- and long-term child outcomes. To rectify this, it is critical that Australian Government funding schemes include parenting interventions as priority areas for funding. IMPLICATIONS FOR PUBLIC HEALTH: Changes in allocation of funding to parenting research will support the establishment of evidence for the effective development, implementation and dissemination of parenting interventions to maximise health outcomes for children and their families.

A Systematic Review of Electronic Medical Record Driven Quality Measurement and Feedback Systems.

Historically, quality measurement analyses utilize manual chart abstraction from data collected primarily for administrative purposes. These methods are resource-intensive, time-delayed, and often lack clinical relevance. Electronic Medical Records (EMRs) have increased data availability and opportunities for quality measurement. However, little is known about the effectiveness of Measurement Feedback Systems (MFSs) in utilizing EMR data. This study explores the effectiveness and characteristics of EMR-enabled MFSs in tertiary care. The search strategy guided by the PICO Framework was executed in four databases. Two reviewers screened abstracts and manuscripts. Data on effect and intervention characteristics were extracted using a tailored version of the Cochrane EPOC abstraction tool. Due to study heterogeneity, a narrative synthesis was conducted and reported according to PRISMA guidelines. A total of 14 unique MFS studies were extracted and synthesized, of which 12 had positive effects on outcomes. Findings indicate that quality measurement using EMR data is feasible in certain contexts and successful MFSs often incorporated electronic feedback methods, supported by clinical leadership and action planning. EMR-enabled MFSs have the potential to reduce the burden of data collection for quality measurement but further research is needed to evaluate EMR-enabled MFSs to translate and scale findings to broader implementation contexts.

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

Interventions for improving executive functions in children with foetal alcohol spectrum disorder (FASD): A systematic review.

Background: The consequences for children born with birth defects and developmental disabilities encompassed by foetal alcohol spectrum disorder (FASD) are profound, affecting all areas of social, behavioural and cognitive functioning. Given the strong evidence for a core deficit in executive functioning, underpinned by impaired self-regulation skills, there has been a growing focus on the development of interventions that enhance or support the development of executive functions (EFs). Objectives: The primary objective of this review is to synthesise the evidence for structured psychological interventions that explicitly aim to improve EF in children. The review also sought to ascertain if the effectiveness of interventions were influenced by characteristics of the intervention, participants or type of EF targeted by the intervention. Search Methods: Sixteen databases, 18 grey literature search locations and 9 trial registries were systematically searched to locate eligible studies (up to December 2020). These searches were supplemented with reference harvesting, forward citation searching, hand searches of topic-relevant journals and contact with experts. Selection Criteria: Studies were included in the review if they reported on an impact evaluation of a psychological intervention aiming to improve EF in children 3-16 years who either had confirmed prenatal alcohol exposure or a formal diagnosis falling under the umbrella term of FASDs. Eligible study designs included randomised controlled trials (RCTs) and quasi-experimental designs with either no treatment, wait list control or an alternative treatment as a comparison condition. Single-group pre-post designs were also included. Data Collection and Analysis: Standard methodological procedures expected by the Campbell Collaboration were used at all stages of this review. Standardised mean differences (SMDs) were used to estimate intervention effects, which were combined with random effects meta-analysis (data permitting). Risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB2) and Cochrane Risk of Bias in Non-Randomised Studies-Interventions tool (ROBINS-I). Main Results: The systematic search identified 3820 unique records. After title/abstract and full-text screening, 11 eligible studies (reported in 21 eligible documents) were deemed eligible, with a combined 253 participants. Of the 11 studies, 6 were RCTs, 1 was a quasi-experiment and 4 were single-group pre-post intervention designs. All studies were rated as having an overall high or serious risk of bias, with some variation across domains for RCTs. For RCT and quasi-experimental studies, the overall effect of EF interventions on direct and indirect measures of EF generally favoured the experimental condition, but was not statistically significant. There was no difference between intervention and comparison groups on direct measures of auditory attention (k = 3; SMD = 0.06, 95% confidence interval [CI] = -1.06, 1.18), visual attention (k = 2; SMD = 0.90, 95% CI = -1.41, 3.21), cognitive flexibility (k = 2; SMD = 0.23, 95% CI = -0.40, 0.86), attentional inhibition (k = 2; SMD = 0.04, 95% CI = -0.58, 0.65), response inhibition (k = 3; SMD = 0.47, 95% CI = -0.04, 0.99), or verbal working memory (k = 1; d = 0.6827; 95% CI = -0.0196, 1.385). Significant heterogeneity was found across studies on measures of auditory attention and visual attention, but not for measures of cognitive flexibility, attentional inhibition or response inhibition. Available data prohibited further exploration of heterogeneity. There was no statistical difference between intervention and comparison groups on indirect measures of global executive functioning (k = 2; SMD = 0.21, 95% CI = -0.40, 0.82), behavioural regulation (k = 2; SMD = 0.18, 95% CI = -0.43, 0.79), or emotional control (k = 3; SMD = 0.01, 95% CI = -0.33, 0.36). Effect sizes were positive and not significant for meta-cognition (k = 1; SMD = 0.23, 95% CI = -0.72, 1.19), shifting (k = 2; SMD = 0.04, 95% CI = -0.35, 0.43), initiation (k = 1; SMD = 0.04, 95% CI = -0.40, 0.49), monitoring (k = 1; SMD = 0.25, 95% CI = -0.20, 0.70) and organisation of materials (k = 1; SMD = 0.25, 95% CI = -0.19, 0.70). Effect sizes were negative and not statistically different for effortful control (k = 1; SMD = -0.53, 95% CI = -1.50, 0.45), inhibition (k = 2; SMD = -0.08, 95% CI = -0.47, 0.31), working memory (k = 1; SMD = 0.00, 95% CI = -0.45, 0.44), and planning and organisation (k = 1; SMD = -0.10, 95% CI = -0.55, 0.34). No statistically significant heterogeneity was found for any of the syntheses of indirect measures of EF. Based on pre-post single-group designs, there was evidence for small to medium sized improvements in EF based on direct measures (cognitive flexibility, verbal working memory and visual working memory) and indirect measures (behavioural regulation, shifting, inhibition and meta-cognition). However, these results must be interpreted with caution due to high risk of bias. Authors' Conclusions: This review found limited and uncertain evidence for the effectiveness of interventions for improving executive functioning in children with FASD across 8 direct and 13 indirect measures of EF. The findings are limited by the small number of high-quality studies that could be synthesised by meta-analysis and the very small sample sizes for the included studies.