Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells.

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: lower rates for 5-years post chemotherapy.

BACKGROUND: The identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis. METHODS: We reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1=541). Cumulative annual breast cancer incidence was assessed at 2,5,10 and >10 years following ovarian cancer diagnosis date. RESULTS: Breast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1=425). Incidence was lower at 2years (1.18%) and 2-5years (1.13%), but rose thereafter for BRCA1 with incidence post 10years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple negative breast cancer and more lower grade hormone-receptor positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer post-ovarian cancer diagnosis were due to breast cancer. CONCLUSION: Women can be reassured that incidence of breast cancer post-ovarian diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years.

Telemental Health Use Is Associated With Lower Health Care Spending Among Medicare Beneficiaries With Major Depression.

BACKGROUND: Some policymakers are concerned that expanding telehealth coverage may increase Medicare expenditures. However, there is limited evidence on the association of telehealth use with utilization and spending among Medicare beneficiaries with major depression. OBJECTIVE: To examine the differences in spending and utilization among telemental health users and non-telemental health users with major depression. METHODS: We examined 2014-2019 traditional Medicare claims data for beneficiaries aged ≥50 years with major depression in Texas. Multivariable generalized linear models were used to assess the relationships between telemental health use and Medicare spending and utilization while adjusting for patient demographics and programmatic and clinical factors. RESULTS: In each of the years between 2014 and 2019, an average of 4.6% Medicare beneficiaries with major depression had at least 1 telemental health visit. Compared with beneficiaries without a telemental health visit, those who had a telemental health visit were significantly more likely to be enrolled in Medicaid, be Medicare eligible due to a disability, live in a lower income area or in a rural area, and have a higher comorbidity index. Beneficiaries utilizing telemental health services incurred higher unadjusted Medicare spending than those not receiving telemental health services. However, this difference appeared due to beneficiary and programmatic characteristics rather than telemental health use. Adjusting for model covariates, the telemental health group had lower overall per member per year predicted spending, inpatient admissions, and emergency department visits than non-telemental health users. CONCLUSION: Our findings suggest that telemental health care use may improve access to mental health care without increasing Medicare spending among telemental health users in Texas.

A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer.

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Exploiting a living biobank to delineate mechanisms underlying disease-specific chromosome instability.

Chromosome instability (CIN) is a cancer hallmark that drives tumour heterogeneity, phenotypic adaptation, drug resistance and poor prognosis. High-grade serous ovarian cancer (HGSOC), one of the most chromosomally unstable tumour types, has a 5-year survival rate of only ~30% - largely due to late diagnosis and rapid development of drug resistance, e.g., via CIN-driven ABCB1 translocations. However, CIN is also a cell cycle vulnerability that can be exploited to specifically target tumour cells, illustrated by the success of PARP inhibitors to target homologous recombination deficiency (HRD). However, a lack of appropriate models with ongoing CIN has been a barrier to fully exploiting disease-specific CIN mechanisms. This barrier is now being overcome with the development of patient-derived cell cultures and organoids. In this review, we describe our progress building a Living Biobank of over 120 patient-derived ovarian cancer models (OCMs), predominantly from HGSOC. OCMs are highly purified tumour fractions with extensive proliferative potential that can be analysed at early passage. OCMs have diverse karyotypes, display intra- and inter-patient heterogeneity and mitotic abnormality rates far higher than established cell lines. OCMs encompass a broad-spectrum of HGSOC hallmarks, including a range of p53 alterations and BRCA1/2 mutations, and display drug resistance mechanisms seen in the clinic, e.g., ABCB1 translocations and BRCA2 reversion. OCMs are amenable to functional analysis, drug-sensitivity profiling, and multi-omics, including single-cell next-generation sequencing, and thus represent a platform for delineating HGSOC-specific CIN mechanisms. In turn, our vision is that this understanding will inform the design of new therapeutic strategies.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Implementing a Treatment for People with Serious Mental Illness in Jail: A Mixed-Methods Study of Stakeholder Perspectives on Feasibility and Acceptability.

People with mental illness are over-represented in the U.S. criminal legal system. Jail presents an optimal opportunity to provide needed mental health care as the entry point to corrections. However, there is a lack of programming available in jails, which may be partly due to limited understanding of how to successfully implement interventions in this complex setting. We implemented a nine-session psychotherapeutic intervention for people with serious mental illness in a county jail. As part of a larger implementation-effectiveness hybrid study, we gathered mixed-methods data from stakeholders (treatment recipients and jail administrators) on the feasibility and acceptability of the intervention's implementation. In focus group discussions and qualitative interviews, treatment recipients (n = 29) provided qualitative and quantitative data on their perceptions of the implementation's feasibility and acceptability. Jail administrators (n = 6) completed two quantitative self-report measures on their perceptions of the treatment's feasibility and acceptability. Qualitative analyses were conducted by two coders using inductive thematic template analysis; seven global themes relating to treatment recipients' perceptions of the assets and hindrances to feasibility and acceptability were developed and are presented with supporting quotations. Quantitatively, all treatment recipients endorsed the intervention's feasibility (100%), and nearly all (97%) endorsed its acceptability. On both self-report measures, jail administrators' mean scores fell above a-priori thresholds indicating feasibility and acceptability. We found qualitative and quantitative support for the use of this intervention in jail from both sets of stakeholders. These results have implications for clinical service and policy in jail, where service providers struggle to meet the considerable demand for mental health services.

A pilot multiple-baseline study of a mobile cognitive behavioral therapy for the treatment of eating disorders in university students.

OBJECTIVE: Eating disorders (EDs) are serious psychiatric disorders associated with substantial morbidity and mortality that are prevalent among university students. Because many students do not receive treatment due to lack of access on university campuses, mobile-health (mHealth) adaptations of evidence-based treatments represent an opportunity to increase treatment accessibility and engagement. The purpose of this study was to test the initial efficacy of Building Healthy Eating and Self-Esteem Together for University Students (BEST-U), which is a 10-week mHealth self-guided cognitive-behavioral therapy (CBT-gsh) app that is paired with a brief 25-30-min weekly telehealth coaching, for reducing ED psychopathology in university students. METHOD: A non-concurrent multiple-baseline design (N = 8) was used to test the efficacy of BEST-U for reducing total ED psychopathology (primary outcome), ED-related behaviors and cognitions (secondary outcomes), and ED-related clinical impairment (secondary outcome). Data were examined using visual analysis and Tau-BC effect-size calculations. RESULTS: BEST-U significantly reduced total ED psychopathology and binge eating, excessive exercise, and restriction (effect sizes ranged from -0.39 to -0.92). Although body dissatisfaction decreased, it was not significant. There were insufficient numbers of participants engaging in purging to evaluate purging outcomes. Clinical impairment significantly reduced from pre-to-post-treatment. DISCUSSION: The current study provided initial evidence that BEST-U is a potentially efficacious treatment for reducing ED symptoms and ED-related clinical impairment. Although larger-scale randomized controlled trials are needed, BEST-U may represent an innovative, scalable tool that could reach greater numbers of underserved university students than traditional intervention-delivery models. PUBLIC SIGNIFICANCE: Using a single-case experimental design, we found evidence for the initial efficacy of a mobile guided-self-help cognitive-behavioral therapy program for university students with non-low weight binge-spectrum eating disorders. Participants reported significant reductions in ED symptoms and impairment after completion of the 10-week program. Guided self-help programs show promise for filling an important need for treatment among university students with an ED.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

Designing and developing a nature-based virtual reality with heart rate variability biofeedback for surgical anxiety and pain management: evidence from total knee arthroplasty patients.

OBJECTIVES: Total knee arthroplasty (TKA) is one of the most common joint surgeries, with over a million procedures performed annually in the US. Over 70% of patients report moderate to high pain and anxiety surrounding TKA surgery, and 96% are discharged with an opioid prescription. This population requires special attention as approximately 90% of TKA patients are older adults and one of the riskiest groups prone to misusing opioids. This study aimed to develop and compare the efficacy of nature-based virtual reality (VR) with heart rate variability biofeedback (HRVBF) to mitigate surgical pain and anxiety. METHODS: This randomized control trial recruited 30 patients (mean age = 66.3 ± 8.2 years, 23 F, 7 M) undergoing TKA surgery and randomly assigned to a control, 2D video with HRVBF, or VR with HRVBF group. A visual analog scale (VAS) was used to measure pain levels before and after the intervention. In addition, a second VAS and the State-Trait Anxiety Inventory (STAI) were used to measure anxiety before and after the intervention. Electrocardiogram (ECG) was used to continuously measure HRV and respiration rate in preoperative and postoperative settings. RESULTS: VR and 2D-video with HRVBF decreased pain and anxiety post-intervention compared with the control group, p's <.01. On analyzing physiological signals, both treatment groups showed greater parasympathetic activity levels, and VR with HRVBF reduced pain more than the 2D video, p < .01. CONCLUSIONS: Nature-based VR and 2D video with HRVBF can mitigate surgical pain and anxiety. However, VR may be more efficacious than 2D video in reducing pain.

Use of Gabapentin for Alcohol Withdrawal Syndrome in the Hospital Setting: A Randomized Open-Label Controlled Trial.

Background/objectives: Patients hospitalized with alcohol withdrawal syndrome (AWS) are typically treated with CIWA-directed benzodiazepines to prevent complications, such as seizures and delirium tremens. Gabapentin is an evidence-based alternative to benzodiazepines in the outpatient setting, but there is limited data for hospitalized patients with AWS. This study compared fixed-dose gabapentin to CIWA-directed benzodiazepines for AWS in the hospital setting. Methods: This open-label, randomized controlled trial enrolled 88 adults from February 1, 2017 to August 16, 2020 with a risk of complicated alcohol withdrawal as defined by the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) ≥4. Patients were randomized within 16 h of admission to either fixed-dose gabapentin taper or continued CIWA-directed benzodiazepine administration. The primary outcome was the length of stay (LOS). Secondary outcomes included seizure, delirium tremens, ICU transfer, and patient-reported symptoms (alcohol cravings, anxiety, sleepiness). Results: LOS was shorter, but not statistically different in the gabapentin group compared to the benzodiazepine group. Because benzodiazepines were received in both gabapentin and benzodiazepine groups before randomization, the mean amount of benzodiazepines received in each group was also not statistically different, although the amount received by the gabapentin group was less than half of that received by the benzodiazepine group (4.3 vs. 10.6 mg, p = 0.146 by per protocol analysis). There were no statistical differences in secondary measures. Conclusions: Fixed-dose gabapentin taper showed similar outcomes compared to CIWA-directed benzodiazepines for the treatment of hospitalized patients with mild/moderate AWS, but the interpretation of the results is limited due to under-enrollment and the use of benzodiazepines in both groups pre-enrollment.Clinical trial registration: NCT03012815.

Examining the relationship between dysmorphia symptoms and suicidality through the lens of the Interpersonal Theory of Suicide.

OBJECTIVE: Using the Interpersonal Theory of Suicide (IPTS) as a framework, this two-study investigation tested whether burdensomeness and low belongingness explained the association between body and muscle dysmorphia symptoms and suicidal ideation (tested in Study 1 and Study 2), and if fearlessness about death and pain tolerance explained the association between dysmorphia symptoms and previous suicide attempt frequency (tested in Study 2). METHODS: Study 1 used a community sample (n = 273) and Study 2 used an at-risk population sample (n = 261). Participants completed cross-sectional questionnaires online. RESULTS: In Study 1, both types of dysmorphic symptoms related to suicidal ideation through burdensomeness, but only body dysmorphic symptoms related to suicidal ideation through low belongingness. In Study 2, results were replicated as both types of dysmorphic symptoms related to suicidal ideation through burdensomeness. While both types of symptoms related to low belonging, low belonging did not relate to suicidal ideation. Neither dysmorphic symptoms nor capability for suicide related to frequency of suicide attempts. CONCLUSIONS: Results suggest that improving interpersonal needs, such as feeling more effective, may be important treatment targets for individuals with dysmorphic symptoms who also experience suicidal ideation. Future work should continue to identify mediators for suicide attempts among individuals with dysmorphia symptoms.

Intellectual deficits and restoration to competency to stand trial: An examination of IQ cut off scores.

Intellectual functioning impacts defendants' competence to stand trial, though research on this population remains limited. This study replicated and advanced prior work, focusing on defendants' demographic, clinical, cognitive, and criminal justice variables and their association with length of hospitalization and restoration determinations. Participants were 74 male and female criminal defendants in a midwestern state who were adjudicated incompetent to stand trial, had a diagnosis related to intellectual deficits, and completed competency restoration. Most defendants (83.7%) were restored to competency. Demographic factors were unrelated to restoration outcomes; violence of alleged offense predicted shorter hospitalization. Receiver Operating Characteristic Curve analyses determined an IQ score cut-off of 63.5 for which participants were of greater likelihood to be determined restored, providing guidance on the likelihood of restoration for defendants with intellectual disability related diagnoses. Specifically, this score can be used with clinical data to inform competency determinations for defendants with cognitive deficits.

The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer.

Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.

BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?

National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.

c-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial.

INTRODUCTION: Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847). MATERIALS AND METHODS: Patients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival. RESULTS: Tissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio [HR] 1.034, 95% confidence interval [95%CI] 1.010-1.059). Women in the c-MET/VEGFR-2HIGH group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus > 60 months; HR 2.00, 95%CI 1.08-3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53-1.03). CONCLUSIONS: In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.

Association of Social Needs and Healthcare Utilization Among Medicare and Medicaid Beneficiaries in the Accountable Health Communities Model.

BACKGROUND: Integration of health-related social needs (HRSNs) data into clinical care is recognized as a driver for improving healthcare. However, few published studies on HRSNs and their impact are available. CMS sought to fill this gap through the Accountable Health Communities (AHC) Model, a national RCT of HRSN screening, referral, and navigation. Data from the AHC Model could significantly advance the field of HRSN screening and intervention in the USA. OBJECTIVE: To present data from the Greater Houston AHC (GH-AHC) Model site on HRSN frequency and the association between HRSNs, sociodemographic factors, and self-reported ED utilization using a cross-sectional design. Analyses included descriptive statistics and multinomial logistic regression. PARTICIPANTS (OR PATIENTS OR SUBJECTS): All community-dwelling Medicare, Medicaid, or dually covered beneficiaries at participating GH-AHC clinical delivery sites were eligible. MAIN MEASURES: Self-reported ED utilization in the previous 12 months served as the outcome; demographic characteristics including race, ethnicity, age, sex, income, education level, number of people living in the household, and insurance type were treated as covariates. HRSNs included food insecurity, housing instability, transportation, difficulty paying utility bills, and interpersonal safety. Clinical delivery site type was used as the clustering variable. KEY RESULTS: Food insecurity was the most common HRSN identified (38.7%) followed by housing instability (29.0%), transportation (28.0%), and difficulty paying utility bills (26.7%). Interpersonal safety was excluded due to low prevalence. More than half of the beneficiaries (56.9%) reported at least one of the four HRSNs. After controlling for covariates, having multiple co-occurring HRSNs was strongly associated with increased risk of two or more ED visits (OR 1.8-9.47 for two to four needs, respectively; p < 0.001). Beneficiaries with four needs were at almost 10 times higher risk of frequent ED utilization (p < 0.001). CONCLUSIONS: To our knowledge, this is only the second published study to report screening data from the AHC Model. Future research focused on the impact of multiple co-occurring needs on health outcomes is warranted.

Perspectives of Patients and Providers in Using Shared Decision Making in Psychiatry.

There is increased interest over the last decade in the use of Shared Decision Making with individuals with serious mental illness to improve engagement in treatment and clinical outcomes. We conducted semi-structured qualitative interviews with 15 individuals with serious mental illness treated in an outpatient transitional care clinic serving people immediately after discharge from a psychiatric hospitalization. Parallel interviews were conducted with a variety of clinical providers (n = 9). Using latent thematic analysis, six themes were identified including: (1) Differences in the Use of SDM, (2) Consideration of Past Experiences, (3) Decisional Power Preferences, (4) Use of SDM in Psychiatry Versus Other Areas of Medicine, (5) Dignity and Disengagement, and (6) External Forces Impacting SDM. Implications for clinical practice and research using a shared decision-making approach within this treatment setting are further discussed.