Homologous Recombination Abnormalities Associated With BRCA1/2 Mutations as Predicted by Machine Learning of Targeted Next-Generation Sequencing Data.

Background: Homologous recombination deficiency (HRD) is the hallmark of breast cancer gene 1/2 (BRCA1/2)-mutated tumors and the unique biomarker for predicting response to double-strand break (DSB)-inducing drugs. The demonstration of HRD in tumors with mutations in genes other than BRCA1/2 is considered the best biomarker of potential response to these DSB-inducer drugs. Objectives: We explored the potential of developing a practical approach to predict in any tumor the presence of HRD that is similar to that seen in tumors with BRCA1/2 mutations using next-generation sequencing (NGS) along with machine learning (ML). Design: We use copy number alteration (CNA) generated from routine-targeted NGS data along with a modified naïve Bayesian model for the prediction of the presence of HRD. Methods: The CNA from NGS of 434 targeted genes was analyzed using CNVkit software to calculate the log2 of CNA changes. The log2 values of various sequencing reads (bins) were used in ML to train the system on predicting tumors with BRCA1/2 mutations and tumors with abnormalities similar to those detected in BRCA1/2 mutations. Results: Using 31 breast or ovarian cancers with BRCA1/2 mutations and 84 tumors without mutations in any of 12 homologous recombination repair (HRR) genes, the ML demonstrated high sensitivity (90%, 95% confidence interval [CI] = 73%-97.5%) and specificity (98%, 95% CI = 90%-100%). Testing of 114 tumors with mutations in HRR genes other than BRCA1/2 showed 39% positivity for HRD similar to that seen in BRCA1/2. Testing 213 additional wild-type (WT) cancers showed HRD positivity similar to BRCA1/2 in 32% of cases. Correlation with proportional loss of heterozygosity (LOH) as determined using whole exome sequencing of 51 samples showed 90% (95% CI = 72%-97%) concordance. The approach was also validated in an independent set of 1312 consecutive tumor samples. Conclusions: These data demonstrate that CNA when combined with ML can reliably predict the presence of BRCA1/2 level HRD with high specificity. Using BRCA1/2 mutant cases as gold standard, this ML can be used to predict HRD in cancers with mutations in other HRR genes as well as in WT tumors.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Court innovations and access to justice in times of crisis.

BACKGROUND: COVID-19 has disrupted not only the health sector but also justice systems. Courts around the world have had to respond quickly to the challenges presented by the pandemic and the associated social distancing restrictions. This has created significant challenges for the justice system and such challenges are likely to be further compounded in the post-pandemic era as there is a 'tsunami' of COVID-19-related disputes predicted. METHODS: This study will examine how global court responses have transitioned from being primarily traditional, face-to-face proceedings to online court processes (as supported by internet technology). By adopting a comparative approach, we will analyse how some countries have adapted to this shift to online mode while also maintaining a focus on access to justice. RESULTS: We argue that online modes of dispute resolution, often referred to as Online Dispute Resolution (ODR), can promote resolution while facilitating social distancing in this new COVID-era. The rapid shift from traditional court processes to an online mode has further assisted the public, lawyers and experts to access the justice system in some jurisdictions, even during the crisis. In light of the scale of recent changes, there have been concerns about the capacity of courts to adopt newer technologies as well as issues relating to the impact of a new online model of justice, particularly in terms of the barriers for more vulnerable members of society. Further, the use of disruptive technologies in some courts have posed questions around whether outcomes generated by these innovations reflect the meaning of 'justice' in its traditional sense. CONCLUSIONS: This article argues that courts should embrace newer technologies that support court services while being mindful of possible tech-related issues that can impact on justice objectives. We argue that by placing further emphasis on alternative dispute resolution methods and ODR into the future, this might offset the likely tsunami of COVID-related litigation which would enable courts, hospitals, medical professionals and patients to settle disputes in a just, equitable and more efficient manner.

Disability Discrimination, Medical Rationing and COVID-19.

The current public health crisis has exposed deep cracks in social equality and justice for marginalised and vulnerable communities around the world. The reported rise in the number of 'do not resuscitate' orders being imposed on people with disabilities has caused particular concerns from a human rights perspective. While the evidence of this is contested, this article will consider the human rights implications at stake and the dangers associated with using 'quality of life' measures as determinant of care in medical decision-making and triage assessments.

Differential impact of cognitive computing augmented by real world evidence on novice and expert oncologists.

INTRODUCTION: Cognitive computing point-of-care decision support tools which ingest patient attributes from electronic health records and display treatment options based on expert training and medical literature, supplemented by real world evidence (RWE), might prove useful to expert and novice oncologists. The concordance of augmented intelligence systems with best medical practices and potential influences on physician behavior remain unknown. METHODS: Electronic health records from 88 breast cancer patients evaluated at a USA tertiary care center were presented to subspecialist experts and oncologists focusing on other disease states with and without reviewing the IBM Watson for Oncology with Cota RWE platform. RESULTS: The cognitive computing "recommended" option was concordant with selection by breast cancer experts in 78.5% and "for consideration" option was selected in 9.4%, yielding agreements in 87.9%. Fifty-nine percent of non-concordant responses were generated from 8% of cases. In the Cota observational database 69.3% of matched controls were treated with "recommended," 11.4% "for consideration", and 19.3% "not recommended." Without guidance from Watson for Oncology (WfO)/Cota RWE, novice oncologists chose 75.5% recommended/for consideration treatments which improved to 95.3% with WfO/Cota RWE. The novices were more likely than experts to choose a non-recommended option (P < .01) without WfO/Cota RWE and changed decisions in 39% cases. CONCLUSIONS: Watson for Oncology with Cota RWE options were largely concordant with disease expert judged best oncology practices, and was able to improve treatment decisions among breast cancer novices. The observation that nearly a fifth of patients with similar disease characteristics received non-recommended options in a real world database highlights a need for decision support.

Real-world economic value of a 21-gene assay in early-stage breast cancer.

OBJECTIVES: Value-based payment reforms shift cost-containment responsibilities to the physician. Although gene expression profiling (GEP) utilizing a 21-gene panel among patients with early-stage, axillary lymph node-negative, hormone receptor-positive, HER2/neu oncogene-negative breast cancer is able to identify a cohort that may achieve excellent outcomes without adjuvant chemotherapy, high up-front costs (list price, $4175) could dissuade usage. STUDY DESIGN: Retrospective review of consecutive patients with breast cancer treated at a single cancer center. METHODS: Chart review of 227 patients 70 years or younger with outpatient costs (ie, drug average sales price, reagent costs, physician charges) during first 6 months of treatment. RESULTS: Of these patients, 68% underwent GEP, with 52%, 43%, and 5% having low, intermediate, and high recurrence risk scores, respectively. Adjuvant chemotherapy was utilized less in genomically profiled cohorts (19% vs 29%; P = .08) and was consistent with recommendations of the recurrence scores. The mean 6-month outpatient costs were $24,955 with adjuvant chemotherapy and $2654 with hormonal therapy. Patients with stage II cancer undergoing GEP received adjuvant chemotherapy at a lower frequency (28.6% vs 86.7%), but patients with stage I cancer who underwent testing were slightly more likely to receive chemotherapy (15.8% vs 14%) because the test identified patients with higher-risk tumors. Universal GEP testing of patients with stage II cancer would have resulted in net savings of $11,494 per patient inclusive of test cost; stage I testing would have increased costs by $4505. Similar trends for grade 2/3 tumors (-$2394) and grade 1 tumors (+$6047) were noted. CONCLUSIONS: Universal GEP testing of women 70 years or younger with stage II or grade 2/3 lymph node-negative breast cancers would result in lower outpatient costs, inclusive of the diagnostic test, within the first 6-month episode of care.

Parenting self-efficacy and empowerment among expectant mothers with substance use disorders.

OBJECTIVE: to describe parenting self-efficacy and family empowerment among expectant mothers with substance use disorders. DESIGN: the study employed a quantitative cross-sectional design. PARTICIPANTS: participants were 71 pregnant women with substance use disorders entering a gender-specific, substance use disorder, residential treatment facility. MEASUREMENTS: measurement tools included: the demographic data form, the Parenting Sense of Competence Scale, the Addiction Severity Index, and the Family Empowerment Scale. FINDINGS: women in their third trimester reported statistically significant higher levels of both parenting self-efficacy and family empowerment than women in their first trimester. KEY CONCLUSIONS: interventions that promote parenting self-efficacy and family empowerment need to target women in their first trimester. IMPLICATIONS FOR PRACTICE: midwives with specialized training in substance abuse disorders are in a unique position to bolster expectant mothers' parenting capabilities during the addiction recovery process.