Search

Purpose: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. Patients and Methods: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. Results: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. Conclusions: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

Although the overrepresentation of people with mental illness in the criminal justice system is known, research is needed to identify the frequency of criminal justice involvement and criminogenic treatment needs in inpatient populations to improve continuity of care and access to appropriate treatments. The purpose of this study is to document the frequency of criminal justice involvement among people receiving inpatient community care, as has been done for persons with mental illness in correctional institutions, and to test the association between criminogenic risk and psychiatric symptomatology. The present study uses two samples (n = 94 and n = 142) of adults from two separate acute psychiatric inpatient hospitals in Texas. Data on psychiatric symptoms, mental health history, criminal risk, and criminal justice history were gathered from file review and self-report. Linear and negative binomial regressions were used to test associations of interest. In both samples, the frequency of prior criminal justice involvement was over 50%. The current results indicate there is a significant, positive association between measures of criminal risk and psychiatric symptoms. These findings highlight the need to address the reciprocal association between mental illness and criminal risk among people receiving inpatient psychiatric treatment with appropriate assessment and treatment.

This chapter will begin with a discussion about the different models and settings of restricted housing and how these can look differently and serve different functions in jails compared to prisons, where individuals can spend years in segregated placements. This chapter will review the current literature on the psychological impact of segregated placement, highlight gaps in this literature, and reconcile these findings with the stories of gross misuse and overuse of solitary confinement in jails that has come to the attention of civil rights advocacy groups, politicians, and the general public. Finally, the chapter will offer recommendations for screening and intervention, with particular focus on reducing the number of people with mental illness who are placed and maintained in these units.

ObjectiveOlaparib 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.MethodsThe 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 aBRCA1/2mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network.ResultsThe myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwentBRCA1/2and 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 aBRCA1/2mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to beBRCA1/2wild-type (n=510) thanBRCA1/2 mutant (n=304). The distribution of GIS was bimodal, withBRCA1/2mutant tumors having a higher mean score thanBRCA1/2wild-type tumors (61 vs 33, respectively, χ2test pConclusionThis 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.

BRCA2 reversion mutation detected in cell-free circulating DNA from patient 16.

Purpose:A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.Patients and Methods:Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies.Results:Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy.Conclusions:A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

Supplementary Methodology.

Liquid biopsy time points.

This chapter outlines several topics relevant to the treatment of justice-involved persons with serious mental illness (SMI). We begin with a historical overview, detailing previous work in conceptualizing and treating this population, followed by a review of contemporary practices and strategies. We describe the proposed co-occurring and reciprocal relation between mental illness and criminal risk, and discuss implications for correctional rehabilitation and psychiatric recovery. Building on the five-level model of risk assessment, we propose an integrated assessment model to advance service matching and delivery for justice-involved persons with SMI, an expansion necessary for holistic consideration of this population’s needs. Finally, we provide recommendations for practice and future research addressing co-occurring criminal risk and mental illness to enhance services for this underserved population.

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

The therapeutic working alliance is an important factor in producing treatment change and positive therapeutic outcomes for people with mental illness, yet little is known about the working alliance's role in treatment change in people with mental illness that is justice involved. In addition to treating the mental illness symptoms of justice-involved people with mental illness, addressing factors known to predict criminal behavior (including criminal thinking) could optimize posttreatment outcomes and reduce future justice involvement. This study examines the role of the working alliance in treatment change in a clinical treatment sample of 265 adult male and female justice-involved people with mental illness and substance use disorders completing probation sentences in a residential treatment facility.Repeated measures moderation analyses were used to test participants' reported working alliance as a moderator of change from pre- to posttreatment scores of self-reported mental illness symptoms and criminal thinking.The working alliance significantly moderated reductions in depression, anxiety, anger, and manic symptoms (R 2 ranging from .03 to .09), and general, reactive, and current criminal thinking (R 2 ranging from .04 to .11).These findings expand the literature on the relation between working alliance and changes in mental illness symptoms by testing this association in the understudied population of justice-involved people with mental illness; these results also suggest the working alliance is associated with changes in criminal thinking. Treatment providers working with justice-involved people with mental illness should assess and emphasize the development of a working alliance to maximize treatment change. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Research on the effects of restricted housing on inmate well-being indicates mild to moderate psychological effects and barriers opportunities for treatment and positive growth. Yet, there are few interventions tailored both to the needs of this high-risk population and to the institutional constraints of their environment. Given the financial and safety burdens associated with housing someone in segregation compared to the general population, correctional psychology should focus on developing programs that work. Using a prepost design, this study presents findings from a pilot investigation (N = 39) on the effects of a new, largely self-directed program (Stepping Up, Stepping Out [SUSO]) for inmates with mental and behavioral health concerns who are placed in restrictive settings. Results suggest that SUSO is associated with meaningful reductions in overall emotional distress and criminal attitudes; however, improvements in more stable criminal thinking patterns (i.e., distorted cognitions that are used to justify and support antisocial behavior; see Walters, 2012) were not observed. Overall, posttreatment working alliance was rated favorably by program participants. Demographic and preintervention comparisons between program completers and dropouts are also reported. Though preliminary findings suggest SUSO is a promising intervention for alleviating distress and aspects of criminal risk for inmates placed in restricted housing, future research should assess fidelity and engagement leading to a randomized controlled trial to determine the effectiveness of this program. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

[Correction Notice: An Erratum for this article was reported online in Psychological Services on Oct 8 2020 (see record 2020-75253-001). In the article, the authors listed the wrong version of a measure in the Method section of Study 2. The article should have listed PICTS-Layperson-Short Form (PICTS-L-SF) instead of the PICTS-Short Form (PICTS-SF) as the measure used. The correct citation for the measure appears in the erratum.] Corrections research literature is replete with treatment and intervention outcome studies but lacking empirical examinations of the process of change in justice-involved populations. The current studies expand upon previous outcome evaluations of Changing Lives and Changing Outcomes (CLCO), a treatment program for justice-involved persons with mental illness, by using process research designs to examine therapeutic mechanisms of change. Study 1 used CLCO participants' (n = 264) pre and post module quizzes to examine differences in content retention between Mental Illness, Criminalness, and Both mental illness and criminalness domains to determine if participants differentially learn treatment content. In Study 2, 1 CLCO module was administered to 9 groups of adult men on probation in a residential treatment facility (n = 4 to 8 per group) in 3 iterations: (a) Mental Illness-only content (n = 16), (b) Criminalness-only content (n = 20), (c) Full module (mental illness and criminalness content; n = 22). Results for both studies indicated significant treatment gains across outcome measures of interest (namely content retention and symptomology). Contrary to expectations in Study 1, effect sizes of Mental Illness and Criminalness content retention were similar, suggesting there are not differential effects in the magnitude of content retained between the 2 domains. In Study 2, the integration of mental illness and criminalness content produced greater global improvement than focusing on mental illness or criminalness alone. These results underscore the necessity and effectiveness of integrating mental illness and criminalness in the treatment of justice-involved persons with mental illness. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

High-grade serous ovarian cancer (HGSOC) is an aggressive disease that typically develops drug resistance, thus novel biomarker-driven strategies are required. Targeted therapy focuses on synthetic lethality—pioneered by PARP inhibition of BRCA1/2-mutant disease. Subsequently, targeting the DNA replication stress response (RSR) is of clinical interest. However, further mechanistic insight is required for biomarker discovery, requiring sensitive models that closely recapitulate HGSOC. We describe an optimized proliferation assay that we use to screen 16 patient-derived ovarian cancer models (OCMs) for response to RSR inhibitors (CHK1i, WEE1i, ATRi, PARGi). Despite genomic heterogeneity characteristic of HGSOC, measurement of OCM proliferation was reproducible and reflected intrinsic tumour-cell properties. Surprisingly, RSR targeting drugs were not interchangeable, as sensitivity to the four inhibitors was not correlated. Therefore, to overcome RSR redundancy, we screened the OCMs with all two-, three- and four-drug combinations in a multiple-low-dose strategy. We found that low-dose CHK1i-ATRi had a potent anti-proliferative effect on 15 of the 16 OCMs, and was synergistic with potential to minimise treatment resistance and toxicity. Low-dose ATRi-CHK1i induced replication catastrophe followed by mitotic exit and post-mitotic arrest or death. Therefore, this study demonstrates the potential of the living biobank of OCMs as a drug discovery platform for HGSOC.

AimsClinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs.MethodsAn observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (ResultsOne hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test pBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39).ConclusionsWe predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

Recent studies have indicated variable reductions in criminal thinking for justice-involved persons with mental illness exposed to cognitive-behavioral treatments. To date, however, no studies have identified risk factors for limited response or modeled observed disparities in responsivity to interventions aimed at reducing criminal thinking. Using an archival data set of 162 probationers with a dual diagnosis who were exposed to

Clinical guidelines recommend testing both germline and tumour DNA forAn observational study that included all tumourOne hundred and thirteen tumourWe predict the likelihood of a tumour

Background Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P P = 2.8 × 10−6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

Interventions that focus on the psychiatric and criminogenic needs of justice-involved persons with mental illness are rare. A Treatment Manual for Justice Involved Persons with Mental Illness: Changing Lives and Changing Outcomes (CLCO) was developed specifically for meeting these co-occurring needs. Although results from an initial evaluation indicated that CLCO successfully resulted in reduced symptomatology and some aspects of criminal risk, much additional work examining the effectiveness of CLCO remains to be done. The present evaluation examined the extent to which offenders gained knowledge (i.e., content retention) throughout the program, the extent to which content retention was predictive of program completion, and the extent to which treatment engagement (i.e., session attendance and homework completion) was predictive of program completion. Participants consisted of male and female felony offenders in a residential treatment facility (n = 130), and dually diagnosed male offenders in a residential treatment facility (n = 39). Results indicated that participants in this intervention retained treatment content, and this content retention was predictive of treatment completion. Implications of these findings suggest that CLCO is a promising new intervention for justice-involved persons with mental illness. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The relationship between criminogenic risk and mental illness in justice involved persons with mental illness is complex and poorly understood by clinicians, researchers, administrators, and policy makers alike. Historically, when providing services to justice involved persons with mental illness, clinicians have emphasized mental health recovery (eg, psychiatric rehabilitation) at the exclusion of treatments targeted at criminogenic risk. More recently, however, researchers have demonstrated with great clarity that criminogenic risk not only contributes but is likely the leading factor in the criminal behavior committed by persons with mental illness. Yet, we still do not know the nature of this criminogenic-mental illness relationship, how this relationship impacts treatment needs, and of ultimate concern, what this relationship means in terms of individual and societal outcomes. In this paper we briefly define criminogenic risk and the research that demonstrates the role of criminogenic risk in criminal justice involvement of persons with mental illness. We also review prevalence rates of persons with mental illness justice involvement, and then discuss important factors to be considered when assessing risk to include both criminogenic and mental illness risk. We conclude this paper by reviewing treatment and management strategies for persons with mental illness that are criminal justice involved particularly reviewing and building off the recommendations put forth by Bartholomew & Morgan.

Changing Lives and Changing Outcomes (CLCO) was developed to address the unique treatment needs of individuals with co-occurring mental illness and criminogenic risk. Previous evaluations of CLCO demonstrated effectiveness for male participants, but did not examine treatment effectiveness across participant sex. Therefore, the aim of this study was to examine differences in treatment outcomes among male and female probationers receiving CLCO. Participants were assessed pre- and posttreatment. Results indicated positive treatment effects across both psychiatric and criminogenic domains, including psychiatric symptomology and global mental health functioning, medication adherence, attitudes toward mental illness recovery, and antisocial cognitions. Female participants demonstrated enhanced treatment responsiveness relative to males across several domains. This study underscores the effectiveness of the program in addressing both mental health and criminogenic needs in correctional populations, while highlighting the differential impact of the program across participant sex. Implications, future directions, and limitations of the present study are discussed.

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).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.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-2In 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.

The Psychological Inventory of Criminal Thinking Styles-Short Form (PICTS-SF) is an abbreviated 35-item version of the PICTS, a measure of cognitions that support a criminal lifestyle. Despite use in research and clinical work, the PICTS-SF’s psychometric properties have not been tested. Using two archival datasets, we analyzed the PICTS-SF’s reliability and structural validity in multiply imputed data from adult males and females on probation in a residential treatment facility ( n = 514). We also tested the PICTS-SF’s reliability and discriminant and postdictive validities among adult males in administrative segregation in prison ( n = 95). We found evidence for the PICTS-SF’s internal consistency (α and ω ≥ .89), structural validity (CFI = .90, RMSEA = .05), discriminant validity (.22 ≤ r ≤ .39), and postdictive validity for receiving disciplinary infractions (incident rate ratio = 1.04). These results support the PICTS-SF’s use in research, and qualified use in clinical applications.

Background Epithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70–80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics. Methods Non-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2–10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models. Results Application of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features. Conclusions This robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes.

Background Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women with BRCA-deficient disease. However, options remain limited for disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase that counterbalances PARP activity, is an emerging target with potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG inhibitors (PARGi) will however require predictive biomarkers, in turn requiring an understanding of their mode of action. Furthermore, differential sensitivity to PARPi is key for expanding treatment options available for patients. Methods A panel of 10 ovarian cancer cell lines and a living biobank of patient-derived ovarian cancer models (OCMs) were screened for PARGi-sensitivity using short- and long-term growth assays. PARGi-sensitivity was characterized using established markers for DNA replication stress, namely replication fibre asymmetry, RPA foci, KAP1 and Chk1 phosphorylation, and pan-nuclear γH2AX, indicating DNA replication catastrophe. Finally, gene expression in sensitive and resistant cells was also examined using NanoString or RNAseq. Results PARGi sensitivity was identified in both ovarian cancer cell lines and patient-derived OCMs, with sensitivity accompanied by markers of persistent replication stress, and a pre-mitotic cell cycle block. Moreover, DNA replication genes are down-regulated in PARGi-sensitive cell lines consistent with an inherent DNA replication vulnerability. However, DNA replication gene expression did not predict PARGi-sensitivity in OCMs. The subset of patient-derived OCMs that are sensitive to single-agent PARG inhibition, includes models that are PARPi- and/or platinum-resistant, indicating that PARG inhibitors may represent an alternative treatment strategy for women with otherwise limited therapeutic options. Conclusions We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.

IntroductionPoly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic BRCA1/2 variant. Consequently, the demand for germline BRCA1/2 testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline BRCA1/2 variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification.MethodsA cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline BRCA1/2 testing by next-generation sequencing and multiplex ligation-dependent probe amplification.ResultsFive hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic BRCA1/2 variant. The prevalence of pathogenic BRCA1/2 variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic BRCA1/2 variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%).DiscussionOur study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic BRCA1/2 variants in epithelial ovarian cancer.

There is currently limited understanding about how best to communicate the results of violence risk assessments to legal decision makers. To advance this literature, a two-part study was co...

The purpose of this study was to determine whether criminal thinking interacts with the rational requirements of human decision-making in a group of college students. A convenience sample of 315 un...

Suicide risk is elevated among psychiatric inpatients; however, research has not examined moderators of the associations between perceived social support and thwarted belongingness (TB) and perceived burdensomeness (PB), such as involvement with criminal associates. Adult psychiatric inpatients (