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Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5-53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy.This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70-1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69-1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68-1.75, P = 0.7). Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel. Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel.Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Data from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

Purpose:Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression.Patients and Methods:Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status.Results:At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status.Conclusions:Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Table from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

BACKGROUND: Venetoclax (VEN) is a potent and selective inhibitor of the anti-apoptotic protein, BCL2. Preclinical studies have implicated the BCL2 family members, BCLXL and MCL1, in VEN resistance, and clinical studies in hematological malignancies have demonstrated subgroups with high ratios of BCL2/BCLXL and BCL2/MCL1 have the greatest VEN antitumor activity. The randomized phase 2 VERONICA study (NCT03584009) evaluated VEN in combination with fulvestrant (F) vs F alone in ER-positive, HER2-negative MBC pts who experienced disease recurrence/progression during or after a CDK4/6 inhibitor. Previously reported results from VERONICA (Lindeman et al. ASCO 2021) did not show an improved clinical benefit rate or progression-free survival (PFS) with VEN+F vs F alone. Here we present exploratory biomarker analyses of the expression of BCL2 family members and genomic alterations in circulating tumor DNA (ctDNA) and association with clinical outcomes from VEN+F vs F. METHODS: Tumor specimens were obtained during screening from 103 patients enrolled in the study, and expression levels of BCL2, BCLXL and MCL1 were analyzed by IHC. Baseline plasma-derived ctDNA was evaluated using the FoundationOne® Liquid assay. Expression of BCL2, BCLXL, MCL1 and mutations in ctDNA were correlated with PFS from VEN+F vs F based on the primary analysis (cutoff: Aug 5, 2020). RESULTS: In the overall population, protein levels of BCL2, BCLXL and MCL1 were similar between the VEN+F vs F arms. Patients whose tumors were BCL2 3+ trended towards having the greatest difference in median (m) PFS (3.9 months [mo] in VEN+F vs 1.7 mo in F; hazard ratio [HR] 0.38 [95% CI 0.09, 1.62]) albeit in a small sample size (n=13). Similarly, subgroup analysis suggested a trend for increasing mPFS and improved HR in VEN+F vs F alone in patients with the lowest BCLXL expression. mPFS in patients with a BCL2/BCLXL ratio ≥1 was 3.7 mo for VEN+F vs 1.8 mo for F (HR 0.67 [95% CI 0.3-1.49]) whereas patients with a BCL2/BCLXL ratio Citation Format: Geoffrey J. Lindeman, Tharu M. Fernando, Rebecca Bowen, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Aulde Fléchais, Timothy R. Wilson, Aditya Bardia. Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-06.

During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential ‘salvage’ measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.

Background: Cognitive-communication impairments following acquired brain injury (ABI) can have devastating effects on a person's ability to participate in community, social, vocational, and academic preinjury roles and responsibilities. Guidelines for evidence-based practices are needed to assist speech-language pathologists (SLPs) and other rehabilitation specialists in the delivery of cognitive rehabilitation for the adult population. Purpose: The American Speech-Language-Hearing Association, in conjunction with a multidisciplinary panel of subject matter experts, developed this guideline to identify best practice recommendations for the delivery of cognitive rehabilitation to adults with cognitive dysfunction associated with ABI. Method: A multidisciplinary panel identified 19 critical questions to be addressed in the guideline. Literature published between 1980 and 2020 was identified based on a set of a priori inclusion/exclusion criteria, and main findings were pooled and organized into summary of findings tables. Following the principles of the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision Framework, the panel drafted recommendations, when appropriate, based on the findings, overall quality of the evidence, balance of benefits and harms, patient preferences, resource implications, and the feasibility and acceptability of cognitive rehabilitation. Recommendations: This guideline includes one overarching evidence-based recommendation that addresses the management of cognitive dysfunction following ABI and 11 subsequent recommendations focusing on cognitive rehabilitation treatment approaches, methods, and manner of delivery. In addition, this guideline includes an overarching consensus-based recommendation and seven additional consensus recommendations highlighting the role of the SLP in the screening, assessment, and treatment of adults with cognitive dysfunction associated with ABI. Future research considerations are also discussed.

The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to BRCA germline and tumor testing in patients with ovarian cancer in routine clinical practice. In particular, the group explored models of consent, quality standards identified at pathology laboratories, and experience and data from pioneering cancer centers. The group liaised with representatives from ovarian cancer charities to also identify patient perspectives that would be important to implementation. Recommendations from these consensus group deliberations are presented in this manuscript.

Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.

Objective(s) To investigate the effects of cognitive rehabilitation in individuals with acquired brain injury. Data Sources Systematic search of 16 databases from 1980 through October 2020. Panel consisted on 9 subject matter experts (4 SLPs, 1 neuropsychologist, 1 patient advocate, 1 physician, 1 OT and 1 vocation rehabilitation specialist) and 2 SLP methodologists. Over 100 included studies identified. Study Selection Inclusion: in English from 1980 onward; original data; participants aged 18 years of age or older with an acquired brain injury; randomized or controlled trial; examined a cognitive treatment, strategy or intervention used by an SLP Data Extraction Data extracted included participants, intervention, characteristics and outcomes of interest. Quality was assessed by same 2 masked reviewers using the Cochrane Risk of Bias Tool. Data Synthesis Overall, cognitive rehabilitation showed small effects ranging from SMD 0.24 (0.07-0.4) to SMD 0.38 (0.23-0.53) depending on outcome compared to no treatment or active control. Heterogeneity of populations (TBI, stroke, hypoxia, anoxia, epilepsy etc.) and treatments (all cog rehab included) contribute to variations. Conclusions Cognitive rehabilitation overall showed small effects compared to control. Contextualized cognitive treatment and memory treatments showed moderate effects compared to control. The guideline panel made a recommendation in favor of cognitive rehabilitation by also considering priority of the problem, balance of desirable and undesirable effects, certainty of evidence, values, cost effectiveness, equity, acceptability and feasibility. Author(s) Disclosures 5/11 authors have declarations, details exceed word count.

The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to

This protocol is designed to help users achieve targeted enrichment for regions of interest using nanopore sequencing, providing higher coverage for myriad future analysis applications. GuideRNA components (crRNA and tracrRNA) were designed using online tools provided by IDT.

BACKGROUND: There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility.METHODS: Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters.RESULTS: We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells.CONCLUSIONS: The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness.

Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.

This protocol is designed to help users achieve targeted enrichment for regions of interest using nanopore sequencing, providing higher coverage for myriad future analysis applications. GuideRNA components (crRNA and tracrRNA) were designed using online tools provided by IDT.

This protocol is designed to help users achieve targeted enrichment for regions of interest using nanopore sequencing, providing higher coverage for myriad future analysis applications. GuideRNA components (crRNA and tracrRNA) were designed using online tools provided by IDT.

1008 Background: Paclitaxel is commonly used as first line chemotherapy for HER2 negative MBC. However, with response rates of 21.5-53.7% and a significant risk of peripheral neuropathy there is a need for more effective and better tolerated chemotherapy (CCT). Methods: This open label randomised (1:1) phase 2 trial compared 6 cycles of cabazitaxel (25 mg/m2) every 3 weeks, with weekly paclitaxel (80mg/m2) over 18 weeks as first line CCT. HER2 negative and performance status ≤1 patients were eligible. Patients on cabazitaxel received GCSF prophylaxis. Primary endpoint was Progression Free Survival (PFS) with 127 events required to detect a hazard ratio (HR) of 0.65 with 85% power. Secondary endpoints included objective response rate (ORR; RECIST 1.1), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited from 14 UK hospitals (79 in each arm). Median age (range) was 56(34-81) in the cabazitaxel arm and 61(34-79) in the paclitaxel arm. 61% of patients were performance status 0. Median time on treatment was 15 weeks for both arms, but more patients on paclitaxel had a treatment delay (61% vs 39%) or dose reduction (37% vs 24%). Comparing cabazitaxel to paclitaxel after 146 PFS events, median PFS was 6.7 vs 5.8 months (HR 0.84; 95%CI 0.60–1.18, P = 0.3). There was no difference in OS, median 19.3 vs 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7), ORR (42% vs 37%) or TTR (HR 1.09; 95%CI 0.68–1.74, P = 0.7). Grade ≥3 adverse events occurred in 42% of patients on cabazitaxel and 48% on paclitaxel. Diarrhoea, febrile neutropenia and nausea were the most common grade ≥3 events in the cabazitaxel arm with rates of 11%, 11% and 10% respectively compared to 1%, 1% and 0% in the paclitaxel arm. In the paclitaxel arm the top grade ≥3 events were lung infection and peripheral neuropathy, 6% and 5% respectively compared to 2.5% and 0% in the cabazitaxel arm. Peripheral neuropathy of any grade was reported by 55% of patients treated with paclitaxel vs 17% on cabazitaxel. Alopecia occurred in 41% of patients on paclitaxel compared to 27% on cabazitaxel. Adverse events leading to discontinuation were more frequent with paclitaxel (22%) than cabazitaxel (14%). Over the course of treatment, mean EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in the cabazitaxel arm compared to paclitaxel suggestive of better QoL on Cabazitaxel. Conclusions: 3 weekly cabazitaxel as first line chemotherapy in HER2 negative MBC does not significantly improve PFS compared to weekly paclitaxel, though it has a lower risk of peripheral neuropathy with better patient reported overall health outcomes. Cabazitaxel is safe and well tolerated for MBC and requires fewer hospital visits, an important consideration in the COVID pandemic and beyond. Clinical trial information: NCT03048942 .

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

Expansions of short tandem repeats are genetic variants that have been implicated in neuropsychiatric and other disorders but their assessment remains challenging with current molecular methods. Here, we developed a Cas12a-based enrichment strategy for nanopore sequencing that, combined with a new algorithm for raw signal analysis, enables us to efficiently target, sequence and precisely quantify repeat numbers as well as their DNA methylation status. Taking advantage of these single molecule nanopore signals provides therefore unprecedented opportunities to study pathological repeat expansions.

Expansions of short tandem repeats are genetic variants that have been implicated in several neuropsychiatric and other disorders, but their assessment remains challenging with current polymerase-based methods1-4. Here we introduce a CRISPR-Cas-based enrichment strategy for nanopore sequencing combined with an algorithm for raw signal analysis. Our method, termed STRique for short tandem repeat identification, quantification and evaluation, integrates conventional sequence mapping of nanopore reads with raw signal alignment for the localization of repeat boundaries and a hidden Markov model-based repeat counting mechanism. We demonstrate the precise quantification of repeat numbers in conjunction with the determination of CpG methylation states in the repeat expansion and in adjacent regions at the single-molecule level without amplification. Our method enables the study of previously inaccessible genomic regions and their epigenetic marks.

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. Results: A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. Trial registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.

The cancer stem cell hypothesis postulates that a single stem-like cancer cell is able to produce all cancer cell types found in a tumor. These cells are also thought to be the causative agents of relapse following therapy. In order to confirm the importance of cancer stem cells in tumor formation and patient prognosis, their role in prostate cancer must be comprehensively studied. This review describes current methods and markers for isolating and characterizing prostate cancer stem cells, including assays for self-renewal, multipotency and resistance to therapy. In particular the advantages and limitations of these approaches are analyzed. The review will also examine novel methods for studying the lineage of cancer stem cells in vivo using transgenic mouse models. These lineage tracing approaches have significant advantages and, if a number of challenges can be addressed, offer great potential for understanding the significance of cancer stem cells in human prostate cancer.

Few prognostic biomarkers for Prostate cancer have been identified and there are clinical difficulties in distinguishing between relapsing and non-relapsing disease. The aim of our study is to investigate the hypothesis that proteins that have been linked to stem cells might be potential biomarkers, that could distinguish between aggressive tumors requiring radical intervention and those that have a good prognosis. One of the potential biomarkers that are being investigated is Sall4, a zinc finger transcriptional factor which has an important role in stem cell development and oncogeneses, including a possible role in prostate cancer progression and relapse. However, its role in prostate cancer remains unclear. Sall4 nuclear staining has been evaluated by immunohistochemistry using two sources of patient samples, a tissue microarray group and a Bath cohort. The tissue microarray group consists of 96 cases including normal prostate, adjacent normal prostate, and prostate cancer samples. The Bath cohort consists of 22 samples, including samples from patients that had recurrent disease and those who remained disease free. Sall4 nuclear staining was found to be decreased in prostate cancer samples compared to benign tissue from the tissue microarray group. Sall4 nuclear staining was also negatively associated with poorly differentiated grades of prostate cancer in the tissue microarray group. The Bath cohort did not have enough benign tissues to confirm the relationship between cancer and benign tissues but showed a negative association with the grade. Sall4 nuclear staining in tissue from both sets of samples was not associated with prostate cancer stages. It can be seen from this preliminary data that Sall4 might play an important role in tumor formation and/or aggressiveness and warrants further investigation to understand its function and establish if it could represent a potential diagnostic biomarker for prostate cancer. Citation Format: Dhafer A. Alghezi, Paul Whitley, Mark Beresford, Rebecca Bowen, John Mitchard, Andrew Chalmers. Expression of SALL4 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2637.

McDonald S, Tate R, Togher L, Bornhofen C, Long E, Gertler P, Bowen R. Social skills treatment for people with severe, chronic acquired brain injuries: a multicenter trial. Objective To determine whether social skills deficits including unskilled, inappropriate behavior, problems reading social cues (social perception), and mood disturbances (such as depression and anxiety) could be remediated after severe traumatic brain injuries. Design Randomized controlled trial comparing a social skills program with social activity alone or with waitlist control. Several participants were reassigned after randomization. Setting Hospital outpatient and community facilities. Participants Fifty-one outpatients from 3 brain injury units in Sydney, Australia, with severe, chronic acquired brain injuries were recruited. A total of 39 people (13 in skills training, 13 in social activity, 13 in waitlist) completed all phases of the study. Intervention Twelve-week social skills treatment program encompassing weekly 3-hour group sessions focused on shaping social behavior and remediating social perception and 1-hour individual sessions to address psychologic issues with mood, self-esteem, etc. Main Outcome Measures Primary outcomes were: (1) social behavior during encounters with a confederate as rated on the Behaviorally Referenced Rating System of Intermediary Social Skills−Revised (BRISS-R), (2) social perception as measured by The Awareness of Social Inference Test, and (3) depression and anxiety as measured by the Depression, Anxiety and Stress Scale. Secondary outcomes were: relative report on social behavior and participation using: the Katz Adjustment Scale−R1; the Social Performance Survey Schedule; the La Trobe Communication Questionnaire; and the Sydney Psychosocial Reintegration Scale (both relative and self-report). Results Repeated-measures analysis of variance indicated that social activity alone did not lead to improved performance relative to waitlist (placebo effect) on any outcome variable. On the other hand, the skills training group improved differentially on the Partner Directed Behavior Scale of the BRISS-R, specifically the self-centered behavior and partner involvement behavior subscales. No treatment effects were found for the remaining primary outcomes (social perception, emotional adjustment) or for secondary outcome variables (relative and self-report measures of social function). Conclusions This study suggested that treatment effects after social skills training in people with severe, chronic brain injuries are modest and are limited to direct measures of social behavior.

The kinetic and thermodynamic consequences of intrinsic disorder in protein-protein recognition are controversial. We address this by inducing one partner of the high-affinity colicin E3 rRNase domain-Im3 complex (K(d) ≈ 10(-12) M) to become an intrinsically disordered protein (IDP). Through a variety of biophysical measurements, we show that a single alanine mutation at Tyr507 within the hydrophobic core of the isolated colicin E3 rRNase domain causes the enzyme to become an IDP (E3 rRNase(IDP)). E3 rRNase(IDP) binds stoichiometrically to Im3 and forms a structure that is essentially identical to the wild-type complex. However, binding of E3 rRNase(IDP) to Im3 is 4 orders of magnitude weaker than that of the folded rRNase, with thermodynamic parameters reflecting the disorder-to-order transition on forming the complex. Critically, pre-steady-state kinetic analysis of the E3 rRNase(IDP)-Im3 complex demonstrates that the decrease in affinity is mostly accounted for by a drop in the electrostatically steered association rate. Our study shows that, notwithstanding the advantages intrinsic disorder brings to biological systems, this can come at severe kinetic and thermodynamic cost.

Objective: Patients with anorexia nervosa (AN) born in the northern and southern hemispheres are more likely to be born during spring months than at any other time of the year. It has been hypothesized that environmental temperature at the time of conception may have a significant role in this pattern of findings. The current study aims to investigate the pattern of birth of early-onset AN patients in an equatorial region (Singapore), where there is little difference in environmental temperature throughout the year. Method: Dates of birth were collected for 102 patients who were born in Singapore and diagnosed with early-onset AN. The patterns of birth were analyzed using chi-square analysis. Results: There was no difference across the year in the birth patterns of patients with early-onset AN in Singapore, nor were there any differences between patients with restrictive and binge/purge AN. Discussion: This lack of seasonal variation in the equator adds support to the "temperature at conception" hypothesis.

The present study investigated the ability of cerebrovascular accident (CVA) patients to perceive emotions portrayed by realistic stimuli. Statistical analyses demonstrated that CVA patients with damage to either the right or left cerebral hemisphere performed, on average, as well as controls did in perceiving emotions. However, a case study of one patient suggested that there may be a subset of CVA patients with right parieto-occipital damage who have deficits in the perception of negative emotions. The performance of this participant also indicated that deficits in emotion perception are ameliorated to some extent when patients are provided with realistic, complex stimuli that include a range of auditory and visual cues.

Objectives:1) Demonstrate that correction of nasal valve collapse leads to improvement in eustachian tube dysfunction. 2) Describe the relationship between eustachian tube dysfunction and nasal valve pathology.Methods:A retrospective analysis of patients who underwent surgical treatment for nasal valve collapse from 2010 to 2011 was undertaken looking for associated eustachian tube dysfunction (ETD) and the effect correction of the nasal valve had on ETD. Each chart was analyzed for preoperative otologic complaints consistent with ETD and the effect correction of nasal valve collapse had on these complaints.Results:Forty patients underwent surgical treatment of nasal valve collapse; 37.5% of these patients reported symptoms consistent with eustachian tube dysfunction. Of these patients 87% reported improvement of their otologic symptoms.Conclusions:The relationship between chronic sniffing and negative middle ear pressures has been well established. Chronic sniffing creates negative middle ear pressures l...

Tracheal diverticula are rarely encountered, and only a handful of cases have been described in the literature. In most of these cases the patient was asymptomatic. When symptoms have occurred, they usually had an airway component such as cough, dyspnea, and recurrent respiratory infection. Imaging techniques—particularly computed tomography—are beneficial for diagnosing a tracheal diverticulum because bronchoscopy can sometimes miss the point of communication with the trachea. We report the case of a 62-year-old woman with a tracheal diverticulum that manifested as an intermittent, painful right neck mass with associated cough, dysphonia, dysphagia/ odynophagia, and an occasional strangulation/choking sensation.

Nitrovasodilators increase both cyclic GMP and cyclic AMP in isolated platelets (Maurice DH, Haslam RJ. Mol Pharmacol 1990;37:671-81). To determine whether this occurs in blood, platelet cyclic[3H]GMP and cyclic [3H]AMP were measured in prelabeled rabbit platelets resuspended in modified Tyrode's solution or citrated blood. In the former medium, increases in cyclic [3H]nucleotides in response to nitroprusside (NP) and 3-morpholinosydnonimine (SIN-1) were maximal by 1 min; in blood, maximal increases were observed only after 10 min and were much smaller. In blood, SIN-1 was more effective than the same concentration of NP. After 10 min, 100 microM SIN-1 increased platelet cyclic[3H )GMP by 475 +/- 58% and cyclic[3H]AMP by 29 +/- 7% (means +/- SEM, 18 experiments). Supraadditive increases in platelet cyclic [3H]AMP in blood were observed when SIN-1 was combined with prostaglandin E1 (PGE1). Thus, after 10 min, SIN-1 (100 microM), PGE1 (20 nM), and SIN-1 + PGE1 increased cyclic[3H]AMP by 25 +/- 7, 35 +/- 6, and 130 +/- 17%, respectively (four experiments). In the same experiments, release of platelet [14C]serotonin by platelet-activating factor (PAF) was inhibited by 22 +/- 5, 2 +/- 2, and 61 +/- 5%, respectively. Increases in platelet cyclic[3H]GMP with SIN-1 were unaffected by PGE1. These results suggest that although cyclic GMP may mediate the effects of SIN-1 alone on platelet function, cyclic AMP mediates the synergistic action of SIN-1 and PGE1. M&B 22,948 (a selective cyclic GMP phosphodiesterase inhibitor) enhanced the increases in platelet cyclic[3H]GMP and cyclic[3H]AMP caused by SIN-1 and also increased the associated inhibition of [14C]serotonin release. M&B 22,948 also augmented the synergistic increases in cyclic[3H]AMP and inhibition of platelet function caused by SIN-1 + PGE1. The results show that a selected nitrovasodilator (e.g., SIN-1), a prostaglandin and a cyclic GMP phosphodiesterase inhibitor can exert synergistic effects on platelets in blood. This may be relevant to the pharmacologic management of thromboembolic disease.

5596 Background: The prognosis for advanced CC and EC pts is poor, with relapse to approved chemotherapies inevitable. In view of the high rate of putative driver mutations, novel MTAs in phase I t...

5560 Background: Relapse to approved anticancer treatments is almost inevitable in AOC pt. Novel agents in phase I trials may benefit such pt. Methods: Retrospective study of pt records 6/1998-10/2...

OBJECTIVES To study a cutaneous flap in an animal model for platelet and leukocyte dynamics after ischemia-reperfusion injury and to explain how such a model is relevant to the understanding of reconstructive flaps in a clinical setting. METHODS Cutaneous flaps based on the inferior epigastric artery were raised on C57BL/6 mice and were subjected to various periods of ischemia followed by reperfusion. We used intravital microscopy to observe and characterize platelet and leukocyte interactions within the microvasculature. RESULTS Platelet and leukocyte adherence to the microvasculature was greater after a longer reperfusion period in contrast to the adherence pattern seen after a shorter reperfusion period. Leukocyte rolling activity occurred at a greater rate after longer ischemia and shorter reperfusion periods, whereas the rate of platelet saltation occurred after shorter ischemia and longer reperfusion periods. CONCLUSIONS With the establishment of an animal model of cutaneous flaps to study cellular dynamics within the microvasculature after ischemia-reperfusion injury, further investigation into the cellular and molecular characteristics of such injury and the analysis of pharmacological interventions is warranted.