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PURPOSE Guidelines recommend somatic and germline testing for men with advanced prostate cancer (PCa). Barriers to widespread implementation result in underutilization of germline testing. Somatic testing alone risks missing pathogenic germline variants (PGVs). We sought to determine whether the addition of germline testing to tumor-only sequencing improves detection of PGVs in men with advanced PCa. Secondarily, we sought to define the added value of combining somatic and germline testing to optimize detection of clinically actionable alterations. PATIENTS AND METHODS We analyzed results of independent germline testing and tumor-only sequencing from 100 men with advanced PCa from a prospective clinical trial (ClinicalTrials.gov identifier: NCT03328091 ). The primary outcome was the proportion of PGVs not reported with tumor-only sequencing. The secondary outcome was the association of locus-specific loss of heterozygosity for PGVs in homologous recombination genes with clinical-genomic features. RESULTS In the 100 men who underwent germline testing and tumor-only sequencing, 24 PGVs were identified, 17 of which were clinically actionable, in 23 patients. Tumor-only sequencing failed to report four (17%) of the PGVs. One additional PGV (4.2%) had variant allele frequency on tumor-sequencing below the threshold for follow-up germline testing. When integrating tumor-only sequencing with germling testing results, 33% of patients harbored clinically actionable alterations. Rates of locus-specific loss of heterozygosity were higher for BRCA2 PGVs in castration-resistant PCa than PGVs in other homologous recombination genes in hormone-sensitive PCa ( P = .029). CONCLUSION Tumor-only sequencing failed to report more than 20% of PGVs in men with advanced PCa. These findings strongly support guideline recommendations for universal germline and somatic testing in this population. Combining tumor and germline sequencing doubled the chance of detecting a clinically actionable alteration.

Supplementary Data from Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications

Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors. Implications: We have established highly clinically relevant PDXs of ADT-induced dormant prostate cancer and identified two dormancy subtypes, leading to the development of a novel predicative gene signature that allows robust risk stratification of patients with prostate cancer to ADT or androgen-receptor pathway inhibitors.

Rebecca Silver looks at the different ways to communicate successfully.

PURPOSE Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy. MATERIALS AND METHODS A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board–approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings. RESULTS Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 v 22.4 months; P < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months v not reached; P < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 v 12 months; P < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 v 40.6 months; P < .01; HR = 4.64 [1.82 to 17.41]). CONCLUSION We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.

Rebecca Silver discusses the importance of face to face and networking for dental nurses

Rebecca Silver explains the ABCDE approach of cardiopulmonary resuscitation (CPR) in the dental practice

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition., Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance

Rebecca Silver breaks down seasonal depression, and the do's and don'ts of coping with it.

Critical reflection for mutual support has never been so important, suggests Rebecca Silver

The discovery of predictive biomarkers of response is critical for forecasting patient benefit from novel immune-modulatory therapeutics. However, their discovery is hindered by the complexity of the drug modes of action and the lack of adequate biological models. We designed an approach to define biomarkers of response by subjecting dissociated tissue from human tumors to T cell-targeting biologics or their combinations, followed by single-cell transcriptomic profiling and TCR clonotype characterization. Responding cells are identified as those showing treatment-specific shifts in gene expression profiles. Specifically for T cells, TCR clonotypes can be used to match responding T cells in treatment conditions to their sister clones in the baseline state. Comparing the baseline gene expression profiles between T cell clonotypes that responded to the treatment and those that did not allows the discovery of gene expression signatures that can predict response. We processed over 20 tumor samples obtained from cancer patients and treated them ex vivo with two novel biologics currently under clinical development - HFB301001, a potentially best-in-class 2nd generation OX40 agonist, and HFB200301, a potentially first-in-class TNFR2 agonist. We applied our biomarker discovery strategy to the pooled scRNA-seq and scTCR-seq data from these samples to define predictive signatures of response to these drugs. To further validate this strategy, we also generated single-cell data in our ex vivo system to characterize response to anti-PD-1 treatment. In the anti-PD-1 predictive response signature, we identified genes involved in inflammatory response and genes in the pathway of other co-inhibitory checkpoints. Application of the anti-PD-1 predictive response signature to bulk transcriptomic data from clinical studies with checkpoint inhibitors successfully stratified patients into two groups with significantly different risk of progression. The predictive response signatures for the two novel agonistic antibodies shared genes involved in inflammatory pathway with the anti-PD-1 signature, but also contained other distinct gene sets. Application of these predictive response signatures to bulk transcriptomic data from TCGA was able to stratify patients across cancer indications by predicted likelihood of response to individual treatments or combinations. The predictive biomarkers of response for the novel OX40 and TNFR2 agonist antibodies will be validated in our Phase I clinical trials. Ex vivo single-cell profiling coupled with TCR clonotype characterization enabled the discovery of predictive response signatures that informed patient selection strategies for the early clinical development of novel therapeutics. Citation Format: Dean Lee, Monika Manne, Roshan Kumar, Rebecca Silver, Alexandra Staskus, Julianna Crivello, Zhiyuan Wang, Dohyun Lee, Ross Fulton, Zhizhan Gu, Christos Hatzis, Francisco Adrian, Andreas Raue, Liang Schweizer. Discovery of predictive biomarkers of response to T cell-targeting biologics using ex vivo single-cell profiling coupled with TCR clonotype characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 618.

Regulatory T cells (Tregs) contribute to immunosuppression within the tumor microenvironment and have been associated with poor outcomes in a range of cancers. Targeted depletion of tumor-infiltrating Tregs (TITRs) is an attractive therapeutic strategy with the potential to enhance antitumor immunity in patients who do not respond to current treatments. However, such approaches have been limited to date by a lack of markers that are highly specific for TITRs. CCR8 is a chemokine G protein-coupled receptor (GPCR) that has recently been shown to be specifically expressed on TITRs as compared to Tregs in the periphery or other T cells within tumors. Here, we report the development and characterization of HFB101110, a humanized monoclonal antibody against CCR8 with potent and specific antibody-dependent cellular cytotoxicity (ADCC) activity. HFB101110 specifically recognizes an epitope on the N-terminus extracellular domain of CCR8 and does not recognize the closely related chemokine receptor CCR4. HFB101110 acts through a dual mechanism of action, by both depleting CCR8+ cells via ADCC and blocking binding of the CCL1 chemokine to its receptor CCR8. Blockade by HFB101110 inhibited calcium flux and chemotaxis induced by the interaction between CCL1 and CCR8. Furthermore, HFB101110 showed potent single agent anti-tumor activity associated with depletion of intratumoral Tregs in a human CCR8 knock-in mouse model. HFB101110 mediated specific ex vivo killing of Tregs from primary patient tumor samples both in the presence, and in some cases the absence, of allogeneic NK cells. HFB101110 showed favorable pharmacokinetic properties and a favorable developability profile, and was well-tolerated in both wild-type mice and cynomolgus monkeys. HFB101110 is currently being developed as a novel immunotherapy for the treatment of solid tumors coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform. Citation Format: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer. Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2899.

Dental Nursing talks to Rebecca Silver about her professional journey

We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy.All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery.Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence.In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.

Background Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known. Objective To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT. Design, setting, and participants We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP. Intervention Intense neoadjuvant ADT followed by RP. Outcome measurements and statistical analysis The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence. Results and limitations Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence–free survival was also similar at 45% (95% confidence interval 7.9–78%) for men with gDDR alterations and 55% (95% confidence interval 44–64%) for men without gDDR alterations. Conclusions gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach. Patient summary Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.

Background Guidelines for optimal sequencing of radium-223 and chemotherapy for metastatic castration resistant prostate cancer (mCRPC) do not exist. This study evaluated treatment patterns and overall survival (OS) among patients with mCRPC treated with radium-223 in an academic clinical setting. Methods A retrospective study was conducted of bone metastases-predominant mCRPC patients treated with radium-223. Treatment patterns from 2013 to 2018 were evaluated in patients treated with radium-223 pre- vs. post-chemotherapy. OS was examined using Kaplan–Meier medians and 95% confidence intervals. Results In total, 220 patients were treated with radium-223 (64 pre-chemotherapy, 83 post-chemotherapy, 73 no chemotherapy). Mean radium-223 injections per patient was 5.3 and 4.3 in the pre- vs. post-chemotherapy cohorts, respectively (p p Conclusions This retrospective analysis of patients treated with radium-223 demonstrates that administration of radium-223 pre-chemotherapy increased likelihood of completion of radium-223 treatment. Radium-223 given pre- or post-chemotherapy and with or without combination therapy did not result in significant differences in OS. Additional studies are needed to determine the optimal sequencing strategy of mCRPC in the modern era.

‘You must be able to read the little cues from patients, such as a raise of the eyebrows or the clench of a fist’ – award-winner Rebecca Silver offers insight into the qualities that make a first-class dental nurse

Rebecca Silver advises on assisting with IV conscious sedation

Our newest editorial board member, Rebecca Silver, turned 30 in May. Here, she shares some tips to spark up your career as a successful dental nurse

Two weeks into lockdown, dental nurse Rebecca Silver found herself fitting FFP3 respirators to frontline workers. Here, she talks us through the process with Tarik Shembesh

Despite the success of immune check point inhibition, identification of other pathways capable of modulating the immune response against the tumor remains challenging. T-cell co-stimulation has been investigated with limited clinical success so far due in part to the fine tuning required for agonist antibodies against those co-stimulatory receptors and to the lack of biomarkers to facilitate the selection of patients likely to benefit from T-cell co-stimulation. TNFR2 belongs to the TNFR family of costimulatory molecules, and its expression on tumor infiltrating lymphocytes across a wide range of tumors make it an attractive target for T-cell co-stimulation. Recently, we identified HFB200301, an anti-TNFR2 antibody with Fc-independent agonist activity that does not block TNFR2 interaction with TNFα. HFB200301 activates CD4+, CD8+ T cells, and NK cells in vitro. In vivo, HFB200301 demonstrated potent single agent anti-tumor activity in syngeneic tumor models and can further increase the antitumor activity in combination with PD-1 blockade. To understand the immunological basis for the anti-tumor efficacy of HFB200301, we investigated the pharmacodynamic effects of HFB200301 in syngeneic mouse tumor models, including immuno-phenotyping and receptor occupancy of tumor infiltrating cells. In hTNFR2 knock-in mice bearing MC38 tumors, HFB200301 induces expansion of CD4+ and CD8+ T cells, and NK cells in the tumor micro-environment without affecting regulatory T cell numbers. We also demonstrate that the anti-tumor efficacy of HFB200301 is correlated with receptor occupancy and circulating soluble TNFR2 in a dose-dependent manner in this model. To discover predictive biomarkers of response to HFB200301, we used primary tumor samples and our proprietary Drug Intelligent Science (DIS™) single-cell platform to establish an immune-related signature. Single-cell RNA sequencing and clonotype barcoding of ex-vivo tumor cultures treated with HFB200301 were used to identify unique T cell profiles with a T cell centric gene panel. These unique T cell profiles may help identifying patients more likely to respond to HFB200301 treatment. In summary, HFB200301 exhibits a unique mechanism of action mainly relying on its agonistic activity on several effector cell types in tumor micro-environment that we expect will benefit a patient population selected with a unique biomarker signature. HFB200301 is currently in preclinical development and a biomarker-driven Phase 1 clinical study is projected for 2021. Citation Format: Shuo Wei, Ross Fulton, Yun-Yueh Lu, Qian Zhang, He Zhou, Andreas Raue, Mingjie Chen, Wenhua Xu, Xing Cai, Juliana Crivello, Zachary Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Dean Lee, Monika Manne, Nicola Beltraminelli, Jinping Gan, Francisco Adrian, Liang Schweizer, Jennifer Watkins-Yoon. Mechanism of action and biomarker strategy for HFB200301, an anti-TNFR2 agonist antibody for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1883.

Agonist OX40 antibodies have shown promising pre-clinical activities, but their clinical activities have been limited thus far. Several reasons may account for this limited clinical activity, including sub-optimal antibody design, dose selection, and lack of a biomarker strategy for indication selection and patient enrichment. Previous clinical trials selected doses that maximized receptor occupancy, but some patients responded at lower doses, indicating nuances to choosing the correct therapeutic doses for an agonist antibody. In addition, preclinical work has demonstrated a so-called “hook” effect whereby agonist activity decreases at higher concentrations, which further emphasizes the need to develop a novel anti-OX40 therapeutic antibody that addresses the previously encountered challenges. HFB301001 is a novel human IgG1 agonist antibody that binds to a unique epitope on OX40. This allows for agonistic activity that does not compete with the endogenous OX40 ligand. Relative to other clinical stage OX40 antibodies, HFB301001 has reduced OX40 downregulation following co-stimulation of T cells, and it has demonstrated superior in vivo anti-tumor activity and pharmacodynamic immune modulation in a human OX40 knock-in mouse model. HFB301001 is well tolerated in cynomolgus monkeys. To progress into clinical studies, we have determined human dose projections for clinical evaluation of HFB301001 using PKPD modeling, serum exposure in non-human primates, antitumor efficacy in mouse models and immune cell pharmacodynamics. We also took advantage of Fc variants to delineate the relative contributions of Treg depletion versus enhancing T cell activity by agonism to efficacy of HFB301001. To further enhance probability of success (POS) in clinical studies, we are applying our single-cell Drug Intelligent Science (DIS™) platform to rationally identify cancer indications and to define novel predictive response biomarkers. We have used single-cell profiling to identify unique tumor-infiltrating T cell signatures that may help identify patients more likely to response to HFB301001 treatment, inform indication selection, and establish a patient stratification biomarker strategy. Finally, we show here our phase I trial design for HFB301001 that implements these findings. In conclusion, HFB301001 is a highly differentiated therapeutic antibody which is well positioned to enter a global, multi-center Phase I clinical trial to explore optimal biologically active dose and evaluate predictive biomarker hypotheses. Here, we present results supporting the rationale for indication selection, biomarker identification, dose selection, and phase I clinical trial design. Citation Format: Ross Fulton, Jinping Gan, Yun-Yueh Lu, Julianna Crivello, Zachery Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Wenhua Xu, Xing Cai, Joyce Pi, Dean Lee, Monika Manne, Ruina Jin, Yuan Wang, Hongkai Zhang, Nicola Beltraminelli, Francisco Adrian, Robert Petit, Liang Schweizer, Andreas Raue. Clinical approach and biomarker strategy for HFB301001, a novel OX40 agonistic antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1882.

238 Background: Patients with high-risk prostate cancer have an increased risk of recurrence and death from prostate cancer. Intense NHT prior to RP has been associated with favorable pathologic responses in a subset of patients with high-risk disease. We conducted a pooled analysis of post-RP outcomes of four, multicenter, randomized, clinical trials of intense NHT prior to RP. Methods: All patients included were enrolled on trials evaluating intense NHT followed by RP. The primary endpoint was time to biochemical recurrence (BCR), defined as the time from RP to prostate specific antigen (PSA) >0.1 ng/mL or start of first post-RP therapy. Secondary endpoints included metastasis-free survival (MFS), overall survival (OS), and time to testosterone recovery. We evaluated outcomes in the overall population, favorable responders (defined as a pathologic complete response or minimum residual disease ≤ 5 mm at RP), and non-responders. We correlated pathologic parameters, including RP pathologic response, PTEN status, ERG status, and presence of intraductal carcinoma with BCR. Results: 121 patients were included of whom 78.5% (n=95) had high-risk disease by NCCN risk categories. Following NHT, 20.7% (n=25) had 0-5 mm of residual tumor (including 9.1%, n=11, with pathologic complete response). Overall, 52 patients (43.0%) experienced BCR, of whom two were exceptional responders (Table). Testosterone recovery was observed in 94.0% of patients (n=109/116). PTEN loss and presence of intraductal carcinoma were associated with shorter time to BCR. Conclusions: In this pooled analysis of clinical trials, we demonstrate that patients who achieve a favorable pathologic response to NHT prior to RP experienced a decreased PSA relapse rate and prolonged time to BCR. Larger residual tumor volumes and tissue-based parameters, including PTEN loss and intraductal carcinoma, were associated with BCR. Additional follow-up is warranted to evaluate the impact on long-term outcomes. Clinical trial information: NCT00298155; NCT00924469; NCT01547299; NCT02268175 . [Table: see text]

1507 Background: Approximately 10% of men with advanced prostate cancer (PC) have pathogenic/likely pathogenic variants (PV) in cancer susceptibility genes and their identification may lead to targeted therapy. Genetic testing (GT) can also guide cancer surveillance and prevention for family members. While GT is recommended for men with potentially lethal PC, traditional testing models are strained, and access limited. The ProGen study examined a novel pretest model aimed at providing access to GT while promoting informed consent. Methods: Inclusion criteria were: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), diagnosis age ≤ 55 years, prior malignancy, family history suggestive of a PV and/or at oncologist’s discretion. Consented subjects from 3 sites were randomized 3:1 to video education (VE) or in-person genetic counseling (GC). Subjects who consented to GT had 67 genes analyzed (Ambry, USA) with results disclosed by telephone by a genetic counselor. Outcomes included GT uptake, PV prevalence, and survey measures of satisfaction, distress, genetics knowledge, family communication, and impact on cancer care (obtained at the time of intervention, and at 1, 4, and 12 months after result disclosure). Two-sided Fischer exact tests were used for between-arm comparisons. Results: Over a 2-year period: 662 subjects were randomized, VE or GC were completed by 604 subjects (VE: 93.1%, GC: 88.8%) of whom 596 subjects (VE:98.9%, GC:97.9%) consented to GT. To date, 591 subjects have completed GT (VE: 99.3%, GC: 98.6%). At the time of intervention, most subjects agreed or strongly agreed that their assigned arm was useful (VE: 95%, GC: 88%). Differences were not statistically significant. Notably, 84 PV were identified in 78 subjects (13.2%), with BRCA1/2 PV accounting for 32% of subjects with a positive result ( BRCA2:21, BRCA1:4). Conclusions: In this randomized trial, both novel VE and traditional GC yielded high GT uptake without significant differences in outcome measures of acceptability and satisfaction. VE enabled access to critical GT results while maintaining the core tenants of informed consent. PV were found in 13.2% of subjects, 32% of whom had BRCA1/2 PV. Analysis of collected survey data to inform strengths and limitations of VE as compared with pretest GC will be presented. Clinical trial information: NCT03328091.

Looking over her 10-year career to date, Rebecca Silver suggests it is a good team who make a difference to the role of a dental nurse. Here, she champions the concept of team spirit

Award-winning Rebecca Silver talks about joining orthodontic patients on a journey beyond the chair

223 Background: Guidelines for optimal sequencing of approved mCRPC therapies do not exist. This study evaluated treatment patterns and overall survival (OS) among patients (pts) with mCRPC treated with Ra-223 in an academic clinical setting. Methods: A retrospective chart review study was conducted at Dana-Farber Cancer Institute of bone metastases-predominant mCRPC pts treated with Ra-223. Treatment patterns from 2013-2018 were evaluated including Ra-223 initiation pre- vs. post-chemotherapy (chemo). OS was examined using Kaplan-Meier medians and 95% confidence intervals (CIs). Results: 220 pts were treated with Ra-223 (64 pre-chemo, 83 post-chemo, 73 no chemo). Median Ra-223 injections per pt was 6.0 and 5.0 in the pre- vs. post-chemo cohorts, respectively (p

43 Background: PARP inhibitors (PARPi) and platinum chemotherapy cause synthetic lethality and result in clinical benefit in men with mCRPC whose tumors harbor deleterious alterations in DDR genes. BRCA2 is the strongest predictor, but data supports a role for BRCA1, ATM, and other genes. PARPi are more expensive than platinum chemotherapy; whether they are more effective is not known. We evaluated outcomes in men with DDR-deficient mCRPC treated with PARPi or platinum chemotherapy. Methods: We identified men treated at Dana-Farber Cancer Institute who received olaparib or carboplatin for mCRPC and underwent tumor mutation profiling. Progression-free survival (PFS) was determined using Prostate Cancer Working Group 3 guidelines. Pathogenic germline or somatic single-nucleotide variants, insertions/deletions, and copy number loss in BRCA2, BRCA1, and ATM, were identified. Log-rank test was utilized to compare differences in PFS. Results: We identified 27 men who received olaparib: 19/27 (70.4%) received prior taxane chemotherapy and 3/27 (11.1%) prior carboplatin; 16 had mono- or bi-allelic alterations in BRCA2 and 2 had alterations in BRCA1 or ATM. We identified 41 men treated with carboplatin: 39/41 (95.1%) received carboplatin in combination with a taxane; 36/41 (87.8%) received prior taxane chemotherapy and 7/41 (17.1%) prior PARPi; 16 had BRCA2 alterations and 5 had alterations in BRCA1 or ATM. Among men with BRCA2 alterations, there was no significant difference in PFS (HR 0.71, 95% CI 0.45-1.11; p = 0.13) between those treated with olaparib (4.9 months [m]) versus carboplatin (5.4 m). Similarly, no difference in PFS (HR 0.80, 95% CI 0.54-1.16; p = 0.24) was observed among men with BRCA2, BRCA1, or ATM alterations treated with olaparib (3.8 m) versus carboplatin (3.6 m). Conclusions: In a small real-world cohort of men with mCRPC harboring deleterious alterations in BRCA2, BRCA1, and ATM, there was no difference in PFS between those treated with olaparib versus carboplatin. These findings support further investigation into the comparative effectiveness and cost-effectiveness of PARPi and platinum chemotherapy in men with DDR-deficient mCRPC.

This study presents a method for assessing subjective organization (SO) after brain injury and techniques for planning cognitive rehabilitation therapy based on the survivor's SO ability. Eighty-seven college students, 50 persons with traumatic brain injury (TBI), and 30 participants with specific learning disability (SLD) learned two overlapping lists of unrelated nouns in which half of the second list were words that the person had learned on the first list. The study assessed whether different patterns of recall for the overlapping words versus the new words on the second list would discriminate persons with brain injury relative to college students and persons with SLD. The results indicated that college students and the SLD participants showed significantly diminished recall of overlapping words on the second list. However, the TBI participants showed significantly improved recall of the overlapping words. The results indicated that this task provides a simple diagnostic assessment of a participant's SO ability. The results also suggested that a TBI survivor's level of SO may moderate the success of prevocational cognitive rehabilitation therapies.

Two experiments compared the subjective organization of memory in college students and persons with brain injury using a part-whole list-learning task. Previous research attributed the negative transfer of learning that college students experience in the part-whole task to their inability to reorganize part-list words when learning the whole list. We reasoned that persons with brain injury would not experience negative transfer of learning in the part-whole paradigm because of their limited organizational skills. Experiment 1 replicated the usual negative transfer of learning with college students. Experiment 2 showed that brain-injured participants did not experience the same negative transfer of learning effects during the same task.

Two experiments examined the effects of iterated polling and feedback on prediction accuracy for volatile world events using the Delphi paradigm. In both experiments, participants predicted rapidly changing geopolitical events. The first experiment occurred during the litigation surrounding the Clinton/Lewinsky affair in 1998. Results indicated that feedback improved individual and group accuracy for predictions of whether an event would occur. These types of predictions derived from group consensus were approximately 90% accurate, which was significantly higher than the average individual participant's accuracy. Neither polling nor feedback had much effect on time course predictions. The second experiment occurred during the American military action against the Taliban regime in Afghanistan in 2001. In Experiment 2, participants were polled three times to determine if increasing the number of iterated polls would improve Delphi accuracy. The results showed that accuracy improved from the first to the second poll but not from the second to the third. The groups predicted whether these scenarios would occur with approximately 75% accuracy, which was significantly higher than the accuracy of any individual participant. Once again, the Delphi procedure did not enhance time course predictions in Experiment 2.

Two experiments examined several variables that influence first impressions between previously unacquainted, opposite gender participants. The first experiment investigated the relationship among measures of extroversion, cheerfulness, and attractiveness during a first encounter. Results showed that measures of attractiveness did not correlate with measures of extroversion and cheerfulness. The second experiment examined galvanic skin response (GSR) from male and female couples engaged in conversation. The results showed a significant direct relationship between the electrical conductivity of the skin for 10 pairs of participants who were engaged in a simple conversation.

BACKGROUND: There is a dearth of systematic studies of expressive writing disorder (EWD) in persons with Traumatic Brain Injury (TBI). It is unclear if TBI survivors' written expression differs significantly from that experienced by persons with learning disabilities. It is also unclear which cognitive or neuropsychological variables predict problems with expressive writing (EW) or the EWD. OBJECTIVE: This study investigated the EW skill, and the EWD in adults with mild traumatic brain injuries (TBI) relative to those with learning disabilities (LD). It also determined which of several cognitive variables predicted EW and EWD. METHODS: Principle Component Analysis (PCA) of writing samples from 28 LD participants and 28 TBI survivors revealed four components of expressive writing skills: Reading Ease, Sentence Fluency, Grammar and Spelling, and Paragraph Fluency. RESULTS: There were no significant differences between the LD and TBI groups on any of the expressive writing components. Several neuropsychological variables predicted skills of written expression. The best predictors included measures of spatial perception, verbal IQ, working memory, and visual memory. CONCLUSIONS: TBI survivors and persons with LD do not differ markedly in terms of expressive writing skill. Measures of spatial perception, visual memory, verbal intelligence, and working memory predict writing skill in both groups. Several therapeutic interventions are suggested that are specifically designed to improve deficits in expressive writing skills in individuals with TBI and LD. Language: en

The aim of this project was to perform seakeeping and resistance tests using the NSWCCD Surface Effect Ship (SES) T-Craft model, DTMB number 5687, in Carderock's 140 foot tow basin. Seakeeping tests were previously performed on this model by the Seakeeping Division (Code 55) in the Maneuvering and Seakeeping Basin (MASK), but underway resistance tests were not performed. This project conducted resistance tests in calm water and various regular wave conditions, zero speed motion tests at headings of 180 and 90 degrees, as well as pitch, heave, and roll decay tests. It was of interest to understand the effect of the SES air cushion on ship motions and resistance, therefore RAO graphs were developed to describe ship motions, along with the resistance graphs at full, half, and zero cushion. Zero speed motions tests were conducted in the 140 ft basin for the same wave conditions used in the earlier MASK tests for comparison.

This research concerns the measurement of self-monitoring in people who were diagnosed with traumatic brain injury (TBI), learning disability (LD) and emotional disorder (ED). Two measures of self-monitoring were evaluated: (1) the correlation between participants' self-predicted and observed standardized sub-test scores (R) on 17 WAIS-III 1 sub-tests and (2) the average difference between the participants' predicted and observed sub-tests scores (B). It was then determined if these measures could discriminate the three diagnostic groups.Canonical analysis assessed the relationship between the self-monitoring measures and four WAIS-III IQ measures. This study also evaluated if the R and B measures could discriminate the diagnostic groups.One hundred and twenty-four participants, 42 with TBI, 42 with LD and 40 with ED predicted their performance on 17 WAIS-III sub-tests.Canonical analysis demonstrated a significant relationship between the R and B measures and four WAIS-III IQ measures. Results of a MANOVA showed that the R and B measures differed significantly among the diagnostic groups.The R and B measures are two valid and reliable indices of self-monitoring that can be conveniently estimated from the WAIS-III.