Citations

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Abstract Background: Fibromyalgia (FM) is a common chronic pain condition that seriously affects the quality of patient lives. Its etiology, pathogenesis, and treatment still remain uncertain. Dietary supplements have been widely trialed for symptom relief for FM. The review aims to synthesize the previous literature publications to assess the impact of herbs and dietary supplements on FM patients. Methods: We will conduct a literature search in the following databases PubMed, MEDLINE, EMBASE, Cochrane Library, Scopus, and Global Health from database inception to December 2019. Clinical studies published in the English language that used human participants and address the efficacy, safety, and acceptability of herbs and dietary supplements on individuals with FM will be included. The risk of bias and quality assessment of each trial will be evaluated. If trials are enough, a meta-analysis will be conducted using software RevMan5.3, Cochrane Collaboration. Result: Our review will be the first attempt to facilitate evidence-based management using herbs and dietary supplements to treat patients with FM. Conclusion: The findings may provide a framework for future research and clinic practice in FM management. PROSPERO registration number: CRD42020149941

Abstract The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.

Abstract INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.

Abstract Background In a phase 2 PIONEER-HCM study, pts with symptomatic, obstructive hypertrophic cardiomyopathy (oHCM) showed improvement in left ventricular outflow tract (LVOT) obstruction, exercise capacity, and symptoms after 12 wk of treatment with the novel myosin modulator, mavacamten (Mava). Purpose To examine the long-term safety and effectiveness of Mava in PIONEER-OLE study Methods PIONEER-OLE (NCT03496168) is an ongoing 2-y multicenter study for adults with symptomatic oHCM who completed PIONEER-HCM (NCT02842242). The starting dose of Mava is 5 mg/d with titration at wk 6 to an individualized therapeutic dose (5, 10, or 15 mg). Evaluations are at wk 4, 6, 8, 12 and every 12 wk thereafter to monitor LV ejection fraction (LVEF), LVOT gradient, New York Heart Association (NYHA) class, NT-proBNP, drug concentration, and safety. Results 13 pts (mean age, 57.8 y; 9 male; 12 on beta-blockers) were enrolled. Mean baseline LVOT obstruction and LVEF, and wk 12 changes from baseline, were similar to those in PIONEER-HCM (Table). Mava significantly reduced resting and provoked LVOT gradients and NT-proBNP at wk 12 and 24 compared with baseline (P<0.004). Of 10 pts who reached wk 24, 8 reported improvement in NYHA class (1 improved Class III to II; 7 improved Class II to I), and 2 pts remained Class II. Mava has been well tolerated up to 40 wk; 31 adverse events (AEs; 22 mild, 5 moderate) were reported in 8 pts; 1 pt had 3 severe and 1 serious AE (cholangiocarcinoma); all AEs were unrelated to study drug. Results from PIONEER-OLE Parameter PIONEER-HCMa PIONEER-OLE Baseline Wk 12 Baselineb Wk 12 Change at Wk 12 Wilcoxon Signed Wk 24 Change at Wk 24 Wilcoxon Signed Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Rank Mean ± SD Mean ± SD Rank (n=13) (n=13) (n=13)c (n=12)c (n=12)c P value (n=10)c (n=10)c P value LVOT Rest gradient, mmHg 69.7±53.9 27.8±31.3 67.3±42.8 12.0±5.4 −57.9±43.2 0.0005 10.5±4.8 −66.6±42.4 0.0020 LVOT Valsalva gradient, mmHg 93.7±55.6 36.8±37.5 89.9±30.7 (n=12) 23.6±20.0 −66.4±35.3 (n=11) 0.0020 21.1±11.5 −67.3±33.5 (n=9) 0.0039 LVEF, % 73.0±5.6 64.6±10.5 72.0±4.9 67.6±7.2 −4.4±5.5 0.0269 68.2±6.5 −3.2±3.3 0.0195 NT-proBNP, pg/mL 1601.3±2782 (n=12) 684±980 1836±2886 181±211 −1759±2789 0.0005 170±225 −2128±3104 0.0039 Data extraction date January 24, 2019. aCombined results shown for pts from PIONEER-HCM originally in cohort A (n=5) and cohort B (n=8). bBaseline in PIONEER-OLE occurred 6–18 months after completion of PIONEER-HCM. cNumber of pts with data available for analysis, unless otherwise specified. Conclusion Despite management with current therapies, pts enrolled in PIONEER-OLE with similar levels of obstruction and hypercontractility as in PIONEER-HCM. In this longest observation period, Mava significantly reduced obstruction (LVOT gradient) in pts with oHCM beyond standard HCM therapy, while maintaining normal LVEF and improving symptoms. Acknowledgement/Funding MyoKardia

Abstract Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

PURPOSE Multiparametric magnetic resonance imaging (mpMRI) is used widely for prostate cancer (PCa) evaluation. Approximately 35% of aggressive tumors, however, are not visible on mpMRI. We sought to identify the molecular alterations associated with mpMRI-invisible tumors and determine whether mpMRI visibility is associated with PCa prognosis. METHODS Discovery and validation cohorts included patients who underwent mpMRI before radical prostatectomy and were found to harbor both mpMRI-visible (Prostate Imaging and Reporting Data System 3 to 5) and -invisible (Prostate Imaging and Reporting Data System 1 or 2) foci on surgical pathology. Next-generation sequencing was performed to determine differential gene expression between mpMRI-visible and -invisible foci. A genetic signature for tumor mpMRI visibility was derived in the discovery cohort and assessed in an independent validation cohort. Its association with long-term oncologic outcomes was evaluated in a separate testing cohort. RESULTS The discovery cohort included 10 patients with 26 distinct PCa foci on surgical pathology, of which 12 (46%) were visible and 14 (54%) were invisible on preoperative mpMRI. Next-generation sequencing detected prioritized genetic mutations in 14 (54%) tumor foci (n = 8 mpMRI visible, n = 6 mpMRI invisible). A nine-gene signature (composed largely of cell organization/structure genes) associated with mpMRI visibility was derived (area under the curve = 0.89), and the signature predicted MRI visibility with 75% sensitivity and 100% specificity (area under the curve = 0.88) in the validation cohort. In the testing cohort (n = 375, median follow-up 8 years) there was no significant difference in biochemical recurrence, distant metastasis, or cancer-specific mortality in patients with predicted mpMRI-visible versus -invisible tumors (all P > .05). CONCLUSION Compared with mpMRI-invisible disease, mpMRI-visible tumors are associated with underexpression of cellular organization genes. mpMRI visibility does not seem to be predictive of long-term cancer outcomes, highlighting the need for biopsy strategies that detect mpMRI-invisible tumors.

Abstract Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART ) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.