Citations

318 Background: Apalutamide, enzalutamide, and darolutamide were approved for non-metastatic castration-resistant prostate cancer (nmCRPC) based on three randomized placebo-controlled trials that showed similar efficacy. Adverse event (AE) profiles have been invoked to differentiate the drugs but have only been informally compared. Methods: We accounted for baseline characteristics, AE collection and reporting, and statistical uncertainty when comparing AE risks in the drug and placebo arms of SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614). Results: Patients in SPARTAN, PROSPER, and ARAMIS had a similar median age (74 years in all studies), median PSA doubling time (3.7-4.7 months) and ECOG performance status (68-80% with ECOG 0). AEs were gathered consistently using CTCAE 4.0 or 4.03. However, PROSPER and ARAMIS reported AEs occurring in ≥5% of patients; SPARTAN reported AEs occurring in ≥15%. Trials also reported 5 to 14 ‘AEs of interest.’ Of 34 AE types reported overall, only 10 were reported in all three trials. Absolute risks of adverse events in the placebo arms differed considerably. Compared to the placebo arm of SPARTAN, AEs were on average 44% less common in the placebo arm of PROSPER (95% CI, 28-56%) and 54% less common in the placebo arm of ARAMIS (95% CI, 41-64%), a difference not explained by length of follow-up. With lower event numbers, relative risk estimates were less precise with wider confidence intervals. For example, comparing treatment vs. placebo arms, the relative risk for fatigue, the most common AE, was 1.45 (95% CI, 1.16-1.80) in SPARTAN, 2.37 (95% CI, 1.86-3.04) in PROSPER, and 1.39 (95% CI, 1.01-1.91) in ARAMIS. Across all AE types, compared to SPARTAN, relative risks from PROSPER were 23% less precise and relative risks from ARAMIS were 30% less precise. Conclusions: While conducted in similar patient populations, these trials had remarkable differences in AE reporting and in absolute AE risks between placebo arms. Rather than indicating better safety, low absolute adverse event numbers decrease confidence in AE profiles. Published data are insufficient to differentiate the AE profiles of these agents in nmCRPC.

PURPOSE To develop recommendations concerning the management of male breast cancer. METHODS ASCO convened an Expert Panel to develop recommendations based on a systematic review and a formal consensus process. RESULTS Twenty-six descriptive reports or observational studies met eligibility criteria and formed the evidentiary basis for the recommendations. RECOMMENDATIONS Many of the management approaches used for men with breast cancer are like those used for women. Men with hormone receptor–positive breast cancer who are candidates for adjuvant endocrine therapy should be offered tamoxifen for an initial duration of five years; those with a contraindication to tamoxifen may be offered a gonadotropin-releasing hormone agonist/antagonist plus aromatase inhibitor. Men who have completed five years of tamoxifen, have tolerated therapy, and still have a high risk of recurrence may be offered an additional five years of therapy. Men with early-stage disease should not be treated with bone-modifying agents to prevent recurrence, but could still receive these agents to prevent or treat osteoporosis. Men with advanced or metastatic disease should be offered endocrine therapy as first-line therapy, except in cases of visceral crisis or rapidly progressive disease. Targeted systemic therapy may be used to treat advanced or metastatic cancer using the same indications and combinations offered to women. Ipsilateral annual mammogram should be offered to men with a history of breast cancer treated with lumpectomy regardless of genetic predisposition; contralateral annual mammogram may be offered to men with a history of breast cancer and a genetic predisposing mutation. Breast magnetic resonance imaging is not recommended routinely. Genetic counseling and germline genetic testing of cancer predisposition genes should be offered to all men with breast cancer.

ObjectivesThe aim of this study was to perform a whole-brain analysis of alterations in brain mechanical properties due to normal pressure hydrocephalus (NPH).Materials and MethodsMagnetic resonance elastography (MRE) examinations were performed on 85 participants, including 44 cognitively unimpaired controls, 33 with NPH, and 8 who were amyloid-positive with Alzheimer clinical syndrome. A custom neural network inversion was used to estimate stiffness and damping ratio from patches of displacement data, accounting for edges by training the network to estimate the mechanical properties in the presence of missing data. This learned inversion was first compared with a standard analytical approach in simulation experiments and then applied to the in vivo MRE measurements. The effect of NPH on the mechanical properties was then assessed by voxel-wise modeling of the stiffness and damping ratio maps. Finally, a pattern analysis was performed on each individual's mechanical property maps by computing the correlation between each person's maps with the expected NPH effect. These features were used to fit a classifier and assess diagnostic accuracy.ResultsThe voxel-wise analysis of the in vivo mechanical property maps revealed a unique pattern in participants with NPH, including a concentric pattern of stiffening near the dural surface and softening near the ventricles, as well as decreased damping ratio predominantly in superior regions of the white matter (family-wise error correctedP< 0.05 at cluster level). The pattern of viscoelastic changes in each participant predicted NPH status in this cohort, separating participants with NPH from the control and the amyloid-positive with Alzheimer clinical syndrome groups, with areas under the receiver operating characteristic curve of 0.999 and 1, respectively.ConclusionsThis study provides motivation for further development of the neural network inversion framework and demonstrates the potential of MRE as a novel tool to diagnose NPH and provide a window into its pathogenesis.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Abstract BACKGROUND Aneurysm recurrence after coiling has been associated with aneurysm growth, (re)hemorrhage, and a greater need for follow-up. The second-generation HydroCoil Embolic System (HES; MicroVention, Inc) consists of a platinum core with integrated hydrogel and was developed to reduce recurrence through enhancing packing density and healing within the aneurysm. OBJECTIVE To compare recurrence between the second-generation HES and bare platinum coil (BPC) in the new-generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT). METHODS HEAT is a randomized, controlled trial that enrolled subjects with ruptured or unruptured 3- to 14-mm intracranial aneurysms amenable to coiling. The primary endpoint was aneurysm recurrence using the Raymond-Roy scale. Secondary endpoints included minor and major recurrence, packing density, adverse events related to the procedure and/or device, mortality, initial complete occlusion, aneurysm retreatment, hemorrhage from target aneurysm during follow-up, aneurysm occlusion stability, and clinical outcome at final follow-up. RESULTS A total of 600 patients were randomized (HES, n = 297 and BPC, n = 303), including 28% with ruptured aneurysms. Recurrence occurred in 11 (4.4%) subjects in the HES arm and 44 (15.4%) subjects in the BPC arm ( P = .002). While the initial occlusion rate was higher with BPC, the packing density and both major and minor recurrence rates were in favor of HES. Secondary endpoints including adverse events, retreatment, hemorrhage, mortality, and clinical outcome did not differ between arms. CONCLUSION Coiling of small-to-medium aneurysms with second-generation HES resulted in less recurrence when compared to BPC, without increased harm. These data further support the use of the second-generation HES for the embolization of intracranial aneurysms. Video Abstract

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.

ABSTRACT Clinical radiotherapy treats life-threatening cancers, but the radiation often affects neighboring normal tissues including bone. Acute effects of ionizing radiation include oxidative stress, DNA damage, and cellular apoptosis. We show in this study that a large proportion of bone marrow cells, osteoblasts, and matrix-embedded osteocytes recover from these insults only to attain a senescent profile. Bone analyses of senescence-associated genes, senescence-associated beta-galactosidase (SA-β-gal) activity, and presence of telomere dysfunction-induced foci (TIF) at 1, 7, 14, 21, and 42 days post–focal radiation treatment (FRT) in C57BL/6 male mice confirmed the development of senescent cells and the senescence-associated secretory phenotype (SASP). Accumulation of senescent cells and SASP markers were correlated with a significant reduction in bone architecture at 42 days post-FRT. To test if senolytic drugs, which clear senescent cells, alleviate FRT-related bone damage, we administered the senolytic agents, dasatinib (D), quercetin (Q), fisetin (F), and a cocktail of D and Q (D+Q). We found moderate alleviation of radiation-induced bone damage with D and Q as stand-alone compounds, but no such improvement was seen with F. However, the senolytic cocktail of D+Q reduced senescent cell burden as assessed by TIF+ osteoblasts and osteocytes, markers of senescence (p16 Ink4a and p21), and key SASP factors, resulting in significant recovery in the bone architecture of radiated femurs. In summary, this study provides proof of concept that senescent cells play a role in radiotherapy-associated bone damage, and that reduction in senescent cell burden by senolytic agents is a potential therapeutic option for alleviating radiotherapy-related bone deterioration. © 2020 American Society for Bone and Mineral Research.

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.

Introduction. Post-operative meningitis (POM) is a life-threatening complication of neurosurgery. Diagnosis is often difficult due to pre-existing inflammation and antecedent antimicrobial use. Bacterial cerebrospinal fluid (CSF) cultures may reveal no growth, but empiric antibiotics are typically given due to the high morbidity and mortality associated with POM. 16S rRNA gene PCR/sequencing is a molecular methodology that can identify the presence of bacteria regardless of viability for culture. Case Presentation. A patient presented with a rapid onset of fever associated with headache, neck pain, nausea and altered mental status 11 days after undergoing laser interstitial thermal therapy for treatment of recurrent astrocytoma at another hospital. Based on clinical presentation and imaging, POM was suspected, and empiric antibacterial therapy was started. Microbiological stains and cultures of CSF were negative. Due to persistent fevers, 16S rRNA gene PCR/sequencing was done on CSF; it detected a member of the order Enterobacteriales most closely resembling Serratia species. All antimicrobials were stopped except for cefepime, which was given for 2 weeks. The patient’s mental status fully recovered. Conclusion. The application of 16S rRNA gene PCR/sequencing in the setting of POM is of value by improving the quality of patient care and decreasing costs by antimicrobial de-escalation. Further studies regarding the positive and negative predictive values of this test are required.