Citations

Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641

Abstract Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

The medicolegal autopsy is part of a death investigation that determines the cause and manner of death and the extent of the testing performed is variable and is directed by the specifics of a particular case. Published studies disagree on the value of routine examination of microscopic sections of internal organs in forensic cases and no studies have specifically reviewed the utility of routine neuropathology microscopic sections. We reviewed the Miami-Dade County Medical Examiner Department and Mayo Clinic computer databases to determine whether routine brain histology is of value in medicolegal autopsies and the impact on the cause and manner of death. Consecutive cases from each institution were analyzed to determine whether the microscopic neuropathological findings revealed a previously unrecognized disease, changed the cause or manner of death, or significantly impacted the death investigation. In the cases in which the immediate cause of death was attributable to central nervous system (CNS) pathology, the cause of death was readily apparent from the gross brain examination. If CNS pathology was the proximate cause of death, contributed significantly to the death, or was a significant part of the death investigation, full appreciation of the neuropathology required microscopic examination and often additional special/immunostains. We conclude that microscopic brain examination is needed in selected medicolegal autopsies to exclude and/or diagnose underlying disease processes, particularly if the gross examination doesn't reveal an obvious explanation of the CNS pathology or the clinical history suggests underlying neuropathology.

279 Background: While bacillus Calmette-Guérin (BCG) is the most effective intravesical treatment for reducing recurrence and progression for high-risk non-muscle invasive bladder cancer (NMIBC), many patients are either refractory to treatment or relapse. We assessed the efficacy and safety of rAd-IFNα/Syn 3 (Instiladrin, FKD Finland), a replication deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG refractory or relapsed NMIBC. Methods: In this open-label, US multicenter (n=13), parallel-arm Phase II study (NCT01687244), 43 patients with HG BCG refractory or relapsed NMIBC were randomized 1:1 to receive intravesical rAd-IFNα/Syn3 at 1x1011 or 3x1011viral particles/mL. Patients responding at months 3, 6, and 9 were re-treated at months 4, 7, and 10. Most patients (n=21) had a primary tumor classification of carcinoma in situ (CIS); 9 had both CIS and Ta/T1 disease and 10 had Ta/T1 disease alone. The primary endpoint was 12-month HG recurrence-free survival (RFS). All patients receiving at least one dose were included in efficacy and safety analyses. Results: Forty patients received rAd-IFNα/Syn3 (1 x 1011 vp/mL: n=21; 3 x 1011vp/mL: n=19) between November 2012 and April 2015. Fourteen patients (35.0%; 90% CI 22.6%, 49.2%) remained free of HG tumor recurrence 12 months after initial treatment. Comparable 12 month HG RFS was noted between dosage arms, as well as between patients with refractory and relapsed NMIBC. Interestingly, the 12 month HG recurrence-free survival for patients with Ta/T1-only disease was 50% (5/10). rAd-IFNα/Syn3 was well-tolerated, with no Grade 5 adverse events (AEs), one Grade 4 AE (COPD; unrelated to treatment), and no patient discontinuing treatment due to an adverse event. The most frequently reported AEs were micturition urgency (n=16), dysuria and pollakiuria (n=13 each), fatigue (n=9), and nocturia (n=10). Conclusions: rAd-IFNα/Syn3 was well tolerated and demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who are unable or unwilling to undergo radical cystectomy. A phase III trial utilizing this novel agent is ongoing. Clinical trial information: 01687244.

Abstract Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

Abstract BACKGROUND Neuroendovascular intervention has become a key treatment option for acute ischemic stroke. The Sofia (6F) PLUS catheter was designed for neurovascular access for diagnostic or therapeutic interventions. OBJECTIVE To report the first series describing use of the Sofia PLUS intermediate/distal access reperfusion catheter in the treatment of acute ischemic stroke. METHODS In this retrospective study, 41 stroke cases were identified in which the catheter was utilized for thrombolysis/thrombectomy. Mean preprocedure National Institutes of Health Stroke Scale score was 16.5 ± 5.2 (range 4-29). Occluded vessels included the M1 segment, M2 segment, internal carotid artery terminus, cervical internal carotid artery, and basilar artery. RESULTS Successful positioning of the Sofia PLUS catheter near the occlusion site was achieved in 38 (92.7%) of 41 cases in which thrombectomy or thrombolysis was attempted using intraarterial tissue plasminogen activator, a direct aspiration first-pass technique, and/or stent retrieval. A postprocedure thrombolysis in cerebral infarction (TICI) score of 2b/3 was achieved in 37 of 41 cases. Of 15 cases where the Sofia PLUS was used for a direct aspiration first-pass technique, TICI 2b/3 was achieved in 11 (73.3%). In one case where intra-arterial tissue plasminogen activator was used as the only treatment modality, TICI 2a was achieved. No device-related or catheter-related complications were observed. The mean 7-d-postprocedure National Institutes of Health Stroke Scale score among the 39 survivors was 8.5 ± 7.3 (range 0-23). CONCLUSION Initial results with use of the Sofia (6F) PLUS for endovascular treatment of acute ischemic stroke have been encouraging. Experience with a larger series is warranted to further evaluate the safety and efficacy of this device and compare it with other reperfusion catheters.