Citations

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.

A healthy 20‐year‐old male presented with aborted sudden death. Both thoracic echocardiography and cardiac computed tomographic angiography demonstrated the characteristic findings of ALCAPA noting a dilated and tortuous right coronary artery, dilated coronary collateral arteries within the interventricular septum or along the surface of the heart, and visualization of the left coronary artery origin from the posterior aspect of the main pulmonary artery. Both imaging modalities demonstrated all three characteristic findings of this rare coronary anomaly and served as complementary imaging studies for surgical correction.

Objective: To report the presentation, diagnosis, management, and convalescence of labyrinthine sequestrum (LS) and summarize all previously published cases. Patient(s): Eleven-year-old female with LS. Intervention(s): Multidisciplinary diagnostic evaluation and treatment. Main Outcome Measures: Imaging and laboratory findings, medical and surgical treatment. Results: We describe a case of LS secondary to medically recalcitrant suppurative otitis media in an 11-year-old female and review all eight previously reported cases. The index patient presented after 6 months of otitis media, profound unilateral hearing loss, with symptoms suggesting meningitis. Temporal bone CT demonstrated marked bony destruction of the left otic capsule. Gadolinium-enhanced MRI showed an enhancing process with evidence of meningitis and subdural empyema. The patient was treated with surgical debridement and culture directed antibiotic therapy. Posttreatment imaging showed resolution of intracranial infection with fibrous bony healing of the otic capsule resembling fibrous dysplasia. Conclusion: LS is a rare form of labyrinthitis characterized by centrifugal destruction of the otic capsule. The current index case highlights the importance of combined medical and surgical treatment and describes for the first time in the literature the fibrous ossification of the otic capsule following disease resolution.

Abstract The mouse eosinophil peroxidase (mEPO) gene was cloned by screening a random-primed bone marrow cDNA library at reduced criteria using a hEPO cDNA. An mEPO cDNA was subsequently used to isolate the mEPO gene from a λ-genomic library. The mEPO gene displays a high degree of conservation with its human homologue: the transcription units are approximately the same size, conserve the relative size and position of the 12 exons associated with each gene, and at a nucleotide level the mouse and human EPO genes are 86% identical in the protein coding regions and 66% identical in the 3'-untranslated trailer regions. This strong conservation extends to the encoded proteins which show ~90% amino acid identity. Expression of the mEPO gene is restricted to tissues containing eosinophil progenitor cells (e.g., bone marrow and spleen), a pattern similar to the expression of another murine eosinophil granule protein, major basic protein.

Abstract We have identified a new eosinophil major basic protein gene family member in the mouse and have given it the designation murine major basic protein-2 (mMBP-2). The gene was initially characterized as a unique expressed sequence tag (EST) clone having significant identity to the previously recognized member of this gene family, mMBP-1. The EST was used to screen and isolate mMBP-2 from a bone marrow cDNA library. In addition, a genomic clone of mMBP-2 was isolated and this gene was shown to be physically linked to within 100 kb of mMBP-1 on the central region of mouse chromosome 2. Progressive similarity alignment of the deduced mMBP-2 open reading frame demonstrates the apparent conservation of the “pre-pro-mature” protein structure found in the other known mammalian MBPs. Mature mMBP-2 maintains the cationic nature associated with these proteins with a predicted pI of 9.95. However, unlike the human MBPs, which display a three orders of magnitude charge difference [hMBP-1 (pI11.4) vs. hMBP-2 (pI8.7)], mMBP-2 is only slightly less cationic than mMBP-1 (pI 10.5). Expression studies demonstrate that transcription of the mMBP-2 gene parallels mMBP-1 and is confined to hematopoietic compartments engaged in eosinophilopoiesis. Moreover, using mMBP-1 knockout mice and immunohistochemistry with an antisera that recognizes both mMBP-1 and -2, we demonstrate that mMBP-2 protein expression is restricted to eosinophil lineage-committed cells. J. Leukoc. Biol. 67: 567–576; 2000.

Background: Use of magnetic resonance imaging (MRI) brain is restricted in patients with cardiovascular implantable electronic devices (CIEDs). We proposed to determine whether mortality difference exists for patients with non–MRI-conditional CIEDs undergoing brain MRI compared with controls. Methods and Results: Retrospective analysis of prospectively collected data was performed to compare all-cause mortality in patients with CIEDs undergoing brain MRI (CIED-MRI) with 3 control groups matched for age, sex, imaging year, and type of CIED: (1) no CIED, brain MRI (no–CIED-MRI); (2) CIED, brain computerized tomography (CT) scan (CIED-CT); and (3) no CIED, brain CT (no–CIED-CT). The primary outcome was a significant difference ( P <0.05) between estimated mortality rates. Secondary outcomes were changes in device function before and after brain MRI. The estimated all-cause mortality at 5 years for the CIED-MRI group [mean age (±SD), 68.2 years (15.3 years); 61.2% men] was not significantly different from patients who underwent CT with or without a device (CIED-CT group: hazard ratio, 0.814; 95% confidence interval, 0.593–1.117; P =0.2; no–CIED-CT group: hazard ratio, 1.149; 95% confidence interval, 0.818–1.613; P =0.4). There was a significant increase in mortality between CIED-MRI and no–CIED-MRI groups (hazard ratio, 1.463; 95% confidence interval, 1.019–2.099; P =0.04). Conclusions: Brain MRI in patients with CIEDs does not carry an increased mortality risk compared with brain CT and can be performed with adherence to appropriate procedural protocols.

ABSTRACT We describe results from a multicenter study evaluating the Accelerate Pheno system, a first of its kind diagnostic system that rapidly identifies common bloodstream pathogens from positive blood cultures within 90 min and determines bacterial phenotypic antimicrobial susceptibility testing (AST) results within ∼7 h. A combination of fresh clinical and seeded blood cultures were tested, and results from the Accelerate Pheno system were compared to Vitek 2 results for identification (ID) and broth microdilution or disk diffusion for AST. The Accelerate Pheno system accurately identified 14 common bacterial pathogens and two Candida spp. with sensitivities ranging from 94.6 to 100%. Of fresh positive blood cultures, 89% received a monomicrobial call with a positive predictive value of 97.3%. Six common Gram-positive cocci were evaluated for ID. Five were tested against eight antibiotics, two resistance phenotypes (methicillin-resistant Staphylococcus aureus and Staphylococcus spp. [MRSA/MRS]), and inducible clindamycin resistance (MLSb). From the 4,142 AST results, the overall essential agreement (EA) and categorical agreement (CA) were 97.6% and 97.9%, respectively. Overall very major error (VME), major error (ME), and minor error (mE) rates were 1.0%, 0.7%, and 1.3%, respectively. Eight species of Gram-negative rods were evaluated against 15 antibiotics. From the 6,331 AST results, overall EA and CA were 95.4% and 94.3%, respectively. Overall VME, ME, and mE rates were 0.5%, 0.9%, and 4.8%, respectively. The Accelerate Pheno system has the unique ability to identify and provide phenotypic MIC and categorical AST results in a few hours directly from positive blood culture bottles and support accurate antimicrobial adjustment.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.