Citations

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) -> AC substantially improves pCR rates over standard TH -> AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.

Key Points The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM. Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.

AbstractBackgroundAlthough many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices.MethodsAn electronic survey was distributed to assess ECP practice internationally.ResultsOf 251 responses, 137 met criteria for analysis. Most respondents were from North America (80%). Nurses perform ECP at most centers (84%) and the majority of centers treat adults only (52%). Most centers treat fewer than 50 patients/year (83%) and perform fewer than 300 procedures/year (70%). Closed system devices (XTS and/or Cellex) are used to perform ECP at most centers (96%). The most common indications for ECP are acute/chronic skin graft versus host disease (89%) and cutaneous T‐cell lymphoma (63%). The typical wait time for ECP treatment is less than 2 weeks (91%). Most centers do not routinely perform quality control assessment of the collected product (66%). There are device‐specific differences in treatment parameters. For example, XTS users more frequently have a minimum weight limit (P = 0.003) and use laboratory parameters to determine eligibility for treatment (P = 0.03). Regardless of device used, the majority of centers assess the clinical status of the patient before each procedure. Greater than 50% of respondents would defer treatment for hemodynamic instability due to active sepsis or heart failure, positive blood culture in the past 24 h or current fever.ConclusionThis survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended.

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

Abstract Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a critical effector pathway for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC) and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP6′s relevant substrates has been obscure. Here we report that the Jak1–STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1–STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression. Cancer Res; 76(18); 5337–47. ©2016 AACR.

SummaryObjectivePosttraumatic seizures (PTS) are well‐recognized acute and chronic complications of traumatic brain injury (TBI). Risk factors have been identified, but considerable variability in who develops PTS remains. Existing PTS prognostic models are not widely adopted for clinical use and do not reflect current trends in injury, diagnosis, or care. We aimed to develop and internally validate preliminary prognostic regression models to predict PTS during acute care hospitalization, and at year 1 and year 2 postinjury.MethodsPrognostic models predicting PTS during acute care hospitalization and year 1 and year 2 post‐injury were developed using a recent (2011–2014) cohort from the TBI Model Systems National Database. Potential PTS predictors were selected based on previous literature and biologic plausibility. Bivariable logistic regression identified variables with a p‐value < 0.20 that were used to fit initial prognostic models. Multivariable logistic regression modeling with backward‐stepwise elimination was used to determine reduced prognostic models and to internally validate using 1,000 bootstrap samples. Fit statistics were calculated, correcting for overfitting (optimism).ResultsThe prognostic models identified sex, craniotomy, contusion load, and pre‐injury limitation in learning/remembering/concentrating as significant PTS predictors during acute hospitalization. Significant predictors of PTS at year 1 were subdural hematoma (SDH), contusion load, craniotomy, craniectomy, seizure during acute hospitalization, duration of posttraumatic amnesia, preinjury mental health treatment/psychiatric hospitalization, and preinjury incarceration. Year 2 significant predictors were similar to those of year 1: SDH, intraparenchymal fragment, craniotomy, craniectomy, seizure during acute hospitalization, and preinjury incarceration. Corrected concordance (C) statistics were 0.599, 0.747, and 0.716 for acute hospitalization, year 1, and year 2 models, respectively.SignificanceThe prognostic model for PTS during acute hospitalization did not discriminate well. Year 1 and year 2 models showed fair to good predictive validity for PTS. Cranial surgery, although medically necessary, requires ongoing research regarding potential benefits of increased monitoring for signs of epileptogenesis, PTS prophylaxis, and/or rehabilitation/social support. Future studies should externally validate models and determine clinical utility.

Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.

AbstractBackgroundNausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG).MethodsGastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting.Key ResultsOf 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI‐SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating.Conclusions & InferencesNausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG.