Citations

Objective: To determine the relative or combined effects of Crohn disease (CD) and ulcerative colitis (UC) and the operation performed on postoperative venous thromboembolism (VTE) to better guide recommendations on extended VTE prophylaxis. Summary Background Data: There is growing evidence to suggest patients with inflammatory bowel disease have an increased risk of postoperative VTE, but prior studies have not accounted for the operation performed nor acknowledged differences between CD and UC. Methods: The American College of Surgeons National Surgical Quality Improvement Project database from 2005 to 2016 was queried for patients with a diagnosis of CD, UC, malignancy, or benign disease (diverticular disease, Clostridium difficile) undergoing major abdominal surgery. Operations with a VTE rate >3% were designated high risk. Operation-specific univariate and multivariable logistic regression analyses were conducted. Results: A total of 231,718 operations were analyzed with 4426 patients experiencing a VTE (1.9%). The overall rate of VTE ranged widely based on the operation performed from 0.7% for enterostomy closure to 5.3% for open subtotal colectomy. Seven operations met our threshold of 3% to be considered high risk. For each operation, postoperative VTE rates were similar regardless of diagnostic indication when performed in the elective setting. However, when performed emergently, the same operations had significantly higher VTE rates. Compared with the malignancy and benign disease groups, neither CD nor UC was associated with increased odds of VTE after any operation. Conclusions: Postoperative VTE risk varies widely by the operation performed, and a diagnostic indication of CD or UC does not play a role. Extended duration VTE prophylaxis should be considered in all patients undergoing high-risk operations, regardless of their underlying diagnosis.

Background Most persistent posttraumatic headaches (PPTH) have a phenotype that meets diagnostic criteria for migraine or probable migraine. Although symptoms of autonomic dysfunction have been well described among those with migraine, the presence and relative severity of such symptoms among those with PPTH have yet to be reported. Objective The objective of this study was to assess and compare symptoms of autonomic dysfunction among those with PPTH attributed to mild traumatic brain injury (mTBI) vs migraine vs healthy controls using Composite Autonomic Symptom Score 31 (COMPASS‐31) questionnaire scores. Methods Individuals with PPTH (n = 56) (87.5% of whom had a migraine/probable migraine phenotype), migraine (n = 30), and healthy controls (n = 36) were prospectively assessed in this cross‐sectional cohort study using the COMPASS‐31 questionnaire. Total COMPASS‐31 scores and individual domain scores (bladder, gastrointestinal, orthostatic intolerance, pupillomotor, secretomotor, vasomotor) were compared between subject groups. Results COMPASS‐31 mean total weighted score was 37.22 ± 15.44 in the PPTH group, 27.15 ± 14.37 in the migraine group, and 11.67 ± 8.98 for healthy controls. COMPASS‐31 mean weighted total scores were significantly higher in those with PPTH vs migraine ( P = .014), for PPTH vs healthy controls ( P = .001), and for migraine vs healthy controls ( P = .001). Those with PPTH had numerically higher scores for all COMPASS‐31 domains compared to those with migraine, and the domain scores were significantly higher for orthostatic intolerance (PPTH = 4.80 ± 2.47 vs migraine = 3.33 ± 2.31, P = .027) and bladder (PPTH = 1.14 ± 1.45 vs migraine = 0.47 ± 0.73, P = .020). Among individuals with PPTH, post hoc correlations indicated a positive association between number of total lifetime TBIs with total weighted COMPASS‐31 scores (rho = 0.32, P = .020), between years lived with headache and vasomotor domain subscores (rho = 0.27; P = .044), and between headache frequency with vasomotor domain subscores (rho = 0.27; P = .041). Conclusions Symptoms of autonomic dysfunction were greatest among those with PPTH compared to migraine and healthy controls. Among individuals with PPTH, number of lifetime TBIs was associated with greater symptoms of autonomic dysfunction, while greater headache burden was associated with higher vasomotor domain autonomic dysfunction subscores, potentially indicating that PPTH patients with higher disease burden have an increased risk for having autonomic dysfunction. Symptoms of autonomic dysfunction should be ascertained during the clinical management of patients with PPTH and might be a characteristic that helps differentiate PPTH from migraine.

Background There is currently a lack of consensus on how health-related quality of life and other patient-reported outcome measures in cancer randomized clinical trials are analyzed and interpreted. This makes it difficult to compare results across randomized controlled trials (RCTs) synthesize scientific research, and use that evidence to inform product labeling, clinical guidelines, and health policy. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data for Cancer Clinical Trials (SISAQOL) Consortium aims to develop guidelines and recommendations to standardize analyses of patient-reported outcome data in cancer RCTs. Methods and Results Members from the SISAQOL Consortium met in January 2017 to discuss relevant issues. Data from systematic reviews of the current state of published research in patient-reported outcomes in cancer RCTs indicated a lack of clear reporting of research hypothesis and analytic strategies, and inconsistency in definitions of terms, including “missing data,”“health-related quality of life,” and “patient-reported outcome.” Based on the meeting proceedings, the Consortium will focus on three key priorities in the coming year: developing a taxonomy of research objectives, identifying appropriate statistical methods to analyze patient-reported outcome data, and determining best practices to evaluate and deal with missing data. Conclusion The quality of the Consortium guidelines and recommendations are informed and enhanced by the broad Consortium membership which includes regulators, patients, clinicians, and academics.

Abstract RNA sequencing detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. Herein we examined multiple in-frame and out-of-frame ESR1 fusions and found only two, both identified in advanced endocrine treatment resistant disease, encoded stable and functional in-frame fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, the N-terminal, DNA binding and dimerization motifs encoded by exons 2-6 were fused to C-terminal sequences from the partner gene. Functional properties included estrogen-independent growth, constitutive expression of ER target genes, anti-estrogen resistance, induction of cellular motility in vitro and the development of lung metastasis in vivo. Chromatin immunoprecipitation and RNA sequencing experiments showed both fusions uniquely activated a metastasis-associated transcriptional program. ESR1-e6>YAP1 and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, palbociclib, and a patient-derived xenograft (PDX) expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Citation Format: Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Jin Cao, Meenakshi Anurag, Purba Singh, Xiaping He, Yoshimasa Kosaka, Ryoichi Matsunuma, Robert Crowder, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Romalho, Raquel M. Peres, Nindo Punturi, Cheryl Schmidt, Alex Bartram, Eric Jou, W V. Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan Parikh, Sherri R. Davies, Shunqiang Li, Cynthia X. Ma, Vera Suman, Kelly K. Hunt, Mark A. Watson, Katherine A. Hoadley, E A. Thompson, Xi Chen, Shyam M. Kavuri, Chad J. Creighton, Christopher A. Maher, Charles M. Perou, Svasti Haricharan, Matthew J. Ellis. Functional and therapeutic significance of ESR1 gene fusions in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5240.

Abstract Background: We previously demonstrated that cancer associated macrophage-like cells (CAMLs) are cancer specific giant polyploid cells circulating in the blood of patients with solid tumors. Building on our initial discovery, others have shown that these hyperploidy cells are an innate immune response that is associated with decreased survival. However to date, no studies have been done to elucidate their clinical significance as in relation to the various stages of malignant disease. We established a 4 year prospective study of 315 patients from a variety of solid tumors (breast, prostate, lung, renal cell, pancreas, and esophageal) comparing the morphological properties of CAMLs in both early and late stage disease as they relate to progression free and overall survival (PFS/OS). These data suggest that CAML size appears have a strong negative correlation with progression and survival of cancer patients, irregardless of stage of disease, indicating their possible use as a non-invasive blood based biomarker in solid tumors. Methods: A prospective multi-institutional study used anonymized peripheral blood from 315 cancer patients [stage I (n=62), stage II (n=72), stage III (n=69) & stage IV (n=106)] from subjects with breast (n=59), esophageal (n=27), lung (n=59), renal cell carcinoma (n=37), prostate (n=74), pancreas cancers (n=59). CAMLs were isolated by the CellSieve™ microfiltration technique at 5 institutions and stained for cytokeratin 8, 18, & 19, CD14 and CD45. After imaging, a size based threshold ≥50µm was used to separate the patient cohorts, based on previously published assessments. Results: At least one CAML was found in 92% of cancer patients (n=289/315), with the lowest sensitivity in stage 1 (86%), followed by stage 2 (90%), stage 3 (97%) and stage 4 (95%). The property of CAML size was then evaluated. Overall, CAMLs of <50µm in size had superior PFS (HR: 3.8; 95% CI 2.8-5.3; p<0.001) and OS (HR=3.8; 95% CI 2.6-5.7;p<0.001) than those with ≥50 µm CAMLs. By each stage individually, stage 1 (PFS HR=7.5; 95% CI 3.2-17.7; p<0.001), stage II (PFS; HR=4.1; 95% CI 1.9-8.8; p<0.001), stage III (PFS HR=3.1; 95% CI 1.7-5.7; p=0.007), and stage IV (PFS HR=2.7; 95% CI 1.6-4.4; p<0.001). Conclusions: In this first large scale prospective study of the clinical utility of CAMLs, it appears that they are present in every stages of invasive solid tumor malignancies, with prevalence increasing with stage. Interestingly decreased CAML size was found to be associated with improved outcome and longer PFS. These data suggest that CAML detection and size assessment constitute a new real time predictor of progression, and survival in both early and late stage disease indicating the need for additional validation studies. Citation Format: Daniel L. Adams, Steven H. Lin, R. Katherine Alpaugh, Thai Ho, Jeffrey R. Marks, Stuart S. Martin, Susan Tsai, Saranya Chumsri, Cha-Mei Tang, Massimo Cristofanilli, Raymond Bergan. Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2631.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

Objective: To characterize the risk of progression to nonserviceable hearing in patients with sporadic vestibular schwannomas (VS) who elect initial observation. Study Design: Retrospective case series. Setting: Two tertiary care centers. Patients: VS patients with serviceable hearing who underwent at least two audiograms and two MRI studies before intervention or loss to follow-up. Main outcome measure(s): Serviceable hearing, defined as the pure tone average ≤ 50 dB HL and word recognition score ≥ 50%. Results: Four-hundred sixty-six patients (median age of 57 yr and median tumor diameter of 7.3 mm) had serviceable hearing at presentation and were followed for a median of 2.3 years (IQR 1.0 – 4.0). Kaplan–Meier estimated rates of maintaining serviceable hearing (95% CI; number still at risk) at 1, 3, 5, 7, and 10 years following diagnosis were 94% (91–96; 357), 77% (73–82; 172), 66% (60–73; 81), 56% (49–65; 31), and 44% (33–59; 10), respectively. Each 10-dB increase in pure-tone averages at diagnosis was associated with a 2-fold increased likelihood of developing nonserviceable hearing (hazard ratio 2.07; p < 0.001). Each 10% decrease in word recognition score was associated with a 1.5-fold increased likelihood of developing nonserviceable hearing (hazard ratio 1.48; p < 0.001). Conclusions: Among patients with sporadic VS, good baseline word recognition score and low pure-tone average are jointly associated with maintenance of serviceable hearing. These data may be used to guide patient counseling and optimize management.