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102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.

Background: Ultrasound-guided fascia iliaca blocks have been used for pain control after hip arthroscopy. There is little evidence regarding their effectiveness in comparison with other pain control modalities in patients who have undergone hip arthroscopy. Purpose: To compare the efficacy of ultrasound-guided fascia iliac block with intra-articular ropivacaine in controlling pain after hip arthroscopy. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Between 2015 and 2017, patients (N = 95) undergoing hip arthroscopy were randomly assigned to 2 groups. The first group received an ultrasound-guided fascia iliaca block with 50 to 60 mL of 0.35% ropivacaine. The second group received an intra-articular injection of 20 mL of 0.5% ropivacaine at the completion of the surgical case. Primary outcomes were postoperative pain scores in the recovery room; at postanesthesia care unit (PACU) discharge; and at 2 weeks, 6 weeks, and 3 months. Secondary outcomes included intraoperative and PACU narcotic usage (converted to morphine equivalent use) as well as readmission rates, PACU recovery time, and postoperative nausea and vomiting. Results: Postoperative pain across all points did not significantly differ between the groups. Intraoperative and PACU narcotics did not differ significantly between the groups. Readmission rates, PACU recovery time, and postoperative nausea and vomiting did not significantly differ between the groups. There were no associated complications in either group. Conclusion: Ultrasound-guided fascia iliaca block for hip arthroscopy had no clinical advantage when compared with onetime intra-articular ropivacaine injection. Registration: NCT02365961 (ClinicalTrials.gov identifier).

Objective: To better evaluate the relationships between training, demographics, and injury, this study sought to define race-related injury risk factors for half- and full-marathon runners. Design: This 3-year, observational cross-sectional study included adults who participated in a half or full marathon. Prerace and 2-week postrace surveys collected data on demographics, training factors, and injuries. Setting: This study took place during a nationally recognized marathon affiliated with a local hospital. Participants: Runners were recruited during the Expo in the days before the race. Postrace surveys were returned by 1043 half marathoners and 624 full marathoners (response rate, 83%). Interventions: This was an observational study; independent variables included demographic data and race year. Main Outcome Measure: The primary outcome was race-related injury that occurred during the race or within 2 weeks after the race. Results: Race-related injuries were reported by 24% of half marathoners and 30% of full marathoners. For half and full marathoners, respectively, significant factors for injuries were previous injury, lower peak weekly training mileage, and lower weekly mileage before race training. Factors significant for only half-marathon injuries were younger age, female sex, shorter distance of longest training run, and no formal training program. Factors significant for only full-marathon injuries were higher body mass index, fewer days running per week, and fewer years of running experience. Conclusions: Previous running injuries, undertraining, and inexperience increased race-related injury risk; women had higher risk than men. Decreased risk of injury was associated with training loads of greater than 23 miles/week for half marathoners and 40 miles/week for full marathoners.

AbstractTrial InformationClick here to access other published clinical trials.Lessons LearnedTrifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy.BackgroundPatients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.MethodsPatients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity.ResultsOf 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.ConclusionFTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Abstract Background Cardiac sarcoidosis (CS) is an infiltrative inflammatory condition defined by infiltration of noncaseating granulomas into the heart. Based on the location of sarcoid lesion involvement, patients can present with symptoms of congestive heart failure, arrhythmias, and even sudden cardiac death. Purpose Diagnosis of CS has been somewhat challenging, with the Heart Rhythm Society (HRS) and Japanese Ministry of Health and Welfare (JMHW) being the 2 widely accepted diagnostic guidelines. Endomyocardial biopsy is the gold standard to prove definite CS but has a low sensitivity. Imaging studies have been helpful as non-invasive methods to diagnose probable CS but these can be logistically difficult and expensive. Thus, investigating for laboratory biomarkers that can act as both diagnostic and prognostic can be crucial in how we diagnose and manage CS in the future. Methods Patients meeting HRS for CS were evaluated at a single institution (n=217). Biomarkers of interest included angiotensin-converting enzyme (ACE), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin-T, 1,25 dihydroxyvitamin D (1,25-OHVit-D), and creatinine. Biomarkers were stratified by clinical variables of interest and their association with prognosis was examined. The primary endpoint was LVAD implantation, transplantation, or death. Results Mean values on presentation were: ACE 32.9±28, ESR 12±13, CRP 7.4±19, NT-proBNP 1630±2923, Troponin-T 0.03±0.1, 1,25-OHVit-D 55.5±20, and creatinine 1.12±0.3. None of the biomarkers differed by sex, definite or probable CS, or a history of immunosuppression. ACE levels were associated with the presence of cardiac fibrosis on cardiac MRI (mean difference 14.7, p=0.032). Troponin-T (p=0.006; HR 1.06 per 0.01 ng/mL), NT-proBNP (p=0.0003; HR 1.31 per 1,000 pg/mL), and creatinine (p=0.01; HR 4.02 per mg/dL) were each associated with the primary endpoint (52/217 patients). Biomarkers associated with long term outcomes in patients with cardiac sarcoidosis Biomarker Hazard ratio P value Troponin-T 1.06 (1.02–1.11)* 0.006 NT-pro BNP 1.31 (1.15–1.48)** 0.0003 Creatinine 4.02 (1.41–9.94)*** 0.01 *Per 0.01 ng/mL change; 99th percentile upper reference limit <0.01 ng/mL; **per 1,000 pg/mL change; ***per 1 mg/dL change. Conclusion Troponin-T, NT-proBNP, and creatinine at presentation predict outcomes in patients with CS. Further investigation on the utility of biomarkers for assessment of disease activity and treatment response is warranted.

OBJECTIVEScoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors’ goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis.METHODSA large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°).RESULTSBased on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB–C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude.CONCLUSIONSSyrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.

Abstract Background: Chronic myelogenous leukemia (CML) is a BCR-ABL1 driven myeloid neoplasm, with excellent response rates to tyrosine kinase inhibitors (TKI). TKI such as imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) currently US FDA approved, have dramatically changed survival outcomes. That being said, two main challenges exist; suboptimal responses and TKI intolerance. The reason why some patients tolerate/respond to TKI better than others is unknown, but is potentially explainable based on drug metabolism. The field of pharmacogenomics (PGX) is rapidly evolving, with commercial panel's rapidly assessing metabolic pathways such as cytochrome P450 (CYP), UGTA1A, p-glycoprotein/ABCB1. We carried out this study using a 22 gene-PGX panel to assess potential causes of TKI related intolerance and suboptimal responses in compliant patients. Methods: Twenty-nine Mayo Clinic patients with CML were prospectively recruited after informed consent. Buccal swabs were utilized for PGX testing to assess variations/polymorphisms involving CYP3A4/5, 1A2, 2C9, UGT1A1, amongst others (www.Oneome.com). Three groups of patients were recruited, those with i) TKI intolerance, ii) suboptimal responses by ELN criteria, iii) and newly diagnosed cases, to assess if PGX testing could explain TKI intolerance or resistance, or alter choice of therapy in newly diagnosed cases. A pharmacology review was obtained to interpret reports in all cases. Results: 29 patients with CML were prospectively enrolled, median age 64 years, 15 (52%) male. At last follow up (median 21 months), 3 (10%) deaths and no disease progressions were documented. 82% received first line IM, whereas 18% received first line DAS. Major metabolic pathways assessed for IM included, CYP3A4 and 5, while minor pathways included 2C19, 2C9 and 2D6. Majority (83%) of IM patients had normal major pathways with 17% being intermediate-normal. With regards to the minor pathways, 25% were rapid metabolizers for 2C19, whereas 29% were intermediate and 4% poor metabolizers for 2C9 and 50% and 16% were intermediate and poor metabolizers for 2D6. In all IM treated patients PGX testing did not completely explain intolerance or resistance and did not change clinical decision making. Front line DAS was used in 18% and the major pathway assessed was CYP 3A4, with 80% being normal and 20% being intermediate metabolizers. Once again PGX testing did not completely explain intolerance/resistance and no therapeutic changes were based on PGX analysis. Seventeen (59%) patients received second line TKI therapy (50% each for intolerance and resistance), with DAS (58%) and NIL (29%), being the two most common. Once again for DAS, 90% had normal 3A4 metabolism while 10% were intermediate and for NIL 80% were normal and 20% intermediate. Only one of 2 NIL treated patients with UGTA1A polymorphisms developed indirect hyperbilirubinemia (grade 1). In the second line setting, PGX testing did not completely explain or alter treatment decisions. BOS was used as a third line agent in 3 (>10%) patients, 2 who remained refractory and one with intolerance, and all three were normal CYP3A4 metabolizers. None of these patients developed diarrhea a common side effect of BOS. PON was used in one patient with intermediate CYP3A4 metabolism as a 5th line agent and the patient continues to have refractory disease with no thrombotic events. In all cases, no changes were made to concomitant medications based on PGX testing. Conclusion: In conclusion, while PGX testing has rapidly evolved and become commercially available, in the context of TKI therapy for CML, while it offers useful insights on minor metabolic derangements and side effects like NIL induced hyperbilirubinemia, in our study, currently limited by a small sample size, it did not completely explain TKI intolerance or resistance. Recruitment of additional patients (n=100) and correlations with plasma drug levels are currently ongoing. Table. Table. Disclosures Al-Kali: Novartis: Research Funding. Stewart:Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding; Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy.

AbstractBackgroundCancer‐associated venous thromboembolism (VTE) carries a high rate of recurrence and death. Guidelines recommend continued anticoagulation therapy as long as active cancer persists. Apixaban 2.5 mg twice daily is the FDA‐approved dose for secondary prevention regardless of VTE causation. Whether this apixaban dose is appropriate for secondary VTE prevention in cancer patients is not clear. The rationale and design of this investigator initiated phase III, multicenter, randomized, double‐blind, trial assessing apixaban 2.5 mg vs 5 mg twice daily for 12 months for the secondary VTE prevention in cancer patients (n = 370) who have completed 6 months (but no more than 12 months) of anticoagulation is provided (NCT03080883).Methods/DesignThe primary study objective is to estimate differences in the combined rate of major plus clinically relevant non‐major bleeding for apixaban 2.5 mg vs 5 mg twice daily. Secondary efficacy outcome is to assess rates of venous or arterial thromboembolism. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium.ConclusionWe anticipate these trial results to provide evidence supporting low‐dose apixaban as a safe agent for secondary prevention of cancer‐associated VTE for patients who have already completed 6‐12 months of anticoagulation.