Citations

Abstract This article is part of the To the Point Series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee. Principles and education in patient safety have been well integrated into academic obstetrics and gynecology practices, although progress in safety profiles has been frustratingly slow. Medical students have not been included in the majority of these ambulatory practice or hospital-based initiatives. Both the Association of American Medical Colleges and Accreditation Council for Graduate Medical Education have recommended incorporating students into safe practices. The Accreditation Council for Graduate Medical Education milestone 1 for entering interns includes competencies in patient safety. We present data and initiatives in patient safety, which have been successfully used in undergraduate and graduate medical education. In addition, this article demonstrates how using student feedback to assess sentinel events can enhance safe practice and quality improvement programs. Resources and implementation tools will be discussed to provide a template for incorporation into educational programs and institutions. Medical student involvement in the culture of safety is necessary for the delivery of both high-quality education and high-quality patient care. It is essential to incorporate students into the ongoing development of patient safety curricula in obstetrics and gynecology.

Abstract Glioblastoma (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide (TMZ) is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance and patients with recurrent glioma have limited treatment options and very poor prognosis. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces cross-links at N7 of guanine causing double-strand DNA breaks and apoptosis independent of MGMT expression against multiple GBM cell lines and cancer stem cells in vitro. VAL-083 cytotoxic activity also appears to be less dependent on wild type p53 compared to other alkylating agents. The main goal of this clinical trial was to determine an appropriate dose for VAL-083 for advancement to Phase II/III trials as a potential new treatment for refractory GBM. METHOD: Open-label, single-arm Phase I dose-escalation study (3+3 design) of IV treatment with VAL-083 on days 1, 2, 3 of a 21-day cycle, until MTD was reached. In Phase II, additional patients with GBM are treated at the MTD to gather further safety and outcomes data. Patients must have histologically confirmed GBM, previously treated with surgery and radiation and must have failed both TMZ and bevacizumab, unless contraindicated. RESULTS: Phase I has been completed and 40 mg/m2/d confirmed as the MTD. 29 GBM patients were enrolled in Phase I across 9 dose cohorts (1.5 - 50 mg/m2/d). Myelosuppression was mild; no drug-related serious adverse events were reported at doses ?40 mg/m2/d. Dose limiting toxicities (DLT), consisting of thrombocytopenia, were observed at 50 mg/m2/d and at an interim 45 mg/m2/d cohort. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short 1-2h plasma terminal half-life; average Cmax 781 ng/mL (5.3μM) at 40 mg/m2/d resulting in estimated CNS concentrations within the IC50 range observed for GBM cell-lines in vitro. A 14 patient Phase II expansion cohort was enrolled at 40 mg/m2/d. Safety observations in the Phase II expansion cohort to date are consistent with Phase I: Observed myelosuppression is mild, with the exception of 1 patient previously treated with CCNU who developed grade 4 thrombocytopenia. To date, 20 GBM patients (6 patients in Phase I and 14 patients in Phase II) have been treated with VAL-083 at therapeutic doses of 30 or 40 mg/m2/d. CONCLUSIONS: VAL-083 at 40 mg/m2/d on days 1, 2, 3 of a 21-day cycle exhibits a favorable safety profile and the Phase I part of the study showed a trend toward clinically meaningful improved survival in refractory GBM patients. Updated safety and outcomes data from the Phase II expansion cohort will be presented. ClinicalTrials.gov Identifier NCT01478178. Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Gerald S. Falchook, Sani H. Kizilbash, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma. [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 CT074.

Abstract Background: MIF is a pleiotropic cytokine involved in tumor proliferation, invasiveness, angiogenesis, and the proinflammatory microenvironment. oxMIF is the pathogenic form mainly in tumor and its surrounding stroma. Imalumab (BAX69) is a novel recombinant, fully-human, monoclonal antibody that targets oxMIF, inhibiting tumorigenesis. Preclinical data demonstrated that imalumab has antitumor activities and acceptable toxicities. Methods: The primary endpoint of this dose-escalation study (3+3 design) was to assess maximum tolerated dose (MTD). The secondary endpoints were to assess antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts) received intravenous (IV) imalumab [28-d cycles; 2 dose schedules (DS)]: biweekly in all solid tumors (DS1); weekly in metastatic colorectal cancer (mCRC), metastatic ovarian cancer (OvCa) and metastatic non-small cell lung cancer (NSCLC) (DS2). Results: As of July 1 2015, 48 pts were treated in this study. DS1 = 19 pts in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and DS2 = 29 pts in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into mCRC, OvCa and NSCLC. AUC and Cmax increased with dose. Dose escalation was stopped at 50 mg/kg (DS1) and 25mg/kg (DS2). An MTD was not reached for either DS. One pt reported dose-limiting toxicities: hypersensitivity pneumonitis (DS1; 50 mg/kg). There were no other grade 3 and 4 treatment related adverse events (trAEs). Grade 2 trAEs include: fatigue (n = 2), constipation (n = 1), peripheral edema (n = 1), infusion reaction (n = 1), and urticaria (n = 1). Stable disease (SD) ?4 mo was seen in 7 heavily pre-treated pts, including 1 pt with NSCLC who achieved SD for 13.4 mo. In DS2; Pre- and on-therapy tumor biopsies showed satisfactory tissue penetration of imalumab resulting in target saturation in all biopsy evaluable patients in all 3 tumor types. Biopsies revealed regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on clinical PK and PD study, 10mg/kg weekly was considered a biologically active dose and sufficient to reach ?95% target binding by the end of first cycle. Conclusions: Imalumab was well tolerated and showed single agent antitumor activity in heavily pretreated pts. An MTD was not reached. Recommended phase II dose (RP2D) is 10 mg/kg IV weekly. NCT01765790 Citation Format: Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Niels Halama, Ramesh K. Ramanathan, John Sarantopoulos, Xiaochun Liu, Salim Yazji, Dirk Jaeger, Deyaa Adib, Randolf Kerschbaumer, Apostolia Maria Tsimberidou. First-in-human phase 1 study assessing imalumab (BAX69), an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors. [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 CT046.

Abstract PURPOSE: Previous mutational analyses have failed to identify a predictive or prognostic marker for pulmonary carcinoid tumors (PCT). The heterogeneity of PCTs coupled with a lack of detailed information about the tumor biology, impedes patient stratification into groups based on tumor phenotypes or treatment response. We sought to use high-throughput next-generation sequencing to improve prognostication. METHODS: We stratified 37 patients with resected PCTs as low risk (n = 17) and high risk (n = 20) based on a 5 year long follow up for recurrence. Patients with no recurrence within 5 years from initial treatment were deemed low risk. Macrodissection was followed by genomic DNA isolation and next-generation sequencing was performed using an Illumina Mate Pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction. RESULTS: Carcinoids commonly harbor rearrangements (median 3.5, range 1-167). Large chromosomal gains or losses were found in 24 of the cases (64.8%). We developed a prognostic score that included the total amount of genetic alterations (deletions and translocations). ROC analysis revealed an AUC of 0.76. High risk patients had a mean score of 20 and low risk patients had a mean score of 5.45 (p value = 0.03, Welch Two Sample t-test). Further analysis of the specific genetic alterations harbored by high and low risk PCTs and correlation with the pathologic and immunohistochemical information is currently underway. CONCLUSION: Large chromosomal rearrangements and aneuploidy portend a poor prognosis for patients with PCTs. Mate Pair sequencing of PCTs provides valuable prognostic information for this highly heterogeneous group of cancers. Citation Format: Konstantinos Leventakos, Aaron S. Mansfield, Stephen J. Murphy, Sarah H. Johnson, Sarah E. Kerr, Marie Christine Aubry, George Vasmatzis, Julian R. Molina. A prognostic model for pulmonary carcinoid tumors based on large chromosomal alterations. [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 4513.

Abstract Circulating tumor DNA (ctDNA) provides great potential for the non-invasive clinical assessment of tumor burden. We developed a monitoring protocol using next generation mate-pair sequencing to identify chromosomal rearrangement signatures in primary tumors to follow ctDNA in blood. Primary tumors of 10 patients with ovarian cancer were sequenced, and individualized tumor-specific panels were designed to detect the junctions in ctDNA. A novel algorithm was developed and applied to data generated by quantitative PCR to calculate the percent of ctDNA. Selected junctions, some with potential as therapeutic targets, were detected in pre-surgically drawn blood in eight out of ten patients. Of these eight, three demonstrated the continued presence of circulating tumor DNA post-surgery, and five had undetectable levels, consistent with their documented presence or absence of disease. The detection of somatic junctions derived from ctDNA could be an effective way to monitor ovarian cancer patients for relapse and therapy response. Citation Format: Faye R. Harris, Irina Kovtun, James Smadbeck, Francesco Multinu, Aminah Jatoi, Kimberly R. Kalli, Stephen J. Murphy, Geoffrey C. Halling, Farhad Kosari, Sarah H. Johnson, Andrea Mariani, George Vasmatzis. Quantification of somatic chromosomal rearrangements in circulating cell-free DNA from ovarian cancers. [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 440.

Glaucoma is one of the leading causes of blindness worldwide. Recent studies suggest that intraocular pressure (IOP) fluctuations, peaks, and rhythm are important factors in disease advancement. Yet, current glaucoma management remains hinged on single IOP measurements during clinic hours. To overcome this limitation, 24-hour IOP monitoring devices have been employed and include self-tonometry, permanent IOP, and temporary IOP monitoring. This review discusses each IOP measuring strategy and focuses on the recently FDA-approved contact lens sensor (CLS). The CLS records IOP-related ocular patterns for 24 hours continuously. Using the CLS, IOP-related parameters have been found to be associated with the rate of visual field progression in primary open-angle glaucoma, disease progression in primary angle-closure glaucoma, and various clinical variables in ocular hypertension. The CLS has been used to quantify blink rate and limbal strain and measure the circadian rhythm in a variety of disease states including normal-tension glaucoma and thyroid eye disease. The effects of various IOP-lowering interventions were also characterized using the CLS. CLS provides a unique, safe, and well-tolerated way to study IOP-related patterns in a wide range of disease states. IOP-related patterns may help identify patients most at risk for disease progression and assist with the development of tailored treatments.

AbstractBackground/AimsInadequate bowel preparations can necessitate early repeat of colonoscopy and increased healthcare costs. Established risk factors for suboptimal bowel preparation are known, yet data are lacking in the specific subgroup of patients with decompensated cirrhosis. The primary aim of this study was to reduce inadequate bowel preparation rates in patients with decompensated cirrhosis undergoing evaluation for liver transplant via a quality improvement initiative targeting patient education.MethodsA total of 121 patients undergoing evaluation at our institution prior to implementation of the quality improvement initiative and 91 patients undergoing evaluation after implementation were included. The initiative was an educational intervention via a 6‐minute colonoscopy and split‐prep bowel preparation educational video during the initial liver transplantation evaluation visit for all patients with scheduled colonoscopy.ResultsInadequate bowel preparation was observed in 36 patients (29.8%) in the pre‐intervention period compared to 29 patients (31.9%) in the post‐intervention period. This corresponded to a lack of a significant difference in both single‐variable analysis and multivariable analysis. Of note, there was a significantly higher rate of inadequate bowel preparation as ascites worsened (P=.028).ConclusionPatient educational video failed to improve bowel preparations in patients undergoing colonoscopy with decompensated cirrhosis.

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.

AimThe aim of this study was to compare passive muscle stiffness in children with cerebral palsy (CP) and children with typical development using a novel ultrasound technique: ultrasound shear wave elastography (SWE).MethodWe conducted a prospective study of 13 children with CP (six females and seven males, median age 5y 1mo [interquartile range 4y 4mo–7y 8mo]) and 13 children with typical development (six females and seven males, median age 5y 3mo [interquartile range 4y 4mo–9y 4mo]). Demographic information and physical exam measurements were obtained in addition to shear modulus measurements (passive muscle stiffness) of the lateral gastrocnemius muscle at 20° plantar flexion, 10° plantar flexion, and 0° plantar flexion using SWE.ResultsChildren with CP had significantly greater shear modulus measurements at all three foot positions (p<0.050). When the shear modulus values were normalized to the baseline value for each child, there was no significant difference between the two groups.InterpretationPassive muscle stiffness, measured without the influence of spasticity, is greater in children with CP than in children with typical development when a muscle is at slack and at stretch. When shear modulus was normalized, the results indicate that muscle in children in both groups responds similarly to passive stretch. Further work includes evaluating effect of botulinum toxin on passive muscle properties.