Citations

Abstract Lessons Learned OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models. In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed. Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma. Background OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. Methods Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit. Results Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days). Conclusion OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.

This study examined the potential correlation between pulmonary embolism (PE) attenuation on computed tomography pulmonary angiography (CTPA) and pulmonary artery hemodynamic response to catheter-directed thrombolysis (CDT) in 10 patients with submassive PE. Treatment parameters, PE attenuation, clot burden, computed tomography signs of right ventricle dysfunction and right ventricular systolic pressure at echocardiography were retrospectively analyzed to determine correlation with pulmonary artery pressure improvement using Spearman correlation. A single reader, blinded to the treatment results, measured PE attenuation of all patients. There was a significant positive correlation between PE attenuation and absolute pulmonary artery pressure improvement with a Spearman correlation of 0.741, p=0.014. When attenuation was greater than or equal to the median (44.5 HU, n=5), CDT was associated with significantly better pulmonary artery pressure improvement ( p=0.037). Clot attenuation at CTPA may be a potential imaging biomarker for predicting pulmonary artery pressure improvement after CDT.

Abstract Background: Germline genetic testing of individuals with a diagnosis of triple negative breast cancer, young age at diagnosis, or a family history of breast and/or ovarian cancer has led to the identification of many unique BRCA2 missense variants of uncertain significance (VUS). VUS in BRCA2 are predominantly missense mutations that have unclear relevance to breast, ovarian, and other cancers. Thus, patients found to have a germline BRCA2 VUS do not know if the variant is associated with high risks of these cancers similar to truncating mutations, intermediate risks more similar to CHEK2 mutations, or low risks of no clinical significance. Furthermore, it is unclear if germline BRCA2 VUS, or somatic VUS identified by tumor sequencing, are associated with hypersensitivity to selected DNA damaging and cross-linking agents. Methods: We have used a homology directed repair (HDR) cell-based assay to characterize missense variants in the DNA binding domain (DBD) of BRCA2. The method has been validated using known pathogenic and known non-pathogenic BRCA2 missense variants and has 100% sensitivity (95% confidence interval (CI): 75.3%–100%) and 100% specificity (95% CI: 81.5%–100%) for pathogenic BRCA2 variants. A classifier of variant pathogenicity based on the mean and variances of the distributions of the HDR results of the known pathogenic and neutral variants has been established. We have also developed PARP inhibitor and cisplatin drug response assays for BRCA2 missense variants. Results: Assessment of 207 BRCA2 missense variants, identified in public databases such as BRCA exchange and ClinVar, by the HDR assay identified 71 deleterious variants with >99% probability of pathogenicity, 116 neutral variants with >99% probability of neutrality, and 20 with hypomorphic activity and potentially intermediate risk. A combination of the functional data and sequence-based predictors of protein activity in a Bayesian prediction model resulted in classification of the deleterious variants as pathogenic cancer predisposing variants and the neutral variants as non-pathogenic with low clinical significance. The influence of the deleterious/pathogenic variants on PARPi and cisplatin response was also assessed. Conclusion: The HDR assay is effective for characterization of BRCA2 VUS. The combination of functional data and in silico prediction models provides a robust tool for clinical annotation of BRCA2 VUS. HDR function of BRCA2 missense variants is strongly correlated with response to targeted therapy. Citation Format: Couch FJ, Shimelis H, Hart SN, Moore RM, Thomas A, Lipton GB, Iversen E. Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance [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 GS4-06.

Purpose To compare the minimum 2‐year outcomes and return to sports in competitive athletes after arthroscopic iliopsoas fractional lengthening (IFL) and treatment for femoroacetabular impingement (FAI) to competitive athletes treated for FAI who did not undergo IFL. Methods Data were prospectively collected and retrospectively reviewed between November 2009 and April 2014. Included patients were high school, collegiate, or professional athletes who underwent arthroscopic IFL, treatment for FAI, and preoperative modified Harris Hip Score, Non‐Arthritic Athletic Hip Score, Hip Outcome Score–Sports Specific Subscale, and visual analog scale. Exclusion criteria were patients younger than 16 years, Tönnis grade >1, microfracture, abductor pathology, and previous hip conditions. A subgroup of athletes were matched to athletes who did not undergo IFL by age ± 5 years, sex, and body mass index ± 5. Results There were 75 athletes eligible for inclusion, 60 (80.0%) of whom had minimum 2‐year follow‐up. All patient‐reported outcome (PRO) scores demonstrated significant improvements at latest follow‐up ( P < .001). Mean satisfaction was 7.9. No patients converted to arthroplasty. Painful snapping was resolved in 55 athletes (91.7%). Nine athletes (15.0%) had nonpainful snapping at follow‐up. Thirty‐nine (65%) returned to their sport. Forty (66.7%) maintained or improved their competitive abilities. There was one case (1.6%) of temporary postoperative numbness. There were no complaints of weakness in hip flexion. Forty‐one IFL athletes were matched to 41 controls. No differences were detected in demographics, follow‐up time, intraoperative findings, procedures, mean magnitudes of improvement, or return to sports. Conclusions In competitive athletes, IFL during hip arthroscopy is safe and demonstrates favorable improvements in PROs and VAS, high satisfaction, and high rate of symptom resolution at a minimum of 2 years postoperatively. Most patients were able to return to sports and maintain or improve their competitive levels. These results were similar to a control group of athletes not requiring IFL. Level of Evidence Level III, case‐control study.

Maximal relaxation of airway smooth muscle (ASM) in response to atrial natriuretic peptide (ANP), which stimulates particulate guanylyl cyclase (pGC), is less than that produced by nitric oxide (NO) and other compounds that stimulate soluble guanylyl cyclase (sGC). We hypothesized that stimulation of pGC relaxes ASM only by decreasing intracellular Ca2+concentration ([Ca2+]i), whereas stimulation of sGC decreases both [Ca2+]iand the force developed for a given [Ca2+]i(i.e., the Ca2+sensitivity) during muscarinic stimulation. We measured the relationship between force and [Ca2+]i(using fura 2) under control conditions (using diltiazem to change [Ca2+]i) and during exposure to ANP, diethylamine-NO (DEA-NO), sodium nitroprusside (SNP), and the Sp diastereoisomer of β-phenyl-1, N2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothionate ( Sp-8-Br-PET-cGMPS), a cell-permeant analog of cGMP. Addition of DEA-NO, SNP, or Sp-8-Br-PET-cGMPS decreased both [Ca2+]iand force, causing a significant rightward shift of the force-[Ca2+]irelationship. In contrast, with ANP exposure, the force-[Ca2+]irelationship was identical to control, such that ANP produced relaxation solely by decreasing [Ca2+]i. Thus, during muscarinic stimulation, stimulation of pGC relaxes ASM exclusively by decreasing [Ca2+]i, whereas stimulation of sGC decreases both [Ca2+]iand Ca2+sensitivity.

This study was done to determine whether, after a meat meal, the outputs of acid in gastric juice and free histamine in urine are related and whether the output of free urinary histamine is increased after transplantation of the gastric antrum to the colon. Dogs with separated gastric pouches (Heidenhain) were used. Gastric juice and urine were collected at hourly intervals before and after the ingestion of the meal and for 24-hour periods before and after transplantation of the gastric antrum to the colon. Similar collections were made when histamine was injected intravenously at different rates. A rough temporal correlation was found between the outputs of HCl in gastric juice and free histamine in the urine after the meal of meat. There was not a significant increase in the 24-hour output of free histamine in the urine of the dogs in which a modest hypersecretion developed following transplantation of the gastric antrum to the colon.

Background: Femoral retroversion has been noted as a possible risk factor for poor clinical results after hip arthroscopic surgery. Purpose: To compare the outcomes of the arthroscopic treatment of hip abnormalities in patients with femoral retroversion to patients with femoral anteversion between 10° and 20°. Study Design: Cohort study; Level of evidence, 3. Methods: Between November 2011 and September 2013, 790 hip arthroscopic procedures were performed at a single institution. Of these, 59 hips (7.5%) were located in patients with femoral version ≤0°, calculated using preoperative magnetic resonance imaging. These patients were pair matched, based on body mass index ±5 kg/m 2 , age ±5 years, and Tönnis grade, with 59 patients with femoral anteversion between 10° and 20°. Exclusion criteria included Perthes disease, inflammatory arthritis, slipped capital femoral epiphysis, previous hip surgery, abductor repair, lateral center-edge angle <20°, Tönnis grade >1, and acetabular profunda or protrusio. Patient-reported outcomes (PROs) were recorded preoperatively, at 3 months postoperatively, and annually thereafter. The PROs utilized were the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and Hip Outcome Score–Sports-Specific Subscale (HOS-SSS). The visual analog scale (VAS) was collected to assess the patients’ pain; patient satisfaction scores (0-10) were also collected. Radiographs were collected at the above time intervals as well. Results: Two patients from the control group and 1 patient from the retroverted group required total hip arthroplasty at a mean 19.5 and 26.3 months, respectively. Both groups demonstrated significant improvement from their preoperative state in all PRO and VAS scores ( P < .001). No differences in preoperative, postoperative, or change in PRO and VAS scores between the groups were noted. Conclusion: Patients with femoral retroversion reported similar outcomes compared to patients with normal femoral version when undergoing hip arthroscopic surgery. Both groups had similar improvements from the preoperative state.

Objective: The European Guidelines Meeting on Laparoscopic Liver Surgery was held in Southampton on February 10 and 11, 2017 with the aim of presenting and validating clinical practice guidelines for laparoscopic liver surgery. Background: The exponential growth of laparoscopic liver surgery in recent years mandates the development of clinical practice guidelines to direct the speciality's continued safe progression and dissemination. Methods: A unique approach to the development of clinical guidelines was adopted. Three well-validated methods were integrated: the Scottish Intercollegiate Guidelines Network methodology for the assessment of evidence and development of guideline statements; the Delphi method of establishing expert consensus, and the AGREE II-GRS Instrument for the assessment of the methodological quality and external validation of the final statements. Results: Along with the committee chairman, 22 European experts; 7 junior experts and an independent validation committee of 11 international surgeons produced 67 guideline statements for the safe progression and dissemination of laparoscopic liver surgery. Each of the statements reached at least a 95% consensus among the experts and were endorsed by the independent validation committee. Conclusion: The European Guidelines Meeting for Laparoscopic Liver Surgery has produced a set of clinical practice guidelines that have been independently validated for the safe development and progression of laparoscopic liver surgery. The Southampton Guidelines have amalgamated the available evidence and a wealth of experts’ knowledge taking in consideration the relevant stakeholders’ opinions and complying with the international methodology standards.