Citations

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.

AbstractBackgroundIL‐10‐producing regulatory B cells (Bregs) are widely ascribed immune regulatory functions. However, Breg subsets in human asthma have not been fully investigated.ObjectiveWe studied Breg subsets in adult allergic asthma patients by assessing two major parameters, frequency and IL‐10 expression. We then investigated factors that affect these two parameters in patients.MethodsPeripheral blood mononuclear cells (PBMCs) of adult allergic asthma patients (N = 26) and non‐asthmatic controls (N = 28) were used to assess the frequency of five subsets of transitional B cells (TBs), three subsets of CD24highCD27+ B cells and B1 cells. In addition to clinical data, IL‐10 expression by individual Breg subsets was assessed by flow cytometry.ResultsAsthma patients had decreases of CD5+ and CD1d+CD5+, but an increase of CD27+ TBs which was significant in patients with moderate asthma (60 < FEV1 < 80). Regardless of asthma severity, there was no significant alteration in the frequencies of 6 other Breg subsets tested. However, we found that oral corticosteroid (OCS) significantly affected the frequency of Bregs in Breg subset‐specific manners. OCS decreased CD5+ and CD1d+CD5+ TBs, but increased CD27+ TBs and CD10+CD24highCD27+ cells. Furthermore, OCS decreased IL‐10 expression by CD27+ TBs, all 3 CD24highCD27+ B cell subsets (CD5+, CD10+ and CD1d+) and B1 cells. OCS‐mediated inhibition of IL‐10 expression was not observed in the other Breg subsets tested.Conclusion & Clinical RelevanceAlterations in the frequency of Bregs and their ability to express IL‐10 are Breg subset‐specific. OCS treatment significantly affects the frequency as well as their ability to express IL‐10 in Breg subset‐specific manners.

Pain is one of the most feared symptoms that concern cancer patients and their families. Despite well-established guidelines set forth by the World Health Organization (WHO) on the treatment of cancer pain, nearly half of cancer patients report poorly controlled pain. One of the most serious side effects of systemic oral opioid use is neurotoxicity, which is characterized by altered mental status and systemic neurologic impairments. Treatment strategies are supportive in nature and focused on reducing or changing the offending opioid and correcting any metabolic deficiencies. Herein, we discuss a case of opioid-induced neurotoxicity treated with intrathecal targeted drug delivery (TDD). The timing and implementation of advanced therapies such as intrathecal TDD is not well delineated. More importantly, patients and their oncologic providers are often unaware of this useful tool in treating challenging cancer-associated pain and significantly minimizing systemic opioid side effects. To ensure that patients have comprehensive oncologic care, best-practice guidelines suggest involvement of an interdisciplinary team and coordinated care. Early referral to a pain and palliative specialist may allow for improved patient outcomes and removal of unnecessary barriers to optimal patient care.

BackgroundUltrasound has become a useful instrument in evaluating musculoskeletal pathology. Recent studies suggest that ultrasound imaging of weight‐bearing menisci may enhance the assessment of knee pathology, such as osteoarthritis (OA) and meniscal injuries.ObjectiveThe primary aim of this study was to determine the intrarater and interrater reliability of ultrasound measurements of medial meniscal extrusion (MME) after a brief training session.DesignProspective reliability study.SettingPhysical medicine and rehabilitation (PM&R) department within a tertiary care institution.ParticipantsForty‐five participants (29 female, 16 male) were recruited to serve as models, 24 of whom had healthy knees and 21 of whom had radiographically confirmed medial compartment knee OA. Three physician sonographers (1 = experienced, 1 = sports medicine fellow, 1 = post‐graduate year [PGY]‐4 PM&R resident) were recruited to serve as operators.Methods or InterventionsOperators received a brief training session on identifying and measuring MME. All operators measured bilateral MME in each model in the standing and supine positions on two separate days. Operators were blinded to all measurements.Main Outcome MeasurementsPrimary outcomes were inter‐ and intrarater intraclass correlation coefficients (ICCs) of MME measurements among operators with different levels of ultrasound experience.ResultsSupine MME intrarater reliability ICCs were 0.927, 0.885, and 0.780 for the experienced physician, sports medicine fellow, and PGY‐4 operators, respectively. Standing MME intrarater reliability ICCs were 0.941, 0.902, and 0.824 for the experienced physician, sports medicine fellow, and PGY‐4 operators, respectively. Interrater reliability ICCs were 0.896 and 0.842 for supine and standing measurements, respectively. There was a statistically significant increase in intrarater reliability with experience between the PGY‐4 resident and experienced physician operators.ConclusionsOperators with different levels of ultrasound experience demonstrated good MME measurement intra‐ and interrater reliabilities in both supine and standing positions.

Abstract Aims In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated. Methods and results We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P &lt; 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%). Conclusion In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

AbstractObjectivesTo evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.MethodsData were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.ResultsA total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.ConclusionsIxazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing.

Background Hyperkalemia has been associated with increased mortality in patients with myocardial infarction, but few data exist regarding hyperkalemia in cardiac intensive care unit ( CICU ) patients. We hypothesize that hyperkalemia is associated with increased mortality in unselected CICU patients. Methods and Results We retrospectively reviewed a historical cohort of 9681 CICU patients admitted from January 2007 to December 2015. Hyperkalemia was defined as admission potassium ≥5.0 mEq/L and hypokalemia as admission potassium <3.5 mEq/L. Multivariate logistic regression was used to determine predictors of in‐hospital mortality. Postdischarge survival was assessed using Kaplan–Meier analysis and Cox proportional hazards models. The mean age of included patients was 67±15 years, with 36% females, and in‐hospital mortality was 9%. Hyperkalemia occurred in 1187 (12.3%) and hypokalemia occurred in 719 (7.4%) patients. Both patients with hyperkalemia (unadjusted odds ratio, 2.85; 95% CI, 2.40–3.39; P <0.001) and patients with hypokalemia (unadjusted odds ratio, 2.31; 95% CI, 1.85–2.88; P <0.001) were at increased risk of unadjusted in‐hospital mortality. After adjustment for illness severity and renal function, only patients with hyperkalemia demonstrated increased risk of in‐hospital death (adjusted odds ratio, 1.44; 95% CI, 1.11–1.87; P =0.006). Among hospital survivors, only patients with hyperkalemia had lower postdischarge survival by Kaplan–Meier analysis ( P <0.001). After adjustment for illness severity and renal function, hospital survivors with admission hyperkalemia remained at increased risk for postdischarge mortality (adjusted hazard ratio, 1.20; 95% CI, 1.08–1.34; P <0.001). Conclusions Hyperkalemia on CICU admission is associated with higher in‐hospital and postdischarge mortality, independent of renal function and illness severity. These findings emphasize the importance of potassium abnormalities as a risk predictor in patients admitted to the CICU .

Abstract Background Transverse abdominis plane (TAP) block is considered an effective alternative to neuraxial analgesia for abdominal surgery. However, limited evidence supports its use over traditional analgesic modalities in colorectal surgery. This study compared the analgesic efficacy of liposomal bupivacaine TAP block with intrathecal (IT) opioid administration in a multicentre RCT. Methods Patients undergoing elective small bowel or colorectal resection were randomized to receive TAP block or a single injection of IT analgesia with hydromorphone. Patients were assessed at 4, 8, 16, 24 and 48 h after surgery. Primary outcomes were mean pain scores and morphine milligram equivalents (MMEs) administered within 48 h after surgery. Secondary outcomes included duration of hospital stay, incidence of postoperative ileus and use of intravenous patient-controlled analgesia. Results In total, 209 patients were recruited and 200 completed the trial (TAP 102, IT 98). The TAP group had a 1·6-point greater mean pain score than the IT group at 4 h after surgery, and this difference lasted for 16 h after operation. The TAP group received more MMEs within the first 24 h after surgery than the IT group (median difference in MMEs 10·0, 95 per cent c.i. 3·0 to 20·5). There were no differences in MME use at 24 and 48 h, or with respect to secondary outcomes. Conclusion IT opioid administration provided better immediate postoperative pain control than TAP block. Both modalities resulted in low pain scores in patients undergoing elective colorectal surgery and should be considered in multimodal postoperative analgesic plans. Registration number: NCT02356198 ( http://www.clinicaltrials.gov).