bluuebunny/crossref_metadata_2025 huggingface dataset:
Breaking immune tolerance for the treatment of glioblastoma: Phase IIb clinical trial experience.
Authors: Hwang Larn , Nam David , Trieu Vuong N.
Published: July 2019

71

Background: Intratumoral heterogeneity (IH) resulting in the temporal and spatial diversification of tumor subclones. IH occurs progressively during tumor development inherent to the individual predilection to mutation and in the face of counterselections by exogenous therapies and/or endogenous immune surveillance. The xenogenization is countered by immunosuppression via overexpression of TGF-β. Here we compare the use of temozolomide (TMZ) and OT-101/TMZ to break immune tolerance to glioblastoma (GBM) for the cure. OT-101 is an antisense against TGF-β2. Methods: This is a phase IIb, multi-national, multi-center, open-label, active-controlled, randomized parallel group dose-finding study to evaluate the efficacy and safety of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week. A total of 134 patients, 89 patients in the OT-101 test group and 45 patients in the standard chemotherapy (TMZ) control group were assessed. Results: Multiple rounds of TMZ broke the immune tolerance as shown by increase in overall survival (OS). mOS increased from 5.6 mos, 7.9 mos, to 36.6 mos with 1 round, 2 rounds, and 3 rounds of TMZ, respectively (p<0.0001). For OT-101, mOS increased from 4.6 mos to 21.6 mos with just one round of TMZ (p<0.0001) reducing the negative side effects of TMZ. Treatment sequencing was important as lead-in OT101 followed with subsequent TMZ was more effective than TMZ prior to OT-101 (26.2 mos vs. 4.8 mos, p<0.0001). Conclusions: The MOA for OT-101/TMZ is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during TMZ. Contrary to traditional tumor vaccine- this is universally applicable to all patients.
The anti-tumor effect of oral cancer vaccine using Bifidobacterium as a platform for displaying Wilms’ tumor 1 protein.
Authors: Minagawa Hikaru , Hashii Yoshiko , Nakagawa Natsuki , Nakajima Hiroko , Oka Yoshihiro , Katayama Takane , Shirakawa Toshiro , Ozono Keiichi
Published: July 2019

72

Background: The gut microbiota plays an important role in shaping systemic immune responses. We have developed a WT1 oral cancer vaccine using a recombinant Bifidobacterium Longum ( B. Longum) as a platform for displaying murine WT1 protein ( B. Longum-mWT1). The Wilms’ tumor 1 (WT1) gene, which encodes a zinc finger transcription factor, is reportedly overexpressing in various tumors and one of the most promising tumor-associated antigens for cancer immunotherapy. In order to examine anti-tumor effects of this oral vaccine, we administered it orally into mice inoculated with WT1+-expressing brain tumor which doesn’t respond to existing treatment. Methods: The synthesized murine-WT1 gene (117-439 amino acid residues) was fused to galacto-N-biose/lacto-N-biose I binding protein (GLBP) coding gene. GLBP is a membrane protein on the wild-type B. Longum cell wall, which is used as an anchor to display antigen. The resulting plasmid carrying GLBP-WT1 was introduced into B. Longum by electroporation. We inoculated mouse glioma cell lines (Gl261) subcutaneously into the C57BL/6J. C57BL/6J mice received oral administration of B. Longum-mWT1 every day or subcutaneous administration of WT1126 peptide with montanide adjuvant on days 1, 8, 15, 22, 29, and 36. Results: The tumor volume of the mice treated with B. Longum-mWT1 (n = 5) was significantly smaller than that of the mice given WT1 peptide vaccine (n = 5) ( P < 0.05). The frequency of CD8+/WT1-tetramer+ CTLs was higher in B. Longum-mWT1 and WT1 peptide vaccine groups than in PBS group, and the high frequency was maintained in B. Longum-mWT1 group. In the mouse with B. Longum-mWT1, the frequency CD8+/WT1-tetramer+ CTLs in mesenteric lymph node and spleen was higher than that in Peyer’s patch. The number of invasive CD8+ T cells in brain tumor was higher in the B. Longum-mWT1 group than in the PBS group. B. Longum-mWT1 induced significantly higher in vitro cytotoxicity against Gl261 cells than WT1 peptide. Conclusions: We confirmed that B. Longum-mWT1 can induce strong cellular immunity and the maintenance of this effect. These results suggest that it is a novel oral anti-cancer agent for treating glioblastoma, for which no effective treatment has been developed.
Enhanced antitumor effect and lower viral reactivation with high doses of ex vivo expanded NK cells administered after haploidentical transplantation.
Authors: Ciurea Stefan O. , Saliba Rima , Soebbing Doris , Rondon Gabriela , Cao Kai , Ahmed Sairah , Olson Amanda Leigh , Bashir Qaiser , Kaur Indreshpal , Shpall Elizabeth J. , Lee Dean Anthony , Champlin Richard E.
Published: July 2019

74

Background: NK cells have potent antitumor and antiviral effects. We hypothesized that multiple infusions of high doses of mb-IL21 ex vivo expanded NK cells administered peri-transplant will enhance graft-versus-leukemia effect and decrease viral reactivation. Methods: In the phase 1 dose escalation study patients received NK cells starting at 1x105 to 1x108/Kg/dose (N = 13). No dose limiting toxicities were observed. In the phase 2 study, 12 patients with myeloid malignancies received mbIL-21 ex vivo expanded NK cells at dose 1x108NK cells/kg with a K562 feeder cell system and with 41BB. NK cells were generated from peripheral blood mononuclear cells of the same donor and infused fresh on day -2, and cryopreserved on day +7 and +28. Conditioning regimen consisted of melphalan, fludarabine and TBI. All patients had bone marrow graft. Here we report updated results of all patients treated to date on this study. Results: Twenty-five patients (18 AML/MDS and 7 CML) were treated to date. The median age was 45 years, the median follow-up of survivors was 28 months. 16/18 AML/MDS patients had high-risk disease. No adverse effects occurred. Engraftment was achieved in all 24 evaluable patients after a median of 19 days. The cumulative incidence (CI) of grade 2 aGVHD was 38% at day 100. No chronic GVHD was observed. The CI of TRM was 21% at 2 years. The CI of relapse at 1 year was 8%. The 2-years PFS was 66%. Ten patients reactivated CMV. Immunologic reconstitution of T cell subsets showed a 5.7 fold higher number of NK cells on day 28 in patients who received highest NK cell doses vs. others. A matched-pair analysis done with an independent CIBMTR cohort of patients who received either MAC (N = 61) or RIC (N = 57), showed a significantly improvement in relapse rate and PFS in favor of patients treated on trial. Conclusions: Administration of higher doses of NK cells was associated with higher NK cell numbers early post-transplant, suggesting that a dose-dependent effect could be achieved. A low relapse rate and lower viral reactivation post-transplant continues to be seen, suggesting that NK cells exert both anti-tumor and antiviral effects in this setting. Clinical trial information: NCT01904136.
Managing immune-related adverse events (irAEs): A new educational resource for health care professionals (HCPs) and patients.
Authors: Wood Laura S. , Hoffner Brianna , Rubin Krista M. , Davies Marianne , Tushla Lisa A. , Guild Valerie , Guild Samantha R.
Published: July 2019

75

Background: Immune checkpoint inhibitors (ICIs) have changed treatment options for many cancer patients. Educating HCPs, patients, and caregivers is crucial to early identification of irAEs, ensuring prompt intervention and improved outcomes. Resources for oncology HCPs are scattered, including published articles, websites, and pharmaceutical materials. These resources are restricted to information from the package insert and limited in the scope of guidance provided. Methods: Melanoma advance practice providers (APPs) collaborated with the AIM at Melanoma Foundation and Terranova Medica in 2016 to create the Melanoma Nurse Initiative, featuring educational information regarding immunotherapy and irAE management. Based on website success (>9200 professional interactions), learner survey data, and continued expansion of agents and indications, the need for a more expansive resource was identified. Results: AIM With Immunotherapy ( www.aimwithimmunotherapy.org/ ) launched in October 2018. Resources were developed by APPs with extensive experience with immunotherapy, education, and irAE management. Care Step Pathways provide comprehensive information on assessment, toxicity grading, and management. The HCP Toolkits include printable pages on drug information, side effect management, clinical pearls, and resources. Patient Action Plans, individualizable for each patient, include many detailed irAE information sheets. Videos for both HCPs and patients as well as a community Q/A panel provide additional multimedia, interactive resources. Learner surveys are planned to gauge how the content is used in the clinic setting and remaining unmet educational needs. Conclusions: Knowledge regarding immunotherapy, irAEs, and management of toxicities unique to immunotherapy is critical to maximizing clinical outcomes and quality of life for patients and their caregivers. AIM With Immunotherapy is a new website developed by expert oncology practitioners that provides comprehensive non-branded HCP resources and printable information to facilitate effective education of patients receiving immunotherapy.
Immune-related adverse event (irAE) education, self-efficacy, and potential irAE experiences in patients treated with immunotherapy for non-small cell lung cancer (NSCLC).
Authors: Mujumdar Urvi , Wang Huifen , Lawler Elizabeth , Lanzarini Victoria , Lowe Maria , Trunova Nataliya , Klein Alyssa B. , Emmas Cathy
Published: July 2019

76

Background: Immunotherapy presents new challenges for effective patient engagement to ensure that irAEs are reported and treated appropriately. This study directly assesses how NSCLC patients in an online community perceived their irAE education and experience of potential irAEs. Methods: PatientsLikeMe is an online community for patients to track and share their experiences with the goal of improving health outcomes across all conditions. For this study, US residents ≥ 18, with self-reported immunotherapy treatment for NSCLC were invited to a baseline survey at enrollment and follow-up survey after 3 months (Dec 2017-Aug 2018). Quantitative and qualitative analyses were performed. Results: Respondents (N = 72) were female (69%), white (94%), and mean age of 64.3 (SD 9.3). Current immunotherapy use was reported by 60 (83%) patients and prior use by 12. Most (66 [92%]) reported that a healthcare provider (HCP) shared information about irAEs before they started treatment and 47 (71%) sought additional information. 43 (60%) reported experiencing a potential irAE while on treatment, 34 (79%) of whom indicated reporting this to a HCP. Free-text responses revealed a need for more clarity on side effects and severity, and that lapses in patient-provider communication sometimes occurred. The 3-month follow-up survey was completed by 39/72 patients; 28 (72%) remained on immunotherapy, and 8 (21%) had stopped since baseline. Of the 20 patients (51%) who reported experiencing a potential irAE in the past 3 months, 15 had also reported this at baseline, and 13 reported this to a HCP. Free-text responses revealed that many patients opted to wait until the next scheduled appointment to report irAEs or they self-managed minor side effects. Conclusions: Patients reported satisfaction with information received and responded appropriately to potential irAEs, but also suggested a need to improve information and communication with care teams. As patients become more accustomed to their treatment, there may be changes in reporting of irAEs. As this data is from a self-selected convenience sample of patients, results may be limited in generalizability.
Prognostic and predictive factors associated with ipilimumab related adverse events: A retrospective analysis of 11 NCI sponsored ipilimumab phase I clinical trials.
Authors: Chauhan Aman , Kabir Tanvir , Wu Jianrong , Wei Jing , Kunos Charles
Published: July 2019

86

Background: We review factors affecting ipilimumab (ipi) associated toxicity in various NCI sponsored phase I clinical trials. Methods: NCI database for NCI sponsored phase I clinical trials evaluating ipilimumab was queried for adverse effects, radiological response data, lymphocyte counts, LDH, albumin, ECOG performance status, duration of treatment and diagnosis. Only treatment related AEs were analyzed. Events repeating across consecutive cycles were treated as a single event. Duration of treatment was calculated starting from cycle 1 day 1 of the treatment. IRB approval from NCI was obtained prior to the study. Results: Data from 373 patients from 11 phase I ipilimumab clinical trials were available for analysis. Median age of the study cohort was 55 years. 68%(n = 235) were males. Number of grade 3 and 4 AEs were associated with better radiological response. Mean grade 3 and 4 AEs in CR+PR cohort was 1.167 vs 0.645 in non-responder cohort (p = 0.001). No significant differences in low or high grade AEs were noticed in study cohorts differentiated based on ECOG PS (0 vs 1/2). ECOG PS 3/4 were not included in clinical trials. Pretreatment lymphocyte count, LDH or albumin was not predictive of increased ipilimumab associated toxicity. Ipilumumab associated grade 3 and 4 toxicity was directly associated with the number of concurrently used study agents. Mean grade 3 and 4 AEs were as follows in following cohorts: ipi alone; 0.631 vs ipi+ 1 drug; 0.877 vs ipi+ 2 drugs; 1.408 (p < 0.0136). Number of low grade (grade 1 and 2) toxicity was associated with duration of treatment. r = 0.456 (p < 0.0001). Number of high grade (grade 3 and 4) toxicity was not associated with duration of treatment with ipilimumab. r = 0.032 (p = 0.546). Conclusions: Ipilimumab associated grade 3 and 4 toxicity predicts response to therapy and is associated with higher CR/PR. ECOG PS, pretreatment lymphocyte count, LDH and albumin levels are not associated with ipilimumab toxicity. Lastly, addition of antitumor agents to ipilimumab has potential to cause a significant increase in serious AE’s.
T-cell lymphoma secondary to checkpoint inhibitor (CPI) used for other malignancies.
Authors: Anand Kartik , Ensor Joe , Pandita Shruti , Pingali Sai Ravi , Pant Shubham , Yee Cassian , Duvic Madeleine , Pandita Tej , Torres-Cabala Carlos A. , Miranda Roberto N. , Zu Youli , Iyer Swaminathan Padmanabhan
Published: July 2019

88

Background: Wartewig et al. (Nature 2017) proved in a preclinical mouse model that anti-PD1 therapy could cause T-cell lymphoma. T-cell lymphoma as an adverse event of CPIs has never been reported. A 75-year-old male with h/o urothelial carcinoma presented with lung metastasis of adenocarcinoma of unknown primary that showed PDL1 staining 5% of cells. Patient was treated with carboplatin & paclitaxel. For progressive disease, the patient received Pembrolizumab. After 4 cycles of CPI he developed lymphocytosis and lymphadenopathy and diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), with bone marrow (BM) involvement. Patient died before receiving any treatment for lymphoma. We hypothesized that CPI caused clonal expansion of T cells. Methods: We performed T-cell receptor (TCR) sequencing by Immunoseq assay in biopsy specimens. We queried FDA Adverse Events Reporting System (FAERS) and VigiBase databases for T-cell lymphoma/leukemia, PTCL, NOS, Mycosis Fungoides, Anaplastic Large & Cutaneous T-cell Lymphoma as an adverse event (AE) secondary to nivolumab, pembrolizumab or ipilimumab. Results: Through TCR sequencing we identified single clonal expansion before PD1 therapy in lung (0.008%) to 11% in bone marrow and 40% in lymph node (post treatment samples). Additional targeted exome sequencing of the lymphoma revealed a TET2 mutation. We conclude that anti-PD1 caused clonal expansion of the T cells harboring TET2 mutation leading to T-cell lymphoma. Findings of FARES and VigiBase review are shown in the Table. Conclusions: T-cell lymphoma is a rare complication of CPIs, with high mortality (20%). Long term follow up of patients receiving CPIs is needed. [Table: see text]
Psychosocial distress and access to resources: Preliminary findings from Immunotherapy & Me.
Authors: Mulcahy Maxwell , House Linda S. , Power Nicholas James , Olson Julie , McManus Shauna , Jones Tameka N. , Schwartzberg Lee S.
Published: July 2019

91

Background: Immunotherapy & Me ( IO & Me) is an innovative program of supportive resources developed by Cancer Support Community to investigate and support the unique needs of immunotherapy patients. Here, we describe psychosocial distress and confidence accessing resources among a sample of program participants. Methods: IO & Me is recruiting at 4 community clinics and 1 academic center. Eligible patients must be on an anti-cancer immunotherapy. At enrollment, participants consent, provide demographic/clinical history, and report level of confidence accessing cancer treatment information and resources related to treatment decision making (TDM) and managing symptoms/side effects (SEs). Distress is reported with CancerSupportSource (CSS), a tool where patients rate level of concern on 15 items. Once enrolled, participants can access educational resources (print materials, SE tracker, eLearning courses) and a toll-free helpline staffed by licensed mental health professionals (Cancer Support Helpline). Follow-up surveys are available every 30 days for 6 months. We present data from 68 participants at enrollment and 22 at first follow-up. Results: Participants were 87% White; 69% male; mean age = 65 years (SD = 13). 43% had lung cancer; 22% melanoma; 9% kidney cancer. At baseline, the frequency who felt very or extremely confident accessing resources related to: TDM = 68%; managing SEs = 60%; treatment information = 75%. For distress, top concerns were: fatigue (35% of participants); health insurance/money worries (34%); exercise/physical activity (32%). After 30 days, the frequency who felt confident accessing resources for: TDM = 100%; managing SEs = 91%; treatment information = 100%. Top concerns were: changes/disruptions in work, school, or home life (14%); feeling irritable (9%); sleep problems (9%). Conclusions: Preliminary results show greater variability in distress and confidence accessing resources at baseline than 1-month into the program, at which time few endorse cancer-related concerns and most feel confident accessing resources. These findings highlight the utility of providing patients with educational/support resources and the value of customizable programs like IO & Me. Clinical trial information: NCT03347058.
A germline microRNA-based biomarker signature of immune-associated toxicity to anti-PD1/PDL1 therapy.
Authors: Weidhaas Joanne B. , Scheffler Aaron Wolfe , Salzman David , Kalbasi Anusha , Wilenius Kirk , Rietdorf Emily , Heilig Mara , Pitka Mattias , Desler Caroline , Ruan Dan , Ribas Antoni , Drakaki Alexandra , Scholz Mark C. , Telesca Donatello
Published: July 2019

96

Background: Treatment with anti-PD1/anti-PDL1 agents is associated with toxicity termed immune related adverse events (iRAEs). While the prevalence of Grade 2 and higher iRAEs is approximately 25-30%, biomarkers have not been previously identified. We tested the hypothesis that functional, germ-line mutations would predict iRAEs. Methods: Four classifiers were trained on a set of 61 melanoma patients evaluated for toxicity and response. Subjects were classified as experiencing high toxicity (≥ Grade 2) vs low toxicity (< Grade 2). Performance of the classifiers was tested on a validation set of 89 cancer patients with a variety of cancer types, with the most common being GU and NSCLC. Classifiers were built for each treatment of marker data including classification trees, LASSO-regularized logistic regression, boosted trees (BT), and random forests. The final performance measures, accuracy, specificity, sensitivity, negative predictive value, positive predictive value, area under the curve (AUC), and F1 score, were reported on the categorical treatment of the training data using leave-one-out cross validation on the validation data. We also evaluated the association between our most significant toxicity biomarker and response to anti-PD1/PDL1 therapy. Results: Within the melanoma training sample, we found a biomarker signature where toxicity is predicted with 79.0% accuracy (F1 = .714, AUC = .827) using BT. The same biomarker panel also accurately predicted toxicity in the validation cohort with 85.6% accuracy (F1 = .760, AUC = .883). Of the most predictive biomarkers, three were in microRNA binding sites in RAC1, CD274, and KRAS, two in immune related genes IL2RA and FCGR2A, and one in the DNA repair gene ATM. Our most significant biomarker in RAC1 did not predict response to anti-PD1/PDL1 treatment (p=0.91). Conclusions: We have identified a germ-line biomarker signature which predicts Grade 2 or higher iRAEs for patients treated with anti-PD1/anti-PDL1 therapy, regardless of cancer type, and does not predict an increased likelihood of response to these therapies. These findings are an important step in defining how to better safely personalize immune therapy, whose use is growing rapidly.
Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.
Authors: Ho William , Nasrah Nicole , Johnson Dan
Published: July 2019

TPS24

Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.
A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).
Authors: Saeed Anwaar , Koestler Devin , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Al-Kasspooles Mazin Francis , Subramaniam Dharmalingam , Anant Shrikant
Published: July 2019

TPS56

Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.
Phase I/II trial of BMS-986205 and nivolumab as first-line therapy in hepatocellular carcinoma.
Authors: Chen Justin , Ji Jingran , Cho May Thet , Monjazeb Arta , Gholami Sepideh , Kim Edward Jae-Hoon
Published: July 2019

TPS57

Background: Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death worldwide and incidence is rising. Sorafenib and lenvatinib are approved for first-line use in unresectable HCC; however, survival benefit remains low. Nivolumab, a human monoclonal antibody to programmed death-1 (PD1) receptor, has been approved as second-line therapy in patients with unresectable HCC refractory to sorafenib. BMS-986205 selectively inhibits human indoleamine-2,3- dioxygenase 1 (IDO1), an intracellular enzyme expressed in various malignancies that promotes immune tolerance. Thus, the combination of PD-1 antibody and IDO1 inhibitor is a promising strategy to augment immunotherapy against HCC. We aim to evaluate the combination of BMS-986205 with nivolumab 3 mg/kg every 2 weeks in unresectable and metastatic HCC. Methods: Primary objectives were to identify tolerable dosing of BMS-986205, and to evaluate safety, tolerability, and efficacy of combination therapy, the latter defined by objective response rate. Secondary objectives were to evaluate disease control rate, duration of response, progression free survival, and overall survival. Phase I (dose escalation phase) will monitor two dose levels of BMS-986205: 50mg daily with conditional escalation to 100mg daily depending on dose-limiting toxicity. Phase II (expansion phase) will begin after maximum tolerated dose is reached. The phase II cohort will be run as a Simon two-stage design to allow for early trial stoppage for futility. Estimated study duration is 36 months with a 24-month accrual period for a total of 17 patients. Patients will be followed for 100 days after the last dose of treatment or until all treatment-related clinical toxicities resolve to baseline or grade ≤ 1. Assessments prior to therapy include imaging, tissue biopsy, serum correlatives, and stool samples. Tissue biopsy will be repeated at 4 weeks. Imaging will be repeated at 8 and 16 weeks, then every 12 weeks until end of treatment. Serum correlatives will be repeated intermittently throughout. At progression, imaging, tissue biopsy, and serum correlatives will be repeated. Data will be reported using 95% confidence intervals, Kaplan-Meier estimates, and frequency tables. Clinical trial information: NCT03695250.
JAVELIN ovarian PARP 100 study design: Phase III trial of avelumab + chemotherapy followed by avelumab + talazoparib maintenance in previously untreated epithelial ovarian cancer.
Authors: Eskander Ramez Nassef , Ledermann Jonathan A. , Birrer Michael J. , Fujiwara Keiichi , Gaillard Stephanie , Richardson Gary Edward , Wei Caimiao , Baig Mahadi Ali , Zohren Fabian , Monk Bradley J.
Published: July 2019

TPS9

Background: Preclinical studies suggest that chemotherapy (CTX) and PARP inhibitors may increase tumor antigenicity, providing a rationale for combined treatment with checkpoint inhibitors in patients (pts) with ovarian cancer (OC). Talazoparib is a potent, orally bioavailable PARP inhibitor with a dual mechanism (PARP trapping and enzyme inhibition) that has shown clinical activity in BRCA-mutated OC and is a US-approved treatment for BRCA-mutated HER2– breast cancer. Avelumab is an anti–PD-L1 checkpoint inhibitor approved for the treatment of metastatic Merkel cell carcinoma and advanced platinum-treated urothelial carcinoma. In phase 1b studies, avelumab showed antitumor activity and acceptable safety in pts with platinum-resistant OC. The JAVELIN Ovarian PARP 100 trial is evaluating the efficacy of avelumab + CTX followed by avelumab + talazoparib maintenance compared with CTX + bevacizumab followed by bevacizumab maintenance in pts with previously untreated epithelial OC. Methods: JAVELIN Ovarian PARP 100 is a phase 3, randomized, open-label, multicenter trial. Eligible pts have previously untreated Stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; are candidates for platinum-based CTX + bevacizumab; and have completed primary debulking surgery or are candidates for neoadjuvant CTX with planned interval debulking surgery. Approximately 720 pts will be randomized in a 2.5:1:2.5 ratio to receive: CTX (paclitaxel 175 mg/m2 + carboplatin AUC 5/6 IV Q3W for 6 cycles) + avelumab (800 mg IV Q3W) followed by avelumab (800 mg Q2W) + talazoparib (0.75 mg QD orally) maintenance for up to 24 months (Arm A); CTX followed by talazoparib (0.75 mg QD) maintenance for up to 24 months (Arm B); or CTX + bevacizumab (15 mg/kg IV Q3W) followed by bevacizumab (15 mg/kg Q3W) maintenance for up to 21 doses or 22 per local approval (Arm C). Pts are stratified by germline BRCA1/2 mutation and resection status. The primary endpoint is progression-free survival (PFS) by blinded independent central review per RECIST v1.1. Other endpoints include overall survival, PFS2, health-related quality of life, and PK. Clinical trial information: NCT03642132.
Regulated Endocrine-Specific Protein-18, an Emerging Endocrine Protein in Physiology: A Literature Review
Authors: Atari Ealla , Perry Mitchel C , Jose Pedro A , Kumarasamy Sivarajan
Published: July 2019

Regulated endocrine-specific protein-18 (RESP18), a novel 18-kDa protein, was first identified in neuroendocrine tissue. Subsequent studies showed that Resp18 is expressed in the adrenal medulla, brain, pancreas, pituitary, retina, stomach, superior cervical ganglion, testis, and thyroid and also circulates in the plasma. Resp18 has partial homology with the islet cell antigen 512, also known as protein tyrosine phosphatase, receptor type N (PTPRN), but does not have phosphatase activity. Resp18 might serve as an intracellular signal; however, its function is unclear. It is regulated by dopamine, glucocorticoids, and insulin. We recently reported that the targeted disruption of the Resp18 locus in Dahl salt-sensitive rats increased their blood pressure and caused renal injury. The aim of the present review was to provide a comprehensive summary of the reported data currently available, especially the expression and proposed organ-specific function of Resp18.
Anesthesia Provider Training and Practice Models: A Survey of Africa
Authors: Law Tyler J. , Bulamba Fred , Ochieng John Paul , Edgcombe Hilary , Thwaites Victoria , Hewitt-Smith Adam , Zoumenou Eugene , Lilaonitkul Maytinee , Gelb Adrian W. , Workneh Rediet S. , Banguti Paulin M. , Bould Dylan , Rod Pascal , Rowles Jackie , Lobo Francisco , Lipnick Michael S.
Published: July 2019

BACKGROUND:

In Africa, most countries have fewer than 1 physician anesthesiologist (PA) per 100,000 population. Nonphysician anesthesia providers (NPAPs) play a large role in the workforce of many low- and middle-income countries (LMICs), but little information has been systematically collected to describe existing human resources for anesthesia care models. An understanding of existing PA and NPAP training pathways and roles is needed to inform anesthesia workforce planning, especially for critically underresourced countries.

METHODS:

Between 2016 and 2018, we conducted electronic, phone, and in-person surveys of anesthesia providers in Africa. The surveys focused on the presence of anesthesia training programs, training program characteristics, and clinical scope of practice after graduation.

RESULTS:

One hundred thirty-one respondents completed surveys representing data for 51 of 55 countries in Africa. Most countries had both PA and NPAP training programs (57%; mean, 1.6 pathways per country). Thirty distinct training pathways to become an anesthesia provider could be discriminated on the basis of entry qualification, duration, and qualification gained. Of these 30 distinct pathways, 22 (73%) were for NPAPs. Physician and NPAP program durations were a median of 48 and 24 months (ranges: 36–72, 9–48), respectively. Sixty percent of NPAP pathways required a nursing background for entry, and 60% conferred a technical (eg, diploma/license) qualification after training. Physicians and NPAPs were trained to perform most anesthesia tasks independently, though few had subspecialty training (such as regional or cardiac anesthesia).

CONCLUSIONS:

Despite profound anesthesia provider shortages throughout Africa, most countries have both NPAP and PA training programs. NPAP training pathways, in particular, show significant heterogeneity despite relatively similar scopes of clinical practice for NPAPs after graduation. Such heterogeneity may reflect the varied needs and resources for different settings, though may also suggest lack of consensus on how to train the anesthesia workforce. Lack of consistent terminology to describe the anesthesia workforce is a significant challenge that must be addressed to accelerate workforce research and planning efforts.
Aviation-Style Computerized Surgical Safety Checklist Displayed on a Large Screen and Operated by the Anesthesia Provider Improves Checklist Performance
Authors: Jelacic Srdjan , Bowdle Andrew , Nair Bala G. , Togashi Kei , Boorman Daniel J. , Cain Kevin C. , Lang John D. , Dellinger E. Patchen
Published: July 2019

BACKGROUND:

Many hospitals have implemented surgical safety checklists based on the World Health Organization surgical safety checklist, which was associated with improved outcomes. However, the execution of the checklists is frequently incomplete. We reasoned that aviation-style computerized checklist displayed onto large, centrally located screen and operated by the anesthesia provider would improve the performance of surgical safety checklist.

METHODS:

We performed a prospective before and after observational study to evaluate the effect of a computerized surgical safety checklist system on checklist performance. We created checklist software and translated our 4-part surgical safety checklist from wall poster into an aviation-style computerized format displayed onto a large, centrally located screen and operated by the anesthesia provider. Direct observers recorded performance of the first part of the surgical safety checklist that was initiated before anesthetic induction, including completion of each checklist item, provider participation and distraction level, resistance to use of the checklist, and the time required for checklist completion before and after checklist system implementation. We compared trends of the proportions of cases with 100% surgical safety checklist completion over time between pre- and postintervention periods and assessed for a jump at the start of intervention using segmented logistic regression model while controlling for potential confounding variables.

RESULTS:

A total of 671 cases were observed before and 547 cases were observed after implementation of the computerized surgical safety checklist system. The proportion of cases in which all of the items of the surgical safety checklist were completed significantly increased from 2.1% to 86.3% after the computerized checklist system implementation (P < .001). Before computerized checklist system implementation, 488 of 671 (72.7%) cases had <75% of checklist items completed, whereas after a computerized checklist system implementation, only 3 of 547 (0.5%) cases had <75% of checklist items completed.

CONCLUSIONS:

The implementation of a computerized surgical safety checklist system resulted in an improvement in checklist performance.
Girl Guides, Athletes, and Educators
Authors: Krais Jakob
Published: July 2019

Algeria is often seen as a major instance of women’s emancipation in the Middle East of the mid-twentieth century. Whereas the scholarly focus has often been on colonial policies, French views, or the female participation in the war of independence, this article looks at the impact that new bodily practices, such as scouting and sports, had on gender relations within Muslim Algerian society during the last three decades of French rule. It contrasts the reformist discourse of the Islamic islah movement on women’s “emancipation” and education with the aspirations of young women themselves who started to challenge patriarchal authority.
Acoustic crypsis in southern right whale mother–calf pairs: infrequent, low-output calls to avoid predation?
Authors: Nielsen Mia L. K. , Bejder Lars , Videsen Simone K. A. , Christiansen Fredrik , Madsen Peter T.
Published: July 2019

Southern right whales (Eubalaena australis) invest substantial amounts of energy in their calves, while facing the risk of having them predated upon by eavesdropping killer whales (Orcinus orca). We tested the hypothesis that southern right whale mother–calf pairs employ acoustic crypsis to reduce acoustic detectability by such predators. Specifically, we deployed multi-sensor DTAGs on nine lactating whales for a total of 62.9 h in a Western Australian breeding ground, and used a SoundTrap to estimate the concomitant acoustic background noise. Vocalisations were recorded at low rates of <10 calls h−1 (1 call per dive) and at low received levels between 123±8 and 134±10 dB re. 1 µPa RMS depending on call type. We conclude that such acoustic crypsis in southern right whales and other baleen whales decreases the risk of alerting potential predators and hence jeopardizing a substantial energetic investment by the mother.
Impact of Exercise and Activity on Weight Regain and Musculoskeletal Health Post-Ovariectomy
Authors: SHERK VANESSA D. , JACKMAN MATTHEW R. , HIGGINS JANINE A. , GILES ERIN D. , FORIGHT REBECCA M. , PRESBY DAVID M. , CARPENTER R. DANA , JOHNSON GINGER C. , OLJIRA ROBERA , HOUCK JULIE A. , MACLEAN PAUL S.
Published: July 2019

The purpose of this study was to determine whether obesity and/or exercise training alters weight regain and musculoskeletal health after ovariectomy (OVX). Female rats were fed high-fat diet (HFD) to reveal obesity-prone (OP) and obesity-resistant (OR) phenotypes. The OP and OR exercising (EX) and sedentary (SED) rats were calorically restricted to lose 15% of body weight using medium-fat diet. Rats were then maintained in energy balance for 8 wk before OVX. After OVX and a brief calorically limited phase, rats were allowed to eat ad libitum until body weight plateaued. Starting at weight loss, EX ran 1 h·d−1, 6 d·wk−1, 15 m·min−1. Energy intake, spontaneous physical activity (SPA), and total energy expenditure were evaluated at the end of weight maintenance pre-OVX, and at three time points post-OVX: before weight regain, during early regain, and after regain. Data are presented as mean ± SE. Exercise attenuated weight regain after OVX in OP only (OP-EX, 123 ± 10 g; OP-SED, 165 ± 12 g; OR-EX, 121 ± 6 g; OR-SED, 116 ± 6 g), which was primarily an attenuation of fat gain. The early post-OVX increase in energy intake explained much of the weight regain, and was similar across groups. Exercising improved bone strength, as did maintaining SPA. Group differences in muscle mitochondrial respiration were not significant. The large decrease in SPA due to OVX was persistent, but early weight regain was dependent on decreased SPA. In conclusion, leanness and exercise do not necessarily protect from OVX-induced weight gain. Exercise prevented weight gain in obese rats, but loss of SPA was the greatest contributor to post-OVX weight gain. Thus, understanding the mechanisms resulting in reduction in SPA after ovarian hormone loss is critical in the prevention of menopause-associated metabolic dysfunction.
Evaluation of the triangular fibrocartilage: comparison of two-compartment wrist CT arthrography using the distal radioulnar and radiocarpal joints and unicompartment wrist CT arthrography using the radiocarpal joint
Authors: Kim Sujin , Lee Guen Young , Lee Jae Sung
Published: July 2019

Objective:

To compare the diagnostic performance of two-compartment wrist CT arthrography of the distal radioulnar and radiocarpal joints and unicompartment wrist CT arthrography of the radiocarpal joint in depiction of the triangular fibrocartilage tear.

Methods:

From January 2016 to December 2017, two-compartment CT arthrography of 74 consecutive patients (36 females, 38 males; mean age, 37.2 years) and unicompartment CT arthrography of 51 consecutive patients (18 females, 33 males; mean age, 40.1 years) were obtained. All CT arthrography images were independently and blindly evaluated by two radiologists for the presence of the triangular fibrocartilage tear by grade (partial or full thickness) per its locations: central disc proper, central-peripheral junction, proximal and distal laminae of its ulnar attachment. Fisher’s exact test was used for a statistical analysis, and a p-value less than 0.05 was considered as significant. The arthroscopic findings of 47 patients (34 patients with two-compartment CT arthrography and 13 patients with unicompartment CT arthrography) were evaluated for calculating sensitivity, specificity, and accuracy.

Results:

All partial and full thickness triangular fibrocartilage tears were identified more commonly by their location except for distal laminae on two-compartment CT arthrography than were unicompartment CT arthrography (p = 0.001–0.022). Two-compartment CT arthrography had high sensitivity (90.9–100%) and low specificity (33.3–76.5%) for detecting central disc proper and proximal lamina tears, comparing with unicompartment CT arthrography.

Conclusion:

Two-compartment wrist CT arthrography is more helpful for detecting triangular fibrocartilage tears than unicompartment wrist CT arthrography.

Advances in knowledge:

It could be important to evaluate the ulnar foveal insertion of the TFCC in clinical practice, which plays the most important role in DRUJ instability and ulnar-sided wrist pain. Two-compartment wrist CTA of the DRUJ and RCJ could improve diagnostic sensitivity in the TFC tear in terms of its location and torn degree over that of unicompartment wrist CTA of the RCJ. Two-compartment wrist CTA of the DRUJ and RCJ may be recommended as a diagnostic imaging, rather than unicompartment wrist CTA of the RCJ, when peripheral foveal tear of TFC is suspected, especially in young patients.
Transthoracic ultrasound sign in severe asthmatic patients: a lack of “gliding sign” mimic pneumothorax
Authors: Del Colle Anna , Carpagnano Giovanna Elisiana , Feragalli Beatrice , Foschino Barbaro Maria Pia , Lacedonia Donato , Scioscia Giulia , Quarato Carla Maria Irene , Buonamico Enrico , Tinti Maria Giulia , Rea Gaetano , Cipriani Cristiana , Frongillo Elisabettamaria , De Cosmo Salvatore , Guglielmi Giuseppe , Sperandeo Marco
Published: July 2019

Transthoracic ultrasound (TUS) is a validate complementary technique widely used in everyday medical practice. TUS is the gold-standard for studying pleural effusion and for echo-guided thoracentesis, moreover, it is employed in detection of pleural and pulmonary lesions adherent to pleural surface and their ccho-guided percutaneous needle biopsy (PTNB). 1 We used TUS technique to study severe asthma patients. We found that several patterns are constant in these patients. One of these patterns, i.e. lack of gliding sign, mimic pneumothorax (PNX). In this study, we attempted an echographic approach to asthma, trying to lay the first stone for the individuation of common ultrasound patterns in this disease.
Comparison between fractal analysis and radiopacity evaluation as a tool for studying repair of an osseous defect in an animal model using biomaterials
Authors: Gomes Nathália R. , Albergaria Juliano D.S. , Henriques Jonathas A. de S. , Amaral Tânia M.P. , Abdo Evandro N. , Silva Gerluza A.B. , Brasileiro Cláudia Borges
Published: July 2019

Objectives:

To evaluate bone repair of an osseous defect in a rat animal model through fractal analysis and radiopacity analysis in radiographic images.

Methods:

120 rats were subjected to extraction of their first molar and divided into four groups (n = 6/group) according to the material used for bone grafting: mineralized bovine bone, demineralized bovine bone (DBB), blood clot (BC - control) or Bio-Oss® (BO). The animals were sacrificed after 1, 7, 14, 21 and 49 days and subjected to radiographic evaluation. For fractal analysis (FA), a square regionof interest of 30 × 30 pixels was used, and radiopacity was measured as the mean gray scale (MGS) value for three points of 5 × 5 pixels in the apical, medial and coronal regions of the defect. Histomorphometric evaluation was realized as the gold standard for bone neo-formation and maturation of the new osseous matrix.

Results:

Histomorphometric evaluation suggested that DBB showed faster mineralized deposition and resulted in more mature bone at the final time point of evaluation. Mineralized bovine bone and Bio-Oss presented similar results. The mineralized groups did not show significant differences in bone maturation. The radiopacity analysis revealed a significant difference (p < 0.05) between the DBB and blood clot groups at the final time point. FA did not show any significant differences at the final time point.

Conclusions:

Mean gray scale seemed to be more effective for the quantification of bone repair than FA in the demineralized group in this animal model. Results for the mineralized groups did not reveal a significant difference, leading to the conclusion that both methods are effective.