tbuckley/cabot-search huggingface dataset:
VOLTAGE: Multicenter phase Ib/II study of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy (CRT) with capecitabine in patients with locally advanced rectal cancer (LARC)
Authors: H. Bando, Y. Tsukada, K. Inamori, S. Fukuoka, T. Sasaki, Y. Nishizawa, M. Wakabayashi, M. Kojima, Y. Togashi, S. Yuki, Y. Komatsu, S. Homma, Y. Hatanaka, Y. Matsuno, M. Uemura, T. Kato, A. Sato, H. Nishikawa, M. Ito, T. Yoshino
Journal: Annals of Oncology (2018)

Introduction: Fluoropyrimidine-based Chemoradiotherapy (CRT) and subsequent radical surgery is widely accepted as the standard treatment for patients with Locally Advanced Rectal Cancer (LARC). Higher pathological complete response (pCR) rates are associated with good clinical outcomes. Recently, improved therapeutic effects have been reported in patients with various types of cancer by combining an immune checkpoint inhibitor with radiotherapy (RT). The purpose of this study is to investigate safety, efficacy and proof-of-concept (POC) of nivolumab monotherapy plus subsequent radical surgery following preoperative CRT with capecitabine, in patients with LARC. Here, we present the results of the phase Ib and the preliminary results of phase II part. Methods: The Phase Ib part was designed to determine the recommended phase II dose (RP2D) in a "3 + 3" cohort-based design of nivolumab (240mg every 2 weeks, maximum of 5 times) and subsequent radical surgery. The Phase II part was designed to evaluate the efficacy and safety of RP2D of nivolumab and surgery for both primary and locally recurrent LARC, respectively. Patients with T3–4 Nany M0 primary LARC or locally recurrent LARC treated with 50.4Gy of RT plus 1,650 mg/m2 of capecitabine were enrolled. The primary endpoint is the pCR rate of primary non-MSI-H LARC by independent central assessment. Disease-free and overall survival, and treatment-related adverse events, are evaluated as secondary endpoints. Totally 52 patients including 5 primary MSI-H (high-level microsatellite instability), 37 primary non-MSI-H, and 10 locally recurrent LARC will be enrolled. Results: Three patients primary LARC were enrolled in phase Ib part. All 3 patients received the full, planned administration of nivolumab without dose modification, as well as radical surgery. During nivolumab treatment, only a single grade 1 pruritus event was observed. During surgery, one grade 2 gastritis, one grade 1 nausea, one grade 1 pain and one grade 1 extrapyramidal disorder were observed, none of which was related to the surgery. No dose limiting toxicities (DLTs) were observed in phase Ib part. Preliminary efficacy assessment of phase Ib/II by local pathologists demonstrated 4 pCR of the 7 patients with primary LARC, including 2 of 3 in phase Ib and 2 of 4 in phase II part, respectively. As of February 2018, 13 patients who received the RP2D were enrolled in the phase II part. Conclusion: Nivolumab monotherapy and subsequent radical surgery following preoperative CRT were safely performed in patients with LARC. According to the preliminary efficacy assessment, promising pCR rate was observed.
Skin disorders and primary tumor location as a prognostic factor of cetuximab plus chemotherapy in the treatment of advanced colorectal cancer
Authors: T. Shinya, S. Tamotsu, K. Fujikawa, T. Kana, F. Yuta, H. Hiroki, E. Masayuki, Y. Takahashi
Journal: Annals of Oncology (2018)

Introduction: Treatment with cetuximab is known to significantly increase overall and progression-free survival in patients with left-sided colorectal cancer, but not in patients with right-sided colorectal cancer. Skin rash is a major side effect of cetuximab treatment, and the presence of skin disorder caused by cetuximab is associated with prolonged survival. To date, however, no report has compared the incidence of skin disorder according to tumor location. Furthermore, no report has evaluated overall survival according to both tumor location and skin disorder presence. Therefore, we investigated the frequency of rash according to primary tumor location (left vs. right) in metastatic colorectal cancer (mCRC), and additionally evaluated overall survival. Methods: This study was a retrospective trial conducted in a single hospital. A total of 50 patients with mCRC were enrolled between January 2011 and December 2015. Among them, 41 patients who used prophylactic steroid ointment were analyzed. We evaluated the associations between tumor location, survival parameters, and skin rash in patients with previously untreated mCRC receiving first-line chemotherapy plus cetuximab. Left-sided primary tumors were defined as tumors from the rectum to the splenic flexure, while right-sided primary tumors were defined as tumors from the cecum to the distal part of the transverse colon. Skin disorder was defined as the appearance of skin symptoms when at least one of the following was observed: acneiform rash, paronychia, or dry skin. Results: Thirty patients had left-sided primary tumors and 11 had right-sided primary tumors. In the left-sided group, 77%, 70%, and 43% of patients had acneiform rash, paronychia, and dry skin, respectively. In the right-sided group, 23%, 36%, and 27% of patients had acneiform rash, paronychia, and dry skin, respectively. We found that rash and tumor location strongly correlated with overall survival. The median survival was 17.6 months in patients with left-sided mCRC and no rash, 56.3 months in patients with left-sided mCRC and rash, and 13.7 months in patients with right-sided mCRC (P < 0.05). Multivariable analysis showed that left-sided mCRC with skin disorder was an independent predictor of OS (median 56.3 vs.11.3 months, HR = 0.23, P < 0.01). Conclusion: Our study shows that the two factors (the primary tumor location and the presence or absence of a skin disorder) are important prognostic factors of mCRC that has not been previously treated. The location of the primary tumor on the left side mCRC and the presence or absence of a skin disorder may be potent predictors of OS in cetuximab therapy. The present study evaluated skin disorders and further conclude that both left-sided tumor location & skin disorder can be a prognostic factor.
Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia
Authors: Elias Jabbour, Ching-Hon Pui, Hagop Kantarjian
Journal: JAMA Oncology (2018)

Remarkable progress has occurred in understanding the pathophysiology and in developing improved personalized therapies in adult acute lymphoblastic leukemia (ALL).We searched MEDLINE (1990-2018), the American Society of Clinical Oncology, and American Society of Hematology websites (2010-2018). We used the search terms "acute lymphoblastic or lymphocytic leukemia" or "ALL." We largely selected publications in the past 5 years but did not exclude commonly referenced and highly regarded older publications. Target therapies toward specific transcripts (eg, BCR-ABL1 tyrosine kinase oncoprotein by tyrosine kinase inhibitors) and specific leukemic cell surface antigens (eg, CD20, CD22, and CD19 monoclonal antibodies) are major breakthroughs. Current treatments produce long-term survival in 50% of patients with precursor B-cell ALL including 50% to 70% with Philadelphia chromosome (Ph)-positive ALL, 50% to 60% with T-cell ALL, and 80% with mature B-cell ALL. Next-generation sequencing and genomic profiling in ALL have identified new prognostic markers, targets, and ALL subtypes (eg, Ph-like ALL). Monoclonal antibodies, bispecific antibody constructs, and chimeric antigen receptor T cellular therapies developed in the past 5 to 7 years have revolutionized the treatment of ALL and resulted in US Food and Drug Administration approvals of blinatumomab in 2014, as well as inotuzumab and tisagenlecleucel in 2017 as ALL salvage strategies. Their use in combined modalities as salvage and frontline therapies is currently under investigation.Therapies targeting specific transcripts or leukemic cell surface antigens are major breakthroughs in the treatment of adults with ALL. The incorporation of new monoclonal antibodies and other targeted approaches into frontline regimens is showing promising results. If confirmed, such strategies may increase the cure rates in adults to levels achieved in pediatric ALL and reduce the need for intensive and prolonged chemotherapy.
HGG-03. PREVALENCE OF BIALLELIC MISMATCH REPAIR DEFICIENCY IN CHILDREN WITH MALIGNANT GLIOMA TREATED AT KING FAHAD MEDICAL CITY (KFMC)
Authors: Nahla Ali Mobark, Othman Mosleh, Amal Abd Al Samie Marie, Latifa AlMubara, Nada AlTassan, Cynthia Howakins, Faris Safaq Faris Safaq Alshammari, Fatimah Ibrahim Al-Huzaimi, Roba Ibrahim Aboabat, Fay Saad AlDossari, Ghaida Ali AlGhamdi, Ali Abdullah O Balbaid, Musa Al-Harbi, Malak Abedalthagafi
Journal: Neuro-Oncology (2018)

Hereditary Constitutional mismatch repair -deficiency (CMMR-D) caused by biallelic mutations in one or more MMR genes a cancer predisposition syndrome with features of neurofibromatosis type 1, often café-au-lait macule, development of different types of cancers in multiple organs. Given the high rate of consgunity in our population, we measure the prevalence of CMMR-D in our pediatric population with gliomas treated at our institution. We retrospectively analyzed demographic, immunohistochemistry, and molecular data for 31 cases diagnosed to have HGG and at KFMC between December 2006 and December 2016. Of the 31 patients (64.5 %) were boys and (35.5 %) girls. The median age at diagnosis was 11 years (range 2 - 17years). The most common pathological subtype was: Glioblastoma (58%) followed by Anaplastic Astrocytoma (19.4%). MMRD was observed in 19.4% of cases. There was no significant difference in the median survival time between MMR-D deficiency cases (1.78 years) and other cases (1.27 year). This is the first study to measure prevalence of CMMRD in Saudi Arabia which is known to have a high rate of consanguineous families. Our data showed around 20% of high grade glioma patients has CMMRD which is confirmed by two testing approaches: immunohistochemistry and molecular. In the era of immunotherapy, identifying CMMRD cases is critical as it opens new avenues for treatment options with check point inhibitors. Limitations in our study including small sample size and retrospective design and future prospective studies with larger sample size will be needed to confirm our results.
MBRS-04. INTERFERING WITH MEDULLOBLASTOMA METABOLISM TO IMPROVE CURRENT THERAPEUTIC AVENUES
Authors: Haydn S Munford, Daniel A Tennant, Andrew C Peet
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant brain tumour arising in paediatric patients. These young patients are typically subjected to harsh regimens of treatments such as chemotherapy and radiotherapy, with varying degrees of success. The stratification of patients has been steadily improving, where patient tumours can be divided into four main groups (WNT, SHH, group 3 and group 4), each having differing prognostic implications, but does not accurately predict response to treatment. Previous work on this cancer, through the use of magnetic resonance spectroscopy (MRS), has uncovered a link between high glutamate concentrations and poor patient survival. Cellular metabolism is now accepted as a hallmark of cancer biology, where tumours are able to reprogram aspects of their metabolism to aid the biosynthetic, bioenergetic and redox burdens associated with increased growth and treatment resistance. We have shown that the medulloblastoma cell lines (ONS-76, DAOY and UW228.3) are addicted to glutamine, which is a precursor metabolite to glutamate. Furthermore, we have elucidated the importance of glutamate in treatment resistance and show the significance of glutathione (GSH) synthesis in this disease model. GSH is a tripeptide consisting of glutamate, glycine and cysteine. Therefore, glutamate has a potent role in the production of GSH, where it can be directly and indirectly utilised. Our research, through RNA inhibition of glutaminase 1 and 2, and the chemical inhibition of the xCT transporter, has pinpointed this metabolism as a potential therapeutic target and a means of sensitising MB cells to chemotherapy and irradiation.
QOL-03. ADDING A PARENT TO THE BRAIN TUMOR TEAM: EVALUATING A PEER SUPPORT INTERVENTION FOR PARENTS OF CHILDREN WITH BRAIN TUMORS
Authors: Mary Nelson, Kathy Riley
Journal: Neuro-Oncology (2018)

Due to the physical and neurocognitive challenges that often result, childhood brain tumors present profound challenges to patients and families. To address these challenges, the California Chapter of the Pediatric Brain Tumor Foundation provides hospital-based support to parents of children with brain tumors from a Veteran Parent (VP). This mixed-methods, cross-sectional study was designed to evaluate the effectiveness of this intervention utilizing validated tools to compare parental resilience and impact of illness on the family between parents who met with the VP and those who did not. Additional qualitative data gleaned from focus groups with stakeholders (healthcare providers and parents) was analyzed using key constructs of Social Support theory. Although there were no significant differences in overall scores on the PedsQL™ Family Impact module or CD-RISC© between groups, parents in the intervention group scored better on items related to handling difficult decisions and painful feelings (p ≤ .02). Parents in both the English and the Spanish focus groups most frequently described support they received from the VP in terms of emotional and informational support. The social identity parents shared with the VP from their common life experiences also provided a safe environment for emotional and informational support. Results characterize the impact of peer parent support and elucidate parental need for emotional and instrumental support.
Allocation of Donor Livers for Transplantation
Authors: David A. Gerber, Prabhakar Baliga, Seth J. Karp
Journal: JAMA Surgery (2018)

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A Prospective, Randomized Multicenter Trial Comparing DoubleLayer and Polyethylene Stents for Malignant Distal Common Bile Duct Strictures
Authors: A. Tringali, M. Mutignani, V. Perri, G. Zuccalà, L. Cipolletta, M. Bianco, G. Rotondano, M. Philipper, B. Schumacher, H. Neuhaus, A. Schmit, J. Devière, G. Costamagna
Journal: Endoscopy (2003)

Background and Study Aims: Endoscopic biliary stenting is an established treatment for malignant obstructive jaundice. Stent clogging continues to be a major problem with plastic stents. The aim of this study was to carry out a prospective comparison of two stents with different materials and shapes: the Olympus DoubleLayer™ stent (DLS; perfluoro alkoxy, without sideholes) and the standard polyethylene (PE) stent (with sideholes). Patients and Methods: A total of 120 patients (70 women; mean age 71, range 36 - 91) with jaundice due to malignant strictures of the middle to distal third of the common bile duct were randomly assigned to receive either DLS (n = 60) or PE (n = 60) biliary stents. Patients with cholangitis, hemobilia, previous biliary drainage, hilar stricture, or ampullary cancer were excluded. Results: In all, 28 DLS patients (47 %) and 17 PE stent patients (29 %) died without clinical evidence of stent occlusion after a mean of 114 and 105 days, respectively (P < 0.05). Twenty-six DLS patients (43 %) and 38 PE stent patients (63 %) had symptoms of stent clogging after a mean of 144 and 99 days, respectively (P < 0.05). Stent dysfunction (stent orifice impacted on the bile duct or duodenal wall, stent migration) was recorded in six DLS patients (10 %) and five PE patients (8 %) (n. s.). Kaplan-Meier analysis of DLS and PE stent clogging-free survival showed a significantly longer patency period with the DLS stents (P = 0.0005) Conclusions: These results show that DoubleLayer stents have a longer patency period than PE stents. Patients who received PE stents had a higher risk of stent occlusion (relative risk 3.05; 95 % CI, 1.57 - 5.89) before death than DLS patients.
Abstract 18640: Recombinant Bone Morphogenetic Protein 9 is a Novel Therapeutic That Rescues Cardiac Fibrosis and Improves Cardiac Function in Heart Failure
Authors: Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Yali Zhang, Mark Aronovitz, Richard Karas, Navin K Kapur
Journal: Circulation (2016)

Cardiac fibrosis remains a significant target of therapy for patients with heart failure (HF). Bone morphogenetic protein 9 (BMP9) is a vascular quiescence factor that signals via the downstream effector, Smad1. No studies have explored a role for BMP9/Smad1 signaling in HF. We hypothesized that BMP9 limits cardiac fibrosis by promoting signaling via Smad1 in HF. We first determined that BMP9 protein levels are increased in the left ventricle (LV) of human subjects with HF compared to non-HF controls (n=8/group) and in male wild-type (WT) mice after 2 and 8 weeks of thoracic aortic constriction (TAC). Next, we tested BMP9-dependent regulation of TGFb1-induced Type I collagen synthesis in vitro using human cardiac fibroblasts (hCF). Compared to scrambled siRNA, silencing BMP9 increased collagen expression in hCF with or without TGFb1 stimulation. In contrast, rBMP9 treatment attenuated TGFb1 induced collagen synthesis by hCF in a dose-dependent manner. Compared to vehicle, recombinant BMP9 (rBMP9) increased pSmad1 and reduced pSmad3 levels after treatment with TGFb1. To explore a role for BMP9 in HF, we identified that, compared to WT, BMP9-/- mice exhibit a 4-fold increase in LV collagen expression after 2 weeks of TAC. We then tested whether treatment with rBMP9 rescues mice with established LV fibrosis. Male WT mice (n=40) were subject to 4 weeks of TAC. After 4 weeks of TAC, 20 mice survived to randomization to once daily rBMP9 or vehicle injections for an additional 4 weeks. Compared to Vehicle, rBMP9 treatment improved LV fractional shortening (p
Dynamics of the monoclonal antibodies (MABs) treatment rate and mortality rate in patients with metastatic colorectal cancer (mCRC) in Russia from 2013 to 2016
Authors: M. Fedyanin, H. Elsnukaeva, E. Polyanskaya, A. Popova, I. Pokataev, E. Ignatova, A. Bulanov, A. Tryakin, S. Tjulandin
Journal: Annals of Oncology (2018)

Introduction: Previously, we revealed inverse significant association between mortality rate from mCRC in 2014 and the irinotecan treatment rate in 2013 in Russian regions (Ann Oncol (2016) 27 (suppl 2): ii15). The aim of this study was to evaluate dynamics of penetration of different chemotherapy drugs and Mabs and mortality rate in a population of patients with mCRC across 82 regions of Russia from 2013 to 2016. Methods: We have compared the mortality rate for mCRC patients sourced by the National Russian State Cancer Register in and the Russian Government purchasing published data on hospital tenders for oxaliplatin, irinotecan, capecitabine and MABs (bevacizumab, cetuximab, panitumumab, aflibercept) at regional level across 82 regions within the period of 2013-2016. Given that the expected median overall survival for mCRC patients varies from 18 to 29 months, the correlation was explored between penetration recorded for 2013/2015 and mortality rate recorded for 2014/2016, accordantly. The penetration was defined as a number of mCRC patients that were enrolled on a particular drug treatment divided by the total number of patients suitable for the particular treatment. The mortality rate was defined as percentage of deaths among of all patients with CRC. Regression test was applied. Statistical analyses were performed using Statistical Package for the Social Sciences Version 22.0 (SPSS Inc., Chicago, IL). Results: We revealed the significant increase of mean number of patients who received chemotherapy in regions from 2013 to 2016: capecitabine (from 51.3 to 56.6, p < 0.01), oxaliplatin (from 67.2 to 88, p = 0.07) and irinotecan (from 31.3 to 45.1, p < 0.01). There was stable level of patients who received MABs from 2013 to 2016: bevacizumab (from 35.1 to 38.9, p = 0.3) and anti-EGFR antibodies (from 18.4 to 18.3, p = 0.2). According to the regression analysis the relationship of penetration for any MABs only (β=-0.09, 95%CI -0.16 - -0.018, p = 0.015) with the mortality decrease has been detected. There weren't any relationship between penetration and mortality rate for oxaliplatin (β=-0.06, 95%CI -0.14 - 0.025, p = 0.16), for irinotecan (β = 0.007, 95%CI -0.067 - 0.081, p = 0.85), for capecitabine (β=-0.037, 95%CI -0.12 - 0.046, p = 0.38), for bevacizumab (β=-0.15, 95%CI -0.12 - 0.024, p = 0.17), for cetuximab (β = 0.018, 95%CI -0.03 - 0.066, p = 0.36), for panitumumab (β=-0.017, 95%CI -0.033 - 0.062, p = 0.54) and for aflibercept (β = 0.046, 95%CI -0.034 - 0.127, p = 0.25). Conclusion: Emerging penetration for any Mabs in mCRC patients population appear to have a significantly correlation with the mortality reduction. Increase of chemotherapy use in the population of patients with mCRC from 2013 to 2015 led to significant effect of penetration of targeted therapy in 2015 on mortality in 2016 in Russia.
HGG-44. STRESSED TO DEATH: EGFRvIII EXPRESSION RENDERS GLIOBLASTOMA CELLS MORE SENSITIVE TO ER STRESS INDUCING CHEMOTHERAPEUTICS
Authors: Regina Graham, Katrina Kostenko, Ingrid Torrens, Nicolas De Cordoba, Melanie Freire, Fedeline Camile, Steven Vanni
Journal: Neuro-Oncology (2018)

Epidermal growth factor receptor (EGFR) is often overexpressed and/or mutated cancer. The most common mutation is EGFRvIII and has been found to correlate with tumor aggressiveness and poor outcome. In glioblastoma (GBM) expression of EGFRvIII is linked to cell-signaling pathways required for increased cell proliferation, cancer stem-cell self-renewal and tumor invasiveness. Although the mechanisms by which EGFRvIII confers increased tumorigenecity are not fully understood, recent evidence suggests that endoplasmic reticulum (ER) proteostasis plays a key role in tumor aggressiveness and resistance to therapy. Here we sought to determine the role of EGFRvIII expression on GBM ER stressed-induced cell death. U87 and U87 EGFRviii expressing cells were exposed to the following ER stress inducers: 2-deoxy-D-glucose (2-DG, 0.5mM), velcade (10nM), tunicamycin (0.05ug/ml) or withaferin A (WA, 1uM) and viability determined by MTS assay. EGFRvIII expressing cells were approximately 2-fold more sensitive to these ER stress inducers; viability of 2-DG, velcade, tunicamycin and WA treated U87 cells was 71.1 + 3.6%, 92.5 + 2.7%, 55.3 + 3.8% and 77.2 + 6%, respectfully, verses 24.5 + 1.1%, 46.8 + 3, 22.7 + 2.1% and 19.5%, respectfully in EGFRvIII expressing U87 cells. Western blot analysis demonstrated higher levels of ER stress markers, GRP78 and CHOP. Effective mediation of ER stress is necessary for cancer cells to maintain uncontrolled growth and enhanced protein production. However this dependence provides a target for treatment intervention. Our data suggests that patients whose tumors express EGFRvIII may benefit from ER stress inducing chemotherapies.