tbuckley/cabot-search huggingface dataset:
A phase 1b dose-escalation study of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor, in combination with cisplatin in patients with advanced cancer.
Authors: Manish R. Patel, David S. Hong, Johanna C. Bendell, Suzanne Fields Jones, Erika Paige Hamilton, Vivek Subbiah, Daniel D. Karp, Judy Sing-Zan Wang, Raid Aljumaily, Scott Hynes, Rod Decker, Michele Niland, Xuejing Aimee Wang, Aimee K. Lin, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2018)

2579 Background: CHK1 is a key kinase for DNA replication and repair. Prexasertib, a CHK1 inhibitor, enhanced the nonclinical activity of cisplatin and is predicted to potentiate the clinical activity of DNA-damaging agents like cisplatin. Methods: This Phase 1b study in patients (pts) with advanced cancer assessed escalating doses of prexasertib with 75 mg/m2 cisplatin by IV infusion every 21 days, and had 3 parts: Part A, prexasertib (20 - 70 mg/m2)/cisplatin given on Day 1; Part A2, prexasertib (40 - 105 mg/m2)/cisplatin on Day 1 with prophylactic G-CSF starting on Day 2; Part A3, cisplatin on Day 1 and prexasertib (40 - 90 mg/m2) on Day 2. Safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), preliminary efficacy, and prexasertib pharmacokinetics (PK) are reported. Results: 57 pts were enrolled (Part A: n = 14; A2: n = 24; A3: n = 19). Study treatment-related common adverse events (AEs) were leukopenia/neutropenia (68%; G4 49%), thrombocytopenia (63%; G4 33%), anemia (46%), nausea (44%), fatigue (32%), and vomiting (23%). 4 pts (7%) experienced febrile neutropenia (2 each in Parts A and A2). The nature of AEs was comparable between Parts. All DLTs were either febrile neutropenia or neutropenia > 5 days. The MTD for Parts A, A2, and A3 were 40, 90, and 80 mg/m2, respectively. The prexasertib PK profile was consistent with the prexasertib monotherapy PK profile across all doses/schedules. In Part A, 3 pts (21%) achieved a partial response (PR: anal squamous cell carcinoma [SCC]; HNSCC; small cell lung cancer [SCLC]), and 2 pts (14%) had stable disease (SD). In Part A2, 12 pts (50%) had SD but no PR/CR. In Part A3, 1 pt (5%) achieved a CR (cholangiocarcinoma) and 2 pts (11%) achieved a PR (SCLC; follicular dendritic cell sarcoma) for a CR/PR rate of 16%; 7 pts (37%) had SD. Of the 6 pts with a CR/PR, 3 pts (at prexasertib doses: 45-90 mg/m2) had previously received prior platinum. None had an objective response to the prior platinum. Conclusions: Prexasertib and cisplatin demonstrated acceptable safety and PK and preliminary evidence of anticancer activity. A dose of 80 mg/m2 prexasertib given 24 h after cisplatin was selected for further study in the ongoing dose expansion. Clinical trial information: NCT02124148.
Overcoming Acquired PD-1/PD-L1 Resistance with CD38 Blockade
Authors: Deepak Mittal, Dipti Vijayan, Mark J. Smyth
Journal: Cancer Discovery (2018)

Abstract Summary: Overexpression of CD38 after PD-1/PD-L1 blockade increases extracellular adenosine levels and may contribute to acquired resistance to anti–PD-1/PD-L1 therapy. Cancer Discov; 8(9); 1066–8. ©2018 AACR. See related article by Chen et al., p. 1156.
A phase III randomized controlled trial of secondary surgical cytoreduction (SSC) followed by platinum-based combination chemotherapy (PBC), with or without bevacizumab (B) in platinum-sensitive, recurrent ovarian cancer (PSOC): A NRG Oncology/Gynecologic Oncology Group (GOG) study.
Authors: Robert L. Coleman, Danielle Enserro, Nick Spirtos, Thomas J. Herzog, Paul Sabbatini, Deborah Kay Armstrong, Byoung Kim, Keiichi Fujiwara, Joan L. Walker, Patrick J. Flynn, Angeles Alvarez Secord, David E. Cohn, Mark F. Brady, Robert S. Mannel
Journal: Journal of Clinical Oncology (2018)

5501 Background: GOG-0213 is an international, open-label, randomized phase 3 trial in women with PSOC with two objectives: 1) to study the addition of B to paclitaxel/carboplatin concurrently and as maintenance; and 2) to evaluate the impact of SSC. The primary endpoint is overall survival (OS). We previously reported the results of Objective 1 [HR 0.829; 95% CI: 0.683-1.005; p = 0.056) Coleman RL, et al Lancet Oncol 2017], and now report the outcomes of Objective 2. Methods: From Dec-2007 until Jun-2017, 485 women with investigator-determined resectable PSOC were randomized 1:1 to SSC followed by PBC (n = 240) or PBC alone (n = 245). Stratification factors included the platinum-free interval (PFI). Surgical candidacy was predicated on the likelihood to achieve complete resection (R0). For Objective 2, the use of B was investigator's choice. The primary endpoint reached maturity for a pre-specified interim analysis in Nov-2017. Results are based on 2-sided alpha = 0.05. Results: 215/240 (90%) evaluable patients who were randomized to SSC underwent the procedure. R0 was achieved in 63%. Adjuvant B was common (84%). Median follow-up duration is 34.6 mos. The HR for death (SSC vs. none) is 1.28 (95%CI: 0.92-1.79) corresponding to a median OS of 53.6 mos vs. 65.7 mos, respectively. There is a significantly different effect of SCC on OS in those receiving PBC+B vs. those who did not (p = 0.022). The HR for death (SCC vs. none) among 77 patients receiving PBC is 2.18 (95% CI: 0.86 – 5.51), while the HR for death among 408 patients receiving PBC+B is 1.03 (95% CI: 0.57 – 1.88). The median progression-free survival was 18.2 mos in the SSC cohort vs.16.5 mos without SCC, HR: 0.88 (95% CI: 0.70 – 1.11). One patient died due to complications from SSC. No new safety signals were observed. Conclusions: SSC can be safely performed in patients with PSOC, but did not improve OS in this population. Additional analyses (e.g. impact of PFI, SSC outcome, disease burden and chemotherapy regimen on OS by SSC allocation) are underway and will be presented. Clinical trial information: NCT00565851.
Molecular diversity and biennial circulation of enterovirus D68: a systematic screening study in Lyon, France, 2010 to 2016
Authors: Rolf Kramer, Marina Sabatier, Thierry Wirth, Maxime Pichon, Bruno Lina, Isabelle Schuffenecker, Laurence Josset
Journal: Eurosurveillance (2018)

BackgroundUnderstanding enterovirus D68 (EV-D68) circulation patterns as well as risk factors for severe respiratory and neurological illness is important for developing preventive strategies. Methods: Between 2010 and 2016, 11,132 respiratory specimens from hospitalised patients in Lyon, France, were screened for EV-D68 by PCR. Phylogenetic relationships of the viral-protein-1 sequences were reconstructed using maximum-likelihood and Bayesian-Markov-Chain-Monte-Carlo approaches. Results: Overall, 171 infections with a biennial pattern were detected, including seven, one, 55, none, 42, one and 65 cases annually during 2010-16. Children (< 16 years-old; n = 150) were mostly affected and 71% (n = 121) of the total patients were under 5 years-old. In 146 patients with medical reviews, 73% (n = 107) presented with acute respiratory distress. Among paediatric patients with medical reviews (n = 133), 55% (n=73) had an asthma/wheezing history, while among adults (n = 13), 11 had underlying diseases. In total, 45 patients had severe infections and 28 patients needed intensive care unit stays. No acute flaccid myelitis (AFM) was detected. We found genotypes A, B1, B2 B3 and D circulating, and no associations between these and clinical presentations. During the study, new genotypes continuously emerged, being replaced over time. We estimated that ancestors of currently circulating genotypes emerged in the late-1990s to 2010. Rises of the EV-D68 effective population size in Lyon coincided with infection upsurges. Phylogenetic analyses showed ongoing diversification of EV-D68 worldwide, coinciding with more infections in recent years and increases of reported AFM paediatric cases. Conclusions: Reinforcement of diagnostic capacities and clinical-based surveillance of EV-D68 infections is needed in Europe to assess the EV-D68 burden.
Survival in right-sided versus left-sided stage IB-IIIA non-small cell lung cancer patients.
Authors: Ziping Wang, Yixiang Zhu, Lu Yang, Xiaoyu Zhai, Qiwen Zheng
Journal: Journal of Clinical Oncology (2018)

e20509 Background: Previous data suggested that right- versus left-sided cancer location was not an independent prognostic factor for long-term survival in lung cancer. However, few studies reported whether location of the disease (left-sided versus right-sided) impacted on disease-free survival (DFS) for non–small cell lung cancer (NSCLC) in Chinese populations. We aimed to explore the issue with propensity score matching (PSM). Methods: Patients with resected stage IB to stage IIIA NSCLC were identified. Patients were categorized into two groups according to the primary tumor location. Survival analysis was performed using Kaplan–Meier estimates and log-rank tests, and both univariable and multivariable Cox regression, as well as PSM were used. Results: A total of 862 resected stage IB to IIIA NSCLC patients with postoperative adjuvant chemotherapy (ACT) met our criteria for analyses. Of them, 485 patients (56.3%) with right-sided lung cancer, and other 377 (43.7%) with left-sided location. After PSM was processed, 596 patients were included and well matched by a 1:1 ratio according to the location. Patients with right-sided malignance had longer DFS than left-sided both prior (25.7 months [95% confidence interval [CI] 22.6 to 35.0] vs. 20.4 months [95% CI 17.9 to 24.3], P = 0.009) and after PSM (28.9 months [95% CI 22.6 to 42.8] vs. 20.9 months [95% CI 17.9 to 25.9], P = 0.014). Conclusions: Our results based on the real-world analysis in Chinese NSCLC patients provided evidence that right-sided lung cancer was associated with a significant longer disease-free survival than for left-sided disease.
Advanced basal cell cancer: concise review of molecular characteristics and novel targeted and immune therapeutics
Authors: M. Nikanjam, P.R. Cohen, S. Kato, J.K. Sicklick, R. Kurzrock
Journal: Annals of Oncology (2018)

Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028%-0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small-molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency and the Food and Drug Administration have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.
Whole exome sequencing (WES) to define the genomic landscape of young lung cancer patients (pts).
Authors: Xiaoliang Wu, Yanwen Chen, Lin Zhu, Eleni Stylianou, Jill Barnholtz-Sloan, Zhenfeng Zhang, Patrick C. Ma
Journal: Journal of Clinical Oncology (2018)

12005Background: Previous studies have identified specific genomic driver alterations in non-small cell lung cancer (NSCLC). However, the causative molecular mechanisms that underlie the pathogenes...
TSNAdb: A Database for Tumor-Specific Neoantigens from Immunogenomics Data Analysis
Authors: Jingcheng Wu, Wenyi Zhao, Binbin Zhou, Zhixi Su, Xun Gu, Zhan Zhou, Shuqing Chen
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database (TSNAdb v1.0), based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen (HLA) allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA). We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients, which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy. TSNAdb is freely available at http://biopharm.zju.edu.cn/tsnadb.
Extensive safety profile of inotuzumab ozogamicin (InO) in relapsed/refractory acute lymphoblastic leukemia (ALL) patients enrolled in the phase 3 INO-VATE trial.
Authors: Ryan Daniel Cassaday, Daniel J. DeAngelo, Giovanni Martinelli, Wendy Stock, Matthias Stelljes, Nicola Gökbuget, Anjali S. Advani, Susan Mary O'Brien, Michaela Liedtke, Akil Abid Merchant, Tao Wang, Erik Vandendries, David I. Marks, Elias Jabbour, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2018)

7029 Background: In INO-VATE, patients (pts) treated with InO vs standard chemotherapy (SC) had significantly greater remission rates and longer overall survival (OS), with 23% reduced risk of death (Kantarjian et al, NEJM 2016). Here we report detailed safety outcomes from long-term follow-up. Methods: Study methods were previously published. Adults with CD22+ ALL in 1st or 2nd salvage were randomized 1:1 to InO (n = 164) or SC (n = 162). Data up to Jan 4, 2017 are reported. Results: Adverse event (AE) and serious AE rates were similar between arms even though more cycles of InO than SC were administered (Table). Grade (Gr) 3-4 AE rates were higher with SC, while more Gr 5 AEs occurred with InO vs SC (6% vs 2%); 5 cases (3%) were veno-occlusive disease (VOD). More pts taking InO discontinued due to AEs, most often from infections (10 [6%]) including pneumonia and sepsis, hepatobiliary disorders (7 [4%]), or blood/lymphatic disorders (BLD) including cytopenias (5 [3%]). For SC, discontinuations were most often from infections (6 [4%]) or BLD (3 [2%]). More hepatic AEs (any Gr) occurred with InO: 83 (51%) vs 52 (36%), including VOD (23 [14%] vs 3 [2%]). A lower percentage of death was seen with InO: 131 (80%) vs 126 (88%) for SC. Fewer InO pts died from ALL: 80 (49%) vs 100 (70%) for SC. Clinical trial information: NCT01564784. Conclusions: Safety data from the final report of INO-VATE are consistent with previous reports of data that also include greater efficacy (longer survival) seen with InO vs SC. Temporary discontinuation and dose reduction of InO were used to manage serious or severe AEs. Data suggest vigilant monitoring, treatment, and/or prevention for the most common events such as VOD and infections are needed to optimize outcomes. Treatment-emergent AEs (TEAEs) Treatment-related TEAEs InO (n = 164) SC (n = 143) InO (n = 164) SC (n = 143) Total AEs 2023 2112 764 980 Pts with AEs, n (%) 163 (99) 143 (100) 144 (88) 130 (91) Serious AEs 85 (52) 72 (50) 52 (32) 42 (29) Gr 3-4 AEs 147 (90) 138 (97) 114 (70) 114 (80) Gr 5 AEs 26 (16) 16 (11) 9 (6) 3 (2) Post AE, n (%): Discontinued 31 (19) 11 (8) 15 (9) 6 (4) Dose reduced 5 (3) 3 (2) 4 (2) 1 (1) Temporary discontinuation 72 (44) 17 (12) 51 (31) 12 (8) Temporary discontinuation + dose reduced 3 (2) 1 (1) 3 (2) 0
I<i>n situ</i> anti-cancer agent derived from [<sup>188</sup>re]rhenium nitro-imidazole ligand loaded poly-l-lysine dendrimer administrated by direct CT guided stereotactic intrahepatic injection.
Authors: Hafid Belhadj-Tahar, Aiping Chen, Yongshi Jia, Shuqiang Wu, Nouredine Sadeg, Haitao Zhao, Caixin Li, Guxingjian Gu, Yong Gao, Guanghua Yang
Journal: Journal of Clinical Oncology (2018)

e15569 Background: Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death worldwide. Patients with metastatic disease to distant organs have an expected 5-year overall survival rate of only 12%. Consequently, there is a clinical need for advances in loco-regional treatments in patients with advanced stage. In this abstract we report the first human administration of "IMDENDRIM" an experimental In situ anticancer treatment of solid tumors non responding to conventional therapy. Methods: The experiment agent "ImDendrim" used in this study is consisting of poly-L-lysine dendrimer as nanovector mixed with complex of 188Rhenium- ligand (nitro-imidazole-methyl-1,2,3-triazol-methyl-di-[2-pycolyl] amine). Protocol (NCT03255343) was carried out in accordance with the strict ethical requirements . The response to treatment was evaluated thanks to quantitative standardized uptake values (SUVs) from [18F]-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Eligible Patient : a 50-year old man, with stage IV adenocarcinoma of the descending colon, was received adjuvant chemotherapy (XELOX) in six courses. During the course of chemotherapy, he developed intestinal occlusion required a surgical resection and a subtotal colectomy followed by FOLFIRI. However, his condition did not improve with chemotherapy. The CT Scan indicated multiple small metastases in lung and two in liver (5 and 7 cm in diameter). The patient was eligible for inclusion of clinical trial and received 50mCi (1850MBq) of ImDendrim by direct CT guided stereotactic intrahepatic injection. Results: There were no complications post-administration and the patient was discharged after 1 week post treatment and followed up regularly. After 30 days, the decrease of SUVs was observed with a pre-/post-treatment ratio of 1.7 (Drop in FDG uptake of 60%) , in presence of large tumoral volume necrosis. The patient was considered as good responder. Conclusions: These preliminary results highlight the safety of the Imdendrim as well as its effectiveness. the clinical trial is currently in progress. Clinical trial information: NCT03255343.
Abstract B006: Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk
Authors: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins
Journal: Cancer Research (2018)

Abstract Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression. Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.
Analysis of tumor-infiltrating immune cells in gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor therapy.
Authors: Peter Hohenberger, Wenyi Zhao, Maria Deligianni, Katia Simon-Keller, Hui Cao, Alexander Marx
Journal: Journal of Clinical Oncology (2017)

11042 Background: There is initial evidence that immune-infiltrates of tumor may correlate with the clinical course of patients with GIST beyond the response to tyrosine kinase inhibitors (TKI) according to the mutational status. We were interested to analyze the composition of tumor-infiltrating immune cells in GIST tumor tissues after different TKI regimens vs untreated controls. Methods: From 40 GIST patients who were treated with imatinib alone (neoadjuvant group) and other TKIs (M1 HEP group, progressing on more than ≥2 TKI inhibitors) prior to tumor removal, surgical specimens were available at ten 10 cases each,. They were compared with 20 untreated primary tumors graded for malignant behaviour (low vs high risk ) acc. to Miettinen&amp;Lasota 2006. 2-μm sections of formalin-fixed, paraffin-embedded tissue samples were used for IHC-staining anti-CD68 (Dako); anti-CD11c, anti-CD11b, anti-FOXP3 (all Abcam); anti-CD163, anti-CD4 , anti-CD8 (all Leica). Evaluation was performed with Dako REAL EnVision Detection System (K5007). The phenotypes of immune cells were compared in the defined GIST groups. In the neoadjuvant group we used recurrence-free survival (RFS) for correlation, and overall survival (OS) after TKI failure in the M1 HEP group. Results: Foxp3+ Tregs, CD163+ M2 macrophages and CD11b+ myeloid cells are significantly higher in TKI resistance or neoadjuvant (viable cells &gt; 30%) tissues compared with neoadjuvant (viable cells &lt; 10%) cases. The rate of CD11c+ M1 macrophages is higher in low-risk GISTs compared to high risk GISTs, but CD11b+ myeloid cells are exactly the opposite. Kaplan-Meier curves show high CD163+ M2 macrophages or CD11b+ myeloid cells to correlate significantly with worse RFS in after neoadjuvant IM (p 0.01). In the TKI resistant condition, patients with high CD11c+ M1 macrophages show better median OS (p = 0.07, ns). Conclusions: Our study reveals dynamic changes of tumor-infiltrating immune cell protagonists in GISTs after different TKI therapeutic regimen and after neoadjuvant treatment. We could not detect a different immune infiltrate in untreated primary tumors of different risk categories.