tbuckley/cabot-search huggingface dataset:
A phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma.
Authors: Narayan Adhikari, Ahitagni Biswas, Ajay Gogia, Ranjit Sahoo, Ajay Garg, Ashima Nehra, Mehar C Sharma, Suman Bhasker, Manmohan Singh, Sreenivas Vishnubhatla, Rohan Chawla, Garima Joshi, Lalit Kumar, Subhash Chander
Journal: Journal of Clinical Oncology (2018)

e14088 Background: The treatment of primary CNS lymphoma(PCNSL) comprises high dose Methotrexate(HDMTX) based chemotherapy followed by whole brain radiotherapy(WBRT), major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in patients with PCNSL. Methods: We screened 35 patients & enrolled 24 patients with PCNSL in a phase II trial. They underwent 5 two-weekly cycles of MVP chemotherapy with HDMTX, Vincristine & Procarbazine. Rituximab was added in 16 patients as per their preference & affordability. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4Gy/13fractions/2.5weeks while those with partial response(PR), stable or progressive disease(PD) were given standard dose WBRT 45Gy/25fractions/5 weeks. Thereafter 2 cycles of consolidation chemotherapy with Cytarabine was given. The primary endpoints of the study were assessment of response rate & progression free survival(PFS). The secondary endpoints were assessment of overall survival(OS), toxicity profile, serial changes in quality of life & neuropsychological parameters. Results: The median age at diagnosis was 50 years. Out of 20 patients who completed induction chemotherapy, 10(50%) achieved CR, 9(45%) had PR & 1 patient had PD. After a median follow-up period of 15.05 months, the estimated median OS was 24.2 months. The median PFS had not been reached. The actuarial rates of 2 year PFS & OS were 61.8% & 54.8% respectively. 4 patients in reduced dose WBRT arm had recurrence & 2 of them died of PD, whereas there was no recurrence or cancer related death in standard dose WBRT arm. On univariate analysis of PFS, age≤60 years(p = 0.004) & use of standard dose WBRT (p = 0.04) led to significantly improved outcome. Serial neuropsychological assessments showed marked improvement in general cognition, verbal fluency & motor speed after induction chemotherapy & treatment completion. Conclusions: In patients with newly diagnosed PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression & early death. Clinical trial information: ctri/2015/10/006268.
Identification of genes associated resistance of everolimus in cutaneous squamous cell carcinoma.
Authors: Jonggwon Choi
Journal: Journal of Clinical Oncology (2018)

e24208 Background: mTOR inhibitor is found to be effective treatments option for immunosuppressive patients with metastatic squamous cell carcinoma. The exact mechanism of mTOR signaling pathway in squamous cell carcinoma have not yet been identified. In this study, we aimed to find out the gene associated with mTOR inhibitor in skin squamous cell carcinoma. Methods: Skin squamous cell carcinoma (SCC) (A431 and HSC-1) obtained from the American Type Culture Collection (ATCC) and Japanese Collection of Research Bioresources (JCRB) Cell Bank (Osaka, Japan), respectively. For determinate gene profiling, A431 and HSC-1 cells were treated with DMSO or 100 nM everolimus for 72 h. The Affymetrix whole transcript expression array process was executed according to the manufacturer's protocol. We exported the result with gene level RMA analysis and performed the differentially expressed gene (DEG) analysis. For identification of gene-network associated with resistance of everolimus in SCC cells, pathway analysis was generated by using Ingenuity pathway analysis tool. Total RNA was extracted using TRI reagent® (Ambion) and then cDNAs were synthesized using M-MLV Reverse Transcriptase (Promega) according to the manufacturer’s instructions, respectively. qRT-PCR reaction was carried out in triplicate using iQ™ SYBR-Green Supermix and a CFX96 qPCR machine (BioRad). Results: In MTT assay, The effects of cell death according to the mTOR inhibitor concentration appeared well in the HSC-1 cell line. The other hand, mTOR inhibitor did not show effective cytotoxic activity in A431 cell line. Western blot analysis showed, p-mTOR concentration was diminished depend on everolimus concentration in HSC-1 cell line. In microarray, MYC / CCND 1 / TP73 / NUPR1 / SBD / ErBB / CDKN2B genes were related with resistance of mTOR inhibitor. Ingenuity pathway analysis showed, CCND1 gene overexpression is most closely related to mTOR inhibitor resistance. Conclusions: We identified resistance gene of mTOR inhibitor, and our findings help to select target therapy in skin squamous cell carcinoma. In the future, it will be necessary to find a driver mutation that is more effective for the mTOR inhibitor.
Patterns of PD-1, PD-L1 and PD-L2 expression in pediatric solid tumors.
Authors: Navin R. Pinto, Julie R. Park, Erin Murphy, Jennifer Yearley, Terri McClanahan, Lakshmanan Annamalai, Douglas S. Hawkins, Erin R. Rudzinski
Journal: Journal of Clinical Oncology (2016)

10561 Background: Significant anti-tumor effects have been observed in a variety of malignancies via blockade of immune checkpoints, leading to T-cell-mediated killing of cancer cells. Interaction of PD-1 with its ligands PD-L1 and PD-L2 serves to suppress T-cell function and restrict immune-mediated tumor killing. We sought to examine the pattern of expression of these proteins in children with solid tumors [Ewing sarcoma(ES), neuroblastoma(NB), osteosarcoma(OS), Wilms tumor(WT) and rhabdomyosarcoma(RM)], as expression of these proteins may serve as biomarkers of response. Methods: Sections cut from formalin fixed paraffin embedded (FFPE) tissue blocks were processed and evaluated for PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC) as well as by mRNA expression. A semi-quantitative 0-5 IHC scoring system (0 = negative, 1 = rare, 2 = low, 3 = moderate, 4 = high, 5 = very high) was applied, with scores incorporating combined prevalence of tumor cell and non-tumor cell labeling. Expression profiling was performed using the NanoString nCounter system according to manufacturers’ recommendations.Data analysis was performed using quantile normalization in which relative ranks of genes (across all genes on the Nanostring codeset) within each sample were replaced by values having the same relative rank from the pooled distribution (from all samples and genes in the dataset). All quantile normalized data underwent subsequent log10 transformation. Results: 124 FFPE blocks were included in the analysis (ES = 20, NB = 31, OS = 25, WT = 25, RMS = 23) . PD-1, PD-L1 and PD-L2 IHC were not evaluable in 8, 0 and 12 blocks, respectively. PD-1, PDL-1 and PDL-2 expression was negative to moderate by both IHC (range 0-3.5) and mRNA expression (range 0-2.62). Correlation between IHC score and mRNA expression was poor for all three tested proteins (PD-1 r2 = 0.06, PDL-1 r2 = 0.007 and PDL-2 r2= 0.15). Conclusions: Expression of PD-1, PD-L1 and PD-L2 is low in pediatric solid tumors. At low levels of expression, IHC score and mRNA expression correlate poorly.
Immune-related gene expression deficit of leukemia stem cells (LSC) in AML.
Authors: Kamal Chamoun, Christopher Brent Benton, Ahmed AlRawi, Rodrigo Jacamo, Patrick Williams, Feng Wang, Jianhua Zhang, Naval Guastad Daver, Guillermo Garcia-Manero, Hagop M. Kantarjian, Andrew Futreal, Michael Andreeff
Journal: Journal of Clinical Oncology (2017)

7011 Background: AML LSC are believed to be responsible for residual and resistant leukemic disease leading to relapse. Understanding differences between bulk AML and the LSC subpopulation may allow the identification of novel LSC targets, especially for the most adverse risk AML where few patients are cured. Targeting LSC may be needed to eradicate AML, and immune-based therapies provide an approach for eliminating LSC. The transcriptional landscape of immune-related genes in LSC is not well understood. Methods: Samples were collected at diagnosis from 12 patients with high-risk AML prior to therapy. Bulk (CD45-dim blasts) and LSC (Lin-CD34+CD38-CD123+) AML marrow cells were FACS-sorted and analyzed using whole genome RNA-sequencing. Transcriptomes were analyzed using AltAnalyze software to identify differentially expressed genes in bulk AML cells and in AML LSC populations. These genes were further assessed by gene enrichment analysis using data from Gene Ontology (GO) and the Cancer Genome Atlas Project (CGAP). Results: Sixty-eight genes were identified with greater than 3-fold differential expression between bulk AML and LSC. GO enrichment analysis demonstrated more than 10-fold enrichment of genes involved in the molecular functions, biologic processes, and cell components related to the antigen presentation pathway, with the comparative down-regulation occurring in LSC. Among the top differentially expressed gene clusters, both the MHC class II and interferon-gamma signaling/response pathway gene expression was blunted in LSC. Additional expression analysis revealed that 42% of a CGAP-curated list of 201 antigen-processing and -presentation genes had significantly decreased expression in the LSC subpopulation compared to bulk AML. Conclusions: LSC from primary AML patient samples are characterized by reduction in expression of MHC class II receptor and antigen presentation genes compared to bulk AML. These results suggest that impairment in the presentation and/or processing of tumor associated antigens by MHC class II on LSC, along with tonic sponging of immune response cells and diversion away from LSC by bulk AML, may contribute to LSC evasion of immune surveillance and response.
Adapting a prescreening program to match molecular alterations in over 5,000 patients’ tumors with targeted agents and immunotherapies in early clinical trials over the last 8 years
Authors: S. Aguilar, A. Vivancos, P. Nuciforo, C. Viaplana, F. Ruiz-Pace, E. Sanchez, J. Rodon, J. Tabernero, E. Garralda, R. Dienstmann
Journal: Annals of Oncology (2018)

Background: Since 2010, when the Molecular Prescreening Program (MPP) was established at VHIO, we have adapted the techniques and procedures to improve the identification of genomic alterations in tumors from patients (pts) eligible to Early Clinical Trials (ECTs). Here we report the clinical utility of our program given the evolving molecular testing landscape and trends in drug development. Methods: In the last 8 years, 5,775 formalin fixed paraffin embedded tumor samples were analyzed: from 2010 to 2014 we used a hotspot mutation panel (Sequenom, 20 oncogenes) plus FISH/IHC of selected markers; from 2015 to 2017 we moved to a custom amplicon-based NGS panel (MiSeq, 61 genes), a copy number (CN) panel (Nanostring, 44 genes) and a fusion + gene expression (exp) panel (Nanostring, 26 genes) with additional FISH/IHC in selected cases, including PDL1 and MSI status. Results: We found a stepwise increase in the MPP, from 207 pts in 2010 to 1168 pts in 2017. Most common tumors were colorectal, lung, breast, gynecologic, pancreatobiliary, head & neck and gastric. In the last 8 years, the number of ECTs increased tenfold: from 13 in 2010 (11 PI3K inhibitor [inh]) to 137 in 2017 (including 55 immunotherapy [IMT], 11 RAF/MEK/ERK inh, 9 FGFR inh, 8 PI3K inh, 6 EGFR/HER2 inh and 6 antibody-drug conjugates). Inclusion rate in ECTs with targeted agents reduced from 2016 to 2017 (228 to 133), while IMT trial recruitment increased (179 to 245). In 2017, 862 tumors had NGS, 708 tested with IHC, 267 CN panel and 342 fusion + exp assay. As a result of this molecular profiling, 116 pts (10%) were enrolled in ETCs with 18 diffent biomarker matches (5.5% mandatory, 4.5% enrichment) and 220 pts (19%) were recruited in unmatched trials. Conclusions: The MPP at VHIO is constantly adapting to the needs of our ECTs portfolio. Biomarker matched trials evolved from a "few targets/ large populations" scenario to a complex situation with "many targets/ small populations". Moreover, the substantial increase of IMT trials had a major impact in trial prioritization, and will guide clinical implementation of new markers currently under development, such as tumor mutational load and inflammatory gene exp signatures. Legal entity responsible for the study: Vall d'Hebron Institute of Oncology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Phase III study comparing triplet chemotherapy with S-1 and cisplatin plus docetaxel versus doublet chemotherapy with S-1 and cisplatin for advanced gastric cancer (JCOG1013).
Authors: Yasuhide Yamada, Narikazu Boku, Junki Mizusawa, Satoru Iwasa, Shigenori Kadowaki, Norisuke Nakayama, Mizutomo Azuma, Takeshi Sakamoto, Kohei Shitara, Tatsuya Okuno, Keisho Chin, Akira Nozaki, Masaki Nakamura, Hiroki Hara, Hiroshi Katayama, Haruhiko Fukuda, Takaki Yoshikawa, Takeshi Sano, Mitsuru Sasako, Masanori Terashima
Journal: Journal of Clinical Oncology (2018)

4009 Background: Doublet chemotherapy with S-1 and cisplatin (CS) is one of the standard first-line chemotherapy for advanced gastric cancer in Japan. Triplet chemotherapy with docetaxel added to CS (DCS) showed a promising activity associated with feasible toxicities in a phase II study. We conducted a phase III study, JCOG1013, to investigate whether DCS improved overall survival (OS) compared with CS. Methods: Patients with previously untreated, human epidermal growth factor receptor 2 negative or unknown, unresectable or recurrent gastric adenocarcinoma, performance status 0 to 1, and adequate organ function were eligible. They were randomly 1:1 assigned to receive CS (S-1 40-60 mg orally twice a day for 3 weeks, cisplatin 60 mg/m2 on day 8, repeated every 5 weeks), or DCS (docetaxel 40 mg/m2, cisplatin 60 mg/m2 on day 1, S-1 40-60 mg orally twice a day for 2 weeks, repeated every 4 weeks). The primary endpoint was OS. A total of 740 patients were required to detect an increase in median OS from 13.5 months in the CS arm to 16.5 months in the DCS arm, corresponding to a hazard ratio (HR) of 0.8435, with a one-sided alpha of 5% and power of 80%. Results: From Apr 2012 to Mar 2016, 741 patients were enrolled in total (CS 371, DCS 370). Median OS was 14.2 and 15.3 months for DCS and CS, respectively (HR 0.99; 95% confidence interval [CI] 0.85-1.16; one-sided stratified log-rank p = 0.47). By histological subtypes, median OS was 13.3 months for DCS and 14.2 months for CS (p = 0.83) in the diffuse type (n = 482), and 17.5 months for both DCS and CS (p = 0.65) in the intestinal type (n = 259). Median progression-free survival was 7.4 months for DCS and 6.5 months for CS (HR 0.99; 95% CI, 0.86-1.15; p = 0.92). The overall response rate was 59.3% for DCS and 56.0% for CS (p = 0.50). The most common adverse events of grade 3 or 4 were neutropenia (DCS 58.5%, CS 32.1%), febrile neutropenia (DCS 7.6%, CS 5.7%), and diarrhea (DCS 7.0%, CS 7.4%). Conclusions: Addition of docetaxel to CS failed to improve OS of patients with untreated advanced gastric cancer. Therefore, CS remains the standard treatment for first-line chemotherapy for advanced gastric cancer. Clinical trial information: UMIN000007652.
A first-in-human study of monoclonal antibody GM102 in patients with anti-Mullerian-hormone-receptor II (AMHRII) positive gynecological cancers.
Authors: Alexandra Leary, Philippe Georges Aftimos, Jean-Pierre Delord, Christophe Le Tourneau, Isabelle Laure Ray-Coquard, Christiane Jungels, Andrea I. Varga, Francesco Ricci, Carlos Alberto Gomez-Roca, Guillaume Bataillon, Nathalie Van Acker, Grégory Noël, Olivier Lantz, Lydie Cassard, Agnès Coste, Bérengère Jean, Isabelle Marie Tabah-Fisch, Anne Vincent- Salomon, Jean-François Prost, Ahmad Awada
Journal: Journal of Clinical Oncology (2018)

5542 Background: AMH and its membrane receptor AMHRII induce regression of Müllerian ducts in the male embryo. AMHRII is constitutively expressed in ovarian granulosa tumors (GCT) and re-expressed in ~70% of gynecological tumors. GM102, a low-fucose IgG1 antibody, binds AMHRII and acts through macrophage engagement via CD16 high affinity binding, resulting in enhanced tumor phagocytosis. Methods: In the completed escalation part, AMHRII-positive ovarian, cervical and endometrial cancer patients (pts), with measurable disease, Performance Status ≤1 and adequate organ function, received GM102 1 to 20mg/kg every 2 weeks (q2w) then 7 and 10mg/kg weekly (qw) in 8 successive cohorts. Expansion phase will include granulosa, epithelial ovarian and cervical cancers. The objective was to determine a recommended dose (RP2D) from safety, pharmacokinetics, pharmacodynamics (PD) and GM102 anti-tumor activity (RECIST) and change in tumor growth rate (TGR = % change in tumor volume/month pre-treatment vs. after 2 cycles). PD included circulating immune cells (CIC) (ICOS, CD14, CD16, CD64, CD69) and in paired biopsies, macrophage (CD68, CD163, CD16) and T cell (CD3, CD4, CD8, FoxP3, Granzyme B) markers. Results: 27 pts with AMHRII+ gynecological tumors (including 4 GCTs) received 1 to 21 GM102 infusions. Terminal half-life was 130-200hrs. No dose limiting toxicity was observed. Treatment-emergent toxicities were mostly grade 1-2 (including rash, influenza-like symptom, 1 pt each). One pt had grade 3 anorexia and weight loss. 8/17 (47%) evaluable pts exhibited a decrease in TGR [45%-169%] under GM102. Among 4 GCT pts, 2 had a partial response and inhibin B decreased in 3. In CIC, T cell, monocyte and neutrophil activation was observed, and circulating CD16+ monocytes decreased suggesting possible recruitment to tumor site. In paired biopsies, CD16 expression increased in macrophages as well as Granzyme B suggesting GM102-induced cellular cytotoxicity. Conclusions: GM102 was well tolerated at all doses and schedules. RP2D includes 7mg/kg qw and 15mg/kg q2w. The encouraging PD and anti-tumor activity warrants further development of GM102, especially in the rare subtype of GCT. Clinical trial information: NCT02978755.
Safety, tolerability, and antitumor activity of once-daily Wee-1 inhibitor AZD1775.
Authors: Naoko Takebe, Geraldine Helen O'Sullivan Coyne, Shivaani Kummar, Khanh Tu Do, Ashley Bruns, Lamin Juwara, Mary Flanagan Quinn, Lyndsay Harris, Richard Piekarz, Sheila Ann Prindiville, Elad Sharon, Howard Streicher, Ganesh Mugundu, Jiuping Jay Ji, Deborah Wilsker, Robert J. Kinders, Larry Rubinstein, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2018)

2587 Background: Wee1 tyrosine kinase promotes G2 cell cycle arrest following DNA damage via inactivating phosphorylation of cyclin-dependent kinase 1. We are conducting a phase I study of the oral Wee1 inhibitor AZD1775 in patients (pts) with advanced solid tumors, examining twice daily (Arm A) and once daily (Arm B) schedules. Results for Arm A have been reported previously, and partial responses (PR) were observed in 2 pts with BRCA mutations. Here, we present results for Arm B. Methods: AZD1775 was given orally once daily (QD) for 5 days during weeks 1 and 2 of a 21-day cycle (Arm B) or twice daily (BID) for 5 doses during weeks 1 and 2 (Arm A). Primary objectives were to determine safety, tolerability, and pharmacokinetics (PK). Secondary objectives were to assess pharmacodynamic (PD) biomarkers of DNA damage in tumor tissue and circulating tumor cells and evaluation of antitumor activity. Dose-limiting toxicity was evaluated during cycle 1, and response was defined by CT using RECIST 1.1. Results: Thirty-four pts have enrolled on Arm B; of the 28 assessable for response, 4 (14%) had a PR (3 ovarian, 1 endometrial) and 18 (64%) experienced stable disease (mean: 7.22 cycles). Of the 9 Arm B pts with confirmed BRCA mutations, 2 had a PR (22%; ovarian) and 6 had SD (67%; mean: 7.17 cycles). The maximum tolerated dose (MTD) for Arm B was 300 mg; dose-limiting toxicities were grade (gr.) 4 myelosuppression and gr. 3 fatigue. The type, rate, and severity of commonly observed gr. 3/4 toxicities were similar between Arms A and B, including (Arm A [%]; Arm B [%]): anemia (28%; 24%), lymphopenia (20%; 35%), neutropenia (16%; 15%), and thrombocytopenia (12%; 12%), and fatigue (0%, 12%). Preliminary PK data indicate improved AZD1775 exposure (AUC and Cmax) for Arm B vs. Arm A MTD cohorts. Conclusions: Once-daily AZD1775 is well tolerated, with toxicities comparable to twice-daily AZD1775. Plasma drug exposure was higher for the QD vs. BID MTD cohort. AZD1775 antitumor activity was observed in pts with and without known BRCA mutations. Accrual to Arm B is ongoing, as is PD analysis. Future whole-exome sequencing analyses may uncover additional predictive biomarkers. Clinical trial NCT01748825. Supported in part by NCI Contract HHSN261200800001E. Clinical trial information: 01748825.
Quality of life in patients with advanced renal cell carcinoma in the randomized, open-label CheckMate 214 trial.
Authors: David Cella, Viktor GrÃ¼nwald, Bernard Escudier, Hans J. Hammers, Saby George, Paul Nathan, Marc-Oliver Grimm, Brian I. Rini, Justin Doan, Cristina Ivanescu, Jean Paty, Sabeen Mekan, Robert J. Motzer
Journal: Journal of Clinical Oncology (2018)

3073 Background: In CheckMate 214, overall survival (OS) with nivolumab + ipilimumab (N+I) was superior to sunitinib (S; HR, 0.63; P<0.001) with a manageable safety profile as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with advanced renal cell carcinoma (aRCC). We report analyses of health-related quality of life (HRQoL). Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 wk for 4 doses then N 3 mg/kg every 2 wk, or S 50 mg/d orally for 4 wk (6-wk cycle). Exploratory HRQoL analyses were conducted on RCC-specific symptoms from the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and general cancer symptoms were assessed using the Functional Assessment of Cancer Therapy-General (FACT-G) instruments. Analyses used t tests (change from baseline [BL] analysis) and mixed-model repeated measures (MMRM; using a predefined 6-m landmark). Results: A total of 847 I/P-risk pts were randomized (N+I, 425; S, 422). HRQoL assessment completion rates were >80% in the first 6 m. Statistically significant differences in change from BL on FKSI-19 total scores (mean BL scores: 60.1 [N+I]; 59.1 [S]) favoring N+I were observed at all but 2 post-BL time points through 2 years of follow-up (P<0.05). MMRM analysis found a statistically significant difference between arms at 6 m favoring N+I in FKSI-19 total score and most subscores (table). Change from BL results for the FACT-G trended in a similar direction, with N+I scores exceeding those in the S arm throughout 2 years of follow-up. Similarly, MMRM of FACT-G total scores showed significant benefit of N+I at 6 m. Conclusions: In addition to the OS benefit and superior safety profile, descriptive data suggest that N+I offers significant and sustained HRQoL improvement vs S in I/P-risk pts with untreated aRCC. Clinical trial information: NCT02231749.MMRM analysis: FKSI-19. Domain Difference N+I vs S (95% CI) Total 2.63 (1.13–4.13)a DRS 0.75 (0.10–1.40)a DRS-Physical 1.19 (0.28–2.11)a DRS-Emotional 0.10 (−0.06 to 0.27) Treatment side effects 1.09 (0.79–1.38)a Functional well-being 0.35 (−0.14 to 0.84) aP<0.05 CI, confidence interval; DRS, disease-related symptoms
TCT-873 Attenuated coronary post occlusive flow, increased inflammatory environment and larger infarct size in STEMI patients with acute peripheral vascular dysfunction
Authors: Nina van der Hoeven, Gladys Janssens, Alexander Nap, Michiel Bom, Henk Everaars, Albert van Rossum, Javier Escaned, Maarten van Leeuwen, Niels van Royen
Journal: Journal of the American College of Cardiology (2018)