tbuckley/cabot-search huggingface dataset:
Leptomeningeal spread of glioma in the molecular era.
Authors: Iyad Alnahhas, Pilar Guillermo Prieto Eibl, Javier Gonzalez, Pierre Giglio, Vinay K. Puduvalli
Journal: Journal of Clinical Oncology (2019)

e13537 Background: Leptomeningeal disease (LMD) is an uncommon event in patients with gliomas which is estimated to occur in 4% of cases and is associated with poor outcome. Genomic alterations in gliomas that precipitate LMD have not been characterized. Methods: We performed a retrospective chart review of patients with gliomas (grade II-IV)- for whom we have genomic testing data at The Ohio State University. We identified patients who developed LMD. LMD was defined as leptomeningeal enhancement as seen on brain or spine imaging. Patients with negative cerebrospinal fluid (CSF) cytology were not excluded if imaging was convincing of LMD. Genomic testing was performed through Foundation One. Results: 129 charts of glioma patients were reviewed. We identified 6 patients with LMD. One is still alive. All patients were diagnosed histologically as glioblastoma. One patient had Lynch syndrome. All patients were men with a median age at diagnosis of 44 (range 20-65). All tumors appeared to have extended into the ventricles on brain imaging. 4 tumors had evidence of subependymal spread prior (range 45-93 days) or at the time of LMD enhancement. 4 patients had available CSF studies: 2 of whom had evidence of atypical or malignant cells. CSF protein was elevated in all four samples (range 113-492 mg/dL). CSF glucose was low in all four samples (range &lt; 10-46 mg/dL). 5 tumor samples were IDH wild type whereas 1 had IDH1 R132H mutation. MGMT promoter was methylated in 3 tumors and unmethylated in 3. The genomic alterations varied among samples and included EGFR V765M mutation (N = 1), PDGFR amplification (N = 1), PDGFRA Y849C subclonal mutation (N = 1), CDKN2A/B loss (N = 3), TP53 mutations (N = 4) and TERT promoter mutations (N = 3). No case had EGFR amplification or EGFRvIII mutation. Other alterations observed included DNMT3A mutation, KIT, MYC and MDM2 amplifications and RB1 losses. PD-L1 expression ranged from 5-40%. One intracranial sample had a 20% PD-L1 expression with LMD from this tumor exhibiting 40% PD-L1 expression. Of the five deceased patients (all IDH WT), median overall survival (OS) was 355 days (range 184-557). Median OS after LMD diagnosis was 84 days (range 58-225). Conclusions: In this series, 4.5% of glioma patients developed LMD. Samples were associated with a variety of genomic alterations but without a specific predictor of leptomeningeal involvement. This is possibly due to the small number of cases. Physical proximity of the tumor to the ventricles appears to be a potential risk factor. Larger studies of LMD in gliomas are warranted to identify potential genetic drivers, if any exist.
Phase I with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
Authors: M. Pia Morelli, Nicole D. Houston, Stan Lipkowitz, Jung-min Lee, Alexandra Dos Santos Zimmer, Farah Z. Zia, Kathrine Trewhitt, Erin Nichols, Mira Pavelova, Stephen M. Hewitt, Massimo Fantini, Philip M. Arlen, Kwong Y. Tsang, Christina M. Annunziata
Journal: Journal of Clinical Oncology (2020)

129 Background: NEO-201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens (TAA) from colorectal cancer. Our preclinical data demonstrated that NEO-201 exerts anti-tumor activity by NK-mediated ADCC and CDC against several tumor types. We identified NEO-201 antigen as a tumor-associated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue. Methods: This is a first-in-human phase 1 study to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood of expression NEO201 antigen and have progressed to standard of treatments. This is a classic 3+3 dose escalation, with cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and at four dose levels (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). Patients are evaluated for safety according to CTCAEv5.0., and for response according to RECISTv1.1. Biological samples are collected to understand NEO-201 pharmacokinetics, the effects on immune profile and the correlation with treatment toxicity and response. Results: Here we report the safety data and pharmacokinetics from DL1 and 2. A total of 9 evaluable patients were enrolled. Prolonged neutropenia, defined as ³G2 neutropenia lasting for &gt;7 days, was observed at DL2. The cohort was expanded to a total of 6 patients and no further DLTs were observed. Seven out of nine of the patients enrolled had colon cancer, two had pancreatic cancer and one had hormone positive breast cancer. The most frequent treatment-related AEs were infusion reaction which was observed in all patients, and moderate fatigue (33%). Best response was SD observed in two patients (one on each of DL1 and DL2). Dose escalation continues on DL3 and DL4. NEO201 antigen expression in patient tumor tissue, circulating CEACAM6/CEACAM5, and MICA will be evaluated to correlate with response and toxicity. Conclusions: NEO201 has shown some promising activity. PK and PD studies are ongoing to better understand dosing schedule, toxicity profile and to identify biomarkers for patient selection. Clinical trial information: NCT03476681.
Modified FOLFIRINOX as a second-line treatment in pancreatic adenocarcinoma patients with poor performance status.
Authors: Adarsh Das, Andrew Peter Dean, Domenic Higgs
Journal: Journal of Clinical Oncology (2019)

e15796 Background: FOLFIRINOX is well known to be a highly effective treatment in pancreatic cancer for young patients with good performance status. As the original ACCORD study was carried out with patient’s performance status 0 or 1, many oncologists feel uncertain administering modified dose FOLFIRINOX (m-FOLFIRINOX) as a second-line therapy. We have previously reported our experience in 35 patients (aged 27 – 85) where we concluded that m-FOLFIRINOX can be administered safely with appropriate dose reductions. More recently, the systematic review and meta-analysis by Tong et al. concluded that m-FOLFIRINOX is a good choice of therapy even for those with poor performance status. This retrospective analysis assessed the efficacy of m-FOLFIRINOX in second-line treatment of pancreatic adenocarcinoma. Methods: Using an electronic database, patients with either locally advanced or metastatic pancreatic adenocarcinoma were identified who had received first-line gemcitabine plus nab-paclitaxel, followed by second-line m-FOLFIRINOX between January 2013 and July 2018. All patients had an ECOG performance status of 2 or less. Overall survival (OS) was estimated by the Kaplan-Meier method. Results: Fifty-two patients were identified, with 65% of the patients having metastatic pancreatic disease. Median age of patients was 75 (range, 27 – 86). Dose intensity of m-FOLFIRINOX was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-fluorouracil (5-FU) and 68% for infusional 5-FU. From diagnosis, the median OS of all patients was 45.0 months (95% CI, 25.0 – 63.0). The median OS of the locally advanced and metastatic pancreatic adenocarcinoma was 63.0 months (95% CI, 45.0 – 70.0) and 22.5 months (95% CI, 18.0, 38.0), respectively. Conclusions: Our study demonstrates the safety and efficacy of m-FOLFIRINOX as a second-line therapy after gemcitabine plus nab-paclitaxel failure. These findings correlate with the findings of Tong et al.’s findings of the benefits of m-FOLFIRINOX for advanced pancreatic cancer in patients with poor performance status.
Polydopamine and collagen coated micro-grated polydimethylsiloxane for human mesenchymal stem cell culture
Authors: Dhavan Sharma, Wenkai Jia, Fei Long, Shweta Pati, Qinghui Chen, Yibing Qyang, Bruce Lee, Chang Kyong Choi, Feng Zhao
Journal: Bioactive Materials (2019)

Natural tissues contain highly organized cellular architecture. One of the major challenges in tissue engineering is to develop engineered tissue constructs that promote cellular growth in physiological directionality. To address this issue, micro-patterned polydimethylsiloxane (PDMS) substrates have been widely used in cell sheet engineering due to their low microfabrication cost, higher stability, excellent biocompatibility, and most importantly, ability to guide cellular growth and patterning. However, the current methods for PDMS surface modification either require a complicated procedure or generate a non-uniform surface coating, leading to the production of poor-quality cell layers. A simple and efficient surface coating method is critically needed to improve the uniformity and quality of the generated cell layers. Herein, a fast, simple and inexpensive surface coating method was analyzed for its ability to uniformly coat polydopamine (PD) with or without collagen on micro-grated PDMS substrates without altering essential surface topographical features. Topographical feature, stiffness and cytotoxicity of these PD and/or collagen based surface coatings were further analyzed. Results showed that the PD-based coating method facilitated aligned and uniform cell growth, therefore holds great promise for cell sheet engineering as well as completely biological tissue biomanufacturing.
Boosting pazopanib exposure by splitting intake moments: A prospective pharmacokinetic study in cancer patients.
Authors: Stefanie L. Groenland, Ruben A.G. van Eerden, Remy B Verheijen, Alwin Huitema, Ron H.J. Mathijssen, Neeltje Steeghs
Journal: Journal of Clinical Oncology (2019)

3119 Background: Pazopanib is approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). Due to high (40-70%) interpatient variability in pharmacokinetic (PK) exposure, 16-20% of patients do not reach the 20 mg/L exposure threshold related to prolonged progression free survival (20 weeks versus 52 weeks, respectively) with the currently used fixed dose of 800 mg QD (Suttle, 2014; Verheijen, 2017). PK simulations showed that, due to non-linear absorption of pazopanib, splitting the intake (400 mg BID) leads to an increase in C min and AUC 0-24h of 75% and 59%, respectively (Yu, 2017). This study aimed to show whether switching patients from an 800 mg QD to a 400 mg BID dose schedule will lead to a significant increase in PK exposure. Methods: We performed a prospective PK trial (NL6137) in which PK sampling at the 800 mg QD dose schedule occurred at day 1, after which the intake moments were split into 400 mg BID during one week, followed by PK sampling at day 8. Paired samples t-tests were used to assess differences in C min , C max and AUC 0-24h between these two dose schedules. To detect an increase in PK exposure of 50% (2-sided α = 0.05 and β = 0.20), 10 evaluable patients were needed. Results: Eleven patients (6 RCC and 5 STS) have been included, of whom ten were evaluable for PK analyses. Using the 800 mg QD dose schedule mean C min , C max and AUC 0-24h were 26.7 mg/L (coefficient of variation (CV%) 44.7), 46.1 mg/L (CV% 37.1) and 809 mg h/L (CV% 42.1), respectively. Switching to 400 mg BID resulted in an increase of both C min and AUC 0-24h to 40.7 mg/L (CV% 37.0, p = 0.013) and 1059 mg h/L (CV% 33.1, p = 0.068), respectively, while C max did not significantly change (56.5 mg/L, CV% 33.2, p = 0.185). One patient (9%) experienced grade 3 diarrhea after splitting intake moments, leading to treatment interruption. This strategy could potentially save up to 2000 USD/patient/month compared to conventional dose increments. Conclusions: This study demonstrates that boosting pazopanib exposure by splitting intake moments leads to a significant increase in C min, of 52%, with acceptable tolerability. Therefore, this new dose schedule offers a safe and cost-neutral opportunity to optimize treatment for patients with low PK exposure. Clinical trial information: NL6137.
Development of the patient-reported outcomes (PRO) based survival prediction model for survivors who underwent lung cancer surgery.
Authors: Jin-Ah Sim, Young Ae Kim, Jong Mog Lee, Moon Soo Kim, Jae Ill Zo, Young Mog Shim, Young Ho Yun
Journal: Journal of Clinical Oncology (2019)

e23084 Background: To construct a prognostic model of 5-year survival among disease-free survivors who underwent lung cancer surgery using socio-clinical and patient-reported outcomes (PRO), and to compare its predictive performance with that of a traditional model based on known clinical variables. Methods: Data on 809 survivors who underwent lung cancer surgery between 2001 and 2006 in two Korean tertiary teaching hospitals were used. The training data set was utilized to generate the prediction model and the remaining 20% was employed as a testing set to estimate the model’s accuracy. Three Cox proportional hazard regression models were constructed and compared that of 5-year survival prediction ability through the evaluation of their performance in terms of discriminative and calibration ability. The three models were constructed with: 1) only clinical and socio-demographic variables, 2) only PROs, and 3) variables from model 1 and 2 considered altogether. The performance of each 5-year survival prediction model was evaluated using C-statistics and Hosmer-Lemeshow-type χ 2 -statistical analyses. Results: From the validation set, the C-statistics for the model 1, 2, and 3 were 0.70 (95% confidence interval [CI], 0.67−0.73), 0.77 (95% CI, 0.74−0.80), and 0.81 (95% CI, 0.78−0.84), respectively. In this study, model 3 (including PRO and other variables together) showed the highest discriminative and calibration ability compared to others. Conclusions: The findings suggested that the PRO included model in addition to clinical and socio-demographic variables, is more accurate in the survival prediction of lung cancer survivors than models constructed with only well-known socio-clinical variables.
DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).
Authors: Hirva Mamdani, Jerry Chen, Seongho Kim, Yahya Ibrahim, Mohammad Fahad Bin Asad, Jorge J. Nieva, Rebecca Feldman, Abdul Rafeh Naqash, Stephen V. Liu, Patrick C. Ma, David Craig Portnoy, Hossein Borghaei, Nagla Fawzy Abdel Karim, Yanis Boumber, Ari M. Vanderwalde, Alexander I. Spira, Shadia Ibrahim Jalal
Journal: Journal of Clinical Oncology (2019)

9100 Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( &lt; 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.
Towards a screening test for cancer by circulating DNA analysis.
Authors: Alain R. Thierry, Rita Tanos, Amaelle Otandault, Caroline Mollevi, Audrey Bauer, Geoffroy Tousch, Laurence Picque Lasorsa, Safia El Messaoudi, Jacques Colinge, Pierre-Emmanuel Colombo, William Jacot, Thibault Mazard, Jose Maria Sayagues, Brigitte Gillet, Denis Pezet, Marc Ychou
Journal: Journal of Clinical Oncology (2019)

e13146 Background: Following works on the clinical potentials of circulating DNA (cfDNA), our group is now particularly focused on evaluating its potential for early detection of cancer. We recently developed a test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences. When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. Methods: We recently developed a screening test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences. When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. Results: We are currently carrying out an extensive evaluation of this test in plasma samples from diagnosed and healthy individuals. Preliminary results on the plasma of 289 healthy subjects and 1,200 patients with various types of cancer (colorectal, breast, lung, liver, pancreatic, ovarian) of all stages, revealed a high potential with an AUC of 0.82 (0.78-0.84, 95% confidence interval, CI) and 70% sens. with 78% spe.. In breast cancer (N = 169), an AUC of 0.82 (0.78-0.86, 95% CI) with 72% sens. and 80% spe. were observed. In all stages CRC patients (N = 887), the results showed an AUC of 0.81 (0.78-0.84, 95%, CI) and 68% sens. with 80% spe.; for CRC stages 0/I/II (N = 249), an AUC of 0.75 (0.71-0.80, 95% CI) and 60% sens. with 79% spe.; and for CRC stage IV (N = 101), a 0.86 AUC (0.82-0.91, 95% CI) with 81% sens. and 78% spe.. When combining the MNR test to a threshold value of the total concentration of cfDNA (AUC = 0.82 (0.79-0.84, 95% CI), 70% sens. and 80% spe. in all stage cancers (N = 1078)), in CRC stages 0/I/II (N = 249) vs Healthy Individuals (N = 289), we observed a 63% sens. with 84% spe. Conclusions: Furthermore we recently discovered that cfDNA fragmentation, as determined by Whole Genome Sequencing using either double or single strand library, is also a parameter enabling discrimination between healthy and cancer individuals. Data on a multi-parametric test combining total cfDNA quantification, MNR and fragmentation biomarkers with help of a ongoing decision tree algorithm in machine learning will be presented during the meeting. Our on-going data suggest that our strategy in targeting cfDNA quantitative/structural features might be powerful for cancer screening/early detection and appears as an alternative or a synergistic combination to searching mutations.
Homologous recombination deficiency as prognostic marker in metastatic gastric cancer.
Authors: Nuno Sousa, Catia Faustino, Lucia Maria Nunes Aguas, João Freire, Camila Coutinho, Ilda Faustino, Andreia Capela, Telma Costa, Andreia Sofia Alves Costa, Sara Coelho, Filipa Pereira, Sofia Coelho Abreu, Ana Sofia Rolo, Andre Albergaria, Jorge Lima, Xiaogang Wen, Carina Mesquita, Claudia Camila Dias, Luis Filipe Azevedo, Fatima Carneiro
Journal: Journal of Clinical Oncology (2019)

4040 Background: Gastric cancer is the 5th cancer diagnosis and 3rd cause of cancer death worldwide. Metastatic gastric cancer (mGC) has a median survival of 11 months. mGC is an heterogeneous disease and different biologic characteristics may justify differential therapeutic opportunities. Tumors with homologous recombination (HR) deficiency may benefit with treatment with PARP inhibitors or immune checkpoint inhibitors. The purpose of this study was to evaluate the prevalence and prognostic impact of altered expression of HR proteins as surrogates for homologous recombination deficiency (HRD) in mGC. Methods: Multicenter retrospective cohort of mGC treated with platinum-based chemotherapy. HRD defined as absence of at least one of the following proteins: ATM, ATR, CHK2, RAD51, RAD52, BRCA1, BRCA2, MRE11 by immunohistochemistry. Survival time calculated as the difference between first cycle of platinum-based chemotherapy and death or last observation. Association between HRD and survival examined with log-rank test. Results: 440 patients included, of which 70% male, with mean age of 58 years (SD: 11). 75% of patients had mGC at diagnosis, 43% had 2 or more organs involved and 63% were registered as ECOG 0 or 1 at the start of first line chemotherapy. The most common histologic subtype was tubular adenocarcinoma (44%) followed by diffuse carcinoma (32%). HRD was noted in 196 (45%) cases (95%CI: 40%-49%). The most commonly altered proteins were ATM (21%) and BRCA2 (18%). In HRD tumors, 99 (51%) had altered expression of only one HR protein; 47 (24%) had altered expression of two HR proteins; the remaining cases had altered expression of 3 or more proteins. After a median follow up of 11 months, median survival for the cohort was 11 months (95% CI 9-12). HRD was associated with an improved survival, HR = 0.61 (95%CI: 0.48-0.78, p &lt; 0.001), that remained significant after adjustment for sex, age, performance status and disease status (HR = 0.63; 95%CI: 0.48-0.82; p &lt; 0.001). Conclusions: HRD phenotype was present in 45% of mGC cases and is associated with improved prognosis for mGC treated with platinum-based first line chemotherapy.