tbuckley/cabot-search huggingface dataset:
Preclinical studies of BMI-1 modulator PTC596 in diffuse intrinsic pontine gliomas, pediatric high-grade gliomas and medulloblastoma.
Authors: Shiva Senthil Kumar, Ashley Adile, Mari Kogiso, Sataupa Sengupta, David Bakhshinyan, Yuchen Du, Chitra Venugopal, Art Branstrom, John Baird, Patricia Ann Baxter, Xiao-Nan Li, Maryam Fouladi, Sheila K Singh, Rachid Drissi
Journal: Journal of Clinical Oncology (2018)

e14051 Background: Diffuse intrinsic pontine glioma (DIPG) is a universally fatal brainstem tumor with survival < 1 year despite multimodal therapy. Similarly, other childhood high-grade gliomas (HGG) have a very poor prognosis with 3 year-overall survival of 10-22%. Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Group 3 is a high-risk MB with 5 year-overall survival of less than 50%. BMI-1 is a member of the Polycomb repressive complex 1 and is highly expressed in DIPG, HGG and group 3 MB patient tumors. Methods: In the current studies, we tested PTC596, a BMI-1 modulator, currently in clinical trials in in vitro and in vivo models of DIPG, HGG and group 3 MB. Results: Pediatric patient-derived HGG cells treated with PTC596 demonstrated sustained suppression of cell growth at nanomolar concentrations and tumor growth inhibition in vivo in patient-derived orthotopic xenograft mouse models. In DIPG patient-derived neurospheres, PTC596 selectively inhibited cell proliferation and induced apoptosis at nanomolar concentrations in all DIPG subtypes. Treatment of primary and recurrent group 3 MB cells with nanomolar concentrations of PTC596 resulted in a decreased cell proliferation and self-renewal capacity in vitro. Subsequent in vivo studies combining PTC596 with radiochemotherapy showed a significant reduction in tumor burden and extended animal survival times when compared to the cohorts that were treated with either PTC596 or radiochemotherapy alone. Conclusions: Collectively, our data identify BMI-1 as a potential therapeutic target and demonstrate that PTC596 may be useful for treatment of children with DIPG, HGG and MB. Building on our pre-clinical studies we developed a Phase I clinical trial to investigate the molecular activity and therapeutic potential of PTC596 in children with newly-diagnosed DIPG and HGG. The trial is being conducted through the Collaborative Network of Neuro-oncology Clinical Trials (CONNECT). These data will be used in the rational design of potential combination studies to improve outcome in children with DIPG, HGG and MB.
Prognosticators of first line treatment for metastatic uveal melanoma (MUM).
Authors: Mathew Nicholas, Leila Khoja, David Hogg, Ian Quirt, Marcus O. Butler, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2016)

9570 Background: Prognosis of MUM is poor yet there is significant inter-patient variability. Delineation of novel prognostic factors in MUM patients may enable stratified treatment algorithms. Methods: We performed a retrospective review of patients who presented with MUM from September 2004 to January 2016 at the Princess Margaret Cancer Centre, Toronto. Information on age, gender, liver involvement, size of largest liver mets, extrahepatic disease, ECOG, and laboratory values (hemoglobin, neutrophil/lymphocyte ratio (NLR), LDH, and ALP) were obtained at diagnosis of MUM. Associations with overall survival (OS), systemic 1stline treatment outcome (clinical benefit (stable disease, partial and complete responses) vs. progressive disease) and time to relapse were explored by univariable and multivariable analysis. Results: We analyzed 132 patients, 41% male with a median age of 58 years (12 - 90 years). 92% presented with liver mets. 79 patients underwent 1st line treatment with the most common being carboplatin and paclitaxel (19%), surgery (16%) or dacarbazine (13%). Age by univariable analysis significantly affected treatment outcome (OR 0.95 p = 0.01) with a trend to inferior outcome with presence of liver mets (OR = 0.13 p = 0.06). Multivariable analysis showed absence of liver mets (p = 0.03) or bone mets (p = 0.04) to predict superior treatment outcome whilst increasing age (p = 0.009) predicted inferior response. Time to relapse after 1st line therapy was affected by liver mets (HR = 2.89 p = 0.02). LDH (HR = 1.00 p < 0.001), ALP (HR = 1.004 p < 0.001), age (HR = 1.02, p = 0.006), NLR (HR = 1.08, p = 0.0135), ECOG (HR 2.21, p = 0.0083), and liver mets (HR = 2.7 p = 0.0102) were significant for OS. Multivariable analysis showed LDH (p = 0.02) was the only significant predictor for time to relapse while LDH (p = 0.0004), age (p = 0.0007), and ECOG (p = 0.0002) were significant prognosticators for OS. Conclusions: Potential predictive factors for treatment response, time to relapse, and OS were highlighted. Further validation is required to assess utility in stratifying 1st line treatment algorithms for MUM patients.
Incidence and risk factors of retinopathy in patients with melanoma treated with high dose of interferon α-2b(HDI).
Authors: Di Wu, Shijie Lan, Zhihua Cui, Qiliang Yin, Lingling Liang, Hua He, Zhen Guo, Zhigang Liu, Hesong Liu, Xuan Wang, Yingying Yu, Wenqiu Zhang
Journal: Journal of Clinical Oncology (2018)

e21635 Background: Retinopathy is one of the rare side effects of interferon α-2b. It has been observed in the treatment of hepatitis with low or middle dose interferon α-2b, but only a few cases have been reported in the treatment of melanoma with high dose. This study were conducted to elucidate the occurrence frequency and risk factors for retinopathy in Chinese patients(pts) with melanoma who are treated with HDI. Methods: We prospectively analyzed 49 pts with melanoma, who went through HDI therapy. Their visual acuity and visual field were measured, and fundus assessments were made at baseline, at 2, 4 weeks post the commencement of induction therapy, and at every 12 weeks in the maintenance treatment period. Results: 37 pts (76%) developed retinopathy, which were all reversible mild changes, including cotton wool spots and retinal hemorrhage. Cotton-wool spots were observed in 18 pts(49%), retinal hemorrhage was observed in 7 pts(19%), and the retinal hemorrhage with cotton-wool spots was found in 12 cases(32%). The median (P25-P75) time to develop the retinopathy was 4(2-6) weeks. All pts had no symptom, except for one patient who developed blurred vision. 5 pts(10%) had diabetes mellitus, 8 (16%) had hypertension and 3(6%) had both diabetes and hypertension. All of these pts developed retinopathy, but there was no statistically significant difference in pts with complications by diabetes and/or hypertension compared with those without these issues(diabetes vs without diabetes:P = 0.427; hypertension vs without hypertension:P = 0.19; diabetes and hypertension vs without diabetes or hypertension:P = 0.545). Comparison of the clinical backgrounds between the pts with retinopathy and those without showed no significant differences in age, gender, primary site, stage, ulceration present,gene mutation, lactate dehydrogenase level, white blood cell count, platelet count, hemoglobin level, blood lipid level or thyroid function. Conclusions: HDI therapy in pts with melanoma may induced mild retinopathy, however it is not necessary to discontinue the therapy. Retinopathy occurred more frequently in pts with diabetes and/or hypertension, and those pts may be required follow-up more carefully. Clinical trial information: NCT02702973.
iCare 1: A prospective clinical trial to predict treatment response based on genomics-informed computational biology in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Authors: Leylah Drusbosky, Kimberly E Hawkins, Madeleine Turcotte, Glenda G. Anderson, Shireen Vali, Taher Abbasi, Fei Zou, Nosha Farhadfar, Hemant S. Murthy, Biljana Horn, Helen Leather, Paul Castillo, Randy Brown, Maxim Norkin, John W. Hiemenz, John R. Wingard, Jack W. Hsu, Christopher R. Cogle
Journal: Journal of Clinical Oncology (2018)

7024 Background: Cytotoxic agents (7+3, HiDAC) and hypomethylating agents (HMAs) fail in the majority of MDS and AML pts. The aim of this study is to determine the predictive values of a genomics-informed computational biology method (CBM) in pts who are treated with standard of care (SOC) therapy. Methods: AML or MDS pts were recruited to a prospective clinical trial to assess predictive values by comparing CBM predictions of treatment response to actual clinical response. Genomic profiling was done by cytogenetics, whole exome sequencing, and copy number variation analysis. All genomic data were entered into CBM, which creates disease-specific protein network maps using PubMed. Digital drug simulations were done by measuring drug effect on a cell growth score. Each pt-specific protein network map was screened for the extent to which each pt’s therapy reduced simulated disease growth. Clinical outcomes were prospectively recorded. For AML, CR+PR was used to define response (IWG 2003). For MDS, CR+PR+HI was used to define response (IWG 2006). Western blots were performed on pathway proteins. 2x2 tables and Fisher’s exact tests were used to compare CBM prediction values vs empiric drug administration. Results: 135 pts were recruited, and 101 have had all genetic tests performed. 50/101 pts received 61 treatments and were eligible for efficacy evaluation. 33/50 had AML, 15/50 had MDS. Western blot validation showed correct prediction of 4 activated networks (Akt2, Akt3, PIK3CA, Erk1/2), with 89% accuracy. 55 drug outcome predictions were correctly matched to their actual clinical outcomes, resulting in 90% prediction accuracy, 93% PPV, 92% NPV, 93% sensitivity, and 88% specificity. The accuracy of CBM was significantly greater than empiric drug administration (p = 1.664e-05 ). Conclusions: CBM that models multiple genomic abnormalities showed high predictive value of protein network perturbations and clinical outcomes after SOC treatments. This technology could be used to establish eligibility criteria for precision enrollment in drug development trials, and will be used in upcoming precision medicine trials. Clinical trial information: NCT02435550.
Health literacy in a comprehensive cancer center in Mexico.
Authors: Emma L Verastegui, Jaime G. De La Garza, Silvia R Allende-Perez
Journal: Journal of Clinical Oncology (2018)

e18661 Background: Understanding cancer information and treatment decision making represents one of the most complicated challenges for patients, particularly those with low levels of health literacy (LHL). Several studies have shown that LHL correlates with poorer outcomes, higher rates of health services utilization, and costs. LHL using different instruments has been reported in the Mexican population living in the US; however, no information is available for Mexico. Methods: Participants were consecutively recruited at the out-patient areas of the Instituto Nacional de Cancerologia (INCan). The study was approved by the IRB, only included patients. HL was evaluated using the Short Assessment of Health Literacy for Spanish-speaking Adults (SAHLSA), cut-off score of less than or equal to 37, Descriptive statistics, including median and inter-quartile range (IQR), frequencies and proportions (Stata Version 12). Results: Four hundred and fifty patients (pt) were included. Median age was 53.5 y/o (19-87 y/o). Average HL was 42.8/50, low HL was present in 15.4%. Those pt with the highest HL, were females, with breast and ovarian cancer, came from urban areas, had better income and education (college, more than 50%). LHL was associated with low income, poor education, some tumor locations (Head and Neck, rectum), advanced tumor stages, these pt were older (OR = 0.97), and live in rural areas. SAHLSA´s Cronbach's alpha was 0.91 Conclusions: According to SAHLSA evaluation, most pt. seen at the INCan have adequate HL. Education, income, and place of residence may have a role in HL; however, other factors could be important. These results contrast with those findings of Mexican patients living in the US. The study has some limitations, no previous information using REALM or TOFHLA is available for this population, and these results may not represent the HL present in the general Mexican population. Additional studies are needed.
Phase III randomized trial of image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) for locoregionally advanced cervical cancer: The INTERTECC-3 trial.
Authors: Loren K. Mell, Igor Sirak, Lorraine Portelance, Aaron Howard Wolfson, Alexandra J. Stewart, Dayanand Sharma, Denis Princ, Umesh Mahantshetty, Mitsuhiro Nakamura, Kimiko Hirata, Stephen F Kry, Lichun Wei, Ronghui Xu, Kaveh Zakeri, Elena Sojourner, Kevin Moore, Michael T. McHale, Cheryl C. Saenz, Catheryn M. Yashar, Arno James Mundt
Journal: Journal of Clinical Oncology (2017)

TPS5600 Background: Cervical cancer is a leading cause of cancer death in women worldwide. Image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) has shown potential to reduce acute toxicity of chemoradiotherapy and improve chemotherapy delivery in phase I and II trials (Mell LK, Sirák I, Wei L, et al. Bone Marrow-sparing IMRT With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys 2017;97:536-545. Mell LK, Saenz CC, Yashar CM, et al. Phase I Trial of Bone Marrow Sparing IMRT With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer (abstr.) Int J Radiat Oncol Biol Phys 2016; 96: S14.). Methods: INTERTECC-3 is a randomized phase III trial designed to test the effect of IG-BMS-IMRT on progression-free survival (PFS) for women with unresected FIGO stage IB-IVA cervical carcinoma (clinicaltrials.gov #NCT01554397). It presently involves centers in the U.S., Czech Republic, U.K., India, Japan, and China. Women are randomized 3:2 to either (A) IG-BMS-IMRT or (B) standard chemoradiation, with 6 cycles of concurrent cisplatin (40 mg/m 2 ) weekly in both arms. Secondary objectives are to compare overall survival, treatment-related toxicity, disease recurrence, quality of life, chemotherapy delivery, and radiation quality assurance. Planning objectives require maintaining pelvic marrow and active marrow mean doses &lt; 27 Gy and &lt; 28.5 Gy respectively. Correlative studies involve longitudinal collection of magnetic resonance restriction spectrum imaging and 18 F-fluorothydimine positron emission tomography scans to assess imaging biomarkers of treatment response in select patients. 415 women will be enrolled to determine if IG-BMS-IMRT improves the median PFS from 3.2 to 5.0 years with 80% power and alpha = 0.05. INTERTECC-3 opened in the U.S. and Czech Republic in 2016. To date, 17 patients have been randomized. The trial will be activated at additional international sites in late 2017 and 2018. We are seeking to recruit sites who wish to collaborate. Clinical trial information: NCT01554397.
Multicenter phase II study of intraperitoneal carboplatin plus intravenous dose-dense paclitaxel in patients with suboptimally debulked epithelial ovarian or primary peritoneal carcinoma.
Authors: Kosei Hasegawa, Muneaki Shimada, Satoshi Takeuchi, Hiroyuki Fujiwara, Yuichi Imai, Norihiro Iwasa, Satoru Wada, Hidetaka Eguchi, Tetsuro Oishi, Toru Sugiyama, Mitsuaki Suzuki, Masahiko Nishiyama, Keiichi Fujiwara
Journal: Journal of Clinical Oncology (2016)

5504 Background: Although intraperitoneal (IP) chemotherapy with cisplatin and paclitaxel demonstrated better survival advantage for optimally debulked stage III ovarian cancer, it has not been widely accepted yet due to its complications. Dose-dense paclitaxel and carboplatin (ddTC) therapy also showed improved survival compared to the conventional paclitaxel and carboplatin. Based on our previous study, IP carboplatin indicated more reasonable pharmacokinetics than intravenous (IV) carboplatin. The efficacy and the safety of IP carboplatin in combination with dose-dense paclitaxel (ddTCip) for advanced ovarian cancer have not been prospectively evaluated yet. Methods: A prospective phase II study to evaluate the efficacy and the safety of ddTCip has been carried out. Patients with stage II-IV ovarian or primary peritoneal carcinoma who underwent primary cytoreductive surgery and had evaluable disease by RECIST after the surgery were eligible in this study. IP carboplatin (AUC = 6) was administered on day 1 and IV paclitaxel (80mg/m2) on day 1, 8 and 15. Primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Interval debulking surgery followed by the same regimen was allowed when indicated. The protocol has been reviewed and approved by the ethics committees in each institution. Results: 117 patients were temporary registered prior to surgery and 76 patients were enrolled in this study. 71 patients completed at least 1 cycle of protocol treatment. We observed 56 (78.9%) patients had clinical response. 8, 48, 13 and 0 patients showed CR, PR, SD and PD, respectively. Median PFS was 18 months, and median OS was 55 months. We observed that 64 (84.2%), 43 (56.5%) and 17 (22.4%) cases had grade 3/4 neutropenia, anemia, and thrombocytopenia, respectively. Port-related adverse events occurred in 9 (11.8%) patients. Conclusions: We suggest that the frontline chemotherapy with ddTCip therapy is safe and effective even for suboptimal residual ovarian carcinoma patients. A randomized phase III trial comparing ddTCip versus ddTC is currently ongoing. Clinical trial information: UMIN000001713.
Predictors of clinical benefit of checkpoint inhibitors-based immunotherapy in advanced non–small cell lung cancer: A meta-analysis.
Authors: Hazem Edmond El-Osta, Syed Hasan Raza Jafri
Journal: Journal of Clinical Oncology (2018)

e21121 Background: Monoclonal antibodies targeting the PD-1/PD-L1 pathway have demonstrated significant activity in the treatment of metastatic non–small cell lung cancer (NSCLC). However, the majority of patients do not respond to this treatment. Identifying clinical predictors of response is crucial in selecting patients who may derive the most benefit from checkpoint inhibitors (CKI). Methods: We searched databases (PubMed and EMBASE) up until October 31, 2017. We selected randomized controlled trials that compared CKI with chemotherapy in stage IV NSCLC. By using random effect model and subgroup analysis by Q-test for heterogeneity, we calculated and compared the pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) according to age, sex, PD-L1 status, history of smoking, and central nervous system (CNS) involvement. Results: 7 clinical trials were identified. The pooled HR for PFS in patients with current or prior exposure to smoking was 0.771 (95% CI 0.590-1.008, p = 0.057) favoring CKI over chemotherapy. In contrast, the pooled HR for PFS in never smokers was 1.678 (95% CI 1.075–2.619, p = 0.023) favoring chemotherapy over CKI. In women and patients negative for PD-L1, chemotherapy was equal to CKI in terms of PFS, whereas in men and patients positive for PD-L1, there was a PFS benefit in favor of CKI over chemotherapy. Indeed, the pooled HR for PFS was 0.991 (95% CI 0.796–1.233, p = 0.934) for PD-L1–negative vs. 0.785 (95% CI 0.640–0.962, p = 0.019) for PD-L1–positive patients (p = 0.126 for the difference between the 2 subgroups by Q-test). The PFS HR was 1.015 (95% CI 0.838–1.229, p = 0.879) for women vs. 0.718 (95% CI 0.555–0.929, p = 0.012) for men (p = 0.035 for the difference between the 2 subgroups). PFS benefit of CKI over chemotherapy was equally observed across both age subgroups (below and above 65). Similarly, the presence of CNS involvement did not influence the PFS benefit of CKI. When similar analysis was conducted for OS, HR favored CKI over chemotherapy in all subgroups. Conclusions: Our meta-analysis revealed that gender, smoking history and PD-L1 expression may help predict the PFS benefit of CKI over that with chemotherapy in metastatic NSCLC.
Abstract IA32: Multiscale modeling of lung cancer
Authors: Olivier Gevaert
Journal: Clinical Cancer Research (2018)

Abstract Vast amounts of biomedical data are now routinely available for lung cancer patients ranging from sequencing of lung tissues to liquid biopsies. In addition, new computational tools for quantitatively analyzing immunohistochemistry (IHC) and radiology images are now available. Multi-scale data is now available for complex diseases at molecular, cellular and tissue scale to establish a more comprehensive view of key biological processes. Intra and inter individual heterogeneities are often quoted as the main challenge for studying cancer. These heterogeneities exist at all scales, from microscopic to macroscopic. However, the technologies used to generate data at a particular scale don’t equally assess the heterogeneity. A single biopsy of a lung tumor does not reflect the potential cellular and spatial heterogeneity. Radiology images on the other hand provide a global picture of the heterogeneity of the complete tumor at the tissue scale. We propose multi-scale modeling to counter heterogeneity and uncover potentially untapped synergies between different data modalities by integrating information across spatial scales. Multi-scale modeling involves linking information from molecules, cells, tissues, and organs all the way to the organism and the population. We propose to use high dimensional molecular data with cellular and tissue scale image data to develop a statistical multi-scale modeling approach of cancer by tapping the previously understudied information in IHC and radiology images. For example, recent reports showed how to integrate transcriptomic data and CT images resulting in intriguing associations between gene expression signatures and CT image phenotypes. Secondly, multiple studies have shown that EGFR mutation status can be predicted from CT images features, opening up avenues for non-invasive therapy monitoring. In addition, computational analysis of IHC and radiology images is able to predict the overall survival of lung cancer patients. Each of these single reports have shown the potential of multi-scale modeling, however a complete multi-scale model of lung cancer is still under development. Overall, multi-scale modeling can have profound contributions toward predicting diagnosis and treatment by revealing synergies and previously unappreciated relationships. Multi-scale modeling also can contribute to a more fundamental understanding of lung cancer development and can reveal novel insights in how data at different scales are linked to each other. Citation Format: Olivier Gevaert. Multiscale modeling of lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA32.