tbuckley/cabot-search huggingface dataset:
A multi-center, randomized, prospective study evaluating the optimal radiation dose of definitive concurrent chemoradiation for inoperable esophageal squamous cell carcinoma.
Authors: Yanjun Xu, Weiguo Zhu, Xiao Zheng, Wanwei Wang, Jiancheng Li, Rong Huang, Han He, Jianxiang Chen, Liping Liu, Zongwen Sun, Xinmei Yang, Huijuan He, Ming Zeng, Juan Pu, Wangyuan Hu, Yong Bao, Zhigang Liu, Jun Ma, Ming Chen
Journal: Journal of Clinical Oncology (2018)

4013 Background: To determine the optimal radiation dose for definitive concurrent chemoradiation in esophageal squamous cell carcinoma (ESCC) using modern radiation technology. Methods: Pathologically confirmed ESCC patients with stage IIA-IVA were randomized into high-dose (60Gy) and low-dose group (50Gy). The total radiation doses were delivered 2 Gy per fraction, 5 fractions per week, by intensity-modulated radiation therapy (IMRT). Concurrent weekly docetaxel (25 mg/m2 ) followed by cisplatin (25 mg/m2 ) and 2 cycles consolidation chemotherapy with docetaxel 70mg/m2 plus cisplatin 25mg/m2 day1-3 were administrated. The primary endpoint was local/regional progression-free survival (LRPFS). Results: From April 2013 to May 2017, 305 patients were randomized into the high-dose (n = 152) and low-dose group (n = 153). There were no significant differences in gender, age, KPS, clinical stage, location, the length of tumor between the two groups. The radiotherapy completion rate was 87.5% (133/152) and 95.4% (146/153) in the high and low dose groups respectively (P= 0.002). The concurrent weekly chemotherapy completion of receiving 5, 4, ≤3 weeks drugs were 61.2% (93/152) 、66.7% (102/153) ;21.1% (32/152) 、20.9% (32/153); 17.8% (27/152) 、12.4% (19/153) (P= 0.406). There was no significantly difference in the completion of consolidation chemotherapy (P= 0.207). At a median follow-up of 14.4 months (1.3-51.4 months), The disease progression rate was 15.8% (24/152) 、15.7% (24/153) in the high-dose and low-dose group, respectively. The 1, 2-year LRPFS rate was 85.8%、74.4% and 85.1%、78.4% (P= 0.676). The 1, 2-year PFS and OS rate was 78.6%、67.6%, 76.9%、67.7% (P= 0.859);84.6%、67.3%, 86.4%、72.2% (P= 0.981). The treatment toxicity equal to or greater than grade 3 included leukopenia; radiation esophagitis and pneumonitis. There were no significant differences between the two groups. Conclusions: There was no difference towards LRPFS, PFS, OS and toxicity between high-dose (60Gy) and low-dose (50Gy) group. A total radiation dose of 50Gy was recommended for definitive concurrent chemoradiation in ESCC. Clinical trial information: NCT01937208.
P39 Predictive Factors of Brain Metastases Development in Non-Small Cells Lung Cancer (NSCLC)
Authors: E. Richardet, E. Pacher, C. Eduardo, M. Cortes, M. Molina, P. Hernandez, L. Acosta, R. Brombin, G. Ferreira, L. Dicalbo, M. Richardet
Journal: Journal of Thoracic Oncology (2018)
An open-label, multidrug, biomarker-directed, multicentre phase II umbrella study in patients with non-small cell lung cancer, who progressed on an anti-PD-1/PD-L1 containing therapy (HUDSON).
Authors: John Heymach, Michael Thomas, Benjamin Besse, Patrick M. Forde, Mark M. Awad, Glenwood D. Goss, Keunchil Park, Naiyer A. Rizvi, Si-Houy Lao-Sirieix, Sabina I Patel, Peter G. Mortimer, Helen Ambrose, Philip John Jewsbury, Kris Sachsenmeier, Leila Khoja, Wolfram Brugger
Journal: Journal of Clinical Oncology (2018)

TPS3120 Background: Immune checkpoint inhibitor (ICI) containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, the majority of patients do not respond or have non-durable responses leading to a new ICI-resistant population. HUDSON addresses the urgent need to identify treatments and understand ICI-resistance for this emerging population. Methods: HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI-resistance and 2) define mechanisms of ICI-resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrolls ICI-resistant/refractory patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, Clinical trial information: NCT03334617.
Effect of mast cells on efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme b.
Authors: Mark Wroblewski, Janna-Lisa Velthaus, Raimund Bauer, Volkmar Müller, Christian Schem, Peter A. Fasching, Thomas Karn, Tanja N. Fehm, Thorsten Kühn, Brigitte Kathrin Rack, Carsten Denkert, Michael Untch, Kornelia Kittel, Melanie Janning, Sarah Minner, Guido Sauter, Carsten Bokemeyer, Gunter Von Minckwitz, Sibylle Loibl, Sonja Loges
Journal: Journal of Clinical Oncology (2017)

11522 Background: Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. As mast cell (MC) density is known to correlate with tumor angiogenesis, we analyzed if inhibition of MC holds potential to increase efficacy of AAT in mice and cancer patients. Methods: C57BL/6J (WT), NSG or MC-deficient Kit W-sh (Wsh) mice were subcutaneously injected with Panc02, EL4 or BxPC3 cells with or without bone marrow-derived MC. Tumors were treated with 20 mg/kg of anti-VEGFR2 antibodies (DC101) or 25 mg/kg cromoglicic acid. Tissue microarrays from n = 299 breast cancer patients from the GeparQuinto Phase 3 clinical trial were stained for MC and MC numbers were correlated with clinical data. Results: We observed that absence of MC reduced tumor growth and increased the efficacy of AAT in different tumor models. Intriguingly, AAT only initially reduced microvessel proliferation but this was abrogated over time as a result of MC-mediated resistance. We show that MC secrete increased amounts of granzyme b upon therapy, which mobilizes alternative pro-angiogenic factors from the tumor matrix. These factors act beside the targeted VEGFA-VEGFR2-axis and reinduce angiogenesis despite the presence of AAT. Importantly, MC-mediated resistance could be overcome using the FDA-approved MC inhibitor cromoglicic acid. In line with our preclinical data, high intratumoral MC density correlated with disease progression in HR+ breast cancer patients when Bevacizumab was added to standard neodjuvant chemotherapy (HR 8.45, p = 0.006). Accordingly, Kaplan-Meier curves indicated that disease free survival of patients with high tumoral MC density was numerically shorter in the whole cohort and significantly shorter in the HR+ cohort upon addition of AAT to chemotherapy (p = 0.168 and p = 0.004, respectively). Conclusions: Here we unravel a novel resistance mechanism, by which MC hamper efficacy of AAT in mice and cancer patients. In preclinical models this effect could be overcome by combining AAT with an FDA-approved MC inhibitor indicating high clinical relevance. Thus, combination of FDA-approved MC inhibitors with AAT might be a suitable approach to increase efficacy of AAT in the clinic.
Does HPV ISH add to the diagnostic performance of P16 IHC in oropharyngeal cancer? Is it worth the extra cost?
Authors: Nagashree Seetharamu, Isabel Ruth Preeshagul, Doru Paul, Sewit Teckie, Nina Kohn, Douglas Frank
Journal: Journal of Clinical Oncology (2016)

6065 Background: Human Papilloma Virus (HPV) related oropharyngeal squamous cell cancer (OPSCC) is distinct from that attributable to tobacco use, with better prognosis and treatment response. While HPV status doesn't currently influence treatment decisions, clinical trials are exploring de-intensification strategies for HPV+ OPSCC. While no gold standard tests exist, immunohistochemistry (IHC) for P16, which is a surrogate marker for HPV and HPV DNA in-situ hybridization (ISH) are commonly used for determining HPV status. Discordance between these tests is frequent, and no guidelines exist with regards to their use. As we advance towards HPV-specific protocols, accurate assessment of HPV status is essential. We evaluated the concordance of HPV P16 and HPV ISH for OPSCC, with special focus on never-smokers, in who tumors are likely HPV-related. Methods: Charts of patients with OPSCC diagnosed between 2012 and 2014 were reviewed. Data included age, gender, stage, smoking, primary site, and HPV status. Descriptive statistics were used to summarize the data. Results: 50 patients were analyzed. 39 were male (78%) and median age was 61.5 years. Most common primary site was base of tongue (n = 28, 56%) followed by tonsil (n = 19, 38%). Most patients had advanced disease: 16 stage III (32%), 31 stage IVA (62 %), 1 stage IVB (2%). P16 IHC was performed in 48 (96%) and ISH in 43 (86%). Wide spectrum (WS) ISH was utilized in 23 (46%) and HPV 16/18 ISH in 23 (46%). P16 stained strong and diffuse in 35 (70%) and weak in 5 (10%). HPV ISH was positive in 20 (40%); 9 WS and 11 HPV 16/18. All HPV ISH positive tumors stained for P16 (100%). Amongst never-smokers (n = 20), P16 was diffusely positive in 19/19 tested (100%), whereas HPV ISH was positive in 8/17 (47%). Conclusions: Discordance between P16 IHC and HPV ISH is high. P16 is more sensitive in never-smokers. We conclude that HPV ISH has low utility and recommend the utilization of P16 IHC only for diagnostic and prognostic purposes in OPSCC pending availability of improved testing techniques.
Incidence of peripheral neuropathy in patients with colorectal cancer receiving oxaliplatin alone vs. radiation therapy and oxaliplatin.
Authors: Matthew Blake Lockwood, Krishna Prasad Joshi, James Mobley, Suneetha Sampath, Eric R Siegel, Rangaswamy Govindarajan
Journal: Journal of Clinical Oncology (2017)

e18281 Background: Peripheral sensory neuropathy (PN) is a known dose limiting toxicity of oxaliplatin, used to treat patients with colorectal cancer. Patients with rectal cancer receive radiation therapy (RT) in addition to oxaliplatin in adjuvant setting. Pelvic radiation causes plexopathy due to demyelination, ischemia due to blood-vessel injury, and nerve fibrosis. To assess if RT increases the incidence of peripheral neuropathy, we conducted an analysis of patients with colorectal cancer treated with oxaliplatin alone vs. oxaliplatin and radiation. Methods: A retrospective analysis of subjects with stages II, III, and IV rectal (R) and colon (C) cancer from 2005 to 2014 was conducted. Only subjects receiving O with or without RT were included. The incidence of PN was compared for increase in subjects receiving both O and RT compared to O alone via one-sided chi-square tests at 5% alpha, both overall and after subgrouping by stage. Results: Out of 261 subjects analyzed, 158 met the study’s criteria. There were 97 C (all received only O) and 61 R (10 received only O; 51 received O+RT). PN occurred in 37% (19/51) of subjects receiving O+RT compared to 22% (24/107) receiving only O ( P= 0.025). In Stage II-III disease, PN occurred at nearly equal rates of 36% (14/39) in subjects receiving O+RT and 33% (16/46) in subjects receiving O only ( P= 0.457). However, in Stage IV disease, PN occurred in 42% (5/12) of subjects receiving O+RT compared to 13% (8/61) of subjects receiving only O ( P= 0.009). Conclusions: In our study, the incidence of PN was higher in subjects receiving both RT and O compared to O alone. Although our study did not show higher PN in stages II and III disease, patients with rectal cancer may have residual neurotoxicity from previous radiation and the subsequent exposure to oxaliplatin may be contributing to the cumulative toxicity. [Table: see text]
TCT-131 Hemopericardium and Cardiac Tamponade As a Complication of Vena Caval Filters: Systematic Review of Published Literature and the MAUDE Database
Authors: Behnood Bikdeli, Ajay Jayant Kirtane, David Jimenez, Philip Green, William Kuo, Harlan Krumholz, Sahil Parikh
Journal: Journal of the American College of Cardiology (2018)
Comparison of response to chemotherapy in non-Hodgkin lymphoma patients depending on their myeloid derived suppressor cell status: Insight on new immune target.
Authors: Kalyan Kusum Mukherjee, Sarbari Ghosh, Subhom Halder, Madhurima Sarkar, Shayani Dasgupta, Mohona Chakraborty, Anamika Bose, Rathindranath Baral
Journal: Journal of Clinical Oncology (2017)

e23155 Background: Non Hodgkin’s Lymphoma shows different disease status after completion of standard 1st line treatment. Low grade follicular lymphoma remains stable after standard treatment for a long time and some times it autoregress . In High grade Lymphoma (Commonly diffuse B-cell lymphoma) relapsed 30-40% after 1 st line treatment. Immunological target for this differentiation in tumor biology is sought for. Methods: Twenty Five CD20 + NonHodgkin's Lymphoma(NHL) patients and one T cell lymphoma were treated with standard chemotherapy (6-8 cycles of RCHOP/CHOP). Within these 25 patients, 10 patients were disease free or exhibited stable disease for two years following the completion of treatment. Rest of the patients showed early relapse (within 6 months) or late relapse (within 18 to 24 months). Eight among 10 disease free patients was suffering from NHL of low grade follicular type. In order to correlate the immune cell status with lymphoma relapse, we have studied a panel of T cells, memory T cells, suppressor cells, after completion of chemotherapy and subsequently in every 6 month interval till relapse. Among several parameters studied a direct correlation between myeloid derived suppressor cells (MDSCs) profile and relapse was noted. Results: CD33 + CD11b + MDSCs were remarkably high in high grade NHL patients in comparison to disease free low grade follicular lymphoma patients (p &lt; 0.01). Moreover, all of these NHL patients possessed significantly greater proportion of MDSCs than normal healthy individuals (p &lt; 0.001). Interestingly, single responding T cell lymphoma patient showed completely normal level of MDSCs. Studies are also being conducted to correlate with the status of memory T cells with disease relapse. Conclusions: Observed correlation between greater proportions of MDSCs with the relapse of diseases suggest MDSCs might be the potential target to enhance the relapse free survival of NHL patients, thus, demands further extensive investigation.
A novel quality improvement approach to measure, benchmark, and feedback multiple clinical oncology practices.
Authors: John Williamson Peabody, David Paculdo, Diana Tamondong-Lachica, Jhiedon Florentino, Othman Ouenes, Riti Shimkhada, Lisa DeMaria, Trever Bradley Burgon
Journal: Journal of Clinical Oncology (2016)

e18173 Background: One important factor that affects clinical outcome is the quality of care delivered by a provider at the bedside. Evidence-based guidelines and pathways have been developed to lower cost and improve quality of care and ultimately outcomes. Despite the promise of advancing practice, these guidelines and pathways alone have shown mixed results or fallen short in increasing adherence to quality of care. Methods: The study focused on measuring variation and improving care quality for common types of breast cancer at four sites across the United States, using a set of 12 Clinical Performance and Value (CPV) vignettes per site. The vignettes simulated online cases that replicate a typical visit by a patient as the tool to engage breast cancer providers and to identify and assess variation in adherence to evidence-based practice guidelines and pathways. The outcomes of interest were overall and domain (history, physical, workup, and diagnosis with treatment plan) adherence to evidence-based guidelines, and areas of care in the management of breast cancer: surgery, axillary management, radiation therapy, chemotherapy, and hormonal therapy. Results: In total, 81 providers participated in all three study rounds. After completion of three rounds of CPV measurement, benchmarking and feedback, we found that overall scores had increased significantly between the baseline round and the final round (P < 0.001) overall and for all domains. By the end, the workup domain had an increase of nearly 18% (P < 0.001), while the diagnosis with treatment plan domain had increased by more than 16% (P < 0.001), both versus baseline. In areas of care, axillary management showed broad increases in adherence across all four sites. Chemotherapy, radiation therapy, and surgery all showed > 10% increased adherence in three of four sites by the end of the study, while hormonal therapy adherence proved the most difficult to improve with only one site showing marked increases. Conclusions: We found that serially engaging breast cancer providers with a validated clinical practice engagement and measurement tool markedly increased quality scores and adherence to clinical guidelines in the simulated patients.
Intravenous ferric carboxymaltose treatment in cancer patients.
Authors: Alma Aslan, Vildan Tasdemir, Neyran Kertmen, Omer Dizdar, Sercan Aksoy
Journal: Journal of Clinical Oncology (2016)

e21597 Background: Iron deficiency (ID) and anemia are frequent comorbidities in patients with a variety of cancers. The negative impact of anemia on physical performance and anti-tumor therapy is well known. Administration of intravenous (IV) iron is a therapeutic option in cancer patients with iron-deficiency related anemia. This study evaluated data on the effectiveness and tolerability of ferric carboxymaltose in cancer patients with iron deficiency anemia. Methods: This is a single-center retrospective study of 134 patients who were treated for anemia and iron-deficiency in cancer patient population from October 2014 to December 2015. They received one dose of ferric carboxymaltose between 500-2000 mg verified by serum iron, ferritin and transferrin saturation (TSA). Results: The median age in this population was 58 (23-90) years, and 52% were male. Of 134 patients, 53.7% (n = 72) had gastrointestinal malignancies and 42.5% (n = 57) had metastatic disease. Most patients received cytotoxic chemotherapy 83 (62 %), and 51 (38 %) patients were not on anti-cancer treatment. Median dose of the ferric carboxymaltose is 1000 mg (500-2000). The median baseline hemoglobin, ferritin and TSA were 10.7 (8-13) g/dl, 26 (2.9-1791) ng/ml and 7 (1-18) %, respectively. The median increase in hemoglobin was 1.9 (0.3-6.9) g/dl in all patients and 2.1 (-0.10-6.9) g/dl in patients whom received cytotoxic chemotherapy. 9 (6.7%) patients received RBC transfusions during chemotherapy. One patient had allergic reaction during IV ferric carboxymaltose administration and we stoped therapy. Conclusions: Intravenous-iron improved hemoglobin in cancer patients with iron deficiency anemias even patients who treated with chemotherapy. This approach is safe and tolerable. This treatment is patient friendly especially in patients receiving chemotherapy. However, the impact of tumor progression on IV iron replacement is unclear, further studies are required.
Adoptive cellular immunotherapy with APN401, autologous cbl-b silenced peripheral blood mononuclear cells: Data from a phase I study in patients with solid tumors.
Authors: Hans Loibner, Guenther Lametschwandtner, Kerstin Westritschnig, Oliver Mutschlechner, Alexander Dohnal, Marc Oliver Salzberg, Pierre L. Triozzi
Journal: Journal of Clinical Oncology (2018)

3055 Background: Casitas-B-lineage lymphoma protein – b (cbl-b), an E3 ubiquitin ligase is an important intracellular checkpoint limiting activation of lymphocytes and NK cells. Silencing of cbl-b enhances T cell and NK cell antitumor activity in mouse tumor models and in-vitro in human immune cells. APN401, an autologous cellular therapy consisting of ex-vivo cbl-b-silenced PBMCs, was evaluated in patients with solid tumors. Methods: Patients with metastatic solid tumors not eligible for standard therapies were included. Patients with autoimmune disease or requirement for immunosuppressive drugs were excluded. PBMCs were obtained by leukapheresis and were transfected with cbl-b- siRNA ex vivo by electroporation, and 5, 10 or 50 x 105 /PBMCs/kg were infused once shortly thereafter over 30 min. Results: 16 patients were treated with APN401. As a consequence of cbl-b silencing, all patient PBMC preparations produced enhanced amounts of cytokines IL-2 and IFN-g upon TCR stimulation in vitro. Moreover, evaluation of patient PBMCs responses to common tumor antigens were stronger over the course of the follow-up period. Four patients (2 pancreas 1colon cancer, 1 renal cancer) had stable disease as best tumor response during the study. The strongest response to tumor antigens was observed in the patient with the best objective clinical response (metastatic colon cancer; disease stabilization > 1 year). Infusions were well tolerated. Dose-limiting toxicities were not observed. Mild chills were the most commonly observed related adverse event, followed by mild anemia and fatigue. There was no immediate hypersensitivity or evidence for autoimmune adverse effects. Conclusions: Cbl-b-silenced PBMCs (APN401) from cancer patients respond to TCR stimulation and activation with tumor antigens. Strongest cell activation was seen in the patient with the best objective clinical response. 50 x 105 / kg APN401 was safe and well tolerated. Multiple infusions of APN401 are currently clinically tested. Clinical trial information: NCT03087591.
TCT-10 Physiological Versus Angiographic Guidance for Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation.
Authors: Mattia Lunardi, Roberto Scarsini, Gabriele Venturi, Gabriele Pesarini, Andrea Gratta, Anna Piccoli, Valeria Ferrero, Flavio Ribichini
Journal: Journal of the American College of Cardiology (2018)