tbuckley/cabot-search huggingface dataset:
Is the neutrophil-lymphocyte ratio (NLR) a predictive and prognostic factor in rectal cancer patients treated with neoadjuvant chemoradiation (nCRT)?
Authors: Ui Sup Shin, Y. Nancy You, Brandee A. Price, Miguel A. Rodriguez-Bigas, John Michael Skibber, Dipen M. Maru, Melissa W. Taggart, Scott Kopetz, Cathy Eng, Bruce D. Minsky, Prajnan Das, Sunil Krishnan, George J. Chang
Journal: Journal of Clinical Oncology (2016)

3605 Background: Response to nCRT is a key prognostic indicator for rectal cancer and may be influenced by the systemic inflammatory response. The purpose of this study was to determine the relationship between pre- and post-treatment NLR and nCRT treatment response and prognosis among patients with locally advanced rectal cancer. Methods: The primary medical records of a consecutive cohort of localized rectal cancer patients treated with nCRT and surgical resection at a single tertiary institution between 1/1998 to 6/2015 were reviewed and the pre- and post-nCRT NLR was recorded. The association of NLR with tumor response and recurrence free survival (RFS) were assessed using logistic (tumor response) and Cox (survival) multivariable regression. Results: A total of 927 patients were analyzed. Median follow-up was 49 months (IQR 23-74). There were 162 (17.2%) patients with complete response (ypT0N0, CR) and 505 (54.5%) with poor response (ypT3/4 or N+, PR). nCRT was associated with an increase in the NLR: mean pre-nCRT NLR = 3.0 (±2.4); post-nCRT NLR = 5.6 (±5.7) (p < 0.0001). Mean pre-nCRT NLR was lower in CR (2.7 ±1.6) than non-CR (3.1 ±2.6) patients, p = .01; however post-nCRT NLR was not different between the response groups. After adjusting for covariates, pre-nCRT NLR ≥ 5 was significantly associated with lower rate of complete treatment response (OR 0.35, p = 0.027). However, only the post-nCRT NLR, and not the pre-, was associated with RFS (HR; 1.74, 95% confidence interval; 1.26-2.42, p = 0.001). Conclusions: The NLR in rectal cancer patients is both predictive of tumor response to nCRT and prognostic for recurrence free survival. It may therefore be considered for identifying patients eligible for novel organ preserving treatment strategies reliant upon good pathologic response to nCRT and for the delivery of personalized rectal cancer care.
TCT-783 Procedural and Clinical Outcomes of Newer Generation Transcatheter Aortic Valves Vs. First Generation Transcatheter Aortic Valves
Authors: Carlos Giuliani, Matias Sztejfman, Henrique Ribeiro, Carlos Sztejfman, Marcelo Bettinotti, Fernando Cura, Antonio Dager, Gabriel Maluenda, Rogerio Sarmento-Leite
Journal: Journal of the American College of Cardiology (2018)
Demographic, clinical and geographical factors associated with lack of receipt of recommended chemotherapy.
Authors: Parijatham S. Thomas, Caleb Class, Tanmay Gandhi, Arvind Bambhroliya, Kim-Anh Do, Abenaa M. Brewster
Journal: Journal of Clinical Oncology (2018)

e13563 Background: There have been significant advances in the systemic treatment of breast cancer over the past decade. Identifying factors associated with disparities in the receipt of chemotherapy may improve breast cancer mortality. The Texas Cancer Registry (TCR) is a population based registry of cancer cases which collects data on whether chemotherapy was recommended by the treating physician and received by the patient. The objective of this study was to assess demographic, clinical, and geographical factors associated with lack of receipt of recommended chemotherapy (RRC) and its association with breast cancer mortality. Methods: The TCR was used to identify women age ≥ 18 with invasive breast cancer diagnosed from January 1st, 2007 to December 31st, 2011. Multivariate logistic regression was used to determine the associations between age, race/ethnicity, poverty level, disease stage, estrogen/progesterone receptor/HER2 status and lack of RRC. Cox regression was used to assess for association of lack of RRC with breast cancer mortality. Spatial analysis of geographical areas associated with lack of RRC adjusted for age, race/ethnicity, and poverty index was conducted using SaTScan. Results: 63,067 breast cancer cases were identified and 38.7% were recommended chemotherapy. Of these cases (n = 24,383), 83.4% received recommended chemotherapy, 5.1% did not receive chemotherapy, and 11.4% was unknown. Older age (p < .001), residence in areas with > 20% poverty (p < .001) and early disease stage (p < .001) were associated with lack of RRC (p < 0.001). In adjusted cox regression analysis, lack of RRC was associated with increased breast cancer mortality (Hazard ratio 1.42, 95% CI 1.25-1.62). Spatial analysis revealed a cluster of 40 counties in West Texas with lower odds of RRC when compared to the rest of Texas (relative risk 0.88, p < .001). Conclusions: The majority of breast cancer patients in Texas receive chemotherapy when recommended by a physician. Identifying and addressing barriers to the receipt of physician recommended chemotherapy associated with older age, increased poverty and specific geographical areas could lead to improvements in breast cancer mortality.
CUDC-907, a dual HDAC and PI3K inhibitor, to inhibit cancer progression both in high and low grade ovarian carcinoma cell lines.
Authors: Marufa Rumman, Ira Seth Winer
Journal: Journal of Clinical Oncology (2018)

e17556 Background: Targeting single pathways in high grade (HG) and low grade (LG) ovarian cancer (OVCA) has provided only incremental improvements in survival. Therefore, identification of novel agents which can target global processes and overcome chemotherapy resistance is critical in recurrent or persistent disease to provide true survival advantages. CUDC-907 is a novel, orally bioavailable, well tolerated, small molecule inhibitor of both Histone Deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), currently in clinical trials for lymphoma. We hypothesized that CUDC-907 would effectively treat both HG/LG-OVCA. Methods: Confirmation of HDAC and PI3K pathway inhibition was performed via Western Blot (WB). Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Necrosis and Apoptosis were studied utilizing Realtime Glo Apoptosis/Necrosis assay (Promega) and flow cytometry in addition to WB analysis. Cell cycle progression was also assessed via Flow cytometry. Results: CUDC-907 significantly inhibited cell viability and migration both in HG and LG OVCA cell-lines in a time and dose dependent manner with IC50’s ~100 nM for both cisplatin sensitive and resistant cell lines and LG-OVCA primary cell lines. In addition, treatment increased the sub-G1 population with increased levels of cleaved PARP, BIM protein expression as well as DR5. Two major signaling pathways, PI3K/AKT/mTOR and Ras/Raf/MEK/ERK were suppressed by CUDC-907 treatment with HDAC inhibition confirmed as well. Conclusions: Our findings demonstrate that CUDC-907 can effectively treat both HG and LG-OVCA cells in vitro via combined HDAC inhibition and blockade of PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways leading to classical apoptosis. This is a promising agent in ovarian cancer therapy and will be studied further in in vivo studies and should be considered for clinical translation.
High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008
Authors: Jeremy Whelan, Marie-Cecile Le Deley, Uta Dirksen, Gwénaël Le Teuff, Bernadette Brennan, Nathalie Gaspar, Douglas S. Hawkins, Susanne Amler, Sebastian Bauer, Stefan Bielack, Jean-Yves Blay, Stefan Burdach, Marie-Pierre Castex, Dagmar Dilloo, Angelika Eggert, Hans Gelderblom, Jean-Claude Gentet, Wolfgang Hartmann, Wolf-Achim Hassenpflug, Lars Hjorth, Marta Jimenez, Thomas Klingebiel, Udo Kontny, Jarmila Kruseova, Ruth Ladenstein, Valerie Laurence, Cyril Lervat, Perrine Marec-Berard, Sandrine Marreaud, Jean Michon, Bruce Morland, Michael Paulussen, Andreas Ranft, Peter Reichardt, Hendrik van den Berg, Keith Wheatley, Ian Judson, Ian Lewis, Alan Craft, Heribert Juergens, Odile Oberlin
Journal: Journal of Clinical Oncology (2018)

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.
Epigenetic control of CD4/CD8 lineage commitment and resistance to tumor infiltrating lymphocyte adoptive cell therapy for metastatic melanoma.
Authors: David Michael Woods, Anders E. Berglund, Amod Sarnaik, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2016)

3008 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) is an effective approach for the treatment of metastatic melanoma, with objective response rates of approximately 50%. An increased understanding of the factors contributing to resistance to this promising therapy is needed. Methods: To determine the role of epigenetic mechanisms in TIL responses, cell infusion products from patients undergoing TIL ACT were separated by magnetic labeled antibodies into CD4 and CD8 populations, and assessed by an Illumina 450K DNA methylation array and chromatin immunoprecipitation of acetylated histone 3 with sequencing. Patient tumor samples were also assessed on a Nanostring platform for epigenetic gene and miR expression. The percentage of CD4 and CD8 T cells in TIL were assessed by flow cytometry. Results: Significant differences in DNA methylation of genes controlling CD4 lineage (CD4, CD8, RUNX3, XCL2, ZBTB7B) were found between responders (R) and non-responders (NR) (p < 0.05). Using a CD4/CD8 differentiation signature, principal component analysis (PCA) revealed clustering based on response, with NR CD8 T cells more closely resembling CD4 T cells (p < 0.05). PCA of acetylated histone 3 also showed differences between R vsNR (p < 0.05). Nanostring analysis of tumor fragments showed decreased expression in NR in several epigenetic regulatory genes including DNA methyltransferases (DNMT1, DNMT3A) and histone deacetylases (HDAC8, SIRT4)(p < 0.05). MiR-148 and miR-185, known regulators of DMNT1, were increased in accordance with the patterns seen for DNMT1, a known regulator of CD4/CD8 lineage commitment. Higher levels of CD4/CD8 double positive TILs were found in NR infusion products. Conclusions: These results demonstrate that resistance to TIL therapy is characterized by altered DNA methylation and histone acetylation patterns accompanied by differences in genes regulating these marks. It is hypothesized that epigenetic dysregulation of CD4/CD8 lineage impairs the therapeutic efficacy of TIL therapy. These data highlight an unexplored mechanism of T-cell dysfunction characterizing resistance to TIL ACT.
TCT-150 Cardiovascular disease and percutaneous coronary intervention in hematological malignancies: knowledge is power
Authors: David Boone, Dominique Monlezun, Frances Cervoni-Curet, Jawad Chohan, Jennifer Sunny, Karan Bhatti, Gloria Iliescu, Teodora Donisan, Dinu Balanescu, Nicolas Palaskas, Juan Lopez-Mattei, Saamir Hassan, Peter Kim, Konstantinos Marmagkiolis, Cezar Iliescu
Journal: Journal of the American College of Cardiology (2018)
P01.068 The anti-tumor effect of androgen receptor antagonist on GBM may result, at least partially, through attenuation of CDK4 and CDC14a expression
Authors: N Zalcman, A Mordechai, A Lossos, I Lavon
Journal: Neuro-Oncology (2018)

We have recently demonstrated that genetic silencing and pharmacological inhibition of androgen receptor (AR) in GBM cell lines induce GBM cell death. Furthermore, enzalutamide (AR antagonist) given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027). This point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease. To elucidate the mechanistic role played by AR in GBM, three GBM cell lines (U87MG, A172, and T98G) were treated with either dihydrotestosterone (DHT) or with elevation concentrations of AR antagonist. Additionally, the cells were transfected with siRNA against AR to knock down its expression. Total RNA was extracted from the various study groups and relevant controls and were subjected to nanostring pancancer pathway array. Gene expression profile of the untreated cells was compared to the manipulated GBM cells. Analysis of the array results revealed that either pharmacological inhibition of AR as well as genetic silencing of the receptor in GBM cell lines reduced the expression of CDK4 and CDC14a; both are involved in cell cycle progression. These results were further validated by qPCR. Analysis of several datasets including the TCGA, using Oncomine™ software revealed that these genes are significantly amplified in GBM and were shown before to be involved in GBM cell cycle progression. This study suggest that the antitumor effect of androgen receptor antagonist on GBM may result, at least partially, through attenuation of CDK4 and CDC14a expression. Additional research is needed to elucidate the mechanism of action of AR in GBM and to clarify the involvement of CDK4 and CDC14a in AR induced cell cycle progression.
Molecular testing in advanced non-squamous NSCLC in a community setting.
Authors: James J. Kim, Ann E Leiss, Alejandro R. Calvo
Journal: Journal of Clinical Oncology (2018)

e21204 Background: Genomic testing became an important tool for the individualized treatment of lung cancer. With the availability of predictive biomarkers, such as EGFR, it is possible to identify patients who would benefit from personalized therapy and therefore have longer survival and better QOL. Despite that, about 1 in 4 patients with advanced NSCLC in North America does not undergo molecular testing. The main focus of this study was to assess the prevalence of EGFR testing in patients diagnosed with non-squamous NSCLC (ns-NSCLC) in a community-based network, as well as the impact of its results. In addition, it aimed to identify specific barriers that impede adequate biomarker testing. Methods: This retrospective study evaluated the prevalence of EGFR testing in all patients diagnosed with advanced ns-NSCLC during a 30 month period at Kettering Health Network (KHN) in Southwest Ohio. Data was obtained via electronic medical records of the hospitals and pathology laboratories. Results: Of the 178 patients diagnosed with advanced ns-NSCLC, 152 (85.4%) underwent EGFR biomarker testing. Positive EGFR mutations were found in 20 patients (11.8%), 7 cases had exon 19 deletion, 6 cases had exon 21 L858R mutation, 7 had uncommon mutations in exons 20, 18 and 10. Insufficient tissue was reported in 7 patients (4.6%). Fourteen of the 20 patients were treated with targeted therapy in accordance with national guidelines. Six patients went directly to hospice or refused therapy. One patient with exon 20 mutation received chemotherapy. Conclusions: The rate of EGFR testing in the KHN was higher than reported by other community centers, yet 15% of patients were not tested as recommended. Molecular testing presents multiple logistical obstacles for the community-based oncologist, including long turnaround times, cost, insufficient tissue, and the resulting potential complications from repeat biopsies. Reflex testing could be a way to ensure that patients have timely access to targeted therapy. Also, implementation of new technologies such as plasma-based testing should be explored. Ultimately, our study strives to promote knowledge of the importance of molecular testing and thereby, ensure adequate treatment for eligible patients.
Who are the high risk medulloblastoma subgroups in Jordan?
Authors: Nisreen Yousef Amayiri, Maisa Swaidan, Ahmad Ibrahimi, Nader Hirmas, Awni Musharbash, Eric Bouffet, Maysa Al-Hussaini*, Vijay Ramaswamy*
Journal: Journal of Clinical Oncology (2018)

e22506 Background: Medulloblastoma is comprised of four distinct molecular subgroups (Wnt, SHH, Group3 ,Group4) with unique clinical and prognostic implications. However, this relationship is rarely reported in the Middle East. Methods: We assembled an institutional cohort of children < 18 years diagnosed with medulloblastoma and received radiotherapy at KHCC/Jordan between 2003-2015 and subgrouped tumours using limited gene expression analysis. Results: Eighty-one patients were identified (36% females) with median age 7.3years (2.9-17.6years). Twenty-six patients (32%) were M1-M3. Twenty-eight patients were treated as standard risk (SR, 47%) and 43 as high risk (HR, 53%). Subgrouping revealed 27 Group4 (33%), 20 SHH (25%), 20 Group3 (25%) and 14 Wnt (17%). The median time between craniotomy and radiotherapy was 45 days (17-155days). Median duration of radiotherapy was 44days (36-74days). Overall 5year EFS was 70.5± 6% and OS 68.8± 6.1%; statistically not significant between SR and HR (p = 0.1). Absence of metastasis had survival advantage (OS 81.3±6.9% for M0 and 43.6±11% for M1-M3, p = 0.001). SHH and Group4 tumors had very good OS (79.7± 10.7% and 81.5± 9.8% respectively). Metastatic Group4 did very well (OS 80± 17.9%) while metastatic Group3 had dismal OS (33.3±13.5%). Unexpectedly, Wnt patients had relatively poor OS (67.9± 15.9%). Conclusions: SHH and Group4 medulloblastomas had an excellent survival comparable to developed countries despite treatment delays. Strikingly, we observed lower survival of Wnt subgroup, suggesting possible background differences compared to other cohorts. This highlights the importance of validation of molecular stratification in the developing world, and suggests that background genetic differences may underlie differences in therapy response.
Efficacy of the addition of cisplatin to single-agent first-line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC): A joint analysis of the multicenter, randomized phase III MILES-3 and MILES-4 studies.
Authors: Cesare Gridelli, Alessandro Morabito, Luigi Cavanna, Andrea Luciani, Paolo Maione, Laura Bonanno, Elena Piazza, Silvana Leo, Saverio Cinieri, Fortunato Ciardiello, Marco Angelo Burgio, Domenica Ferrara, Diego Cortinovis, Francesco Rosetti, Agnese Montanino, Anna Manzo, Gennaro Daniele, Francesco Perrone, Ciro Gallo, Maria Carmela Piccirillo
Journal: Journal of Clinical Oncology (2017)

9002 Background: The role of platinum in first line treatment of elderly patients with advanced NSCLC is still debated. We tested its efficacy in two parallel phase 3 trials. Methods: Advanced NSCLC patients, &gt; 70 years, ECOG performance status 0-1, were eligible. In MILES-3 (started in 2011) patients with any tumor histology were randomly assigned 1:1 to cisplatin/gemcitabine (C 60 mg/m² d1, G 1000mg/m² dd1,8) or gemcitabine (G 1200 mg/m² dd1,8). In MILES-4 (started in 2013 with a factorial design) patients with non-squamous histology were randomly assigned 1:1:1:1 to CG, G, cisplatin/pemetrexed (C 60 mg/m² d1, P 500 mg/m² d1) or pemetrexed (P 500 mg/m² d1). Six cycles were planned. In each trial, to have 80% power in detecting a HR of death 0.75 (corresponding to 3-month prolongation of median survival), with 0.05 two-tailed α, 382 events were required. The two trials were closed prematurely because of slow accrual but a joint analysis allowed to properly perform the final analysis, according to IDMC advice. Analysis was based on intention-to treat and adjusted by possible confounding factors. Results: From Mar 2011 to Aug 2016, 531 patients (MILES-3: 299, MILES-4: 232) were assigned to cisplatin-doublet (n = 263) or single-agent chemotherapy (n = 268). Median age was 75, 79% were male, 70% had non-squamous histology. Median number of cycles was 4 and 3 with and without cisplatin, respectively. With a median follow-up of 2 years, 384 deaths and 448 progression-free survival (PFS) events were reported. With and without cisplatin, median OS was 9.6 vs 7.5 months (HR 0.86, 95% CI: 0.70-1.04, p = 0.14); median PFS was 4.6 vs 3.0 months (HR 0.76, 95% CI: 0.63-0.92, p = 0.005); response rate was 15.5% vs 8.5% (p = 0.02). Significantly more severe hematologic toxicity and fatigue were reported with cisplatin. Conclusions: Although improving PFS and response rate, addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival of elderly patients with advanced NSCLC. QOL data will be reported separately. Partially supported by AIFA (grant FARM8KAJZK) and Eli Lilly. Clinical trial information: NCT01405586 and NCT01656551.