tbuckley/cabot-search huggingface dataset:
Safety evaluation of nivolumab (Nivo) concomitant with cetuximab-radiotherapy for intermediate (IR) and high-risk (HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG 3504.
Authors: Robert L. Ferris, Maura L. Gillison, Jonathan Harris, A. Dimitrios Colevas, Loren K. Mell, Christina Kong, Richard Jordan, Kevin Moore, Minh Tam Truong, Claudia Kirsch, David Anthony Clump, James Ohr, Kai He, Dukagjin Blakaj, John F. Deeken, Mitchell Machtay, Walter John Curran, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2018)

6010 Background: Nivolumab, which inhibits the programmed death-1 (PD-1) receptor, improved survival for patients (pts) with platinum-refractory recurrent/metastatic HNSCC compared with standard therapy. This trial evaluates the safety of adding nivo to 4 standard radiotherapy (RT) regimens for pts with newly diagnosed IR/HR HNSCC (Table). Safety data for cohort 3 (cetuximab) are reported. Efficacy data for cohorts 1, 2, and 3 will be reported at the presentation. Methods: Eligibility includes IR (p16+, oropharynx (OP) T1-2N2b-N3/T3-4N0-3, >10 pack-years (pys) or T4N0-N3, T1-3N3 ≤10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) OP, stage T1-2N2a-N3 or T3-4N0-3). 10 pts are enrolled to obtain 8 evaluable pts. Primary endpoint is dose-limiting toxicity (DLT), defined as nivo-related: ≥grade 3 adverse event (AE) unresolved to ≤grade 1 in ≤28 days; RT delay >2 wks; incomplete RT; or inability to receive ≥70% of cetuximab. DLT window was from first nivo dose (day -14) to 28 days post RT. >2 DLTs in 8 evaluable pts is unacceptable. Results: Of 10 enrolled pts for cohort 3: median age 61.5, 80% male, 70% Caucasian, 70% PS 0, 80% >10 pys, 60% p16(+) OP cancer, 60% T3-4 and 100% N2-3 disease. 1 pt was inevaluable for DLT due to withdrawal of consent and 1 pt has not yet completed the DLT observation period. 1 DLT (mucositis) was reported in 8 evaluable pts; 1 other grade 3 AE attributed to nivo was reported (lipase increase) but was not a DLT. 11 SAEs in 3 pts, but none nivo-related. 7/8 pts completed RT, 7/8 pts completed cetuximab; 5 pts completed 10 concurrent doses of nivo, 1 pt received 6 doses, 1 pt 7 doses, and 1 pt is ongoing after 8 doses. Conclusions: Nivo is safe and feasible to administer concomitant with a cetuximab-RT regimen for patients with newly diagnosed IR/HR HNSCC. Clinical trial information: NCT02764593.Cohort Cis Eligible Nivo C: concurrent A: adjuvant Chemotherapy RT IMRT 70 Gy/7 wk N enrolled 1 Y C: 240 mgs q14d X10 A: 480 mgs q28d X7 Weekly Cis (40 mg/m2) Y 10 2 Y C : 240-360 mg q21d X6 A : 480 mg q28d X7 High dose Cis (100 mg/m2 q 21d) Y 10 3 Y C: 240 mgs q14d X10 A: 480 mgs q28d X7 Cetuximab Y 10 4 N C: 240 mgs q14d X10 A: 480 mgs q28d X7 -- Y 5
Survival and side effects from novel alternative regimen for squamous cell head and neck cancer.
Authors: Rohit Bishnoi, Harini Bejjanki, Jeffery A Bennett, David Reisman, Chintan Shah
Journal: Journal of Clinical Oncology (2017)

e17515 Background: Toxicity of the standard regimens is a major limitation in treatment of head/neck cancer which impacted about 61,000 persons in 2016 in USA of which 13,000 died. We present data herein with low dose chemotherapy (metronomic) using commonly used drugs Taxols, Platins, 5-Flurouracil and EGFR inhibitors. We achieved equal or better outcomes as compared to standard dosing with minimal side effects (level 3/4). Methods: This is a retrospective study on squamous cell head and neck cancer patients where standard first line therapies were started at ½ normal dosing and was increased until the emergence of side effects and titrated thereafter. Results: Patient population consisted of 32 patients with 87% males and with median age 65.2 years where 59% had recurrent disease, 71% locally advanced and 28% had metastatic disease. Total 270 chemotherapy cycles were delivered among these 32 patients with median of 9 cycles. Median dose for Cispatin was 45mg/m2, Paclitaxol was 80mg/m2, 5-FU was 360mg/m2/day. Cetuximab was used at standard doses. 6 patients who achieved long-term disease control were then placed on immunotherapy with either Nivolumab (median dose of 3mg/kg) or Pembrolizumab (median dose of 2mg/kg) and got median of 7 cyles. Out of 32, 9 patients (28%) achieved complete remission, 3 patients (9%) achieved near-complete remission with more than 95% reduction in tumor size. Overall disease control rate was 68% and overall response rate was 59%. Out of 9 patients who achieved complete remission 5 underwent surgical exploration and 1 went for cryo-ablation and no residual tumor was found. Measuring tumor volume in patients who achieved disease control showed volume reduction of 53%, 62% and 78% in 1 st , 2 nd and 3 rd follow up surveillance studies at mean interval of 101 , 186 and 331 days showing steady response. Median Progression free survival was 17.8 months and overall survival at 40 months was 54%. Notable high-grade toxicities were generalized fatigue in 12.5% (n = 4), grade 3 neutropenia in 18% (n = 6) and grade 4 neutropenia in 1 patient. Conclusions: These excellent results, low toxicity and subsequent good quality of life encourage patient tailored approach rather than one-size fits all approach.
Differing pattern of biological characteristics of early operable primary breast cancer according to age.
Authors: Binafsha Manzoor Syed, Andrew R. Green, Dal Morgan, Ian O. Ellis, Kwok-Leung Cheung
Journal: Journal of Clinical Oncology (2016)

e23272 Background: Emerging evidence suggests that breast cancer in the older population tends to have less aggressive biological characteristics. This study aimed to explore a possible differing pattern of tumour biology according to age. Methods: The study included 2,383 women with T0-2 N0-1 M0 breast carcinoma managed in a dedicated breast cancer facility. Among these patients 575 were ≥ 70 years of age derived from a consecutive series. The younger ( < 70 years) patients (N = 1808) were from a previously characterized series. . All patients were treated by primary surgery with tissue micro-arrays constructed from their surgical specimens. Indirect immunohistochemsitry was used for analysis of a panel of biomarkers. Results: There were age-related changes in the pattern of positivity of ER, PR, HER4, E-Cadherin, Ki67, p53, CK5/6, CK7/8, CK14, CK17, CK18 and bcl2. The following patterns were observed: 1. A gradual rise starting at 40 years – ER, PgR, Muc1 and CK18. 2. A gradual decline starting at 40 years – Ki67, HER2, CK17 and E-Cadherin. 3. A rise at 70 years – Bcl2, CK5/6 and CK 14. 4. Two peaks at 40/50 years and at 70 years – CK7/8, CK19, HER4 and p53. Conclusions: Biological characteristics of breast cancer show a differing pattern according to age, with 40 and 70 years being key milestones. The pattern suggests < 40 years as representing an aggressive phenotype, > 70 years as less aggressive and between 40 – 70 years as the transition. Recognition of such pattern supports the use of a personalized treatment approach based on precision biological assessment.
Subclonal mutational heterogeneity and survival in cisplatin-resistant muscle-invasive bladder cancer.
Authors: David Liu, Philip Abbosh, Daniel Keliher, Brendan Reardon, Kent William Mouw, Amaro Taylor-Weiner, Stephanie Anne Mullane, Garam Han, MinYuen Teo, Jaegil Kim, Hikmat Al-Ahmadie, Gopa Iyer, Essel Dulaimi, David Chen, Jean H. Hoffman-Censits, Scott L. Carter, Joaquim Bellmunt, Elizabeth R. Plimack, Jonathan E. Rosenberg, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2017)

4512 Background: Biomarkers of survival and resistance in chemotherapy-resistant muscle-invasive bladder cancer (MIBC) are not well-characterized, but may inform management in this setting. Methods: Matched pre- and post-neoadjuvant cisplatin-based chemotherapy (NAC) tumor samples were obtained from 30 MIBC patients with gross residual disease (≥ pT2) at cystectomy, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). Phylogenetic analysis of matched tumor samples was performed to identify subclones, their associated mutations, and the corresponding enrichment in post-treatment tumors. Intratumoral heterogeneity was assessed by the proportion of mutations that were subclonal; the number of inferred subclones; and associated with overall survival using a Cox Proportional Hazards model. Results: Increased proportion of subclonal mutations in post-treatment tumors was associated with worse overall survival (HRR 1.86 [95% CI 1.12-3.06], p = 0.02), whereas pre-treatment proportion of subclonal mutations was only borderline statistically significant (HRR 1.48 [95% CI 0.99-2.20], p = 0.052). The total number of inferred tumor subclones in pre- or post-treatment tumor (or both) was associated with overall survival (HRR 1.60 [95% CI 1.05-2.43], p = 0.03), interpreted as a 60% increase in death rate per additional inferred subclone. While no single gene was statistically significantly enriched for new alterations in the post-chemotherapy resistant samples, we observed new post-treatment amplifications in cell-cycle genes ( E2F3, c-JUN), biallelic events in cell-cycle regulators ( FBXW7), and amplification of immune checkpoint genes ( PDL1/2). Conclusions: These results suggest that intratumoral heterogeneity (particularly post-therapy) predicts survival in a chemotherapy-resistant cohort. Further, alterations in cell cycle regulation may contribute to the mechanism of chemotherapy resistance. Finally, we observe evidence of immune checkpoint gene amplification post-treatment, suggesting that testing immune checkpoint blockade during NAC or, in high risk patients, following NAC may be warranted.
RPS6 through the activation of NRF2 causes resistance to antiHER2 drugs in HER2 amplified gastric cancer (GC) models
Authors: V. Gambardella, F.G. Valiente, N. Tarazona, D. Roda, P. Tolosa, T. Fleitas Kanonnikoff, B. Garcia Mico, M. Huerta, S. Rosello, C. Martinez-Ciarpaglini, A. Cervantes, J. Castillo
Journal: Annals of Oncology (2018)

Background: Molecular mechanisms responsible for resistance to targeted agents are no longer clear and need to be clarified. Many pathways have been stressed to be responsible for acquired resistance in HER2 amplified GC, among them, PI3K/AKT/mTOR plays a relevant role. NRF2 was recently identified as a possible mechanism implicated in resistance to chemotherapy. Methods: OE19 and NCIN87, HER2+ GC cell lines were treated with increasing doses of Lapatinib (L) and Trastuzumab (T) to obtain resistant clones. These were isolated and characterized by performing mutational analysis and protein expression by Western blot (WB). Genome expression profile was done by ClariomS microarray. Inhibition of the altered pathways was evaluated using a panel of selected drugs. siRNAs were performed to characterise the role of the inhibition of selected proteins. An in vivo experiment was conducted to corroborate results. A retrospective cohort of HER2 amplified patients treated with T was analysed. An immunohistochemistry (IHC) analysis to evaluate the altered pathway detected in preclinical models was conducted. Results: L and T resistant clones were obtained. In resistant cells, protein expression underlined the activation of PI3K pathway and of its downstream effector RPS6 protein. Analysing microarray, it was possible to identify, the activation of a large number of genes regulated by NFR2. Its expression was confirmed by WB; NRF2 nuclear activation was detected by nuclear fractionating WB and immunofluorescence. A panel of target agents was used to evaluate NRF2 changes. It was possible to observe the its expression strongly decrease by using PI3K pathway inhibitors, suggesting a relation between this pathway and NRF2. To better clarify this phenomenon, siRNA of RPS6, that was detected to be activated in resistant cells, was performed and it was possible to observe a strong decrease of NRF2 expression and sensitivity to antiHER2 drugs was restored. IHC of both RPS6 and NRF2 were performed suggesting that the activation of both RPS6 and NRF2 related with less clinical benefit of T. Conclusions: RPS6 through the activation of NRF2 should be considered a new mechanism responsible for antiHER2 drugs resistance in GC. Further investigations are needed. Legal entity responsible for the study: INCLIVA Biomedical Research Institute. Funding: INCLIVA Biomedical Research Institute. Disclosure: All authors have declared no conflicts of interest.
Large scale training of oncology providers and staff to improve care delivery.
Authors: Monica Salama, Joseph Rodgers Steele
Journal: Journal of Clinical Oncology (2017)

e18282 Background: UT MD Anderson Cancer Center began participating in the Press Ganey survey in 2014, and the initial feedback was disappointing. Imaging outpatient services scores were lower than expected, and a difference of opinion between providers and patients was believed to be a contributing factor. Imaging providers defined “care” as the technical quality of the study and the accuracy of the report, while patients associated the term “care” with their healthcare experience. Methods: To improve the patient and family experience and better equip the staff and providers, the Service Excellence Academy (SEA) was created. This ten-hour, three-module program was developed at UT MD Anderson Cancer Center in collaboration with UNLV and MGM Resorts. The program combined didactic and interactive education by leveraging clinical examples and role-playing. A train-the-trainer format was used, including Institutional and Departmental leaders to facilitate the classes. Over 800 participants completed the SEA over 9 months. Questionnaires were administered to the participants before and after the sessions. Results: Since launching the SEA June of 2015, the outpatient Press Ganey scores have improved, and continue their upward trend. All metrics show percentile improvement ranging from 9% to 34%. Additionally, participants felt a greater connection with the institutional mission, vision, and heritage, were more comfortable making decisions, felt more empowered, and had developed greater empathy and skills to meet the needs of others. Conclusions: Large scale training of oncology providers and staff is possible and effective. Implementation of a Service Excellence Academy demonstrated both objective and subjective improvement of patient and employee satisfaction.
TCT-570 In-Hospital Outcomes of Transcatheter Aortic Valve Replacement After Non-Elective Admission in Comparison with Elective Admission
Authors: Tomo Ando, Oluwole Adegbala, Pedro Villablanca, Emmanuel Akintoye, Said Ashraf, Mohamed Shokr, Mohit Pahuja, Alexandros Briasoulis, Hisato Takagi, Cindy Grines, Luis Afonso, Theodore Schreiber
Journal: Journal of the American College of Cardiology (2018)
Impact of socioeconomic status on anal cancer survival.
Authors: Daniel Lin, Heather Taffet Gold, David Schreiber, Lawrence P. Leichman, Scott Sherman, Daniel Jacob Becker
Journal: Journal of Clinical Oncology (2017)

e18060 Background: Despite an increase in incidence of anal cancer over recent decades, improvements in awareness and therapy have improved survival outcomes. We hypothesized that the gains in outcomes were not shared equally by patients of disparate socioeconomic status (SES). We investigated whether area-based median household income (MHI) predicts survival of patients with anal cancer, after controlling for known predictors. Methods: Patients diagnosed with squamous cell carcinoma of the anus (SCCA) as the first primary malignancy from 2004 to 2013 in the Surveillance Epidemiology and End Results (SEER) registry were included. SES was defined by census-tract MHI, and divided into quintiles. Multivariable Cox Proportional Hazards models were used to evaluate the effect of (MHI) on cancer-specific (CSS) and overall survival (OS). A multivariable logistic regression was used to assess whether these same measures predicted receipt of radiation. Results: A total of 9,550 cases of SCCA were included; median age was 58 years, 63% were female, 85% were white, and 38% were married. In multivariable analyses, patients living in areas with lower MHI had worse OS and CSS compared to those in the highest income areas. Mortality HR’s in order of lowest to highest income were 1.32 (95%CI 1.18-1.49), 1.31 (95%CI 1.16-1.48), 1.19 (95%CI 1.06-1.34), 1.16 (95%CI 1.03-1.30); CSS HR similarly range from 1.34-1.22 from lowest to highest income. Other significant predictors of increased cancer specific mortality included older age, black race (HR 1.44, 95%CI 1.26-1.64), male gender, un-married, earlier year of diagnosis, higher grade, and later stage. Income level, however, was not associated with odds of initiating radiation in multivariable analysis (OR 0.87 for lowest to highest income level, 95%CI 0.63-1.20). Conclusions: SES measured by area-based MHI independently predicts cancer-specific and overall survival outcomes in patients with anal cancer, despite similar rates of initiating radiation therapy. Black race remains a predictor of anal cancer outcomes despite controlling for income. Further investigation is warranted to understand the mechanisms in which socioeconomic inequalities affect cancer care and outcomes.
Clinical impact of a comprehensive molecular approach in advanced gynecologic tumors
Authors: F. Lefort, C. Chakiba, E. Khalifa, S. Cousin, Y. Laizet, S. Croce, T. Grellety, A. Italiano, A. Floquet, I. Soubeyran
Journal: Annals of Oncology (2018)

Background: Although knowledge of the molecular landscape in gynecologic tumors is increasing, the clinical impact of an extensive screening remains unclear. The aim of this monocentric study was to characterize molecular alterations in advanced gynecologic tumors, and to evaluate the clinical benefit of corresponding targeted agents. Methods: Advanced gynecologic cancers were prospectively included in our molecular screening program. DNA and RNA extracted from tissue samples were analyzed by next generation sequencing, and when necessary, by comparative genomic hybridization array, polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry. Patients were enrolled, when possible, in early trials according to our molecular tumor board recommendations. We assessed clinical benefit with disease control rate (objective response and stable disease) and Growth Modulation Index (GMI defined as: time to progression under the early phase trial treatment/time to progression of the previous line of treatment) > 1.3. Results: 245 patients (ovary, n = 135; endometrium, n = 57; cervix, n = 37; uterus, n = 12; vulva, n = 3; vagina, n = 1) were recruited from February 2013 to May 2017. 115 (47%) patients had at least one actionable alteration. 131 different molecular alterations were found. The most frequent actionable alterations were PIK3CA (n = 45), hormone receptor expression (n = 38), KRAS (n = 23), BRCA1 and BRCA2 (n = 18) and HER2 (n = 16). Median number of previous lines of treatment was 2. 47 patients received a treatment matched with tumor molecular profile. Main reasons for non-inclusion were non-progressive disease (n = 24, 51%) and general status deterioration or death (n = 13, 28%). Median progression-free survival was 12,1 weeks (95% CI 8,3-16). Median overall survival was 34,6 weeks (95% CI 46,9-104,6). Disease control rate was 38%, and 14 % of patients had a GMI > 1.3. Conclusions: Molecular profiling for gynecologic tumors is feasible and detects molecular alterations with a positive clinical impact. The yield of this procedure could be improved by higher throughput sequencing techniques, wider access to genotype-matched treatments, and an earlier screening during the course of the disease. Legal entity responsible for the study: Institut Bergonié. Funding: Has not received any funding. Disclosure: T. Grellety: Paid for consulting role for Novartis during the past 2 years. All other authors have declared no conflicts of interest.
Imaging of metastatic medulloblastoma in the molecular era.
Authors: Michal Zapotocky, Alvaro Lassaletta, Eric Bouffet, Ute Katharina Bartels, Suzanne Laughlin, Cynthia Hawkins, Uri Tabori, Michael Taylor, Charles Raybaud, Vijay Ramaswamy
Journal: Journal of Clinical Oncology (2016)

e22003 Background: Recently it has been shown that the four principle subgroups of medulloblastoma can be discerned using conventional MRI. Herein we aim to provide robust neuroimaging correlates of medulloblastoma metastases in a subgroup dependent manner. Methods: We identified 35 metastatic cases of medulloblastoma (out of 154 – 22.7%). Samples were subgrouped using limited gene expression profiling and/or genome wide methylation arrays. Diagnostic MRI scans were blindly reviewed and correlated with molecular subgroup. Results: Molecular subgrouping was available in 29 metastatic cases (SHH = 5, Group 3 = 11, Group 4 = 13). No WNT metastases were identified in this cohort. In SHH two cases had multi-lobulated lesions previously interpreted as metastatic disease. Although Group 4 tumors frequently do not enhance, the enhancement pattern of metastases is heterogeneous and metastases frequently enhance, although more apparent with diffusion weighted imaging. Interestingly metastatic Group 3 patients had significantly smaller primary tumor at the time of diagnosis. Metastatic spread to the suprasellar region was observed in 8 patients (22.8% of all metastatic, 5.2% of all medulloblastoma) and were mainly restricted to Group 4 (n = 6) and Group 3 (n = 2). Three patients with solitary suprasellar metastases were Group 4. No visual or endocrine impairment was observed in these cases. Conclusions: The imaging characteristics of medulloblastoma metastases are highly subgroup specific. Group 4 tumors can present with non-enhancing metastases more obviously detected by diffusion weighted imaging and have a strong predilection for the suprasellar region without visual and endocrine deficits. Clinical trial consortiums need to take into account the unique pattern of Group 4 metastases when evaluating children with metastatic medulloblastoma.