tbuckley/cabot-search huggingface dataset:
Polymorphisms in toll-like receptor (TLR) genes in the prediction of outcome for cetuximab-based treatment in patients with metastatic colorectal cancer (mCRC).
Authors: Satoshi Okazaki, Sebastian Stintzing, Yu Sunakawa, Shu Cao, Wu Zhang, Dongyun Yang, Yan Ning, Martin D. Berger, Jordan David West, Roel Gopez, Yuji Miyamoto, Mitsukuni Suenaga, Marta Schirripa, Afsaneh Barzi, Diana L. Hanna, Akihito Tsuji, Wataru Ichikawa, Volker Heinemann, William DePaolo, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3588 Background: TLR7 and TLR9 signaling pathways are implicated in the regulation of immune system through type-I interferon induction. Immune responses within the tumor microenvironment may influence the efficacy of chemotherapy. TLR7 and TLR9 agonists showed promising results in preclinical and/or clinical trials for cancer patients (pts), in particular in association with cetuximab (cet). We tested the hypothesis that genetic variations in TLR7 and TLR9, and their downstream molecule IRF5 and IRF7, will be associated with outcome in mCRC pts receiving cet-based chemotherapy. Methods: This study included 3 independent cohorts: pts treated with FOLFIRI + cet in the FIRE-3 trial as a discovery set (FIRE3-Cet cohort, n = 299); pts treated with FOLFIRI + bevacizumab in FIRE-3 trial as a control set (FIRE3-Bev cohort, n = 293), pts treated with FOLFOX (or SOX) + cet in JACCRO-CC05/06 trial as a validation set (Japanese cohort, n = 76). Genomic DNA was isolated from tissue samples. 6 single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5, and IRF7 were analyzed by PCR and direct sequencing. These SNPs were tested for the association with PFS and OS. Results: Main patients characteristics’ were the following: FIRE3-Cet cohort M/F 68/32%, median age 64, KRAS-status wild/mutant 82/18%; FIRE3-Bev cohort M/F 66/34%, median age 64, KRAS-status wild/mutant 84/16%; Japanese cohort M/F 58/42%, median age 63, all pts were KRAS-wild type. Median follow-up times were 41.8, 40.9, and 24.7 months, respectively. Among KRAS-wild type pts in the discovery set (FIRE3-Cet), pts with TLR7 rs3853839 G/G variant showed a trend toward longer PFS compared to those with any C (median 10.0 vs. 11.8 months, HR 1.39, P= 0.092). This preliminary association was confirmed in the Japanese cohort, and pts with G/G genotype showed a PFS benefit compared to those carrying any C (univariate: 9.1 vs. 11.6 months, HR 2.04, P= 0.005, multivariate: HR 2.02, 95%CI: 1.14-3.55, P= 0.015). In the control set (FIRE3-Bev), this correlation of TLR7rs3853839 with PFS was not observed. Conclusions: Our findings suggest that TLR7 rs3853839 may predict outcome of cet-based chemotherapy in KRAS-wild type mCRC pts.
Validation of the pathological classification of lymph node metastasis for head and neck tumors (HNSCC) according to the 8th edition of the TNM Classification of Malignant Tumors (8th TNM).
Authors: Antonio Lopez-Pousa, Jacinto Garcia, Montserrat Lopez, Silvia Bague, Esther Granell, Laura Lopez Vilaro, Nuria Farre, Katerina Majercakova, Alejandro Fernández, Oscar Gallego Rubio, Andrés Barba, Marta Andrés, Paula Gomila, Luis Paul Del Carpio Huerta, Ana Virgili, Miquel Quer, Ivana GABRIELA Sullivan, Xavier Leon
Journal: Journal of Clinical Oncology (2017)

6014 Background: Changes in 8 th TNM edition are a specific staging for p16+oropharyngeal carcinoma and the inclusion of extracapsular spread (ECS) in N extension. We evaluate the improvement in prognostic capacity from the inclusion of the ECS in HNSCC patients treated with a neck dissection (ND). Methods: Retrospective study based on prospectively collected information of 1188 HNSCC patients (oral cavity, HPV-oropharynx, hypopharynx, or larynx) diagnosed from 1990 to 2013, treated with unilateral or bilateral ND and a minimum fw-up of 2 years. We performed 1820 ND: 410 radical, 1410 selective ND; 683 patients (60.1%) had bilateral ND. Mean lymph nodes/patient: 32.6 (SD 19.9, 7-118). In 157 cases (13.8%) ND was performed after radiotherapy (RT, n =71) or chemoradiotherapy (CHRT, n = 86) with a median interval of 8.5 weeks (6-10). 596 patients (52.4%) had postoperative RT (n=525) or CHRT (n=71). Mean fw-up: 5.6 years (SD 4.9): 213 patients (18.7%) had local failure, 158 (13.9%) regional failure, 172 (15.14%) metastases. Results: 570 patients (50.1%) had lymph node metastases, 288 (50.5%) with ECS. The 8 th TNM produced upstaging of 20.9% of pN1 patients to pN2a (n=33), and of 58.4% of the patients classified as pN2 to pN3b (n=220). The 7 th TNM Classification (7 th TNM), 5-year cause-specific survival for pN2 (35.5%) was similar to pN3 (21.6%). In the 8 th TNM, 5-year cause-specific survival for pN2 (53.3%) sits in an more intermediate position between pN1 (70.5%) and pN3 (24.0%). Five-year cause-specific survival for pN2 patients with ECS (n=217) was 22.4%, and for patients without ECS (n=157) was 51.4%. There were statistically significant differences in survival between the two reclassified groups (P=0.0001). pN1 patients in the 7 th TNM did not show survival differences when stratified by the presence of ECS: 5-y SV: 63.5% for ECS (n=33), 70.5% for non-ECS (n=125) (p=0.838). Conclusions: Inclusion of ECS in the pathological classification of the 8 th TNM Classification edition improved the prognostic capacity, as compared with the previous version, basically produced by the migration of 58.4% of pN2 in the 7 th TNM to the new pN3b category
Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: Maturing safety and activity profile from the FORWARD II phase 1b study.
Authors: David M. O'Malley, Lainie P. Martin, Lucy Gilbert, Ignace Vergote, Ursula A. Matulonis, Michael J. Birrer, Cesar Martin Castro, Karim S. Malek, Antonio González-Martín, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2018)

5549 Background: Mirvetuximab soravtansine is an ADC, comprising a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, currently being evaluated in combination with bevacizumab as part of an ongoing Phase 1b trial (FORWARD II; NCT02606305) in pts with platinum-resistant ovarian cancer. Methods: Pts were administered mirvetuximab soravtansine (6 mg/kg; adjusted ideal body weight) in combination with bevacizumab (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: To date, a total of 51 pts have received combination therapy at this dose level: 11 in dose escalation; 40 during the expansion stage. Pts had a median age of 64 years and received a median of 3 prior lines of systemic therapy (range 1-8); 51% and 29% of pts had received prior therapy with bevacizumab or a PARP inhibitor, respectively. The four most commonly reported AEs were nausea, fatigue, diarrhea, and blurred vision (45-57% of pts), which were primarily grade 1 or 2. The most frequent grade 3 AE was hypertension (8 pts - 16%). For the efficacy evaluable population (49 pts), objective tumor responses were observed in 19 pts for a confirmed overall response rate (ORR) of 39% and a median progression-free survival (mPFS) interval of 9.5 months (95% CI, 4.6, -). In a subset analysis of pts (n = 20) with ≤ 3 prior therapies and medium to high FRα levels (i.e., ≥ 50% of cells with ≥ 2+ staining intensity) the ORR was 55% with mPFS not yet reached, with a median follow-up of 5.7 months (range 1.3-11.7). Updated results will be presented. Conclusions: The mirvetuximab soravtansine-bevacizumab combination continues to display a manageable safety profile in pts with platinum-resistant ovarian cancer. The encouraging efficacy results justify further exploration of this novel therapeutic combination in this difficult to treat population. Clinical trial information: NCT02606305.
Randomized, open-label, multicenter, controlled study of galeterone vs enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC) expressing AR-V7 splice variant (ARMOR3-SV).
Authors: Emmanuel S. Antonarakis, Johann S. De Bono, Karen J. Ferrante, Kerry Horgan, Jun Luo, Fred Saad, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2016)

TPS5085 Background: The androgen receptor (AR) splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the C-terminal ligand binding domain (LBD). Mechanistically, enzalutamide and abiraterone both require a functional AR-LBD for their activity. Preliminary data suggest that the presence of AR-V7 may predict drug resistance to both enzalutamide and abiraterone in patients with mCRPC. Galeterone is an oral small molecule that disrupts AR signaling via multiple pathways: AR degradation, CYP17 lyase inhibition, and AR antagonism. In preclinical models, galeterone has demonstrated activity against the full-length AR and AR alterations including AR-V7 and ARv567es splice variants, and against activating AR mutations. These data, combined with activity seen in mCRPC patients with loss of LBD in the phase 2 ARMOR2 study, supported the design of the ongoing pivotal phase 3 study ARMOR3-SV. Methods: ARMOR3-SV is a randomized, open-label, multicenter study that compares galeterone vs enzalutamide in men with mCRPC. Eligible patients are prescreened and subsequently enrolled only if they have circulating tumor cells that express AR-V7 mRNA. Patients must maintain castrate testosterone levels, and must not have received prior chemotherapy, abiraterone, or enzalutamide for CRPC. ARMOR3-SV is the first precision medicine-based registration study in prostate cancer. A total of 148 patients will be randomized (1:1) to receive once-daily oral galeterone 2550 mg or enzalutamide 160 mg. The primary endpoint is radiographic progression-free survival determined by independent blinded, central radiologic review. Key secondary endpoints include time to next anticancer therapy and overall survival. Other endpoints include time to first symptomatic skeletal event, PSA response rate, time to PSA progression, and objective response rate (in men with measureable disease [RECIST1.1]). The safety and pharmacokinetics of galeterone will be assessed. CTCs will be enumerated and characterized molecularly, and changes in the levels of AR-V7 transcript will be assessed serially over time. Clinical trial information: NCT02438007.
A systematic review and meta- analysis of randomized controlled trials to evaluate the risk of pulmonary toxicities in patients with advanced breast cancer treated with everolimus.
Authors: Sriman Swarup, Kyaw Zin Thein, Anita Sultan, Rachana Yendala, Fred L. Hardwicke, Catherine Jones, Sanjay Awasthi
Journal: Journal of Clinical Oncology (2018)

e13086 Background: Pulmonary toxicities have significant impact on morbidity, mortality, drug dosing inconsistencies and financial burden among patients undergoing chemotherapy. Everolimus (E), an oral mTOR inhibitor, mediates via PI3K/AKT/mTOR signaling pathway and was shown to benefit in endocrine and trastuzumab resistant advanced breast cancer (ABC). Yet the risk of pulmonary toxicities remains considerable. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of pulmonary toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention pulmonary toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase 3 RCTs with a total of 1992 patients with advanced breast cancer were eligible for analysis. Studies compared E+ paclitaxel(P) + Herceptin(H) vs P+H, E+ exemestane(Ex) vs Ex, E+ vinorelbine(V)+ H vs V+H. The RR of all-grade side effects were as follows: cough, 1.49 (95% CI: 1.13-1.97, p = 0.005); dyspnea, 1.82 (95% CI: 1.23-2.71, p = 0.003); URI, 1.17 (95% CI: 0.83-1.64, p = 0.36); peripheral edema, 1.62 (95% CI: 1.18-2.21, p = 0.002); interstitial lung disease(ILD), 6.59 (95% CI: 1.97-21.99, p = 0.002); pneumonia, 2.35 (95% CI: 1.36-4.04, p = 0.002); and pneumonitis, 4.20 (95% CI: 1.17-15.04, p = 0.02). The RR of high-grade side effects were as follows: cough, 1.04 (95% CI: 0.25-4.24, p = 0.94); dyspnea, 1.57 (95% CI: 0.50-4.84, p = 0.43); peripheral edema, 1.07 (95% CI: 0.32-3.58, p = 0.90); ILD, 7.81 (95% CI: 1.004-60.78, p = 0.05); pneumonia, 3.73 (95% CI: 0.54-25.78, p = 0.18); and pneumonitis, 3.96 (95% CI: 0.35-44.92, p = 0.26). Conclusions: Our study showed that patients on everolimus experienced a significant increase in all grades of ILD with a relative risk of 7.81 for grade 3 and 4 ILD. They also contributed to all-grade cough, dyspnea, peripheral edema, pneumonia and pneumonitis.
TCT-413 National Trends and Outcomes of transcatheter aortic valve replacement in patients with bicuspid aortic valve stenosis
Authors: Mohamad Soud, Yasser Al-khadra, Homam Moussa Pacha, Fahed Darmoch, Abdulah Alrifai, Amr Idris, Amir Kaki, Zaher Fanari, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
Frequency of genomic biomarkers of response to immunotherapy in sarcoma.
Authors: Sally E. Trabucco, Siraj Mahamed Ali, Ethan Sokol, Alexa Betzig Schrock, Lee A. Albacker, Jon Chung, Marin Feldman Xavier, Umut Disel, Vincent A. Miller, Jeffrey S. Ross, Garrett Michael Frampton, Breelyn A. Wilky, Vinod Ravi, Mrinal M. Gounder
Journal: Journal of Clinical Oncology (2018)

11579 Background: Recent data (D'Angelo et al, 2018) has suggested possible benefit for a subset of sarcoma patients from immune checkpoint inhibitors (ICPI). We assessed a large sarcoma population for genomic alterations (GA) suggesting benefit from ICPI including high tumor mutational burden (TMB-H) [ > = 20 mutations/mb (m/mb)], presence of microsatellite instability (MSI-high) and genomic amplification of PDL1. Methods: Hybrid capture based comprehensive genomic profiling including RNA-seq in a subset of cases was performed on > 6100 cases of sarcoma and included TMB and MSI status. UV exposure signature was determined as previously described (Zehir et al, 2017). Results: TMB was distributed throughout sarcoma cases with a median of 1.7 (range 0-160) and 2% TMB-H. The sarcomas frequently TMB-H were skin atypical fibroxanthoma (86%, 6/7), skin sarcoma NOS (50%, 3/6), and lung sarcoma (14%, 2/14). Presence of a fusion gene, such as the frequent fusions EWSR1:FLI1, SS18:SSX1, and STAT6:NAB1, were mutually exclusive with TMB-H, PDL1 amplification and MSI-high (p < 0.0001). MSI-high cases (0.23%), with median TMB of 26 (11-67), were predominantly a subset of TMB-H. 0.83% of sarcoma cases had PDL1 amplification (6/51 TMB-H), most frequently soft tissue sarcoma NOS (35% of PDL1 amplified cases). 2% of sarcoma cases have a UV signature, with median TMB of 36 (2.4-160), and make up 72% of TMB-H sarcomas. Notably, 14% of angiosarcomas have a UV signature; these cases have median TMB of 19 m/mb (2.4-148). Of sarcomas with a UV signature, 26% harbored GA associated with melanoma (BRAF V600x, NRAS or KIT mutation) and 27% were assayed from a cutaneous specimen. An index case of high grade sarcoma with an initial intrabdominal presentation was identified as harboring high TMB and a UV signature on CGP. Conclusions: Identification of one or more of TMB-H, PDL1 amplification and/or MSI-high is detected in 2.8% of unselected sarcoma cases, which may be more likely to benefit from ICPI and such cases lack oncogenic fusions. Notably, 72% of the TMB-H cases harbored a UV signature which may raise the possibility of an alternative diagnosis of melanoma, particularly desmoplastic melanoma.
<i>Notes from the Field:</i> Mumps Outbreak Associated with Cheerleading Competitions — North Texas, December 2016–February 2017
Authors: Diana Cervantes, Heidi Honza, Daphne Lynch, Nicolette Janoski, Jawaid Asghar, Laura Lockwood, Charles Cohlmia
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

An outbreak of 12 mumps cases (five confirmed and seven probable) in five counties was identified in persons who were nonathlete participants or attendees at three cheerleading competitions or were household contacts of mumps patients. This outbreak is the first documented report of mumps transmission during a sporting event with the majority of cases occurring in nonathlete participants or attendees.
Abstract MP60: Depressive Symptoms and Risk of Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis
Authors: Parveen K Garg, Wesley T O'Neal, Ana V Diez Roux, Alvaro Alonso, Elsayed Soliman, Susan Heckbert
Journal: Circulation (2018)

Background: Depression has been suggested as a potential risk factor for atrial fibrillation (AF) through effects on the autonomic nervous system and hypothalamus-pituitary-adrenal axis. Current literature examining the prospective relationship between depression and AF is inconsistent and limited to studies performed in predominantly white populations. We determined the relationship of both depressive symptoms and anti-depressant use with incident AF in a multi-ethnic cohort. Methods: The Multi-Ethnic Study of Atherosclerosis is a prospective study of 6,814 individuals without clinical cardiovascular disease. Depressive symptoms were assessed at baseline by the 20-item Center for Epidemiologic Studies Depression Scale (CES-D) and use of anti-depressant medications. Five CES-D groups were created based on the score distribution in approximate quartiles, and the top quartile split in 2 such that the top group represented persons with a score ≥16, a value commonly used to identify clinically relevant symptoms. Incident AF was identified from study ECGs verified for AF, ICD-9 hospital discharge diagnoses consistent with AF, and, for participants enrolled in fee-for-service Medicare, inpatient and outpatient AF claims data. Results: 6,644 participants (mean age=62; 53% women; 38% white; 28% black; 22% Hispanic; 12% Chinese-American) were included and followed for a median of 13 years. In separate adjusted Cox proportional hazards analyses, a CES-D≥16 (referent=CES-D&lt;2) and anti-depressant use were each associated with higher incidence of AF (Table). Associations did not differ by race or gender (interaction p-values of 0.18 and 0.17 respectively). Similar results were obtained using time-updated measures of depression. Conclusions: Depressive symptoms are associated with an increased risk of incident AF. Further study into whether improving depressive symptoms reduces AF incidence is important.
The comparison of tumor mutational burden (TMB) in patients of early and late stage lung adenocarcinoma in China.
Authors: Kai Zhang, Shihong Fei, Jing Lu, Qifan Yang, Jinsong Yang, Yulan Zeng, Yuting Liu, Gang Xiong, Xiaodong Jiao, Ye Tao, Zhen Yuan, Wei Gao, Zhao Wei, Di Liu, Tongfu Xu, Shangli Cai, Fu-Gen Li, Rubo Cao, Li Liu
Journal: Journal of Clinical Oncology (2018)

8520 Background: Although PD-L1 positivity improves immunotherapy efficacy, PD-L1 testing alone is insufficient for patient selection in most malignancies. High tumor mutational burden (TMB) is an emerging positive biomarker of immunotherapy in a growing number of malignancies. In this study, a method for TMB by cancer-gene panel (CGP) was set up, by which TMB from Chinese lung adenocarcinoma samples was measured to analyze the association between TMB and genes alterations in the implications for immunotherapy. Methods: The accuracy of TMB detection by our CGP was confirmed from data of TCGA and whole exome sequencing (WES) in our clinical samples. TMB detection method by CGP was further validated from sequencing accuracy, coefficient of variation, and the limit of detection of tumor purity. The level of TMB in Chinese lung adenocarcinoma samples and its correlation with genes alterations were then analyzed. Results: In our study, TMB measured by CGP has a high correlation with that measured by WES in 31 clinical tumor samples (R2= 0.9111). Immunotherapy from the Rizvi cohort confirmed the accuracy of TMB detection by CGP. The mean level of TMB measured by CGP from 599 Chinese lung adenocarcinoma samples was similar with that from 389 TCGA lung adenocarcinoma samples (7.29 vs 7.6 mutations/Mb). We found that high level of TMB was significantly correlated with several genes alterations including TP53, KRAS and genes in DNA damage response pathway as BRCA1/2, ATR, CHEK2, POLE and MMR genes. However, low level of TMB was correlated with EGFR and ALK alteration obviously. Of note, we first discovered that the level of TMB was lower in the early stage lung adenocarcinoma compared with that in the late stage lung adenocarcinoma from Chinese clinical samples. Conclusions: TMB calculated by CGP and WES was highly correlated via analyzing data both from TCGA and our tumor samples. We found that the level of TMB was effected by several genes alterations in the analysis of our samples. We also found that the low level of TMB might imply a poor effect of mono-immunotherapy in the treatment of early stage lung adenocarcinoma. Of note, combining immunotherapy with DNA damaging agents could be a good way to improve efficacy.
Correlation between 24-hour urine protein and spot urine protein-to-creatinine ratio in multiple myeloma.
Authors: Saad Jamshed, Jonathan Bress, Qiu Tong, Roberto Vargas
Journal: Journal of Clinical Oncology (2018)

e20042 Background: Multiple myeloma (MM) disease assessment requires 24 hour urine protein measurement at different times during disease course. Obtaining 24 hr urine sample is cumbersome, time consuming & frequently raises concerns for accuracy. Use of an untimed collection to provide a protein-to-creatinine ratio has been proposed as a feasible alternative due to good correlation between spot urine protein-to-creatinine ratio (SPOT) & 24 hr protein excretion in other diseases with significant protein excretion. This study was designed to evaluate correlation of SPOT sample to 24 hr collection in patients with MM. Methods: After obtaining consent, we collected & analyzed data from MM patients. They were given detailed instructions & supplies for 24-hr urine collection. Both samples were collected at time of submission. Each pt was allowed to submit upto 3 samples at different time points. Urine protein was measured by benzethonium chloride turbidimetry & creatinine by an IDMS-standardized enzymatic method on a Siemens ADVIA 1800. Pearson’s correlation method using R version 3.2.2 was used to correlate values obtained by the two methods. A Bland-Altman plot was used to analyze the limits of agreement. Results: We collected 36 samples from 15 pts between 2015 - 2017. Mean age was 63.8 years (median of 67). 47% were females. 8 had light chain only disease, 7 had either IgG/IgA paired ƙ/ƛ myeloma. 10 (67%) were on therapy at the time of sample collection. Given that only 4 samples had 24 hr urine protein content of > 1,000 mg, only samples with under 1,000 mg were analyzed. The average 24 hr protein was 138.6 +/- 197.7 mg. The average spot ratio was 93.4 +/- 108.6 mg/g. The linear regression line was y = -21.3 + 1.7x where y is the 24 hour urine protein & x is the spot ratio value. The slope was significant (p < 0.001). The adjusted R2 value was 0.88 for the model. Conclusions: In MM pts there is strong linear correlation between 24 hr urine protein & spot urine protein-to-creatinine ratio at levels of proteinuria under 1,000 mg. Given the inconvenience of 24 hr urine collections, a spot urine protein-to-creatinine ratio may be substituted in patients with proteinuria under 1,000 mg.