tbuckley/cabot-search huggingface dataset:
Outcomes of postoperative treatment with concurrent chemoradiotherapy (CRT) in high risk resected oral cavity squamous cell carcinoma (OCSCC): A multi-institutional collaboration.
Authors: Jessica Lyn Geiger, Neil McIver Woody, C. Jillian Tsai, Ahmed I. Ghanem, Neal Dunlap, Howard Liu, Brian B. Burkey, Eric Lamarre, Jamie Ku, Joseph Scharpf, Nikhil Purushottam Joshi, Jimmy J. Caudell, Farzan Siddiqui, Sandro Porceddu, Nancy Y. Lee, Shlomo A. Koyfman, David J. Adelstein
Journal: Journal of Clinical Oncology (2019)

6080 Background: Adjuvant CRT with high-dose cisplatin remains standard treatment for OCSCC with high risk pathologic features of positive surgical margins (SM+) and/or extranodal extension (ENE). High-dose cisplatin is associated with significant toxicities, and alternative dosing schedules or treatments are used. We evaluated outcomes associated with different systemic therapies concurrent with RT and the effect of cumulative dosing of cisplatin. Methods: An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I-IVB AJCC 7th edition) treated with primary surgical resection between 1/1/2005 and 1/1/2015 with or without adjuvant therapy was established from 6 academic institutions. Pts were categorized by systemic therapy received, and resultant groups compared for demographic data, pathologic features, and outcomes by t-test and Chi-squared tests. Kaplan-Meier curves, log-rank p-values, and multivariate analysis (MVA) for disease free survival (DFS) and freedom from metastatic disease (DM). Results: From a total sample size of 1282 pts, 196 pts were identified with high risk features (SM+, ENE) who were treated with adjuvant CRT. Median age was 56 years, 63.3% of pts were men, 81.1% were Caucasian, 70.9% had significant tobacco history. 35.7% of pts had SM+, 82.7% ENE, 65.3% with perineural invasion (PNI), 49% had lymphovascular space invasion (LVSI). There was a trend associating higher cisplatin dose delivered with improved locoregional control, DM, and overall survival (OS) (p-values 0.131, 0.084, and 0.187, respectively). DFS was significantly better with higher cisplatin dose (HR = 0.95 per 100 mg/m 2 increase in cisplatin). Administration schedule of cisplatin (weekly versus high-dose) was not significantly associated with DFS. On MVA, PNI and higher cisplatin dose remained statistically significant for DFS (p &lt; 0.001 and 0.007). Median OS by cisplatin dose was 10.5 ( &lt; 200 mg/m 2 ) vs. 20.8 months ( &gt; / = 200 mg/m 2 ). Conclusions: This multi-institutional analysis demonstrated cumulative cisplatin dose &gt; / = 200 mg/m 2 was associated with improved DFS in high risk resected OCSCC pts. It remains unclear by this analysis if cisplatin administration schedule has any prognostic implication. Further study is warranted to elucidate the optimal cisplatin schedule for this population.
Efficacy of hypofractionated radiotherapy (Rx) in melanoma patients who failed anti-PD-1 monotherapy: Assessing the abscopal effect.
Authors: Philippe Saiag, Bouchra Baghad, Magali Fort, Iman Aouidadd, Anissa Roger, Jean-Jacques Mazeron, Yves Otmezguine, Astrid Blom, Christine Longvert, Blandine Boru, Elisa Funck-Brentano
Journal: Journal of Clinical Oncology (2019)

9537 Background: Radiotherapy (Rx) and anti-PD-1 mAb are potentially synergistic. No study has tested this combination only in pts who failed on anti-PD-1 mAb, which allows to assess the abscopal effect. We evaluated this combination in a cohort of advanced melanoma pts after failure of anti-PD-1 monotherapy. Methods: Analysis of a prospective database in a referral center searching for advanced melanoma pts with confirmed (2 CT-scans) progressive (PD) or stable (SD) disease on anti-PD-1 monotherapy, who later received concurrent Rx without modification of anti-PD-1 mAb regimen. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions, with abscopal effect defined as a partial (PR) or complete (CR) response outside radiated fields. Results: 26 pts (21 achieving PD, 5 SD, 10 pt ≥3 involved organs), mean age 70 Y, were included. Anti-PD-1 mAb was first line in 50% of pts. Rx, consisting of hypofractionnated Rx (3-5 sessions, 26 Gy), standard palliative Rx, or gamma-knife in respectively 23, 2, and 1 pts, was begun on a single site in 73% of pts or on 2 sites after a median of 5 m after beginning anti-PD-1 mAb. Median follow-up after onset of anti-PD-1 mAb was 17 (7-35) m, with 65% of pts alive at last follow-up. Best response was 7 CR (27%, including CR in 4 pts with prior PD) 1 PR, 3 SD (12%), 15 PD (58%). Abscopal effect was seen in 10 pts (38%). No correlation between the occurrence of CR and BRAF/NRAS mutation status, number of metastatic sites, presence or absence of brain metastases, and LDH level was seen. Anti-PD-1 mAb could be discontinued in 6 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: In pts who have previously failed on anti-PD-1 mAb, obtaining with concurrent Rx and without modifying anti-PD-1 mAb, CR or PR in 30% of pts, median OS not achieved, and abscopal effect in &gt; 1/3 of pts is probably not due only to late efficacy of anti-PD-1 mAb but suggests a synergy with RT. Release after radiation of tumor neoantigens may stimulate immune response. Hypo-fractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in melanoma pts who failed on anti-PD-1 mAb. Controlled studies are needed.
FDG uptake to reflect NLR and expression levels of TILs and PD-L1 in patients with primary breast cancer: Tumor inflammation and immunity.
Authors: Takaaki Fujii, Tomoko Hirakata, Sasagu Kurozumi, Ayaka Katayama, Keiko Yanai, Naoko Tokuda, Yuko Nakazawa, Sayaka Obayashi, Reina Yajima
Journal: Journal of Clinical Oncology (2019)

e12110 Background: 18 F-Fluorodeoxyglucose-positron emission tomography(FDG-PET) is used to evaluate the glucose metabolic rates of cancers. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer (BC).However, FDG-uptake is influenced by many factors, including inflammation and immunity. In this study, we investigated the relationship between FDG uptake and inflammation and immunological factors, including Neutrophil/lymphocyte ratio (NLR) and degrees of Tumor-infiltrating lymphocytes (TILs), programmed cell death ligand 1 (PD-L1). Methods: We retrospectively investigated the cases of 96 consecutive invasive ductal carcinoma patients who underwent surgery andunderwent FDG-PET preoperatively. The evaluation of PET was determined using standardized uptake value max (SUVmax). We divided the cases into two groups based on the value of SUVmax; low (&lt;2.5) and high (≥2.5) and the value of NRL; low (&lt;1.7) and high (≥1.7). Grade of stromal-TILs was immunohistochemically (IHC) evaluated using the criteria of the International Working Group for TILs in BC: low (10-20%), intermediate (20-40%) and high (50-90%). PD-L1 positive were evaluated by IHC. The relationships between SUVmax and NLR and expressions of TILs, PD-L1 were investigated. Results: Among the 96 patients, 52 (54.2%) had high SUVmax in the primary tumor. The multivariate analysis revealed that large tumor size (p&lt;0.001), high nuclear grade (p=0.016), high NLR (p=0.037), and PD-L1 (p=0.003) were significantly associated with high SUVmax in the primary tumor.There were associations between SUVmax and NLR(r=0.319, p&lt;0.001) and TILs (r=0.298, p&lt;0.001). Among the 96 cases with, there was 4 cases (4.2%) had recurrent disease, while 3 cases among the 4 cases with recurrent disease was low TILs and the one case was high TILs and PD-L1 psitive. disease recurrence.It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. Conclusions: The present study demonstrated thatthe finding of preoperative FDG uptake in BC may be reflective of poor prognosis and high NLR and the grades of high TILs and expression of PD-L1in the tumor. From these findings, preoperative high FDG uptake in BC may be reflective of tumor microenvironmentincluding inflammatory or immunological features in addition to aggressive features among patients with BC.
Phase 1, open-label, dose-escalation study of M3814 + avelumab ± radiotherapy (RT) in patients (pts) with advanced solid tumors.
Authors: Johanna C. Bendell, Michael Rahman Shafique, Bradford Perez, Sarah Chennoufi, Frank Beier, Ky Trang, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2019)

TPS3169 Background: DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage response (DDR) pathway for double-strand break (DSB) repair. DNA-PK inhibition augments DNA DSB damage generated by many antitumor therapies, including RT. DNA damage and repair impact the interaction of tumors with the immune system; combining immune checkpoint inhibitors (CPIs) with RT + DDR-targeted agents may modulate the tumor immune microenvironment, enhancing responsiveness to CPIs. M3814 (small molecule selective DNA-PK inhibitor) has demonstrated monotherapy activity in several tumor cell lines, and M3814 + RT combined with avelumab (programmed death ligand 1 mAb) significantly delayed tumor growth vs either agent alone + RT in MC38 syngrafts. This study will evaluate the clinical utility of M3814 combined with avelumab ± RT in pts with advanced solid tumors. Methods: NCT03724890 is a 2-part first-in-man study in adult pts with advanced or metastatic solid tumors. Part A is enrolling pts with measurable/evaluable solid tumors (RECIST v1.1); Part B will enrol pts with primary or metastatic tumor(s) in the lung which is/are amenable to be irradiated. In Part A, M3814 will be given orally twice daily. In Part B, M3814 + TRT will be given once daily, 5 days/wk for 2 wk. In both parts, pts will receive avelumab iv once every 2 wk from Day 1 until disease progression/unacceptable toxicity. Part B will initiate once the Safety Monitoring Committee declares the first dose level of Part A to have acceptable safety/tolerability. Primary objectives are to define the recommended Phase 2 dose (RP2D) of M3814 when combined with avelumab (Part A) and with avelumab + TRT (Part B) via dose-limiting toxicities (DLTs) occurring during the first 3/4 (Part A/B) wk of treatment. Secondary objectives include safety/tolerability, pharmacokinetics, immunogenicity, preliminary antitumor activity (BOR, PFS, OS). Sample size for each part depends on the number of DLTs/dose levels for M3814; dose escalation will be based on a Bayesian logistic regression model with overdose control. Part A aims to include 6–24 pts (≤4 dose levels), Part B 6–18 pts (≤3 dose levels). Recruitment began in Dec 2018. Clinical trial information: NCT03724890.
Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment.
Authors: Ippokratis Messaritakis, Michail Nikolaou, Filippos Koinis, Eleni Politaki, Anastasios Koutsopoulos, Eleni Lagoudaki, Vassilis Georgoulias, Athanasios Kotsakis
Journal: Journal of Clinical Oncology (2019)

e20086 Background: The aim of the study was to characterize and evaluate the presence of DLL3-positive Circulating Tumor Cells (CTCs) in SCLC patients receiving front-line chemotherapy and assess their clinical relevance. Methods: Peripheral blood was obtained from treatment-naïve patients with SCLC (n = 108 patients), after one-etoposide/platinum cycle (n = 68 patients) and on disease progression (n = 48 patients). CTCs were detected after immunofluorescence staining using antibodies against the DLL3, cytokeratins (CK), CD45 and vimentin (Vim). Results: Before treatment, 74.1% of patients had detectable CTCs (DLL3 + /CD45 - ). One-treatment cycle significantly decreased both the detection rate of DLL3 + /CD45 - CTCs ( p&lt; 0.001) and their absolute number ( p&lt; 0.001). Triple immunofluorescence staining using anti-CK, anti-Vim and anti-DLL3 antibodies revealed an important CTC heterogeneity since DLL3 could be detected in Vim + , Vim - , CK + and CK - CTCs. On disease progression, both the detection rate of DLL3 + /CD45 - CTCs as well as their number were significantly increased compared to post-1 st cycle values ( p&lt; 0.001 and p= 0.002, respectively). In addition, 22.7% of patients had detectable DLL3 + /CD45 - cells which could not be captured by the CellSearch assay. In multivariate analysis, the detection of DLL3+/CD45 - CTCs at baseline was significantly associated with decreased progression-free survival (HR = 10.8; p= 0.005) whereas their detection on disease progression was associated with decreased overall survival (HR: 28.2; p= 0.016). Conclusions: These findings demonstrate an important heterogeneity of CTCs, based on the expression of CK, Vim and DLL3, in patients with SCLC and the changes of DLL3 + /CD45 - CTCs during treatment seem to be a dynamic biomarker associated with treatment efficacy and patients’ clinical outcome.
Tumor dynamics with fluorouracil/folinic acid, irinotecan, and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (mCRC): Central radiologic review of VOLFI—A randomized, open label, phase-2 study (AIO KRK0109).
Authors: Dominik Paul Modest, Dominik Noerenberg, Max Seidensticker, Jens Ricke, Uwe Marc Martens, Jorge Riera-Knorrenschild, Jobst Greeve, Axel Florschütz, Swen Wessendorf, Thomas Jens Ettrich, Stephan Kanzler, Swantje Held, Petra Buechner-Steudel, Jens Atzpodien, Volker Heinemann, Andrea Tannapfel, Anke C. Reinacher-Schick, Michael Geissler
Journal: Journal of Clinical Oncology (2019)

3530 Background: The VOLFI trial demonstrated improved objective response rate (ORR) with the addition of pmab to modified triplet chemotherapy with FOLFOXIRI in a 2:1 (63 patients FOLFOXIRI plus pmab; 33 patients FOLFOXIRI) randomized, controlled, phase II trial in patients with untreated RAS wildtype mCRC. Methods: Radiologic images from the study were centrally examined according to RECIST 1.1. We further assessed early tumor shrinkage (=ETS: 20% shrinkage of tumor diameter at first re-assessment) and depth of response (=DpR= maximum shrinkage of lesions defined as relation of smallest tumor diameter to baseline). Moreover, time to depth of response was calculated (randomisation to depth of response image). Results: Images were available for 88 of 96 patients (91.7%), 86 patients (89.6%) had at least one follow-up image and were included in the central review. According to central review, objective response rates were 89.2% vs 66.7% with FOLFOXIRI plus pmab vs FOLFOXIRI alone (P=0.02). ETS was also significantly more frequent (Fisher’s exact test; P=0.01)) and DPR (Wilcoxon test; P= 0.004) significantly greater with pmab as compared to chemotherapy alone. See table for details. Time to DpR was similar in the panitumumab- vs chemotherapy alone arm (3.9 (95% confidence interval 2.8-4.7) vs. 4.2 (95% CI 3.6-5.7) months, respectively. P=0.63). Conclusions: In this central review, pmab significantly improves ORR, the rate of ETS and also DpR when added to a mFOLFOXIRI regimen. Our findings underline the potential of this highly active regimen in patients with RAS wildtype mCRC that need to achieve early and profound shrinkage of the tumor. Additional analysis including molecular subgroups and tumor sidedness will be shown at the meeting. Clinical trial information: NCT01328171. [Table: see text]
Highly sensitive detection of rare mutant alleles by combining argonaute-based enrichment and XNA-PCR.
Authors: Jinzhao Song, Michael Joseph Powell, Wei Liu, Junman Chen, Haim Bau
Journal: Journal of Clinical Oncology (2019)

e14605 Background: Characterization of disease-associated, cell-free nucleic acids (liquid biopsy) provides a powerful, minimally-invasive means for early disease detection, genotyping, and personalized therapy. Detection of alleles of clinical interest is often challenged by their low concentration and sequence homology with the much more abundant wildtype nucleic acids. Methods: Argonuate (Ago) from the thermophilic bacterium Thermus thermophilus ( TtAgo) utilizes short DNA guides to specifically cleave complementary DNA and RNA targets. We found that under optimized conditions, TtAgo cleaves DNA and RNA complementary to the guide DNA with high efficiency, but spares nucleic acids with a single nucleotide mismatch at and around its catalytic site with high sensitivity. Based on these findings, we designed a new multiplexed enrichment assay, dubbed NAVIGATER (Nucleic Acid enrichment Via DNA Guided Argonaute from Thermus thermophilus), that utilizes TtAgo, to specifically cleave perfectly complementary DNA and RNA while sparing alleles of interest. Results: NAVIGATER greatly increases the fractions of rare mutant alleles with single nucleotide precision enhancing the sensitivity of downstream detection methods such as XNA-PCR. We demonstrate 60-fold enrichment of KRAS G12D in blood samples from pancreatic cancer patients and over ten-fold improved sensitivity of XNA-PCR, enabling multiplex detection of KRAS and EGFR mutants at 0.01% fractions. Conclusions: NAVIGATER has important advantages over other mutant allele enrichment assays such as the ones based on CRISPR-Cas. It does not require the target to contain a protospacer-adjacent motif; is a true (turnover) catalyst; can cleave both DNA and associated exosomal RNA targets, improving sensitivity; and can operate at elevated temperatures for higher selectivity and compatibility with detection schemes.
Influence of tumor size and Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline on patient (pt) outcomes in lenvatinib-treated radioiodine-refractory differentiated thyroid cancer (RR-DTC).
Authors: Lori J. Wirth, Sophie Leboulleux, Naomi Kiyota, Makoto Tahara, Kei Muro, Myung-Ju Ahn, Yuichi Ando, Matthew H. Taylor, Shunji Takahashi, Sung-Bae Kim, Soamnauth Misir, Corina E. Dutcus, Ran Xie, Prashant Ramesh Joshi, Brett Gordon Maxwell Hughes, Javier Aller, Monika K. Krzyzanowska, Jaume Capdevila
Journal: Journal of Clinical Oncology (2019)

6081 Background: In SELECT, lenvatinib significantly improved progression-free survival (PFS) of pts with RR-DTC versus placebo (18.3 v 3.6 months; hazard ratio [HR]: 0.21 [99% CI: 0.14, 0.31]; P&lt;0.001). Here we examine the treatment of RR-DTC with lenvatinib in relation to tumor size (sum of all targeted lesions) and ECOG PS. Methods: In this post hoc analysis of SELECT with pts randomized to receive lenvatinib, Kaplan-Meier estimates of time to ECOG PS ≥2 were calculated for subgroups of pts according to baseline ECOG PS or tumor size. Objective response rate (ORR) and Kaplan-Meier estimates of overall survival (OS) and PFS according to ECOG PS (0 or 1) at baseline were calculated. Correlations between ECOG PS at baseline (0 or 1) and maximum tumor shrinkage were calculated using one-way analysis of variance. Results: Pts with ECOG PS 0 or 1 at baseline had similar demographic and disease characteristics. ORR was 78.5% and 51.0% for pts with ECOG PS 0 and 1 at baseline, respectively (odds ratio [95% CI]: 3.508 [2.018, 6.097]). Mean maximum percent decrease in tumor size was significantly greater in pts with baseline ECOG PS 0 (-46.13%) versus pts with ECOG PS 1 (-37.16%; P=0.0017). For pts with ECOG PS 1 at baseline, time to ECOG PS ≥2 was numerically shorter with tumor size &gt;60 mm versus tumor size ≤60 mm (HR [95% CI]: 1.450 [0.708, 2.967]). Additional results are summarized in the table. Conclusions: Among pts with RR-DTC, PFS, OS, ORR, and time to ECOG ≥2 were generally better for patients with lower ECOG PS or smaller tumor size at baseline. These results may indicate that it is beneficial to start lenvatinib in pts with RR-DTC early, before ECOG PS worsens and tumor size increases. Clinical trial information: NCT01321554. [Table: see text]
Longitudinal circulating Epstein–Barr virus DNA response to induction chemotherapy and chemo-radiotherapy to identify biological phenotypes in EBV-associated nasopharynx of head and neck cancer.
Authors: Jia-Wei Lv, Ying Sun, Yu-Pei Chen, Guan-Qun Zhou, Kuan Rui Lloyd Tan, Jun Ma, Melvin L.K. Chua
Journal: Journal of Clinical Oncology (2019)

6021 Background: Liquid biopsies have the utility for detecting minimal residual disease in several cancers, but its clinical utility for real-time treatment adaptation remains limited. We adopted Epstein-barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) as a model to investigate its potential. We characterize longitudinal response of circulating EBV DNA to induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) in locally advanced NPC (LA-NPC), and investigate the association of complete biological response (cBR, undetectable cfEBV DNA) during treatment to prognoses. Methods: The medical records of 673 LA-NPC cases with serial EBV DNA measurements (pre-treatment, after each IC cycle, post-CCRT) were extracted. Cox regression and landmark analysis were used for survival analyses. Results: Four distinct phenotypes were identified based on their longitudinal cfEBV DNA response: 1) Early responders (200/673[29.7%]) achieved cBR post-IC 1 ; 2) Intermediate responders (332/673[49.3%]) included patients with cBR post-IC 2-4 , and cBR post-CCRT after two IC cycles or following a temporary bounce (detectable reading following initial cBR); 3) Late responders (75/673[11.2%]) achieved cBR only post-CCRT after 3-4 IC cycles; 4) Treatment-resistant (66/673[9.8%]) patients demonstrated non-cBR post-IC+CCRT. These phenotypes were significantly correlated with prognoses, adjusted for pre-treatment EBV DNA load, N-category and chemotherapy intensity (AHR DFS = 3.46[2.01–6.25], intermediate; 7.50[4.24–14.77], late; 17.33[10.06–33.38], treatment-resistant vs. early responders, P all &lt; 0.01). Interestingly, intermediate and late responders without cBR post-IC 2 had inferior survival despite more IC (HR DFS = 1.83[1.17–2.84], &gt; 2 vs. &gt;2 IC cycles, P &lt; 0.01). For treatment-resistant patients, adjuvant chemotherapy following IC+CCRT reduced risk of distant metastasis (HR DMFS = 0.42[0.24–0.74], P &lt; 0.01). Conclusions: We propose investigate risk-adapted chemotherapy de-intensification and intensification strategies based on the four novel phenotypes, which could shape the individualized treatment of LA-NPC. Our study highlights the feasibility of liquid biopsy for real-time therapeutic adaptation.
Endolysin treatment against Staphylococcus aureus in adults with atopic dermatitis: A randomized controlled trial
Authors: Jill de Wit, Joan E.E. Totté, Minke M.F. van Mierlo, Joyce van Veldhuizen, Martijn B.A. van Doorn, Frank H.J. Schuren, Sten P. Willemsen, Luba M. Pardo, Suzanne G.M.A. Pasmans
Journal: Journal of Allergy and Clinical Immunology (2019)