tbuckley/cabot-search huggingface dataset:
Gemcitabine and oxaliplatin (GEMOX) alone or with cetuximab in first-line treatment of advanced biliary cancers (ABC): Exploratory analyses according to tumor KRAS/BRAF mutations and EGFR expression in a randomized phase II trial (BINGO).
Authors: David Malka, Pascale Cervera, Stephanie Heurteau-Foulon, Dominique Wendum, Tanja Trarbach, Christelle De La Fouchardiere, Eveline Boucher, Laetitia Fartoux, Sandrine J. Faivre, Jean-Pierre Pignon, Olivier Rosmorduc, Tim F. Greten
Journal: Journal of Clinical Oncology (2013)

4127 Background: Gemcitabine-platinum regimens are the standard of care for ABC. Whether GEMOX-cetuximab may be beneficial in ABC patients (pts) was tested in BINGO, an international, open-label, randomized phase II study (ASCO 2012). With a 4-month progression-free survival (PFS) rate of 63% [CI: 52-74], the primary endpoint was met (target, ≥60%; GEMOX, 54% [43-65]). However, median PFS (6.1 vs. 5.5 months) and overall survival (OS) (11.0 vs. 12.4 months) were similar in both arms. Available data on KRAS/BRAF mutation rates in ABC pts are sparse. Methods: Planned exploratory endpoints included tumor KRAS/BRAF mutational status (high-resolution melting and DNA sequencing) and EGFR expression score (immunohistochemistry [IHC]), and their impact on patient outcome according to treatment arm. Results: Tumor samples were collected for 91 (61%) consenting pts among the 150 randomized pts, and were suitable for DNA analysis and IHC in 75 (50%) and 77(51%) pts, respectively. Tumor KRAS and BRAF mutations (MT) were found in 14 (19%) and 4 (5%) pts, respectively. High EGFR score (≥ 200) was observed in 18 (23%) pts. 4-month PFS rates did not differ according to tumor KRAS MT (wild-type [WT] vs. MT: 62% vs. 57%, p=0.72), BRAF MT (61% vs. 75%, p=1.00) or EGFR score (≥ vs. &lt;200: 56% vs. 63%, p=0.42) overall, or according to treatment arm (table). PFS and OS (log rank test) also did not significantly differ according to these biomarkers, overall or between treatment arms. Conclusions: Tumor KRAS/BRAF mutations and EGFR overexpression were found in 24% and 23% of pts respectively. With the limit of statistical power in these exploratory analyses, they had no statistically significant prognostic or predictive impact. Clinical trial information: 2007-001200-20. [Table: see text]
Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE)
Authors: A. Perotti, M. Maur, L. Viganò, E. Gallerani, R. Angst, J. Albanell, C. Sessa, R. Laliberte, S. Marsoni, L. Gianni
Journal: Journal of Clinical Oncology (2006)

3065 Background: AP23573 is a novel mTOR inhibitor with anti-tumor activity in Phase1 and 2 trials. In vitro, AP23573 is at least additive with chemotherapy agents including 5FU. CAPE is activated to 5FU by thymidine phosphorylase which may be highly expressed in tumors and correlates with progression through angiogenic mechanisms controlled by mTOR. Given the potential for a positive interaction, this trial studied the combination of AP23573 and CAPE in adult patients with solid tumors. Methods: Starting doses were: AP23573 25 mg i.v. on Days 1, 8, and 15 of a 28-day cycle, and CAPE 1650 mg/m 2 p.o. daily on Days 1–14. Planned PK and PD studies include analysis of plasma VEGF, PBMC, skin, and tumor samples for effects on pathways associated with mTOR and on the metabolism of CAPE and fluoropyrimidines. Dose limiting toxicity (DLT) was defined as: febrile neutropenia; neutrophils &lt;500x10 6 /L for ≥ 5 days; ≥ Grade 3 (CTC) thrombocytopenia; non-haematological toxicities ≥ Grade 2 (diarrhea, cardiac or renal); or missing two consecutive weekly doses due to any toxicity. Results: 15 patients have been treated. Three dose levels of weekly AP23573 (25, 37.5 and 50 mg) were completed without DLT. Treatment-related toxicity was mostly mild or moderate (≤ grade 2), with mucositis/stomatitis the most frequent. Anti-tumor activity included a partial response in a case of endometrial cancer, and stable disease &gt; 4 months in 3 cases (1 renal, 1 uterine and 1 head &amp; neck cancer). AP23573 did not affect the PK of CAPE or 5FU but a trend toward a decreased exposure to the catabolite 5-FuH2 was apparent in the presence of AP23573. In keeping with this observation, the activity of dihydro-pyridine-dehydrogenase gradually decreased to 60% of that before AP23573. This decrease was not associated with reduced tolerability. Conclusions: The combination of AP23573 with CAPE is safe with initial indications of anti-tumor activity. This is the first description of a feasible combination of an mTOR inhibitor with an anti-metabolite. Additional dose levels of AP23573 (75 mg) and CAPE (1850 mg/m 2 /day) are ongoing and PK and PD studies are continuing. [Table: see text]
Tumor interface stability on CT imaging is an early marker of response to cytotoxic therapy in pancreatic ductal adenocarcinoma.
Authors: Christopher Wilke, Ahmed Amer, Dalia Elganainy, Priya Bhosale, Ott Le, Yeonju Lee, Jordan Cloyd, Huamin Wang, Joseph M. Herman, Cullen M. Taniguchi, Andrew Rhim, Jason B. Fleming, Anirban Maitra, Robert A. Wolff, Gauri R. Varadhachary, Jeffrey Edwin Lee, Matthew H. G. Katz, Eric P. Tamm, Eugene Jon Koay
Journal: Journal of Clinical Oncology (2017)

284 Background: There is currently no reliable biomarker for assessing the response to therapy of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated how changes in the tumor/parenchyma interface associate with response. Methods: We reviewed pre- and post-therapy scans of patients who received chemotherapy and/or chemoradiation for both localized and metastatic PDAC. We classified the interface between the PDAC tumor and surrounding pancreas parenchyma as stable (remains or becomes well-defined) or unstable (becomes poorly defined) using a novel visual scoring system and quantified changes in enhancement at this interface (Philips Intellispace Portal, quantitative European Association for the Study of Liver [qEASL]). Results: Three retrospective datasets were used to develop this method with consensus visual scoring performed by 3 radiologists. The first dataset included 99 patients with localized PDAC who received neoadjuvant chemoradiation. Patients who were classified as having a stable interface had significantly higher probability of achieving a complete or near-complete pathologic response (21% vs 0%, p = 0.01) and additionally demonstrated an improved median disease-free survival (DFS, 20.9 vs 7.9 mos., p &lt; 0.01) and overall survival (OS, 47.7 vs 19.1 mos., p &lt; 0.01). These results were validated in a separate dataset of 94 patients receiving protocol-based chemotherapy and chemoradiation (chemoRT cohort) and a cohort of 86 patients with stage IV disease. In both cohorts, a stable interface was associated with a significant improvement in progression free survival (PFS, Hazard Ratio [HR] 0.44, p = 0.01 for chemoRT and HR 0.70, p = 0.16 for stage IV) and OS (HR 0.42, p &lt; 0.01 for chemoRT and HR 0.59, p = 0.05 for stage IV). Multivariate analyses for each cohort showed interface stability to be independently associated with both DFS/PFS and OS. Measurements obtained using qEASL were concordant with the visual scoring results. Conclusions: The interface stability of PDAC is an early readout of response to therapy. Integration of this imaging feature into clinical trials for localized and metastatic PDAC may aid in the future development of adaptive treatment strategies.
Efficacy and safety of daclatasvir plus asunaprevir for Korean patients with HCV genotype Ib infection: a retrospective multi-institutional study
Authors: Byeong Wook Cho, Seok Bae Kim, Il Han Song, Sae Hwan Lee, Hong Soo Kim, Tae Hee Lee, Young Woo Kang, Seok Hyun Kim, Byung Seok Lee, Hee Bok Chae
Journal: Clinical and Molecular Hepatology (2017)

The combination of daclatasvir (DCV) and asunaprevir (ASV) has demonstrated a high sustained virologic response at 12 weeks (SVR12) and a low rate of adverse events in previous clinical studies. The purpose of this study was to clarify the results of treatment and side effects in Korean patients with chronic hepatitis C virus (HCV) genotype Ib infection.We retrospectively analyzed clinical data from chronic HCV genotype Ib patients treated with DCV+ASV from August 2015 to September 2016 at five hospitals in the Daejeon-Chungcheong area.A total of 152 patients were examined for resistance associated variants (RAVs). Among them, 15 (9.9%) were positive for Y93 and one (0.7%) was positive for L31. Of 126 patients treated with DCV+ASV, 83 patients completed treatment and 76 patients were included in safety and efficacy analysis. Five (6.6%) were positive for Y93 and 12 (15.8%) exhibited cirrhotic change. DCV+ASV was the first-line treatment for 58 (76.3%) patients. Eleven (14.5%) patients relapsed after previous treatment that included interferon and seven (9.2%) of these patients were found to be intolerant of interferon. Adverse events occurred in 10 (13.2%) patients and two patients stopped the medication because of severe itching and skin rash. SVR12 was 89.5% (68/76) in all patients and 91.5% (65/71) in RAV-negative patients.DCV+ASV showed good efficacy in patients with HCV Ib infection in Korea. Close monitoring is needed for severe adverse events and treatment failure, which were uncommon.
Resource utilization in patients with breast cancer treated with generic versus branded docetaxel.
Authors: Stephen E. Jones, Laura Liao, Zhimin Xiao, Yan Liu, Sheikh Usman Iqbal, Quanwu Zhang
Journal: Journal of Clinical Oncology (2014)

1015 Background: This study was to assess health resource utilization in patients with breast cancer (BC) treated with generic (available in US since 2011) vs branded docetaxel. Methods: A retrospective inception cohort was analyzed in Clinformatics DataMart healthcare claims database. Patients (female, aged ≥18 years) were identified between Apr 1, 2011 and Jun 30, 2012 if they had an ICD-9:174 for BC, initiated docetaxel, and had 6-month continuous insurance coverage pre (baseline) and post (follow-up) docetaxel initiation. The 50 most frequent claims for clinical diagnoses, procedures and prescriptions were evaluated between generic and branded docetaxel along with health resource utilization and expenditures, with hierarchical mixed effects model adjustment for potential confounding. Results: 1,955 patients diagnosed with BC were identified, of which a total of 98 generic and 262 branded docetaxel users were included in the final analysis. For the majority of patients, the source of docetaxel was not apparent. Patient characteristics were comparable at baseline between study groups. During follow-up, the generic cohort showed a higher rate of claims for neutropenia (67.3% vs 48.9%; p<0.01) and malaise and fatigue (22.4% vs 13.7%; p<0.05) among medical diagnoses. The branded was higher in nausea and vomiting (43.5% vs 29.6%; p=0.02). The rate of neutropenia remained higher in generic vs branded (73.9% vs 52.8%; p<0.01) even after adjusting for history of neutropenia and baseline use of G-CSF and fosaprepitant. The generic cohort had more fosaprepitant use at follow up (54.1% vs 30.2%; p<0.01). The higher odds of neutropenia was observed in generic with (OR=2.49; p= 0.03) or without (OR=1.41; p= 0.31) fosaprepitant use during follow up. Mean outpatient costs excluding docetaxel drug costs were higher in the generic ($59,177 vs $50,243; p<0.01), and remained significantly higher ($54,282 vs $46,698; p=0.03) after adjustment for baseline healthcare costs, inpatient admissions, etc. Conclusions: Use of generic vs branded docetaxel in BC was associated with about 40% more medical claims for neutropenia and higher ambulatory care costs at 6 months follow up. Further research is needed to confirm these findings.
Measuring the impact of provider education to referral rate in survivorship care.
Authors: Ursula S Canli, Patricia E. Hershberger, Cathleen M. Schaeffer, Kent Hoskins, Oana Cristina Danciu
Journal: Journal of Clinical Oncology (2017)

14 Background: There will be an estimated 19 million cancer survivors by 2024. Survivors are often lost to follow-up after active treatment due to poor coordination of care between clinical oncologist and primary care providers. Lack of awareness of survivor needs including insufficient monitoring of late effects after oncologic care contribute to poor care coordination. While cancer centers have gradually introduced survivorship care, it remains challenging for some providers to refer their patients to a survivorship visit once their cancer treatment is completed. Continuing education is known to improve provider knowledge and may lead to an increased number of patients referred to survivorship. Methods: Survivorship starts when completing the initial treatment (surgery, chemotherapy or radiation therapy). The project will implement the review of an education module regarding survivorship through the National Comprehensive Cancer Network (NCCN) education website by breast cancer (BC) medical oncologists and their fellows in training at a cancer center in the Midwest. Providers are to complete “Comprehensive Care for Cancer Survivors”, a free continuing education module, on the NCCN continuing education website. Pre intervention data was retrospectively collected, including all BC cases from June 2016 to August 2016. Post intervention data will be prospectively collected over 1 month. Pre and post intervention referral rates will be compared using descriptive statistical methods. Results: A baseline 3 months review of 349 encounters noted 22 of 28 (78.6%) BC survivors were referred to the breast cancer survivorship visit. Results for this project are ongoing, and will include the analysis of referral rates by medical oncologists or fellows during the 1 month post completion of the NCCN education module. These results will be compared to the previous 3 months Conclusions: While data collection is pending, we hope to show that providers who have completed formal education regarding survivorship are more likely to refer breast cancer survivors to a survivorship visit. If the project is effective it will help increase the number of cancer patients seen in the BC survivorship clinic and improve the health outcome of BC survivors.
Cell free circulating tumor DNA (ctDNA) landscape in patients with advanced gastroesophageal adenocarcinoma (GEC).
Authors: Daniel V.T. Catenacci, Rebecca J Nagy, Fadi S. Braiteh, Seung Kim, Eunice Lee Kwak, Steven Brad Maron, Kimberly C. Banks, Richard B. Lanman, Amirali Talasaz, Jeeyun Lee
Journal: Journal of Clinical Oncology (2017)

47 Background: Esophageal (EC), gastroesophageal junction (GEJ) and gastric cancer (GC), together GEC, have a poor prognosis with few targeted therapeutic options. As genomic profiling is becoming increasingly useful, we queried whether comprehensive genomic profiling of ctDNA would reveal relevant genomic alterations leading to targeted therapies. Methods: Patients (pts) with advanced GEC undergoing next-generation sequencing (NGS) of ctDNA in a CLIA certified lab were identified. ctDNA was analyzed using Guardant360, a digital NGS assay to identify single nucleotide variants, indels, amplifications and fusions in 54-70 genes. Results: 546 pts with GEC had ctDNA testing and 54 pts (10%) had more than one ctDNA test (range 2-6). Pts were similar across the 3 groups, with the exception of an increased male:female ratio (5:1) in the GEJ and EC cohorts. Mean age was 61.5 yrs (range 24-91). ctDNA alterations were detectable in 455 pts (83.3%). Recurrent alterations and therapeutic options for each cohort are shown in Table 1. Serial monitoring of ctDNA correlated with tumor markers, imaging and clinical response. Multiple antitumor responses to targeted therapy will be presented. Conclusions: ctDNA was detected in 83.3% of pts with advanced GEC with a frequency similar to TCGA. The diverse genomic landscape of GEC, obtained noninvasively, along with matched therapies have potential to improve outcomes for this aggressive disease. [Table: see text]
Efficacy based on tumor PD-L1 expression in KEYNOTE-002, a randomized comparison of pembrolizumab (pembro; MK-3475) versus chemotherapy in patients (pts) with ipilimumab-refractory (IPI-R) advanced melanoma (MEL).
Authors: Igor Puzanov, Reinhard Dummer, Jacob Schachter, Anna C. Pavlick, Rene Gonzalez, Paolo Antonio Ascierto, Kim Allyson Margolin, Omid Hamid, Sanjiv S. Agarwala, Matteo S. Carlino, Jochen Utikal, Michal Lotem, Antoni Ribas, Peter Mohr, Charlotte M. Roach, Marisa Dolled-Filhart, Xiaoyun Nicole Li, Scot Ebbinghaus, Soonmo Peter Kang, Adil Daud
Journal: Journal of Clinical Oncology (2015)

3012 Background: Pembro is an anti–PD-1 antibody approved for treating advanced MEL that progressed following IPI and, if BRAFV600 mutant, a BRAF inhibitor. In KEYNOTE-002 (NCT01704287), pembro doses of 2 mg/kg and 10 mg/kg every 3 wk (Q3W) significantly improved PFS compared with investigator-choice chemotherapy in IPI-R MEL (P < .0001), with no difference between pembro doses (P = .44). Data from KEYNOTE-001 showed that PD-L1 positivity was correlated with a higher ORR and longer PFS in MEL pts. We evaluated efficacy in PD-L1+ and PD-L1– MEL pts enrolled in KEYNOTE-002. Methods: 540 pts with advanced IPI-R MEL were randomized 1:1:1 to pembro 2 or 10 mg/kg every 3 wk (Q3W) or chemotherapy. PD-L1 expression was assessed centrally by IHC using the 22C3 antibody. The cut point for positivity was staining in ≥1% of tumor cells. Response was assessed at wk 12 and every 6 wk thereafter (RECIST v1.1, central review). Primary end points were PFS and OS (final analysis planned after 370 deaths occur). ORR and the relationship between PD-L1 expression and efficacy were secondary end points. Data for the pembro arms were pooled. Results: 421/540 pts enrolled (78%) had tumors evaluable for PD-L1 expression; 291 (69%) were PD-L1+, 130 (31%) were PD-L1–. Pembro prolonged PFS and increased ORR compared with control in PD-L1+ and PD-L1– pts (Table). Among pembro-treated pts, ORR was higher in PD-L1+ pts, but the CIs were overlapping, and there was no difference in duration of response (DOR) based on PD-L1 expression. There was no prognostic effect in the control arm. Conclusions: Pembro improved efficacy over chemotherapy in both PD-L1+ and PD-L1– IPI-R advanced MEL. These data indicate that in IPI-R MEL pts, pembro therapy should not be limited to pts with PD-L1+ tumors. Clinical trial information: NCT01704287. Total PD-L1+ PD-L1– Pembro n = 361 Control n = 179 Pembro n = 193 Control n = 98 Pembro n = 93 Control n = 37 PFS, HRa (95% CI) 0.53 (0.43–0.65) 0.52 (0.39–0.68) 0.60 (0.38–0.94) 6-mo PFS, % 36 16 40 13 26 22 ORR, % (95% CI) 23 (19–28) 4 (2–9) 26 (20–33) 4 (1–10) 15 (8–24) 8 (2–22) DOR, wk, median (range) NR (5+ – 50+) 37 ( 7+ – 41) NR (5+ – 50+) 41 (18 + – 41) NR (6+ – 48+) 37 (7+ – 37) aPembro vs control.
Behavioral counseling to prevent sexually transmitted infections
Authors: Ned Calonge, Diana B. Petitti, Thomas G. DeWitt, Allen J. Dietrich, Leon Gordis, Kimberly D. Gregory, Russell Harris, George Isham, Rosanne Leipzig, Michael L. LeFevre, Carol Loveland-Cherry, Lucy N. Marion, Virginia A. Moyer, Judith K. Ockene, George F. Sawaya, Barbara P. Yawn, US Preventive Serv Task Force
Journal: Annals of Internal Medicine (2008)
Effect of tumor-treating fields on DNA repair in cancer cell lines.
Authors: Eilon David Kirson, Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Uri Weinberg, Yoram Palti
Journal: Journal of Clinical Oncology (2013)

e22138 Background: TTFields Therapy is an antimitotic treatment modality approved by FDA for the treatment of patients with recurrent glioblastoma (GBM). TTFields act by disruption of spindle microtubule arrangement during metaphase and interference with cytokinesis during anaphase and telophase. These effects are the result of rotation of charged and/or polar macromolecules in the direction of the applied antimitotic fields. We hypothesized that the negatively charged, double stranded DNA fragments induced by ionizing radiation (RT) or ultraviolet light (UV) undergo similar rotation. Double strand break repair relies on proper alignment of the strands during the process of homologous recombination. Thus application of TTFields during the DNA repair process holds the potential of interfering with normal DNA repair. Methods: Cancer cells (786-O renal cell carcinoma) were exposed to TTFields for various durations up to 4 hours after UV or RT treatment. The extent of DNA repair over time was evaluated using the alkaline comet assay (Trevigen, USA). This assay allows the computation of the relative proportion of intact DNA strands and DNA fragments in individual cells after inducing DNA breaks. Results: Exposure of UV treated cells to TTFields for 4 hours led to a significant increase in the content of DNA fragments per cell compared to the content without TTFields exposure (45 + 14%; p=0.012). This increase was accompanied by a significant decrease in the intact DNA content per cell compared to the content of cells not exposed to TTFields (47 + 14%; p=0.005). Inhibition of DNA repair was apparent 1-4 hours after irradiation depending on the extent of DNA damage. Similar results were seen after exposure of the cultures to 2Gy RT (17% increase in DNA fragment content and 14% decrease in intact DNA content at 4 hours). Interestingly, while TTFields did not lead to any DNA damage when applied alone, the application of TTFields for one hour after UV exposure led to a 27 + 29% (p=0.02) increase in the extent of the DNA damage (fragment content). Conclusions: This is the first demonstration that, in addition to its known anti-mitotic effect, TTFields Therapy also inhibits DNA repair and may thus lead to an increase in the cytotoxic effects of therapeutic irradiation.