tbuckley/cabot-search huggingface dataset:
Cell-free circulating tumour DNA as a tool for monitoring response to anti-EGFR therapies of mCCR.
Authors: Estela Vega, Antonio Cubillo, Rodrigo Toledo, Elena Garralda, Rafael Alvarez-Gallego, Lisardo Ugidos, Jesus Rodriguez-Pascual, Cesar Munoz, Susana Hernandez Prieto, Pedro P. López-Casas, Fernando Lopez Rios, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2016)

e23059 Background: RAS/RAF/PIK3CA mutations are frequent drivers of secondary drug resistance to cetuximab in mCCR, which typically occurs within 3-12months from the start of therapy. The emergence ofmutant clones can be detected non-invasively months prior to radiographic progression through liquid biopsy We aimed to analyze the plasma genetic status and relate this with clinical outcome Methods: Patients with no prior chemotherapy for KRAS wt mCRC received FOLFIRI-Cetuximab until progression or unacceptable toxicity. Objective tumor response was evaluated using modified Response Evaluation Criteria in Solid Tumors (RECIST) every 2months. Blood samples for liquid biopsy were collected before treatment and with each tumor assessment. KRAS(G12S/R/C/V/A/D, G13D, Q61H, A146T); NRAS(Q61K/R/L/H); BRAF(V600E); PIK3CA(E542K, E545K/G, Q546K, M1043I, H1047Y/R/L) hotspot mutations were assessed in the tumor samples using Ion Torrent NGS or Cobas kits, and in the plasma cell-free DNA by BEAMing technique Results: 25 patients were included, from which 1 was considered non evaluable (second synchronous primary lung carcinoma). 3 patients harbored BRAF/PIK3CA somatic mutations before treatment; all of which presented a quick clinical progression with median PFS 2.1 months(0.8-3.3). Continuous wt liquid biopsy results were observed in patients with prolonged response to cetuximab. 18 cases(75%) presented disease control(CR/PR/SD), 13 with partial/complete response. 6 underwent surgery after response, and 11 maintained prolonged response to the treatment(median follow up 19.3 months; median time to response duration is not reached). Emerged KRAS/PIK3CA mutations were found in three patients, two of whom initial responder that subsequently developed imminent progression; with median PFS 2.5 months Conclusions: Our results showed that patients with prolonged response maintained wt circulating status throughout the period of anti-EGFR therapy while circulating mutation levels upsurges are associated with imminent clinical deterioration and metastasis spread. It suggests that wt circulating status during treatment with anti-EGFR is a potential biomarker of prolonged good response in mCRC patients Clinical trial information: NCT01943786.
Letter to the editor: Occurrence of modified measles during outbreak in Taiwan in 2018
Authors: Chih-Jung Chen, Tzou-Yien Lin, Yhu-Chering Huang
Journal: Eurosurveillance (2018)

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Unresectable hepatocellular carcinoma treated with lenvatinib or sorafenib: A disease modeling study.
Authors: Gabriel Tremblay, Ronda Copher, Shan Ashton Garib, Janice Pan
Journal: Journal of Clinical Oncology (2018)

e16157 Background: In the published multicenter, randomized REFLECT study in unresectable hepatocellular carcinoma (HCC), the treatment effect of lenvatinib on the overall survival (OS) of patients with unresectable HCC was demonstrated by confirming non-inferiority compared to sorafenib, and demonstrated improved progression-free survival (PFS), time to progression, and objective response rate. The objective of this study is to extrapolate and compare survival among patients with unresectable HCC treated with sorafenib or lenvatinib. Methods: A partitioned survival model was constructed. It included three mutually exclusive health states: pre-progression; post-progression; death. The intention-to-treat (ITT) population of the clinical trial was used for this analysis. The OS and PFS were extrapolated over the lifetime of patients. Since the proportion of patients with baseline alpha-fetoprotein (AFP) levels ≥200 ng/mL, was greater in the lenvatinib arm than in the sorafenib arm (46.4% vs 39.3%), an additional scenario that involves a covariate analysis where both OS and PFS were adjusted for AFP was performed. Six survival distribution forms (Weibull, Exponential, Log-Logistic, Log Normal, Gamma and Gompetz for three different model class (PH parametric model, individual parametric models, piecewise models) were evaluated to determine the optimal approach. Results: The individual model with a log-logistic form was selected as best fitting for OS and with a gamma form was selected for PFS. For ITT population, it generated 1.84 years and 1.70 years of survival for lenvatinib and sorefinib treated patients, respectively. It generated 0.88 and 0.50 progression free years for lenvatinib and sorefenib treated patients, respectively. For AFP- adjusted population, it generated 1.75 years and 1.51 years of survival for lenvatinib and sorafenib treated patients, respectively. It generated 0.87 years and 0.79 years of progression free years for lenvatinib and sorafenib treated patients, respectively. Conclusions: The model suggests that over a lifetime a patient population treated with lenvatinib is expected to have longer OS and PFS compared to those treated with sorafenib.
Meta-analysis reveals multiple drivers of colorectal cancer pathogenesis.
Authors: Kamal Khorfan, Jihad Aljabban, Laraib Safeer, Hisham Aljabban, Maryam Panahiazar, Anne M. Noonan, Dexter Hadley
Journal: Journal of Clinical Oncology (2018)

e15601 Background: Colorectal cancer (CRC) is the third most common cancer globally. Most cases are not linked with known genetic risk factors but rather with old age and lifestyle. While cancers that are confined to the wall of the colon are curable with surgery, cancers that have disseminated are challenging to treat. Current research aims to identify biomarkers that can predict cancer activity and serve as therapeutic targets. Methods: We employed our Search Tag Analyze Resource (STARGEO) platform to conduct meta-analysis using the National Center for Biotechnology’s (NCBI) Gene Expression Omnibus (GEO) to define CRC pathogenesis. We tagged 1808 colorectal samples from CRC patients and used an equal number of healthy colorectal samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis (IPA), restricting genes that showed statistical significance (p < 0.05) and an absolute experimental log ratio greater than 0.15 between disease and control samples. Results: Our meta-analysis identified activation of the agranulocyte and granulocyte adhesion and diapedesis and estrogen-mediated-S-phase entry canonical pathways. We also found inhibition of Csk-homologous kinase (CHK) cell cycle regulation, cAMP and protein kinase A-mediated signaling, and cell cycle G2M DNA damage checkpoint regulation. We identified ERBB2, TGFB1, and VEGF as activated top upstream regulators. Tumorigenic proteins such as cell migration inducing protein (CMIP), FOXQ1 (a transcription factor), CCAT1, CDH3, and CXCL8 were strongly upregulated. Additionally, there was downregulation of anti-tumor proteins, such as carbon anhydrase 4 and MS4A12, as well as proteins that maintain normal intestinal epithelial function and environment including AQP8 (a water channel protein), claudin 8, and SLC4A4 (maintains normal alimentary pH). Conclusions: Our analysis builds off known drivers and biomarkers of CRC pathogenesis while introducing new candidate therapeutic and prognostic targets.
Second malignancies in patients with neuroblastoma: A report from the International Neuroblastoma Risk Group Project.
Authors: Mark A. Applebaum, Zalman Vaksman, Eric Hungate, Tara O. Henderson, Wendy B. London, Navin R. Pinto, Samuel Louis Volchenboum, Julie R. Park, Arlene Naranjo, Andrew DJ Pearson, Barabara Hero, Susan Lerner Cohn, Sharon Diskin
Journal: Journal of Clinical Oncology (2016)

10547 Background: Radiation and chemotherapy exposure are associated with the development of second malignant neoplasms (SMN) in neuroblastoma survivors. However, whether the incidence of SMN has changed with modern, intensive treatment is unknown. Further, the role genetic factors play in the etiology of SMN remains unclear. Methods: The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1974-2013 was analyzed. SMN risk was measured by cumulative incidence, standardized incidence ratios (SIR) and absolute excess risk (AER). Poisson regression estimated incidence rate ratios (IRR). Genes previously linked to SMN were evaluated in a candidate association study identifying germline polymorphisms associated with this phenotype. Results: 9,269 of 16,520 patients in the INRG database had SMN data. 81 (0.87%) patients developed SMN, including leukemia/lymphoma (n = 40), sarcomas (n = 19), carcinomas (n = 10), CNS tumors (n = 10), hepatoblastoma (n = 1), and nephroblastoma (n = 1). The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% CI: 1.2-2.5%) compared to 0.43% (95% CI: 0.19-0.89%) for low-risk patients (p = 0.002). Compared to 1990-1997, those treated after 1997 when stem cell transplant became standard practice had an IRR of 1.97 (95% CI: 1.16-3.55; p = 0.007). The SMN incidence of the entire cohort was 9-fold higher than expected (SIR = 9.2 (95% CI: 7.3-11.4), AER = 13.7). High-risk patients had a 20-fold higher incidence of SMN than expected (SIR = 20.5 (95% CI: 15.0-27.4), AER = 33.3). Intermediate-risk patients showed a 6-fold rise in SMN (SIR = 6.2 (95% CI: 3.3-10), AER = 8.3) and low-risk patients showed a 3-fold increase (SIR = 3.0 (95% CI: 1.2-6.2), AER = 3.5). rs861539 in XRCC3 (p = 0.004) and rs17036651 in MSH2 (p = 0.009) were most associated with developing SMN though neither retained significance after multiple testing corrections. Conclusions: Exposure to modern, high-risk neuroblastoma therapy increases the SMN risk. Genomic variation in DNA repair genes may influence SMN susceptibility. Further understanding of treatment exposures and genomic variables enhancing SMN risk is critical for optimizing survivorship care.
OrienX010 oncolytic viral therapy in phase â b trial of intralesional injection in unresected stage â¢c to â£ acral melanoma patients in China.
Authors: Chuanliang Cui, Zhihong Chi, Lu Si, Xinan Sheng, Dan Li, Xuan Wang, BIN LIAN, Bixia Tang, Li Li Mao, Xieqiao Yan, Li Zhou, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2016)

e21001 Background: Acral melanoma (MEL) was the main subtype in Chinese patients (pts), which was prone to intralymphatic diseases available for intralesional injection. The safety and efficacy of OrienX010, a herpes simplex virus type 1-derived oncolytic immunotherapy with expression of gene encoding human GM-CSF, was tested in phase Ⅰb trial of unresected stage ⅢC to Ⅳ (M1a/M1b) acral MEL pts. Methods: Phase 1b08 (n = 10) studied safety of OrienX010 (8×107 pfu/ml) at ≤ 4×108 pfu q2w according to size of injectable lesions (1-10cm). Objective response rate (ORR) was evaluated q12w. If there was no DLT, the maximum dose would be escalated to ≤ 8×108 pfu q2w in phase 1b09 (n = 10). Treatment continued until DLT, intolerance, or disease progression per Immune Related Response Criteria. DLT was any grade (gr) ≥ 4 adverse event (AE) or gr ≥ 3 immune-related AE within first 6 wks. Results: From Feb 2014, 12 pts received OrienX010 up to 4×108 pfu: 50% stageⅢC, 42% M1a, 8% M1b. Mean injection times were 10 (3-27). Mean size of all injectable lesions was 65.9mm(18.0- 99.0). AEs were all gr 1/2, pyrexia 66.7%, injection site pain 50%, leucopenia 25%, rash 16.7%, nausea16.7%. No DLTs were reported. ORR was 16.7% (2 PR), SD 41.7%. Time to response was 6-12 wks, median PFS 12.0wks (95%CI 9.3-14.7), and duration of response 24.0 wks (95%CI 19.3-28.7). OS was not reached. From May 2015, another 11 pts with stage ⅢC/M1a were enrolled in dose escalation up to 8×108 pfu, with mean injectable size of 77.0 mm(14.0-108.0). A shorter time to regression (4-8 wks) could be seen. ORR was 27.3% (3 PR); 36.4% had SD. Most AEs were similar, but nodal disease ulceration (36.4%) occurred more often after injection. By Jan 2016, the duration of response had reached 24.0 wks (95%CI 19.3-28.7). Conclusions: OrienX010 appears to be tolerable with no DLTs. Higher dose might result in shorter time to response, also longer duration of response in Chinese acral MEL pts. Phase 2 and combination trial are pending. Clinical trial information: CTR20140631, CTR20150881.
A comparison of outcomes, presentation, and treatment in pediatric (Ped) versus adult patients (Pts) with Ewing sarcoma.
Authors: Eric B Schwartz, Lili Zhao, Brittany Siontis, Laurence H. Baker, Rama Rao, Elizabeth R. Lawlor, Scott Schuetze, Rashmi Chugh
Journal: Journal of Clinical Oncology (2018)

11528 Background: Ewing Sarcoma (ES) afflicts 225 children and 180 adults in the US annually, but the vast majority of research is in ped pts. In multiple series, adults have poorer outcomes. The aim of this study is to evaluate clinical features that correlate with overall survival (OS)/progression-free survival (PFS). Methods: ES pts at University of Michigan from 2007-15 were identified using an institutional database. Charts were reviewed for demographic and clinical data. Ped pts were defined as age ≤18 at diagnosis. Two-sample t-tests or Chi-squared tests/Fisher’s exact tests were used for comparisons. Survival outcomes were analyzed using Kaplan-Meier methods and Cox proportional hazards regression models. Results: Seventy-eight ES pts (26 peds, 52 adult) were included in analysis. Factors evaluated in multivariate analysis model included localized disease, age, surgery, radiation, tumor size, cumulative doxorubicin (DOX), osseous primary and no. of first-line chemo cycles. Localized disease correlated with improved PFS (HR = 0.20, p = < 0.0001) and marginally with OS (HR = 0.386, p = 0.0580). Five-yr OS was higher in ped pts vs adults (81% vs. 49%, p = 0.0218). Ped pts received more cycles of first-line chemo (14.0 vs 11.8, p = 0.003), which positively correlated with OS (HR = 0.78, p = 0.002) and PFS (HR = 0.82, p = 0.024). Other differences included higher cumulative DOX dose and increased incidence of extraosseous ES in adults, but these did not correlate with OS/PFS. Conclusions: In our series, younger age correlated with improved OS. Ped pts were more likely to have osseous ES and less DOX, but only increased number of first-line chemo cycles was associated with improved outcomes. Further evaluation of potential tissue biomarkers to differentiate the two groups and early progressors is planned. Variable Peds (n = 26) Adult (n = 52) p-value Localized disease, n (%) 17 (65.4) 33 (63.5) 0.867 Mean no. of first-line chemo cycles 14 11.8 0.003 Cumulative DOX (mg/m2) 357.9 445.6 < 0.0001 Osseous primary, n (%) 21 (84) 22 (45.8) 0.002 Mean tumor size, cm (range) 8.2 (3.2 – 19.3) 9.6 (1.8 – 23.5) 0.384 Surgical Resection, n (%) 19 (73.1) 28 (53.8) 0.142 Progression during first line rx, n (%) 1 (4.2) 7 (15.2) 0.249
A phase II study of perioperative intraperitoneal paclitaxel plus S-1/paclitaxel for curatively resectable gastric cancer with serosal invasion: The GAPS study.
Authors: Seiji Ito, Motohiro Imano, Yoshikazu Uenosono, Takaaki Arigami, Hiroshi Yabusaki, Yasuo Hirono, Shugo Ueda, Tatsuki Matsumura, Ryoji Fukushima, Atsushi Takeno, Kentaro Kishi, Yasutaka Chiba, Sachi Chiba, Haruhiko Imamoto, Yuichi Ito, Atsushi Matsuki, Hironori Ishigami, Hironori Yamaguchi, Joji Kitayama, Hiroshi Furukawa
Journal: Journal of Clinical Oncology (2018)

4033 Background: The prognosis of gastric cancer with serosal invasion is extremely poor. Despite various perioperative adjuvant therapies, peritoneal recurrence is still difficult to control. Since the clinical efficacy of intraperitoneal (IP) paclitaxel (PTX) was suggested for the treatment of gastric cancer with peritoneal metastasis and positive cytology, IP PTX is a promising strategy for curatively resectable gastric cancer with serosal invasion. This multicenter, phase II study evaluated the efficacy and safety of IP PTX plus S-1/PTX for this target. Methods: Eligibility criteria included pathologically confirmed gastric adenocarcinoma with serosal invasion, but no peritoneal or distant metastases. Patients received three courses of preoperative IP PTX plus S-1/PTX (IP PTX 20 mg/m2, intravenous PTX 50 mg/m2 on days 1 and 8, and S-1 80 mg/m2/day on days 1-14, q3 weeks) followed by D2 gastrectomy, and they then received three courses of IP PTX plus intravenous PTX postoperatively. The primary endpoint was the proportion of the completion of protocol treatment (% protocol completion). Secondary endpoints were safety, overall survival, and the response rate (RR). The sample size was calculated to be 50 cases, under the hypothesis of expected % protocol completion of 80% and threshold % protocol completion of 60% with one-sided testing at the 2.5% significance level and power of 80%. Results: Between May 2014 and August 2016, 51 patients were enrolled. Among the 51 eligible patients with a median age of 66 years, 41 completed the protocol treatment (80.4% completion; 95% confidence interval 66.9–90.2%, p = 0.0016). During perioperative chemotherapy, grade 3/4 neutropenia occurred in 31.4%, and grade 3/4 non-hematological adverse events occurred in 19.6%. The incidence of adverse events related to surgery was 19.1%. There were no treatment-related deaths. Follow-up for long-term survival is continuing. The clinical RR of preoperative chemotherapy was 71.4% (5/7). The pathological RR (residual tumor < 2/3) was 68.1% (32/47). Conclusions: Perioperative IP PTX plus S-1/PTX is a safe and promising treatment for gastric cancer with serosal invasion. Clinical trial information: UMIN000013109.
Effect of Positron Emission Tomography Imaging in Women With Locally Advanced Cervical Cancer
Authors: Lorraine M. Elit, Anthony W. Fyles, Chu-Shu Gu, Gregory R. Pond, David D’Souza, Rajiv Samant, Margaret Anthes, Gillian Thomas, Marc Filion, Julie Arsenault, Ian Dayes, Timothy J. Whelan, Karen Y. Gulenchyn, Ur Metser, Kavita Dhamanaskar, Mark N. Levine
Journal: JAMA Network Open (2018)

In women with locally advanced cancer of the cervix (LACC), staging defines disease extent and guides therapy. Currently, undetected disease outside the radiation field can result in undertreatment or, if disease is disseminated, overtreatment.To determine whether adding fludeoxyglucose F 18 positron emission tomography-computed tomography (PET-CT) to conventional staging with CT of the abdomen and pelvis affects therapy received in women with LACC.A randomized clinical trial was conducted. Women with newly diagnosed histologically confirmed International Federation of Gynecology and Obstetrics stage IB to IVA carcinoma of the cervix who were candidates for chemotherapy and radiation therapy (CRT) were allocated 2:1 to PET-CT plus CT of the abdomen and pelvis or CT alone. Enrollment occurred between April 2010 and June 2014 at 6 regional cancer centers in Ontario, Canada. The PET-CT scanners were at 6 associated academic institutions. The median follow-up at the time of the analysis was 3 years. The analysis was conducted on March 30, 2017.Patients received either PET-CT plus CT of the abdomen and pelvis or CT of the abdomen and pelvis.Treatment delivered, defined as standard pelvic CRT vs more extensive CRT, ie, extended field radiotherapy or therapy with palliative intent.One hundred seventy-one patients were allocated to PET-CT (n = 113) or CT (n = 58). The trial stopped early before the planned target of 288 was reached because of low recruitment. Mean (SD) age was 48.1 (11.2) years in the PET-CT group vs 48.9 (12.7) years in the CT group. In the 112 patients who received PET-CT, 68 (60.7%) received standard pelvic CRT, 38 (33.9%) more extensive CRT, and 6 (5.4%) palliative treatment. The corresponding data for the 56 patients who received CT alone were 42 (75.0%), 11 (19.6%), and 3 (5.4%). Overall, 44 patients (39.3%) in the PET-CT group received more extensive CRT or palliative treatment compared with 14 patients (25.0%) in the CT group (odds ratio, 2.05; 95% CI, 0.96-4.37; P = .06). Twenty-four patients in the PET-CT group (21.4%) received extended field radiotherapy to para-aortic nodes and 14 (12.5%) to common iliac nodes compared with 8 (14.3%) and 3 (5.4%), respectively, in the CT group (odds ratio, 1.64; 95% CI, 0.68-3.92; P = .27).There was a trend for more extensive CRT with PET-CT, but the difference was not significant because the trial was underpowered. This trial provides information on the utility of PET-CT for staging in LACC.ClinicalTrials.gov Identifier: NCT00895349.
EXTH-40. OPTIMIZING ARRAY LAYOUTS FOR GLIOBLASTOMA THERAPY WITH TUMOR TREATING FIELDS (TTFIELDS) –USE OF OBLIQUE ARRAY LAYOUTS SURPASS DEFAULT LEFT-RIGHT/ANTERIOR-POSTERIOR POSITIONS IN A COMPUTER SIMULATION MODEL
Authors: Anders Korshoej, Nikola Mikic, Gorm von Oettingen, Jens Christian Sørensen, Axel Thielscher
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields, Optune®) is an effective treatment for glioblastoma. The antimitotic effects of TTFields are induced by low-intensity, intermediate frequency (200 kHz) alternating electric fields, delivered through two pairs of transducer arrays placed on the patient’s scalp. The present study aimed to identify optimal array positions that induced the highest electric field in the tumor by analyzing systematic variations in array layouts. TTFields distribution was computed using finite element methods with a realistic computational head model. A standard anterior-posterior (AP) layout was rotated in 15-degree intervals in the same plane around a central cranio-caudal axis of the head to investigate thirteen array positions. During subdivision, tumors were placed at nineteen different frontoparietal positions in the array rotation plane. TTFields distribution was affected by different array layouts. Two array layouts were identified to be suitable for most tumors. These identified positions led to TTFields intensities that were approximately 30–40% higher in the tumors than in standard AP and left/right (LR) layouts. The two optimal layouts were oriented at 90-degree intervals to each other. Subsequent analysis of combining two array pairs revealed a single optimum layout. For each tumor position, only one optimum layout combination was identified, which was usually oriented in 15–45 degree angles relative to the sagittal plane. In each case, an oblique layout that was orientated at 45 degrees to the sagittal plane was effective for most tumor localizations and superior to the default AP/LR layout combination. Determining factors for layout optimization were high field intensities at transducers located on the edges of the arrays, with high fields close to the peripheral transducers. The present study provides guiding principles for optimal TTFields layout design and planning. Individual patient-specific models should be used to determine TTFields distributions more accurately.