bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of radiofrequency ablation and stereotactic body radiotherapy for the treatment of hepatocellular carcinoma: An analysis of the SEER-Medicare database.
Authors: Feng Mary Uan-Sian , Marshall Vincent D. , Parikh Neehar 
Published: February 2017

463 Background: Hepatocellular carcinoma (HCC) is an increasingly common and highly morbid malignancy worldwide, including the US. For early stage patients ablative strategies are important potentially curative treatment options. Stereotactic body radiotherapy (SBRT) has emerged as a promising non-surgical ablative therapy, although it is technically demanding and its comparison with radiofrequency ablation (RFA) remains confined to a single institution retrospective review. We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to assess RFA and SBRT use in the US. Methods: We identified patients greater than 65 years old who were diagnosed from 2004-11 with stage I or II HCC and treated with RFA or SBRT. Survival analysis was conducted using Kaplan-Meier curves and log rank test. Factors associated with overall survival (OS) and early ( ≤ 90 day) hospital admission post-treatment were identified using propensity score (PS) adjusted multivariate analysis. Results: 825 patients were identified, 747 treated with RFA and 78 SBRT. 22 pts received both treatments and were excluded from this analysis. The mean Charlson comorbidity index was 1.0±1.1. Median age was 74, range 66-90. Patients who received RFA were more likely to live in the West and have liver decompensation. Patients who received SBRT were more likely to be white and treated in the Midwest. After using PS matching there were 78 in each cohort. In these patients, mean overall survival (OS) was 2.25 and 2.04 yrs for RFA and SBRT, p = 0.06. Younger age, lack of liver decompensation, treatment in the West, and liver transplantation were associated with longer OS, HR 0.96, p = 0.05; HR 0.37, p = 0.002; HR 0.57, p = 0.04; HR 0.18, p = 0.008, respectively. 90 day hospitalization rates did not differ between treatments; only liver decompensation was predictive of hospitalization, OR 3.33, p = 0.032. Conclusions: In a national cohort of early stage HCC patients, treatment with RFA vs SBRT resulted in no significant difference in OS. SBRT appears to be a comparable ablative strategy to RFA in this population. This highlights the need for a randomized trial comparing these two modalities.
Expression of ERCC1, TUBB3, BRCA1, and TS as predictive markers of neoadjuvant chemotherapy for squamous cell carcinoma of the esophagus.
Authors: Ojima Toshiyasu , Nakamori Mikihito , Nakamura Masaki , Katsuda Masahiro , Hayata Keiji , Matsumura Shuichi , Kato Tomoya , Yamaue Hiroki 
Published: February 2017

47 Background: No predictive biomarker of the response to neoadjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil (NAC-DCF) is available for patients with squamous cell carcinoma of the esophagus (SCCE) in a clinical setting. The aim of this study was to identify the biomarkers associated with chemotherapeutic efficacy and long-term survival for patients with advanced SCCE who had received NAC-DCF followed by surgery. Methods: This study included 45 patients with advanced SCCE who received NAC-DCF between January 2008 and December 2012. The NAC-DCF was conducted as a phase II study (UMIN000007408). The expressions of excision repair cross-complementing-1 (ERCC1), class III beta-tubulin, breast cancer susceptibility gene I (BRCA1), and thymidylate synthase were investigated simultaneously in the pre-treatment endoscopic tumor biopsy samples. Results: The multivariate logistic regression analysis indicated that pathological responses were significantly associated with tumors with low ERCC1 expression (P = 0.016) and with tumors with high BRCA1 expression (P = 0.014). The incidence of pathological responses to DCF in patients with low ERCC1 and high BRCA1 expressions was 100%. The multivariate Cox proportional hazard model analysis for relapse-free survival (RFS) revealed tumors with high BRCA1 expression (P = 0.031, hazards ratio, 4.39) as independent prognostic factors. Conclusions: Low ERCC1 expression and high BRCA1 expression in patients with SCCE were predictive biomarkers for chemotherapeutic efficacy. High BRCA1 expression was considered as prognostic factors for long-term RFS. These results may be a helpful tool for tailoring chemotherapy of patients with SCCE. Prospective validation of this biomarker panel is warranted. Clinical trial information: UMIN000007408.
Differential radiographic appearance of BRAF V600E mutant metastatic colorectal cancer (mCRC) in patients matched by primary tumor location.
Authors: Greene Claire , Atreya Chloe Evelyn , McWhirter Ryan , Ikram Nabia , Van Loon Katherine , Venook Alan P. , Yeh Benjamin M. , Behr Spencer 
Published: February 2017

554 Background: BRAF mutation status and location of CRC primary each correlate with pattern of metastatic spread. We sought to determine whether presence of a BRAF V600E (BRAF) mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: 40 patients with BRAF mutant mCRC were matched to 80 patients with BRAF wild-type CRC by location of primary tumor (right colon, left colon or rectum), sex, and age ( < 50; 50+). CT scans were reviewed for disease characterization. BRAF mutation status, clinicopathological characteristics, and sites of metastatic disease were associated using proportion tests. Results: Of the 120 matched patients,60% were female. The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Median age at diagnosis was 57, range 20-88 yrs. Significantly higher frequencies of peritoneal metastases (p = 0.045) and ascites (p = 0.0038) occurred in patients with BRAF mutant tumors. Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. In patients with left colon primaries, BRAF mutations associated with less frequent liver metastases (42% vs. 79%, p = 0.024) and more frequent ascites (58% vs. 12%, p = 0.0038). Disease was not measurable by RECIST version 1.1 criteria in 20% of patients with BRAF mutations, most often with peritoneal metastases and ascites. Conclusions: Presence of a BRAF V600E mutation associated with a greater proportion of peritoneal metastases and ascites, even among patients matched for primary tumor location. Of 20 patients with BRAF mutant mCRC and peritoneal metastases plus ascites, 6 patients (30%) had disease that was not measurable by RECIST version 1.1. Radiographic characterization provides a window on BRAF mutant mCRC biology and also reveals a challenge for response evaluation on clinical trials. [Table: see text]
Prognostic impact of tumor-associated B cells and plasma cells in colorectal cancer.
Authors: Berntsson Jonna , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin 
Published: February 2017

587 Background: Multiple studies have described associations between infiltrating immune cells, prognosis and treatment response in cancer. However, the clinical relevance has most often been attributed to the T-cell linage, whereas the humoral immune response is less investigated. In colorectal cancer (CRC), accumulation of CD20-positive B lymphocytes at the advancing margin of metastatic CRC has been demonstrated to correlate with prolonged survival. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in colorectal cancer (CRC). Methods: Immunohistochemical expression of CD20 and CD138 in was analyzed in tissue microarrays with tumors from 557 incident cases of CRC from the Malmö Diet and Cancer Study, a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20 and CD138 expression on 5-year overall survival (OS). Results: CD20 expression could be evaluated in 549 (98.6 %) cases and CD38 in 534 (95.9 %) cases. CD20 expression correlated significantly with both immune cell-specific and tumor-specific expression of CD138 (p < 0.001 and p = 0.001, respectively). Furthermore, immune cell-specific CD20 and CD138 expression as well as tumor-specific CD138 expression correlated significantly with lower T-stage (p < 0.001, p < 0.001 and p = 0.002, respectively). A higher density of CD20+ cells correlated significantly with an improved OS (HR = 0.66, 95 % CI 0.50-0.86), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR = 0.65; 95% CI 0.48-0.90). Neither immune cell nor tumor cell-specific CD138 expression was significantly associated with prognosis. Conclusions: Our results demonstrate that increased B cell infiltration in CRC is an independent factor of improved prognosis. Moreover, the study provides a first demonstration of the expression and clinicopathological correlates of immune cell-specific CD138 expression in CRC, thus providing a further characterization of the immune landscape in this type of cancer.
Effect of 5-fluorouracil on membranous PD-L1 expression in colon cancer cells.
Authors: Goel Gaurav , Ramanan Krishnaveni , Kaltenmeier Christof , Zhang Lin , Freeman Gordon J. , Normolle Daniel Paul , Tang Daolin , Lotze Michael T. 
Published: February 2017

592 Background: Colorectal cancer (CRC) is a major public health problem worldwide. Chemotherapy consisting of a fluoropyrimidine backbone constitutes a major therapeutic modality used in the treatment of CRC patients. However, cancer cells often develop resistance to such cytotoxic chemotherapy and this represents a major therapeutic challenge. B7-homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1) is an immunoregulatory protein that belongs to the B7 family of T-cell co-regulatory molecules, and is overexpressed in several human tumors. Upregulation of PD-L1 expression is an important mechanism by which tumor cells can escape host T-cell immunity. Emerging evidence suggests that chemotherapeutic agents can regulate PD-L1 expression on cancer cells, which may have an impact on anti-tumor immunity and immune evasion. We performed this study to evaluate the effect of 5-Fluorouracil (5-FU) on PD-L1 expression in colon cancer cell lines, using an in vitro approach. Methods: Flow cytometry and western immunoblot analyses for PD-L1 expression were performed on human colon cancer cell lines (HCT116-WT, HCT116-p53 KO, SW480, HT29) upon treatment with IFN-ɣ and 5-FU. Results: We found that the tested human colon cancer cell lines rarely expressed PD-L1 protein on their cell surface at baseline, but a high level of expression was induced by treatment with IFN-ɣ. More importantly, we demonstrated that the chemotherapeutic agent 5-FU induces PD-L1 expression in colon cancer cells. Conclusions: It is therefore plausible that combining 5-FU with PD-1/PD-L1 blockade might help overcome some of the chemoresistance to 5-FU and thereby enhance its anti-cancer activity. Further experiments are being planned to formally test this hypothesis.
Hypermethylated circulating DNA detection using picoliter droplet-based PCR in colorectal cancer.
Authors: Perkins Geraldine , Garrigou Sonia , Garlan Fanny , Normand Corinne , Didelot Audrey , Le Corre Delphine , Mulot Claire , Niarra Ralph , Aucouturier Pascaline , Chatellier Gilles , Peyvandi Sanam , Bouche Olivier , Emile Jean-Francois , Pezet Denis , Bibeau Frederic , Link Darren R , Zaanan Aziz , Sobhani Iradj , Laurent-Puig Pierre , Taly Valerie 
Published: February 2017

622 Background: Circulating tumor DNA (ctDNA) is thoroughly investigated as a surrogate biomarker of tumor follow-up, in different cancer types, such as colorectal cancer (CRC). Droplet-based digital PCR (ddPCR) is a highly sensitive and also quantitative method for detection of very low amount of ctDNA. Since many different genes can be mutated within a specific tumor type and also wide mutation spectrum can occur within a specific gene, procedures for ctDNA monitoring can be time consuming and need to be improved for a routinely use. To overcome these drawbacks, we characterized the methylation status of 3 genes frequently hypermethylated in CRC to identify universal markers for tumor follow-up. Methods: The characterization of the methylated status of the WIF, NPY and PENK genes in the tumor DNA was performed in 56 CRC of different stages and 45 corresponding plasma samples using droplet-based dPCR, after DNA bisulfite conversion. A two-panels assay (with albumin as a reference) was developed. Methylation level of these 3 genes in tumor tissues was compared to corresponding normal tissues (n = 22) and plasma samples (MetctDNA). To validate, plasma samples of additional 91 patients were analyzed for the presence of ctDNA both by the characterization of KRAS, BRAF, TP53 and PIK3CA mutations (MutctDNA) and of MetctDNA, at various stages of their follow-up, and 9 of them had MetctDNA assessment during treatment follow-up. Results: All tumor samples were positive for WIF1 and/or NPY markers. Hypermethylation of these two genes was significantly higher in tumor tissue compared to normal, independently of the tumor stage (p < 0.0001). MetctDNA could be detected in 75% of metastatic CRC patients and 24% of localized CRC patients (stage 1 to 3). MetctDNA and MutctDNA fractions were strongly correlated (R2 > 0.9, p < 0.0001). During follow-up, MetctDNA levels changes allowed monitoring of tumor evolution in different stages CRC patients. Conclusions: These results indicate that determination of MetctDNA by droplet-based dPCR can reach same efficiency than MutctDNA for ctDNA assessment, using only 2 markers, and thus could be considered as a universal surrogate marker of tumor follow-up in CRC patients.
The prospective French participitation to IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study in stage III colon cancer: Patients’ characteristics and safety analysis of 3 versus 6 months of adjuvant chemotherapy.
Authors: Andre Thierry , De Gramont Aimery , Mineur Laurent , Desramé Jérôme , Faroux Roger , Bennouna Jaafar , Dauba Jérôme , Louvet Christophe , Pernot Simon , Dupuis Olivier Jean Marie , Becouarn Yves , Mabro May , Egreteau Joëlle , Bouche Olivier , Bonnetain Franck , Hug de Larauze Marine , Le Malicot Karine , Taieb Julien ,   GERCOR, FFCD, and UNICANCER (PRODIGE) Study Groups
Published: February 2017

633 Background: The IDEA international collaboration was established to prospectively combine/analyze data from six randomized trials to assess whether a 3-month course of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month current standard treatment in stage III colon cancer (CC). The primary endpoint of IDEA was 3-year disease-free survival. The accrual goal for the French IDEA study was 2,000 patients. Methods: French IDEA randomized patients with stage III CC between 3 months (arm A) and 6 months (arm B) of adjuvant CT with modified (m) FOLFOX6 or XELOX (depending on physician/patient choice). Oxaliplatin was stopped in case of persistent neuropathy grade ≥2 with fluoropyrimidines continuation for the planned duration. Toxicity was graded during treatment and follow-up using NCI-CTCAE v3.0. Results: From May 2009 to May 2014, 2,023 patients were randomized in 129 French centers either to arm A (n=1009, 49.9%) or to arm B (n=1014, 50.1%). 2012 (99.5%) patients had stage III disease (N1: 75%; N2: 25%) and 11 patients had stage II (n=2) or stage IV disease (n=9). Median age was 64 years (18-85). 89.4% of patients received mFOLFOX6, 10.1% of patients received XELOX, and 0.5% of patients did not receive any study treatment. Overall, 94.1% and 77.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin dose was 500 mg/m2 in arm A and 747 mg/m2in arm B. Toxicity profiles depended on the FU backbone with more grade 3/4 neutropenia on mFOLFOX6 (15.0% vs 6.5%) and more grade 3/4 diarrhea (4.7% vs 8.1%) on XELOX. Grade 2/3-4 peripheral neuropathy was less common in arm A than in arm B (23.2/6% vs 37.9/20.4%). Grade 2/3-4 residual neuropathy for patients with a follow-up of at least 3 years (n=811, median follow-up of 3.91 years) was 2.3/0.5% in arm A vs 3.9/ 2.4% in arm B. At 6 months after randomization, mortality rate was 0.7% (n=7) on arm A and 0.5% (n=5) on arm B. Median follow-up is 2.74 years for the whole population. Conclusions: Both mFOLFOX6 and XELOX were safe. Peripheral neuropathy was lower in arm A than in arm B. Clinical trial information: 2009-010384-16.
TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial.
Authors: Mayer Robert J. , Ohtsu Atsushi , Yoshino Takayuki , Falcone Alfredo , Garcia-Carbonero Rocio , Tabernero Josep , Sobrero Alberto F. , Peeters Marc , Benedetti Fabio , Makris Lukas , Ambe Hiroshi , Zaniboni Alberto , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Van Cutsem Eric ,   on behalf of the RECOURSE Study Group
Published: February 2017

634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial. Original results of RECOURSE based on the cut-off date of January 24, 2014, in which 72% of mortality events had occurred, demonstrated a significant improvement in overall survival (OS) with TAS-102 vs placebo. Here we report results of an updated survival analysis from RECOURSE and a retrospective analysis of OS outcomes based on a clinical prognostic risk index. Methods: Patients were randomized 2:1 to receive TAS-102 or placebo. Study treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was OS; final survival data were collected on October 8, 2014. A clinical OS prognostic risk score was assessed to evaluate OS effect in patients from low to high prognostic score. Prognostic factors contributing to the risk index were from those prespecified in the multivariate modeling assessment of OS outcome. Results: At data cut-off for the final survival analysis, 89% of the 800 patients randomly assigned to TAS-102 or placebo had died, accounting for 138 events in addition to 574 (72%) events included in the original analysis. The updated results for OS are shown in the Table. Conclusions: An updated survival analysis confirmed that OS benefit with TAS-102 was maintained and increased to a full 2 months; improvement in 1-year survival surpassed 10% in these heavily pretreated patients. OS benefit appears to be maintained for all patients in the trial regardless of prognostic status at trial entry. Clinical trial information: NCT01607957. [Table: see text]
Efficacy and safety of first-line cetuximab + FOLFIRI in older and younger patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the CRYSTAL study.
Authors: Van Cutsem Eric , Köhne Claus-Henning , Folprecht Gunnar , Guenther Silke , Beier Frank , Papamichael Demetris 
Published: February 2017

647 Background: Pts with mCRC are often older, thus prompting interest in subgroup analyses based on age. Adding cetuximab to FOLFIRI in the first-line CRYSTAL trial improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in pts with RAS wt mCRC. This subgroup analysis evaluated the efficacy and safety of FOLFIRI ± cetuximab within age-defined subgroups from the RASwt population of CRYSTAL. Methods: PFS, OS, ORR, and safety were evaluated in RAS wt pt subgroups in CRYSTAL, defined by age and treatment arm. Older pts were categorized as aged ≥65 y; younger pts were aged <65 y. Among pts ≥65 y, only 26 and 10 pts in the cetuximab + FOLFIRI arm and only 10 and 10 pts in the FOLFIRI arm were aged 70-75 y and ≥75 y, respectively; therefore, an analysis of an older-age cutoff was not performed. Results: Among 367 pts with RASwt tumors, 115 were older and 252 were younger. Baseline characteristics were similar between treatment arms in the younger subgroup; however, in the older subgroup, baseline ECOG status (ECOG=0; 45.9% vs 61.1%) and quality of life (>median; 36.1% vs 51.9%) favored the FOLFIRI arm. This study was not designed to assess differences within and between age subgroups; therefore, interpretation is limited by baseline imbalances and the small number of older pts. Efficacy and safety data are summarized below. Conclusions: In RAS wt CRYSTAL pts, adding cetuximab to FOLFIRI improved ORR, PFS and, to a lesser extent, OS in both older and younger pts. Clinical trial information: NCT00154102. [Table: see text]
Outcome of patients with KRAS exon 2 wildtype (KRAS-wt) metastatic colorectal carcinoma (mCRC) with cetuximab-based first-line treatment in the noninterventional study ERBITAG and impact of comorbidity and age.
Authors: Sahm Stephan , Goehler Thomas , Hering-Schubert Christiane , Janssen Jan , Neumann Ulf Peter , Schwittay Michael , Zahn Mark-Oliver , Stenzel Karsten Guenter , Steinbach-Buechert Alma Katharina , Overkamp Friedrich 
Published: February 2017

651 Background: Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase ORR, PFS, OS of KRAS-wt mCRC patients (pts). ERBITAG aimed to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in pts with unresectable KRAS-wt mCRC. Methods: KRAS-wt pts on a cetuximab-based first-line treatment with written informed consent could be enrolled in this prospective, non-interventional study. Primary endpoint was ORR, secondary endpoints were amongst others PFS, OS, TTF, and resection rate of liver metastasis. Comorbidities were documented and evaluated by the Charlson Comorbidity Index (CCI). Results: 817 eligible KRAS-wt mCRC pts were enrolled at 144 sites across Germany, documentations for 456 pts were finalised and evaluated. The median age was 65 [27-87] yrs, with 51.5% ≤65 yrs, 34.0% >65-75 yrs, and 14.5% >75 yrs. ECOG performance status was 0, 1, 2, or missing in 34.4%, 49.6%, 8.8%, and 7.2% of pts, respectively. CCI was 0 in 54.4%, and ≥1 in 45.6%. Resection of liver and/or lung metastases was done in 17.3% of pts, 13.4% were R0 resected. For pts with liver limited disease resection rate and R0-rate were 29.3% and 23.8%, respectively. Pts with CCI 0 had no different outcome regardless of age (table). Pts with CCI ≥1 and >75 yrs had a lower ORR and decreased TTF, pts >65-75 yrs had only a decreased TTF as compared to the ≤ 65 yrs age group (table). Conclusions: In this large observational trial outcomes (ORR and PFS) of KRAS-wt mCRC pts on a cetuximab-based first-line treatment were comparable to those reported in pivotal trials. Pts older than 75 yrs without comorbidities (CCI =0) showed no difference to younger pts in ORR, PFS, and TTF. Pts >75 yrs with CCI ≥ 1 had a significant lower ORR and decreased TTF. Clinical trial information: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_455. [Table: see text]