bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lung metastasis as predictor for prognosis in metastatic colorectal cancer with mutated KRAS.
Authors: Boursi Ben , shacham-Shmueli Einat , Lawrence Yaacov Richard , Yang Yu-Xiao , Reiss Kim Anna , Golan Talia , Mamtani Raashi , Halpern Naama , Aderka Dan , Giantonio Bruce , Margalit Ofer 
Published: January 2019

636 Background: Previous studies have shown that prognosis in metastatic colorectal cancer (mCRC) may vary according to sites of metastasis. We evaluated prognosis in individuals with single site metastasis, according to several clinical and genetic variables. Methods: Using the National Cancer Database we identified 58,044 mCRC patients with a synchronous single site of metastasis. We first examined the effect of metastasis site on prognosis. In a secondary analysis, among individuals who had not undergone surgery or received radiotherapy, we examined the prognostic value of chemotherapy intensity, KRAS status, primary tumor location and CEA levels. Results: Individuals with lung metastasis had the best prognosis (HR = 0.80, 0.77-0.83), followed by those with liver metastasis (HR = 1.11, 1.07-1.15), while those with bone or brain metastasis had the worse prognosis. In a subgroup analysis, we assessed prognosis among individuals who received multi-agent chemotherapy and had not undergone surgery or received radiotherapy. Individuals with lung metastasis and mutant KRAS had better prognosis compared with those with liver metastasis, (HR = 0.69, 0.54-0.88), regardless of primary tumor location or CEA levels. Conclusions: Single site metastasis to the lungs is associated with better prognosis in mCRC, specifically among KRAS mutant tumors. This survival advantage should be taken into consideration in clinical decision-making.
A novel patient derived orthotopic xenograft model of gastro-esophageal junction cancer: Key platform for translational discoveries.
Authors: Veeranki Omkara Lakshmi 
Published: January 2019

64 Background: Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. Current GEJ models have limited applications in tumor microenvironment, immune oncology and metastatic studies. Methods: A novel patient derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via surgical implantation. Patient tumor was compared to subcutaneously implanted PDX and PDOX by H&E, IHC, and next generation sequencing (T200.1 panel). Drug efficacy studies of 5-flurouracil with and without radiotherapy are being performed. Results: Mechanical abrasion of mouse GEJ prior to implantation of patient derived tumor in situ promotes tumor engraftment (100%, n = 6). Complete PDOX engraftment was observed with rapid intra and extra luminal tumor growth as evidenced by MRI. Patient derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Next generation sequencing with the T200.1 revealed that the loss of heterozygosity of NOTCH3, TGFβ1, EZH2, and MLL3 are maintained with similar allelic frequency between the patient tumor and the xenografts. Additional somatic SNVs such as ARID1A, NSD1 (CDS157-158), NSD1 (CDS158-159), KDM6A, XPO1, MAPK1 and EGFR were found to be acquired in xenograft tumor tissues that were not observed in patient tumor. Drug and radiation efficacy studies are ongoing, tumor response to radiation was observed. Conclusions: A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating to clinics. This model can be applied to address importance of tumor microenvironment in metastatic and immunological studies, and to develop novel therapeutic approaches for the treatment of GEJ cancer.
Implementing DPYD*2A genotyping in clinical practice, the Quebec experience.
Authors: Jolivet Catherine , Amireault Carl , Ayoub Jean-Pierre M. , Beauregard Patrice , Blais Normand , Carrier Christian , Cloutier Alexis-Simon , Desnoyers Alexandra , Jolivet Jacques , Lemay Anne-Sophie , Lemay Frederic , Letendre Francois , Loungnarath Rasmy , Soulieres Denis , Tehfe Mustapha , Viens Daniel , Weng Xiaoduan , Aubin Francine 
Published: January 2019

650 Background: Fluoropyrimidines (FU) are part of chemotherapy combinations for multiple gastrointestinal cancers. Deficient dihydropyrimidine deshydrogenase (DPD) activity can lead to severe life-threatening toxicities in 3-5% of populations tested. The DPYD*2A polymorphism leading to deficient DPD activity is one of the most studied variants. Methods: We retrospectively performed chart reviews of all patients that tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec (Canada). The study objective was to document the impact of implementing this test in routine clinical practice, including the effects on treatment types, delays and toxicities. Results: 2,617 patients were tested by PCR for the presence of DPYD*2A in a period of 17 months: 25 patients tested positive. All were Caucasian. 24 of the 25 patients were heterozygous (0.92%) and one was homozygous (0.038%). A chart review was available for 20 patients: 15 were tested upfront while five were performed following severe toxicities on the first cycle of FU-based chemotherapy. Of the five patients identified following toxicities, all had grade 4 cytopenias, 80% grade ≥ 3 mucositis, 20% grade 3 rash and 20% grade 3 diarrhea, with an average of 15 days of hospitalisations due to febrile neutropenia. Seven of the 13 patients identified upfront received FU-based chemotherapy at reduced initial doses ranging from 25 to 50%. The average dose during the course of chemotherapy was 50% and two patients reached 100% dosage. No grade ≥ 3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation according to 99% of queried physicians. Conclusions: Upfront genotyping before FU-based treatment is feasible in clinical practice. It may prevent severe toxicities and hospitalisations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.
EXPERT study: Randomized phase III trial of radical surgery and postoperative mFOLFOX6 versus perioperative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases (CLMs).
Authors: Mise Yoshihiro , Hasegawa Kiyoshi , Oba Masaru , Yamaguchi Kensei , Uetake Hiroyuki , Yoshino Takayuki , Morita Satoshi , Takahashi Keiichi , Unno Michiaki , Shimada Yasuhiro , Muro Kei , Yoshida Kazuhiro , Mori Masaki , Baba Hideo , Shimada Mitsuo , Saiura Akio , Matsumura Masaru , Ishigure Kiyoshi , Sugihara Kenichi , Kokudo Norihiro 
Published: January 2019

652 Background: Up-front radical surgery and adjuvant chemotherapy were regarded as one of the standard-of-care (SOC) in patients with resectablecolorectal liver metastases (CLMs), while perioperative chemotherapy plus surgery is also accepted. We conducted a multicenter randomized phase III trial to compare radical surgery and post-operative mFOLFOX6 with peri-operative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable CLMs. Methods: Patients who had KRAS wild-type resectable CLMs having one to eight liver nodules without extrahepatic disease, were randomly assigned to groups: Group A (reference), hepatectomy and 12 cycles of post-operative mFOLFOX6: Group B (experimental), six cycles of preoperative mFOLFOX6 plus cetuximab (loading dose with 400mg/m2and thereafter 250mg/m2weekly), hepatectomy and six cycles of postoperative mFOLFOX6 plus cetuximab. Primary endpoint was progression-free survival (PFS). We hypothesized that 3-year PFS in Group B would be 25% with the hazard ratio (HR) being 0.75. Considering 3 year follow-up period with 5% of two-sided alpha error and 80% of power, target number were set as 500 (250 each). Study was registered in the University Hospital Medical Information Network (UMIN000007787). Results: This study was initiated since June 2012. However, the enrollment was terminated according to the recommendation from the monitoring committee on 2015 due to a slow accrual. A total of 77 patients (Group A 37 vs. Group B 40) were analyzed. Baseline characteristics were well-balanced between groups. Median numbers of liver mets were two each, ranging from one to eight. The HRs for PFS and overall survival (OS) showed no significant difference (PFS, HR = 1.18 [0.69-2.01], p = 0.54: OS, HR = 1.03 [0.46 – 2.29], p = 0.95). There were 3-year PFS of 35% in Group A vs. 30% in Group B, and 3-year OS: 86% vs. 74%, respectively. Conclusions: No additional survival benefits adding on peri-operative cetuximab were indicated, of which findings is consistent with the previous clinical studies, although there were small number of enrolled patients. Clinical trial information: UMIN000007787.
Clinical impact of D3 lymph node dissection preserving left colic artery (LCA) compared to D3 without preserving LCA: Exploratory subgroup analysis of data from randomized controlled trial of laparoscopic versus open surgery for colon cancer from Japan Clinical Oncology Group study JCOG0404.
Authors: Akagi Tomonori , Hara Takao , Inomata Masafumi , Mizusawa Junki , Katayama Hiroshi , Shida Dai , Ohue Masayuki , Hamaguchi Tetsuya , Ito Masaaki , Kinugasa Yusuke , Saida Yoshihisa , Masaki Tadahiko , Sato Takeo , Yamamoto Seiichiro , Hanai Tsunekazu , Otsuka Koki , Watanabe Masahiko , Fukuda Haruhiko , Kanemitsu Yukihide , Kitano Seigo 
Published: January 2019

653 Background: In curative resection of sigmoid colon and rectal cancer, it is unclear whether D3 lymph node dissection preserving left colic artery (LCA) (Group A) is beneficial compared to D3 without preserving LCA (Group B) in terms of clinical outcomes. Preservation of LCA is expected to maintain blood supply which results in preventing anastomotic leakage, intestinal paralysis, and so on. Methods: The data of JCOG0404 (which is a randomized controlled trial comparing open to laparoscopic surgery for stage II/III colon cancer) were used. Eligibility criteria in JCOG0404 included histologically proven colon cancer; T3 or deeper lesion without involvement of other organs; N0-2 and M0. D3 lymph node dissection with or without preserving LCA was identified according to the photographs of the resected field collected for central surgical review in JCOG0404. The short and long-term outcomes were compared between each procedure. Results: Among all randomized 1057 patients in JCOG0404, 631 patients who received assigned sigmoid colectomy and anterior resection were included in the subgroup analysis. The number of patients were 135 in Group A and 496 in Group B. The patient backgrounds did not differ between groups. The median operative time, median blood loss, and the proportion of grade 1 or more anastomotic leakage and intestinal paralysis were not remarkably different (Group A vs. Group B: 185 min vs 186 min, 60 ml vs. 50 ml, 3.0% vs. 5.0%, and 2.2% vs. 3.8%). However, overall postoperative complication occurred more in Group B than in Group A (9.6% and 21.6%, p = 0.022). In terms of efficacy, 5-year relapse-free survival (RFS) and overall survival (OS) tended to be better in Group A than Group B (RFS: 83.7% and 80.5%, HR 1.25 (95% CI 0.79-1.96), OS: 96.3% and 91.1%, HR 2.47 (95% CI 1.13-5.40)). Conclusions: Short and long-term outcomes were better in Group A than Group B. It was considered that D3 lymph node dissection preserving LCA could be alternative treatment for D3 lymph node dissection. Clinical trial information: C000000105.
Long-term outcomes of surgical resection of lung metastases from colorectal cancer.
Authors: Mori Ryota , Kagawa Yoshinori , Yukawa Yoshiro , Toya Keisuke , Takase Kouki , Nose Yohei , Kawai Kenji , Sakamoto Takuya , Naito Atsushi , Murakami Kohei , Katsura Yoshiteru , Ohmura Yoshiaki , Masuzawa Toru , Takeno Atsushi , Takeda Yutaka , Kato Takeshi , Yamamoto Aya , Toda Michihito , Iwata Takashi , Murata Kohei 
Published: January 2019

655 Background: The lungs are one of the most frequent sites of metastases from colorectal cancer(CRC). Surgical resection has been widely performed on patients with pulmonary metastases from CRC with favorable outcomes. Surgical treatment is considered an effective option, but the surgical indications of lung resection have institutional bias. In our hospital, we aggressively perform surgery for lung metastases when the primary tumor and other metastases are controlled and all lung metastases are resectable. In this study, the aim is to investigate the long-term outcomes of resections of lung metastases from CRC in our institute. Methods: Between April 2009 and November 2017, patients who underwent lung resections for metastases from CRC with curative intent in our hospital were investigated retrospectively. Kaplan-Meier survival curves, log-rank tests, chi-squared test and T-test were used to analyze the survival rates and the factors predicting recurrence. Results: Sixty-seven patients underwent lung resection of metastases from CRC. The median follow-up period was 25.3 (6-60) months. Five-year disease free survival was 33.6 % and 5-year overall survival was 63.9%. Because of pulmonary recurrence, second surgery was performed in 16 patients and a third surgery in three patients. 5-year overall survival rate after first lung resection in patients who underwent repeated lung resection was 49.2%. There was no significant difference between the number of patients with pulmonary recurrence and those with no recurrence after lung resection (p = 0.38). Twenty-one patients had experienced prior liver resection; the 5-year overall survival rate after lung resection in these patients was 57.9 %. Factors predicting recurrence were vascular invasion (v ≥ 2) of primary tumor (p = 0.02), pre-operative serum CEA (p = 0.03) and CA-19-9 (p = 0.04). Conclusions: The outcome of lung resection of metastases from CRC in our hospital was satisfactory. Aggressive lung resection for cases even after liver resection and repeated pulmonary recurrence may improve long-term outcomes.Vascular invasion of primary tumor and the pre-operative serum CEA and CA 19-9 level can be predictive markers for recurrence.
Safety of bevacizumab in cancer patients with inflammatory bowel disease.
Authors: Herrera Gomez Ruth Gabriela , Gallois Claire , Adler Marcel , Malka David , Planchard David , Pistilli Barbara , Ducreux Michel , Mir Olivier 
Published: January 2019

664 Background: Digestive and non-digestive cancers in patients with inflammatory bowel disease (IBD) are potentially sensitive to bevacizumab-based chemotherapy. Previous reports have suggested an increased toxicity in IBD patients receiving anti-VEGF agents. The safety of bevacizumab in this population is poorly documented. Methods: A retrospective review of records of patients with IBD treated with bevacizumab-containing chemotherapy for metastatic solid tumors in Gustave Roussy hospital between 2007 and 2016. Results: Twenty eight patients (median age 43, range: 23-73) with a past history of IBD (6 ulcerative colitis, 22 Crohn’s disease) were identified. IBD was considered severe in four pts (13%). Patients presented a good control of IBD symptoms with a median number of 0 (range: 0-2) disease flares during the two years before bevacizumab initiation. Three patients were receiving corticosteroids, and another four were receiving mesalazine for IBD. No patient had abscess, fistula or hemorrhage at the time of bevacizumab initiation. The treated cancer was: colon (n = 8), rectum (n = 5), small bowel (n = 5), NSCLC (n = 4), ovary (n = 1), breast (n = 3) and other (n = 2). Patients received chemotherapy [5-FU-based (LV5FU2, FOLFOX or FOLFIRI) in 17, oxaliplatin in 7, irinotecan in 8, taxanes in 7] with bevacizumab given at the approved dose-intensities of 2.5 mg/kg/week (19 pts) or 5 mg/kg/week (7 pts). Records of chemotherapy from 2 patients were missing. A median number of 8 cycles of bevacizumab(range: 2-39) was given concomitantly to chemotherapy and then as maintenance therapy, with the following grade ≥2 toxicities: hypertension in 6 cases (20%) and proteinuria in 3 cases (10%). No dose-limiting toxicity was observed. No change in IBD treatment was required. One patient developed grade 2 rectorragia (identified as Crohn’s disease flare-up) after 6 months of bevacizumab+ FOLFIRI. After withdrawal of irinotecan, the patient was re-challenged with bevacizumab for another 6 cycles without recurrence of bleeding. Conclusions: In our experience, bevacizumab can be given to cancer patients with quiescent IBD at conventional doses with good clinical tolerance.
Examining the effects of BET, HDAC2, and EZH2 inhibition on esophageal adenocarcinoma (EAC) cell line proliferation.
Authors: Kofonikolas Kleovoulos , Frankell Alex M , Smyth Elizabeth Catherine , Fitzgerald Rebecca C. 
Published: January 2019

68 Background: EACs often carry amplifications in MYC (19%) and mutations in the SWI/SNF complex (13%) which act as oncogenic drivers. Targeting of MYC-amplified tumors via BET inhibition, as well as HDAC2 or EZH2 inhibition in SWI/SNF-mutated tumors, show promise in hematological cancers, and solid tumors, respectively. Herein, we investigate the effects of BET, HDAC2, and EZH2 inhibition on EAC cell line proliferation. Methods: MYC-wild type (n = 5), MYC-amplified (n = 2), SWI/SNF-wild type (n = 6) and SWI/SNF-mutant (n = 1) EAC cell lines that have undergone whole genome sequencing (WGS) were plated at 10% confluency and treated with BET (JQ1), pan-HDAC (SAHA), and EZH2 (EPZ-6438) inhibitors at various concentrations. The CellTiter-Glo cell proliferation assay was used to compare the effects of drug treatment on proliferation between different cell lines and drug concentrations before and after treatment. Results: MYC-amplified EAC cell lines were more sensitive to BET inhibition (Table); GI50 concentrations for JQ1 are comparable to those achieved in melanoma and lymphoma cell lines, cancer types in which clinical activity has been demonstrated. ERBB2 amplified or ERBB2 mutant EAC cells were also sensitive to BET inhibition. HDAC2 inhibition reduced proliferation of both SWI/SNF-wild type and mutant cell lines at high concentrations, whilst all cell lines were resistant to EZH2 inhibition, even at the highest concentrations used. Conclusions: MYC amplified EAC tumors appear to be sensitive to BET inhibition; these results warrant further evaluation in pre-clinical models and clinical trials. HDAC2 and EZH2 inhibition were ineffective in both the SWI/SNF-wild type and mutant type EAC cell lines; these therapies are less likely to provide benefit for EAC patients. [Table: see text]
A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic colorectal cancer (CRC).
Authors: Turk Anita Ahmed , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Mulkerin Daniel , Kim David H. , Matkowskyj Kristina , Weber Sharon M. , Abbott Daniel , Eickhoff Jens C. , Bassetti Michael F. , Deming Dustin A. 
Published: January 2019

680 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intratumoral and a rapid influx of responding immune cells. We hypothesize that radiation enhances immunogenicity of MSS CRC and potentiates effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety of this regimen and the recurrence rate at one year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: Nine patients (median age 61.5 [range 39-69]) have completed the intended neoadjuvant therapy, operative management and at least one adjuvant cycle of Pem. All patients received prior FOLFOX. Any-grade AEs (> 20%) through cycle 2 of Pem attributable to SBRT include fatigue (44%) and nausea (22%). Any-grade AEs related to Pem include lymphopenia (25%). Postoperative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. One patient developed a rash following SBRT and Pem which may be an immunotherapy-related toxicity. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT, Pem, and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity. Clinical trial information: NCT02837263.
Wait times for colorectal cancer patients in a universal healthcare system over a decade: Is it sustainable?
Authors: Delisle Megan E , Helewa Ramzi , Park Jason , Hochman David J , McKay Andrew 
Published: January 2019

697 Background: Delays in treatment for colorectal cancer (CRC) may worsen prognosis and increase patient anxiety. This study aims to understand population-based trends and variations in wait times (WTs) for CRC in a universal healthcare system over a decade. Methods: Patients diagnosed with stage I-IV CRC in Manitoba, Canada between 2004 and 2014 were included. Data were obtained through province-wide administrative claims and cancer registry. WTs were defined as time from index contact to pathological diagnosis (diagnosis WT), time from pathological diagnosis to first treatment (treatment WT) and total (diagnosis + treatment WT). Index contact was the consult preceding the first gastrointestinal investigation in the year preceding the date of diagnosis. First treatment was radiation, chemotherapy or surgery. The association between WTs and year of diagnosis was estimated using Negative Binomial regression and reported as incidence rate ratio (IRR). Variability in WTs by year were estimated using the Coefficient of Variation (CV) and average annual percent change (AAPC). A CV > 100 indicates high-variability and < 100 indicates low-variaability. Results: A total of 5359 patients were diagnosed with CRC (1802 rectal vs 3557 colon). WTs increased overall. Total WTs for rectal cancer increased by 6% (IRR 1.06, 95% CI 1.04-1.07, p < 0.01) per year from a median of 90 days in 2004 to 147 days in 2014. This was due increases in time to diagnosis (IRR 1.07, 95% CI 1.06-1.09, p < 0.01) and treatment (IRR 1.04, 95% CI 1.03-1.06, p < 0.01). Total colon cancer WTs increased an estimated 5% (IRR 1.05, 95% CI 1.04-1.06, p < 0.01) per year from a median of 89 days in 2004 to 110 days in 2014. This was due to both time to diagnosis (IRR 1.05, 95% CI 1.04-1.07, p < 0.01) and treatment (IRR 1.03, 95% CI 1.02-1.04, p < 0.01). There was increasing variability in total WTs. The CV increased from 87 in 2004 to 102 in 2014 in rectal cancer (AAPC +3.85%) and from 86 in 2004 to 128 in 2014 in colon cancer (AAPC + 5.04%). Conclusions: Total WTs for CRC in Manitoba have increased from 2004 and 2014. This may reflect the growing challenges in providing increasingly complex cancer care to geographically dispersed populations in a universal healthcare system.