bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal).
Authors: Dumont Frederic , Boisdron-Celle Michele , Hiret Sandrine , Senellart Helene , Raimbourg Judith , Campion Loic , Pein Francois J. L. , Bakrin Naoual , Raoul Jean-Luc , Glehen Olivier , Thibaudeau Emilie 
Published: May 2019

e15027 Background: The pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new route of intraperironeal drug administration that enhances the absorption of oxaliplatin. The objectives were to determine the MTD and PK of Oxaliplatin administred via the PIPAC technic. Methods: This was a phase I two center study with standard 3 x 3 design for pts with extended peritoneal carcinomatosis from gastrointestinal cancer (gastric PCI>4, small bowell PCI>13, colorectal PCI>15), ECOG PS≤1 and no organ dysfunction. The primary endpoint are dose determining dose limiting toxicity (DLT), maximum tolerable dose (MTD), recommandation dose for the phase 2 (RD2P) and PK of oxaliplatin. The dose escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m² and starting with 90 mg/m². Pts were monitored for DLT from the first PIPAC up to 4-6 weeks after the second PIPAC. Each patient who experiences good tolerance will be invited to receive two to five PIPAC procedures at 4–6 week intervals. A systemic chemotherapy was allowed between the PIPAC session. Adverse event (AEs) were defined according NCI-CTCAE toxicity scale version 4. Results: To date, 10 patients received 31 PIPACs procedures and were treated in 2 differents dl. Two DLTs (grade 4 allergic reaction and grade 3 neutropenia) occurred at second level dose of 140 mg/m2 and no one at 90mg2. Frequent treatment related AE (TRAE) grade ≤ 2 during PIPACs sessions were nausea (9/31), abdominal pain (8/31) and fatigue (7/31). Nine patients were evaluable for response after at least 2 PIPACs. The histologic peritoneal regression grading score (PRGS) were 4 (no response), 3 (minor response), 2 (major response), and 1 (complete response) in respectively 0, 5, 2 and 2 pts. Pts with PRGS 1 underwent complete cytoreductive surgery and HIPEC. In this ongoing study, the PK profile is currently investigated. Conclusions: The RP2D of oxaliplatin during PIPAC was 90mg/m2 with correct tolerance and some patient have experienced of major histological response allowing a secondary complete resection. The study was opened for phase II enrollement. Clinical trials informations: NCT03294252 .
Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.
Authors: Sahin Ibrahim Halil , Chen Wanqi , Sonbol Mohamad Bassam , Das Satya , Chen Zhengjia , Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Ahn Daniel H. , Ciombor Kristen Keon , Borad Mitesh J. , Berlin Jordan , Bekaii-Saab Tanios S. , Draper Amber , El-Rayes Bassel F. , Wu Christina 
Published: May 2019

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]
A phase I clinical trial of fluorouracil (5-FU) + devimistat (CPI-613) combination in previously treated patients (pts) with metastatic colorectal cancer (MCR).
Authors: Rocha Lima Caio Max Sao Pedro , Alistar Angela Tatiana , Desnoyers Rodwige J. , Sorscher Steven , Yacoub George Hosni , Dressler Emily Van Meter , Pardee Timothy S. , Grant Stefan C. , Luther Sanjeev , Butler Destini , Ogburn Olivia , Strickland Kristin , Pasche Boris 
Published: May 2019

e15054 Background: MCR that failed standard lines of therapy have a poor outcome. Inhibition of glutamine metabolism potentially can synergize with chemotherapy and reverse resistance. Devimistat is a novel anti-mitochondrial agent that alters energy metabolism and redox processes, leading to apoptosis, necrosis, and autophagy. Methods: Phase Ib dose escalation (3+3 design) to determine the MTD of devimistat, when used in combination with fixed doses of bolus and infusional 5-FU, in non-resectable MCR, ECOG PS 0-3, and good organ function who have failed, or could not tolerate, prior standard therapies. A cycle was 2 weeks. Escalating doses of devimistat were given IV over 2 hrs via central line on days 1-4. On Day 2 when both devimistat and bolus 5-FU were given, devimistat was given first, followed by 5-FU bolus (400 mg/m2) followed by infusional 5-FU over 46 hrs (2,400 mg/m2) on Days 2-4. Plasma samples to measure devimistat and metabolites were collected before and after the first and last dose of devimistat on cycle 1. Results: 19 pts enrolled from 1/20/2015 to 1/16/2019. One was never treated with devimistat and was excluded from analyses. Median age was 63 (range 32-83). 10 males and 8 females. Median devimistat cycles were 4 (range 1-8). Dose levels of devimistat: 1 pt treated at 2,000 mg/m2, 1 pt treated at 2,250 mg/m2, 7 pts treated at 2,500 mg/m2, then dose was de-escalated for an additional 9 pts treated at 2,250 mg/m2. Two of 7 pts had a DLT at the devimistat 2,500 mg/m2 dose level; a grade 3 and a grade 4 creatinine level. The dose of devimistat was de-escalated to 2,250 mg/m2 with a total of 10 pts being treated without DLTs observed (2 still on treatment). Other G1-2 non-hematologic and G1-3 hematologic toxicities were observed but related to 5FU except for two episodes of G1 intravascular hemolysis. No radiologic responses were observed. Four pts had SD and two pts at 2,250 mg/m2 of devimistat continue on therapy. Median PFS and OS are currently 2.73 and 5.75 months respectively. Conclusions: Devimistat and 5FU combination demonstrated a tolerable safety profile in heavily pretreated MCR pts. Durable SDs observed at the MTD suggest antitumor activity at the 2,250 mg/m2 devimistat dose level. Clinical trial information: NCT02232152.
Characteristics and outcomes of patients with colorectal cancer and bone metastasis.
Authors: Shahjehan Faisal , Kamatham Saivaishnavi , Cochuyt Jordan , Li Zhuo , Colibaseanu Dorin , Merchea Amit , Kasi Pashtoon Murtaza 
Published: May 2019

e15063 Background: Bone metastasis from colorectal cancer is a relatively rare phenomenon. The aim of this study is to identify the risk factors and survival patterns of bone metastasis after colorectal cancer diagnosis. Methods: A total of 23,846 colorectal cancer patients who were diagnosed between 1972 and 2017 at Mayo Clinic were included in the analysis. Freedom from bone metastasis since diagnosis at 5, 10, 15, 25 and 35-years were estimated using Kaplan-Meier method. Multivariable Cox regression models were used to assess the differences in overall survival rate for patients with different cancer sides and cancer locations. All tests were two-sided with alpha level set at 0.05. Results: A total of 798 (3.3%) patients had a diagnosis of bone metastasis after colorectal cancer diagnosis over a median follow up of 3.2 years. Thirty-five year freedom from bone metastasis was 83% (95%CI: 80%-86%) for all patients, and were 87.13%, 82.29% and 77.26% for left colon, right colon and rectal cancer patients. Male gender, recent surgical years, and higher cancer stage were associated with higher risk of developing bone metastasis after colorectal cancer diagnosis. Rectal cancer patients had higher hazard of developing bone metastases compared to left and right colon cancer patients. Conclusions: We were able to identify several patient and tumor-related factors associated with the development of bone metastasis in patients with colorectal cancer. The proportion and factors identified are similar to other studies. Future directions would be to analyze other molecular determinants within this subset of patients.[Table: see text]
Clinicopathologic predictors of worse outcome in early onset colorectal cancer (EO-CRC): A single-institution experience.
Authors: Rao Devika , Acuna Villaorduna Ana , Kaumaya Meghan , Ashai Nadia , Tolu Seda , Chergui Adel , Rajdev Lakshmi , Goel Sanjay 
Published: May 2019

e15064 Background: A growing body of evidence indicates an increasing incidence of CRC diagnosis prior to age 50 years. Despite improvements in morbidity and mortality in metastatic CRC (mCRC), racial disparities persist. Limited data is available on the influence of clinical and pathologic factors on outcomes in EO-CRC. We aim to analyze variables which may serve as prognostic markers in a racially diverse, under-served EO-CRC population. Methods: All mCRC patients (n=321) diagnosed between 2004-12 were identified through the institutional tumor registry and charts were reviewed for age at diagnosis, gender, race, site of primary and metastatic tumors and histologic grade. Clinical outcome was measured in terms of overall survival (OS). Clinicopathologic characteristics were compared with a t test between EO and standard onset (SO) groups. Multivariate analyses were performed to assess influence on EO-CRC. Results: Of the 321 patients, 60 (18.7%) had EO-CRC, with median age at diagnosis 42 years. Both groups showed a female preponderance (Table), with colon being the prevalent primary site (~70%). On analysis of racial distribution, non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) had a lower incidence of EO-CRC compared with Hispanic (H) and Asian (A) patients (12.7% v 17.6% v 26.7% v 40%, p= 0.07). Additionally, EO-CRC had a higher incidence of high-grade histology (42.6% v 25.8%, p=0.09), which on multivariate analysis had a significant influence on clinical outcome (p<0.01). Median OS in the EO group was 2.1 years compared to 2.7 years in the SO group. Conclusions: EO-CRC is an aggressive malignancy with distinct pattern of racial distribution. Histologic grade has the potential to serve as a negative prognostic marker. Further analysis of patients diagnosed between 2013-18 is underway. [Table: see text]
BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.
Authors: Kasi Pashtoon Murtaza , Kamatham Saivaishnavi , Colibaseanu Dorin , Shahjehan Faisal , Merchea Amit 
Published: May 2019

e15065 Background: Colorectal cancer (CRC) is a heterogeneous disease. Specifically for patients with BRAF-V600E mutations and/or mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-High), there have been significant advances in terms of treatment options. Early identification of these subsets of patients has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests i.e. carbohydrate cancer antigen 19-9 and carcinoembryonic antigen tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients. Methods: We included and analyzed the ratio of CA-19-9/CEA levels in patients with metastatic CRC at Mayo Clinic from December 2016 to February 2019, where both the results were available. Non-parametric tests were done to compare and contrast the differences in the median ratio and tumor marker levels. Results: BRAF-V600E mutant CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. The median CA-19-9/CEA ratio was 20 (range: 0.3-167.3) in BRAF-V600E MSS patients as opposed to 4.40 (range: 0.003-216.2) in all other patients, p-value of 0.007 (Table). Similarly, the mean CA-19-9/CEA ratio for BRAF V600E MSS tumors was 57.15 (S.D.± 62.76) versus 10.5 (S.D.± 33.90) for all other types. Furthermore, this discordant elevation is not seen in BRAF-mutant MSI-High or any MSI-High patients (median CA-19-9/CEA ratio - 0.46). Conclusions: To date, this is the first report utilizing the ratio of tumor markers CA-19-9/CEA as predictive rather than just prognostic markers. It clearly identifies BRAF-V600E MSS and the MSI-High CRC patients from other subsets.[Table: see text]
Simultaneous resection of colorectal cancer with synchronous liver metastases: A survey-based analysis.
Authors: Serrano Aybar Pablo Emilio , Griffiths Christopher , Bogach Jessica , Ruo Leyo , Hallet Julie , Simunovic Marko 
Published: May 2019

e15073 Background: Patients with colorectal cancer and synchronous liver metastases may undergo simultaneous or staged resection. Methods: We electronically surveyed members of the Society of Surgical Oncology, Canadian Hepato-Pancreato-Biliary Association and the College of Physicians and Surgeons of Ontario with a pilot-tested questionnaire. Four clinical scenarios were presented. Perceived outcomes of and barriers to simultaneous resection were assessed on a Likert scale using Mann-Whitney U and Chi-square tests for ordinal and categorical variables, respectively. We compared results between general and hepatobiliary surgeons. We sought to determine surgeons’ attitudes and perceived barriers to simultaneous resection and compare them between general and hepatobiliary surgeons. Results: The response rate of 20% (234/1166) included 50 general and 134 hepatobiliary surgeons. A high likelihood score (Likert ≥5-7) for support of simultaneous resection among general and hepatobiliary surgeons, respectively, included the following: for minor liver and low complexity colon, 83% and 98% (p < 0.001); for minor liver and rectal resection, 57% and 73% (p = 0.042); for complex liver and low complexity colon resection, 26% and 24% (p = 0.858); and, for complex liver and rectal resection, 11% and 7.0% (p = 0.436). Among hepatobiliary surgeons, the most common barriers for simultaneous resections were patient comorbidities and extrahepatic disease, whereas general surgeons additionally identified transferring care to another facility. Lack of information regarding non-responders is relevant given our relatively low response rate. Our respondents mostly worked in academic settings, which may not be representative of the majority of surgeons who manage colorectal cancer. Conclusions: Surgeon support for simultaneous resection increased with less complex surgery and was similar among hepatobiliary and general surgeons. Surgeons’ perceived practice patterns and barriers to simultaneous resection should inform clinical trials and disease care pathways.
Radiomics features on CT scans to predict response to HER2-targeted therapy of hepatic metastases from colorectal cancer.
Authors: Giannini Valentina , Mazzetti Simone , Defeudis Arianna , Cappello Giovanni , Vassallo Lorenzo , Vanzulli Angelo , De Mattia Cristina , Torresin Alberto , Siena Salvatore , Sartore-Bianchi Andrea , Leone Francesco , Martino Cosimo , Zagonel Vittorina , Marsoni Silvia , Regge Daniele 
Published: May 2019

e15086 Background: Metastatic Colorectal cancer (mCRC) is the 2nd cause of cancer death worldwide. Repeated cycles of therapies, combined with surgery in oligo-metastatic cases, are the therapeutic standard in mCRC. However, this strategy is seldom resolutive. Different lesions in in the same patient could have different responses to systemic therapy. Recently, CT texture analysis (CTTA) had been shown to potentially provide with prognostic and predictive markers, overcoming the limitations of biopsy sampling in defining tumor heterogeneity. The aim of this study is to use CT texture analysis (CTTA) to identify imaging biomarkers of HER2+ mCRC able to predict lesion response to therapy. Methods: The dataset is composed of 39 extended RAS wild type patients with amplified HER2 mCRC enrolled in the HERACLES trial (NCT03225937) that received either a lapatinib+trastuzumab treatment (n = 23) or a pertuzumab+ trastuzumab-emtansine treatment (n = 16). All patients underwent CT examination every 8 weeks, until disease progression. All mCRC on baseline CT were semi-automatically segmented and quantitative features extracted: size, mean, percentiles, 28 texture features. A logistic regression model was created using: (i) the whole dataset of mCRC as training and test set and (ii) 100 randomly generated training sets (with 70% of responder (R+) mCRC and an equal number of non-responder (R-) mCRC), and 100 test sets including the remaining mCRC. A mCRC was classified as R+ if size decreased (-10%) or was stable (±10%); as R- if size increased (+10%), during subsequent CT scans. Results: A total of 199 metastases were included (75R+ and 124R-). The training set was composed of 53R+ and 53R- mCRC and the test set of 22R+ and 71R- mCRC. Using the whole dataset, the model reached an AUC = 0.82 (sensitivity = 84%, specificity = 70%), while it reached a mean AUC of 0.70 (sensitivity = 68%, specificity = 67%) within the 100 repetitions. Conclusions: CTTA might help in stratifying different behaviors of mCRC, opening the way for lesion-specific therapies, with conceivable cost and life savings. Further extended analysis is needed to better characterize and validate predictive value of these biomarkers.
Genetic characteristics of lung metastasis and liver metastasis from left-sided colorectal cancer with microsatellite stability.
Authors: Wang Zhenghang , Zheng Xue , Li Jian , Wang Xicheng , Gao Jing , Li Zhongwu , Yu Jianing , Yang Wanning , Mao Beibei , Zhang Henghui , Shen Lin 
Published: May 2019

e15097 Background: Metastases from colorectal cancer (CRC) are common and develop in 40 to 60% of the patients. The liver and lung are the most frequently metastatic sites. Although lung metastasis (LuM) is characterized with slower growth rate and longer survival duration compared to liver metastasis (LiM). Little is known about the genetic differences between LuM and LiM CRC patients. Methods: The LuM cohort was composed of 18 patients with isolated lung metastasis and LiM cohorts was composed of 18 patients with liver metastasis. All the 36 patients were left-sided CRC and all lesions were microsatellite stability (MSS). The two cohorts were matched case by case according to age, gender, primary location, T stage and N stage. The Control cohort involved 10 patients who had locally advanced tumors, received R0 resection and suffered no relapse in at least five years. Based on a 1408 cancer-related gene panel (covering 967010 bases), the next-generation sequencing (NGS) of primary tumors and metastases was performed on the primary and metastatic lesions of these patients. Results: For primary tumors, results showed that the frequency of BRD4 amplification in the LuM cohort (n = 16 ) was 50%, which was much higher than that in the LiM (n = 16) and Control cohorts (n = 10) ( p < 0.05). U2AF1 amplification in the LuM (30%) was more common than that in LiM (0%) patients ( p= 0.043). For metastatic lesions, amplification of MET and SDHC and Hippo pathway activation were more frequently observed in LuM cohort (n = 15) than that in LiM (n = 18). Median TMB of the primary tumors and metastases in the LuM cohort were 9.518 and 6.022 mutations/Mb, respectively, which were both much higher than that in the LiM and Control cohorts ( p< 0.05). Conclusions: Amplification of BRD4 and U2AF1 was the characteristic feature of primary tumors which metastasized to the lungs, indicating this genetic alteration might be used in identifying patients at risk of developing LuM. MET amplification and Hippo pathway activation were promising therapeutic targets of left-sided CRC-LuM with MSS. Patients with LuM might respond well to immunotherapies due to relatively high level of TMB. Expanded prospective cohorts are warranted to further elucidate these findings.
Effect of JAG2 on migration and invasion in colorectal cancer cell by PRAF2, independent of epithelial-mesenchymal transition.
Authors: He Wan , Wu Han , Liu Dongcheng , Li Wenwen , Xu Ruilian , Zou Chang 
Published: May 2019

e15107 Background: Our previous studies revealed the increased expression of Jagged 2 (JAG2) in most intestinal cancer tissues. In colon cancer cell lines, JAG2 involved in the regulation of migration and invasion without affecting cell proliferation. This study further explored the mechanisms of how JAG2 promotes migration and invasion of colorectal cancer cells. Methods: We analyzed the expression of JAG2 mRNA and protein in normal human colon tissue cells and colorectal cancer cells. The promotive role of JAG2 in migration and invasion was tested by JAG2 siRNA and JAG2 overexpression in various colon cancer cell lines. To understand the mechanisms, we first treated HT29 cells with LY2157299, a TGF-β signaling pathway inhibitor, and Slug siRNA, to identify the cross-talk between JAG2 and EMT pathway. In addition, co-expression status of JAG2 and TGF-β-induced epithelial-mesenchymal transition (EMT) markers was analyzed. Finally, by using siRNA and proteomics technology, co-expressed proteins of JAG2 in colorectal cancer cells were identified. Results: JAG2 was abnormally expressed in colorectal cancer tissues and directly related with clinical stages. Similar to the findings in human tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. Interestingly, the promotion of JAG2 in migration and invasion was independent of EMT pathway. Furthermore, we found that the expression of JAG2 was correlated with PRAF2 (PRA1 Domain Family Member 2), a protein involved in the formation of exosome-like vesicles. In the presence of PRAF2, JAG2-rich exosome promoted migration and invasion. JAG2 might regulate the migration and invasion of colon cell through PRAF2. Conclusions: This is the evidence supporting the biological function of JAG2 in migration and invasion through non-EMT-dependent pathways and also the first exploration of the role of PRAF2 in colorectal cancer cells. These findings provide the theoretical basis for potential targeted therapy against JAG2/PRAF2.