bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preparing the peritoneal surface for intraperitoneal chemotherapy using high-intensity ultrasound (HIUS): Investigation of technical feasibility, safety and possible limitations.
Authors: Khosrawipour Veria , Frelkiewicz Piotr , Reinhard Sören , Nicpon Jakub , Khosrawipour Tanja , Lau Hien , Pieczka Marek , Pigazzi Alessio , Knoefel Wolfram Trudo , Mikolajczyk Agata 
Published: May 2020

e16045 Background: The penetration of chemotherapeutic drugs into metastatic peritoneal nodules remains at levels well below 1 mm, thus significantly limiting the antitumor effect of intraperitoneal chemotherapy (IPC). Recently, high-Intensity ultrasound (HIUS) has been discovered as a potential tool to improve peritoneal diffusion rates. Despite promising preliminary data, basic aspects regarding its technical feasibility, safety and possible limitations remain unclear. This study aims to enhance our current understanding of HIUS and test its applicability using an ex-vivo swine model. Methods: Three postmortem swine were subject to laparotomy with consecutive lavage with 0.9%NaCl saline and HIUS application. For this purpose, a large HIUS radiating pen was introduced into the abdominal cavity and HIUS was applied on two of the four abdominal quadrants for 300 seconds each at an output power of 70 W, 50 % amplitude and 20 kHz frequency. Following the procedure, small intestinal tissue samples were removed for further analyses. Results: In all specimen, peritoneal and subperitoneal layers showed structural changes only visible on a microscopic level. The peritoneal layer was transformed into a mash-like structure while the subperitoneal layer (depth of 142 +/- 28 µm) exhibited microcavities and vascular detachment from surrounding tissues. No bowel rupture or vascular perforations were observed. Conclusions: Our data indicate that HIUS is a technically feasible add-on procedure for IPC with measurable microscopic changes on the peritoneal surface and no apparent bowel toxicity. Pretreatment of the abdominal cavity with HIUS could significantly improve IPC efficacy. Further studies are required to optimize and evaluate this novel approach.
Phase I results from a phase 1/2 multi-center study of nab-sirolimus combined with mFOLFOX6+bevacizumab (FB) as first-line (1L) therapy in patients (pts) with metastatic colorectal cancer (mCRC) with or without PTEN loss.
Authors: Sharma Sunil , Chiorean E. Gabriela , Alistar Angela Tatiana , Braiteh Fadi S. , Matrana Marc Ryan , Becerra Carlos Roberto , Grigorian Berta , Hou Shihe , Schmid Anita N. , Desai Neil 
Published: May 2020

e16050 Background: The PI3K/mTOR pathway overactivation and loss of PTEN occur in 20-40% of mCRC pts. A recent phase 1/2 study in mCRC pts showed evidence that everolimus added to 1L SOC treatment improved outcomes, in particular in pts with PTEN loss (Gilcrease, 2019). This prospective, single-arm phase 1/2 study aims to identify the optimal dose and schedule of nab-sirolimus (ABI-009), an mTOR inhibitor, plus FB and evaluate the safety and preliminary efficacy of this regimen. Methods: Eligible pts have no prior therapy, ≥18 years old, ECOG performance status of 0-2. PTEN loss (by IHC) is evaluated for all pts. nab-Sirolimus IV starting dose and schedule was 30mg/m2 weekly for 3 weeks followed by a week of rest (on D1, 8, and 15 in a 28-day cycle, qw3/4) plus standard doses of FB on D1 and D15. Dose escalation to 45 and 60mg/m2 or de-escalation to 20 and 10mg/m2 followed the 3+3 design. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: As of Jan 31, 2020, 24 pts were treated in the phase 1 study and 18 were evaluable for response. No DLTs were observed in the first 3 pts treated with nab-sirolimus at 30mg/m2 qw3/4; however, all 3 pts missed D8 doses (due to G2 thrombocytopenia and G3 neutropenia) and the cohort expanded to additional 3 pts for further observation. 5/6 pts missed D8 doses and a new dose cohort enrolled pts at 20mg/m2 qw3/4. No DLTs were observed and the cohort was expanded to 10 pts. A safety review of the first 18 pts observed that 9/18 pts missed doses on D8 and a new cohort was added to enroll pts at 20 mg/m2 q2w (D1 and D15, as for FB). This cohort enrolled 8 pts with no DLTs and represents the recommended-phase-2-dose (RP2D) and continues enrollment in phase 2. For all pts, 15/24 (63%) pts had G3-4 treatment-related adverse events (TRAEs); most common were neutropenia (6/24, 25%) and thrombocytopenia (4/24, 17%). At the RP2D 3/8 (38%) pts had G3-4 TRAEs (thrombocytopenia, weight loss, and hypertension, 1 pt each). Among 18 evaluable pts, best response was: 7/18 (39%) partial response, 10/18 (56%) stable disease, and 16/18 (89%) had tumor shrinkage. PTEN was assessed in 14 pts: 4/14 (29%) had PTEN loss, 2/4 (50%) PTEN loss pts responded, while 3/10 (30%) pts that were PTEN+ (WT) had a response. Conclusions: The RP2D of nab-sirolimus is 20mg/m2 q2w in combination with standard mFOLFOX+bevacizumab. The phase 2 portion of the study is ongoing. Clinical trial information: NCT03439462 .
Microsatellite instability and KRAS mutation in stage 4 CRC: Prevalence, geographic discrepancies and outcomes from the National Cancer Database.
Authors: Uhlig Johannes , Cecchini Michael , Stein Stacey , Lacy Jill , Kim Kevin 
Published: May 2020

e16052 Background: To assess microsatellite instability (MSI) and KRAS mutation prevalence, discrepancies and their impact on outcome in AJCC stage IV colorectal adenocarcinoma (colorectal cancer; CRC). Methods: The 2010-2016 United States National Cancer Database was queried for stage IV CRC patients > 18yo and information on MSI and KRAS mutation. Microsatellite status was stratified as stable microsatellites (MSS, including low instability) and microsatellite instability high (MSI-H). KRAS status was stratified as mutation and wildtype. Prevalence and discrepancies were evaluated according to patient demographics, US geography and CRC factors. Overall survival (OS) was assessed using Cox proportional hazards models adjusting for age, gender, race, comorbidities, metastatic burden, CRC treatment, treatment center type, and year of CRC diagnosis. A priori, a statistical interaction test between microsatellite status, KRAS status and primary CRC site was planned. Results: Microsatellite/KRAS status was available for n = 10,844/n = 25,712 patients, respectively. OS was assessed in n = 5,904 patients with data on both microsatellite and KRAS status, and follow-up. Overall prevalence of MSI-H was 3.1% and KRAS mutation 42.4%. Microsatellite and KRAS status varied according to primary CR site, as presented in Table. Further variation was evident according to US-geography, with MSI-H rates ranging from 1.6% to 4.1%, and KRAS mutation rates ranging from 41.1% to 44%. On multivariable analyses, longer OS was observed in patients with KRAS wildtype versus mutation (HR = 0.91, 95% CI: 0.85-0.97 p = 0.004), MSS versus MSI-H (HR = 0.75, 95% CI: 0.62-0.9, p = 0.003), and left-sided versus right-sided CRC (HR = 0.65, 95% CI: 0.6-0.7, p < 0.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (interaction p = 0.002). Conclusions: Depending on its primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, MSI-H and primary CRC sidedness independently affect overall survival and interact with distinct prognostic profiles. Generically classifying adenocarcinomas of different site as “CRC” might deprecate this diversity. [Table: see text]
Meta-analysis and systematic review of the cardiotoxicity of TAS-102.
Authors: Lopez Carlos Alberto , Azimi-Nekoo Elham , Chung Su Yun , Newman James , Shen Janice , Saif Wasif M. 
Published: May 2020

e16053 Background: Fluoropyrimidines such as 5-FU and capecitabine are known to be cardiotoxic drugs. TAS-102 (trifluridine-tipiracil) is a novel oral fluoropyrimidine that was recently FDA approved to treat gastric and colon cancer. However, the incidence of cardiac related events of TAS-102 is not fully ascertained. We performed a meta-analysis and systematic review to determine the incidence of cardiotoxic events associated with TAS-102. Methods: We performed a literature search through PubMed, Embase, and Web of Science to identify any publications in any language up to December 31st, 2019 where TAS-102 (and equivalent terms such as “trifluridine-tipiracil” and “Lonsurf”) was used. These were then manually reviewed to identify any publications reporting cardiac events. Randomized controlled trials (RCTs) were included for meta-analysis to determine the incidence of cardiotoxic events, which were summarized as pooled odds ratios (OR) when compared to placebo. Non-randomized, non-controlled clinical trials (phase I and phase II studies) were included in the systematic review but excluded from the pooled OR calculation. Results: 869 publications were identified in the initial literature search, of which 17 trials (3 Phase III studies, 6 Phase II studies, and 8 phase I studies) met inclusion criteria. A total of 1,877 patients among 4 RCTs were included in the meta-analysis. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR 1.97 95% CI [0.22-17.89]), hypertension (OR 0.73 95% CI [0.37, 1.44]), palpitations (OR 1.51 95% CI [0.30, 7.56]), cardio-pulmonary arrest (OR 0.83 95% CI [0.11-6.32]), or syncope (OR 1.50 95% CI [0.06-37.14]). Among the 1,252 patients receiving TAS-102, the overall incidence of cardiovascular events was low, with hypertension being the most common side effect (21 events), followed by palpitations (6 events), cardiopulmonary arrest (2 events), and myocardial infarction (3 events), though there was no statistically significant increased risk compared to placebo. No deaths were reported. Conclusions: Unlike other fluoropyrimidines, TAS-102 appears to be a cardiogentle drug, with no increased risk of cardiac events compared to placebo. Since fluoropyrimidines remain the backbone of treatment for gastrointestinal malignancies, TAS-102 can offer an alternative to patients who developed cardiotoxicities from other agents. Prospective studies with consideration of cardiac risk factors are required.
Correlation between DIDO1 variation and MSI-status in colorectal cancer.
Authors: Zhang Xingwei , Cai Yonghua , Hou Yujie , Hu Huanxin , Chen Yaoxu , Huang Mengli , Kang Liang 
Published: May 2020

e16054 Background: Several studies have displayed a sustained clinical response to immune checkpoint inhibitors with profound clinical improvement in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). MSI-H tumors may display higher numbers of TILs, many of which can be directed against tumor-related neoantigens. We set out to examine the underline mechanism in gene level to further explain the differences between MSI-H and MSS CRC. Methods: Whole exome sequencing(WES) was performed on 68 CRC patient.MSI status of these patients were determined using a targeted next generation sequencing panel covering 100 MSI loci. TCGA database was used to analyze WES data of 364 CRC patients with different MSI states, and immune signature was used to analyze the corresponding relationship of immune cell expression in different populations. Results: Of 56 MSS patients, 58.9% (33/56) had copy number variants (CNV) in DIDO1, and 1.8 (1/56) had single nucleotide variants(SNV) in DIDO1. Of 12 MSI-H patients, 33.3% (4/12) had SNV in DIDO1 gene, None had CNV in DIDO1. TCGA database showed that of 308 MSS patients, 8% (24/308) had CNV in DIDO1 and 3% (9/308) had SNV in DIDO1. Of 56 MSI-H patient, 39% (22/56) had SNV in DIDO1 and only one patent had both SNV and CNV in DIDO1. Gene variation of DIDO1 of 68 CRC patients showed a correlation with TCGA database. Gene variation of DIDO1 in MSI-H patients are mainly SNV, and the incidence of CNV is very small (4.3% of DIDO variation).While, gene variation of DIDO1 in MSS patients are mainly CNV, followed by SNV, indicating DIDO1 CNV are highly possible occurring in MSS patients. Furthermore we analyzed the relationship between the copy number of DIDO1 and immune signature through CRC TCGA database. The results showed increase of DIDO1 copy number was negatively correlated with the abundance of NK cells (P = 0.00048), T cells (P = 8.23×10-5) and macrophages (P = 1.75×10-8). Conclusions: Our results showed that different MSI status display unique patent of DIDO1 gene variation, which may be related to different immune micro environment among MSI-H/MSS patients.
Stage II high-risk colon cancer: A retrospective analysis of the benefit of chemotherapy in patient subgroups based on the risk factor.
Authors: Jacob Linu Abraham 
Published: May 2020

e16068 Background: Adjuvant chemotherapy is routinely recommended for patients with high risk stage II colon cancer. However the risk conferred by each high risk feature (HRF) may be different. This study was done to analyze the magnitude of benefit of chemotherapy in individual HRF patient subgroups. Methods: Resected stage II colon cancer patients during the period January 2012 to March 2018 were retrospectively analyzed for risk features, chemotherapy treatment and survival. Statistical analysis was done with SPSS 16.0. Results: A total of 41 patients were identified as having pathological stage II colon cancer during the study period - 63.4% were males and 36.6%, females. 68.3% had left sided tumor while 31.7% had right sided tumor. 29.3% had none of the high risk features and received no adjuvant chemotherapy. 70.7% patients had at least one of the high risk features and received adjuvant chemotherapy with fluoropyrimidine ± oxaliplatin. 90.2%, 7.3% and 2.5% had stage IIA, IIB and IIC disease respectively. 36.6%, 43.9% and 19.5% had grade I, II and III tumors respectively. Lymphovascular invasion (LVI) and perineural invasion (PNI) were present in 14.6% and 19.5% patients respectively. 29.3% had inadequate lymph node dissection. 22.0% patients had elevated CEA prior to surgery and 4.9% patients had presented with intestinal obstruction. After a minimum follow up period of 20 months the median disease free survival (DFS) was 26 months for the entire cohort. Left sided tumors had significantly prolonged median DFS compared to the right sided tumors (31 vs 26 months; p = 0.05). Median DFS was 24 months for the high risk group compared to 33 months for the low risk group (p = 0.002). On subset analysis T4 HRF subgroup had superior DFS, while LVI HRF subgroup had inferior DFS both of which were statistically significant. Conclusions: Magnitude of chemotherapy benefit was highest in the T4 subgroup, while it was lowest in the LVI subgroup in resected stage II high risk colon cancer [Table: see text]
Age-dependent prognostic value of KRAS mutation in metastatic colon cancer.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Sanford Nina Niu , Aguilera Todd Anthony , Kainthla Radhika , Jones Amy Little , Sanjeevaiah Aravind , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali 
Published: May 2020

e16085 Background: KRAS mutation is associated with poor prognosis in metastatic colon cancer (mCC). However, the age-dependent prognostic value of KRAS status is unknown. We aimed to confirm if the prognostic impact of KRAS is dependent on the age of diagnosis in mCC. Methods: We identified adult patients with mCC diagnosed between 2004 and 2016 using the NCDB. We compared patients with KRAS mutation and KRAS wild type, stratified according to age group < 50, 50-70, and ≥70. Categorical variables were compared using the chi-square test. We performed the Kaplan-Meier and Cox regression methods for survival analyses. We adjusted for patient and tumor characteristics (included KRAS status, MSI, 18q loss of heterozygosity, side of the primary tumor). Results: A Total of 19,875 patients had KRAS status reported; 43% had KRAS mutation, and 57% were KRAS wild type. Patients with KRAS mutation were more likely to be female, black, have elevated CEA, and have right-sided tumors (all p < .001). In the overall population, patients with KRAS mutation had significantly worse OS compared to patients with KRAS wild type (20 vs. 22 months, p < .001), and this difference was maintained after multivariable Cox regression analysis ( p < .001) (Table). Young patients ( < 50 years) with KRAS mutation had a worse prognosis than those with KRAS wild type in the tumor (23 vs. 29 months, p < .001). KRAS status did not maintain its prognostic value among older age (≥70 years) patients (14 vs. 14 months, p = NS). Conclusions: In this analysis of a national cancer registry, we confirmed that KRAS mutation was an independent poor prognostic factor for mCC. This effect persisted after adjusting for patient and tumor characteristics, including sidedness and MSI status. However, we identified that this prognostic value of KRAS mutation is significant in young mCC patients < 50 years, as compared to older patients. [Table: see text]
Incidence of and risk factors for hospitalizations from chemotherapy among patients with stage III and stage IV colorectal cancer.
Authors: Falconi April , Fishman Ezra , Barron John , Eleff Michael , Fisch Michael Jordan , Chi Winnie 
Published: May 2020

e16090 Background: Despite the decreasing colorectal cancer (CRC) mortality rate over the past decade, complications from CRC treatment remain a challenge. Prior research has shown that a majority of patients with stage III CRC in the adjuvant setting experience hospitalizations due to chemotherapy-related toxicity. Minimal research, however, has examined risk factors of these events and the prevalence of hospitalization among stage IV CRC patients. Methods: We used claims data from a geographically-diverse private health insurer—including both commercially-insured and Medicare Advantage patients—to estimate and characterize risk factors of hospitalizations among Stage III or IV CRC patients. We compared sociodemographic, clinical, as well as provider characteristics and cancer treatment regimens between patients with and without hospitalizations from the initiation of chemotherapy to 60 days after the end of chemotherapy. Results: Incidence rates for hospitalization from chemotherapy were 49% and 70% for stage III and IV CRC patients, respectively. Although the oldest stage III CRC patients (age 75+) were the most likely to experience hospitalizations, the youngest age group (age 18-49) of stage IV patients experienced the highest incidence (74%) of hospitalizations (p < 0.05). Higher values of the Elixhauser comorbidity index was associated with a higher risk for hospitalizations among patients with stage III CRC (p < 0.001). Both stage III and stage IV patients with diabetes were more likely (p < 0.05) to have hospitalizations from chemotherapy (55% and 73%, respectively). Conclusions: Hospitalization from chemotherapy is very common among stage III and IV CRC patients. These data identify subgroups at higher risk. Study findings may inform choice of cancer treatment regimen and focus on key underlying medical needs
Sensitivity of colorectal or pancreatic cancers with high DDX5 and mutations in Kras and p53 genes to FL118 treatment.
Authors: Ling Xiang , Wu Wenjie , Liao Jianqun , Santha Sreevidya , Aljahdali Leman , Wang Jue , Fountzilas Christos , Iyer Renuka V. , Boland Patrick M , Li Fengzhi 
Published: May 2020

e16102 Background: FL118 is a small molecule anticancer drug with novel mechanisms of action, although its chemical structure is similar to camptothecins. Currently, FL118 is completing its IND process to enter clinical trials for patients with advanced colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) cancers. Precision medicine is becoming a trend for modern cancer treatment. Thus, identification of drug efficacy-relevant biomarker(s) for patient selection is critical for enhancing patients’ response rates and avoiding unnecessary treatment in the clinic. Methods: Animal models of CRC and PDAC patient-derived xenograft (PDX) tumors were used to test FL118 efficacy; next generation sequencing (NGS) was used to determine PDX tumor molecular profiles; Western blots (WB) and real time RT-PCR were used to determine gene expression and/or apoptosis; Immunoprecipitation (IP) plus WB was used to determine protein phophorylation. Proteasome inhibitor was used to determine protein expression pathway. FL118 affinity purification was used to identify FL118 binding protein(s). Results: In association with WuXi Apptec, we have completed FL118 CMC and produced a clinical compatible product formulation. In this new product format, FL118 exhibits excess toxicity at a dose of ≥ 7.5 mg/kg via weekly x 4 schedules in mice. However, dosages of ≤ 6 mg/kg via the same schedule are tolerable. FL118 can eliminate the Kras/p53/APC triple-mutated SW620-established CRC tumors in a high percentage of mice at doses of 6 (maximum tolerated dose, MTD), 5, 4, 3, and 2 mg/kg. Tumor elimination under MTD is a typical characteristic of targeted drugs, which do not need MTD but only need the target to be saturated with drug for maximal efficacy. High expression of DDX5 (also called p68), a multifunctional oncogenic transcriptional co-activator and a DEAD-box RNA helicase, is associated with high FL118 efficacy in both CRC and PDAC PDX tumors. Mechanistically, FL118 binds to DDX5 to induce DDX5 tyrosine dephosphorylation and protein degradation without decreasing its mRNA. Tumors with Kras mutation (mKras) and/or TP53/p53 mutation (mp53) possess intrinsic resistance to multiple classic chemotherapeutic agents. However, PDAC PDX tumors with mp53 exhibit higher mKras expression and greater sensitivity to FL118 than tumors with wild type p53 and mKras. Conclusions: DDX5, mKras and mp53 appears to be favorable biomarkers for predicting FL118 high efficacy. However, further studies with a large cohort will be needed for confirmation.