bluuebunny/crossref_metadata_2025 huggingface dataset:
An evaluation of RAS testing and survival among mCRC patients in the United States.
Authors: Kiprilov Enko , Sangaré Laura , Lowe Kimberly , Christodoulopoulou Alexandra
Published: May 2019

e15144

Background: The status of mutations in the rat sarcoma viral oncogene homolog ( RAS) family of genes, which includes Kirsten RAS ( KRAS) and Neuroblastoma RAS ( NRAS) predicts response to anti-EGFR therapies in metastatic colorectal cancer (mCRC) patients. Current treatment guidelines recommend all mCRC patients to receive RAS testing prior to initiating treatment with an anti-EGFR agent. This study sought to establish estimates of RAS testing among mCRC patients in the US prior to initiation of first and third lines of treatment, and to describe median survival by treatment groups. Methods: Data from the Oncology Services Comprehensive Electronic Records (OSCER) 2.0 dataset were utilized. Patients diagnosed with mCRC between January 1, 2011 and July 31, 2017 were eligible. Patients were followed for up to 1 year, or until death, following their mCRC diagnosis. Results: A total of 17,387 mCRC patients were included in the analysis, among which 69% were RAS tested and 31% were never tested. Among the RAS tested patients, 23% were tested prior to their mCRC diagnosis 60% received RAS testing following mCRC diagnosis but prior to first line of treatment, 3% were tested following first line treatment but prior to third line, and the remaining 14% were tested following third line. Demographic variables did not differ between tested and untested groups, overall and by line of treatment. The overall median survival of RAS WT patients was 31.1 months (95% CI: 30.0, 32.4). MCRC patients who were not RAS tested had a lower median survival of 20.7 months (95% CI: 19.1, 22.5). Conclusions: The timing of when patients are being tested varies greatly. While nearly 70% of patients had a RAS test, approximately 30% failed to be tested, identifying a large gap in testing practices. Universal RAS testing provides patients and their physicians with knowledge of their anti-EGFR treatment options and may result in improved survival.
Prevalence of DNA damage response and repair, cellular signaling, tumor suppressor, and immune checkpoint gene mutations in gastrointestinal cancers.
Authors: Burke Aidan M , Prins Petra , Yeh Celine , Weinberg Benjamin Adam , Kim Sunnie S. , He Aiwu Ruth , Pishvaian Michael J. , Marshall John , Unger Keith Robert
Published: May 2019

e15149

Background: The prevalence of genetic mutations in gastrointestinal (GI) cancers is not well characterized. Molecular targeted therapies have substantial potential to improve outcomes. As next-generation sequencing (NGS) has become more commercially available, there may be additional opportunities to find novel targets for therapy or identify predictors of response to chemotherapy and radiotherapy. Commercially available DNA sequencing was conducted on patients with GI cancers to identify novel therapeutic and prognostic factors. Methods: A total of 86 solid tumor biopsy specimens from GI cancers were submitted for molecular profiling with NGS. Tumor molecular profiles were reviewed to identify frequently occurring pathogenic mutations in DNA damage and repair (DDR), cell cycle (CC), tumor suppressor (TS) and immune checkpoint (IC) pathways. DDR genes included MGMT, MSH 2/6 and ERCC1. CC genes included cMET, EGFR and KRAS. TS genes included APC, PTEN and TP53. IC genes included PD-1 and PDL-1. The overall frequency of mutations as well as the frequency of mutations for each primary site was analyzed. Results: Samples from colorectal (CRC, n=36), gastroesophageal (GE, n=5), liver and bile duct (LBD, n=14), pancreatic (PC, n=26) and other (OC, n=5) GI cancers were analyzed. Overall 46.3% of samples had at least one DDR mutation and commonly occurred in PC (57.7%) and CRC (50.0%).The most commonly mutated DDR genes were MGMT, TOPO1 and TOP2A. 55.2% of samples had at least one CC mutation and were most common in PC (69.2%), CRC (61.1%) and LBD (42.9%). The most common CC mutations were PTEN, P53 and KRAS. 65.5% of samples had at least one TS mutation with TP52 and PTEN being the most common. TS mutations occurred commonly in CRC (80.6%) and GE (60.0%). Mutations in PD-1 and PD-L1 (IC) were present in 25.3% of samples and occurred most frequently in GE (80.0%) and LBD (28.6%). Conclusions: Mutations were commonly seen in DDR (46.3%), CC (55.2%), TS (65.5%) and IC (25.3%) genes in GI primaries, providing a path to explore the role of novel therapeutic agents and how these mutations might be used to predict clinical outcomes.
Distance from the anal verge as an indirect measure to predict response to anti-EGFR therapy in left side metastatic colon cancer.
Authors: Armentano Daniela Pezzutti DOMINGUES , Monteiro Mariana Ribeiro , Araujo Raphael , Arakelian Renata , Cardoso Paula Freire , Tsukamoto Jessica , Moreira Raphael Brandao , Picon Fernando
Published: May 2019

e15153

Background: Right and left sided colon cancers (RC, LC) differ with respect to biology and response to therapy. Several retrospective analyses have assessed the clinical effect of epidermal growth fator receptor (EGFR) targeted agents in patients with metastatic CRC (mCRC) according to the primary tumor location. Differentiating only right from left. But can in the LC responses differ according to the distance from the anal verge (DAV)? Methods: Exploratory retrospective analyses was planned to evaluate if LC responses differ according to the DAV. LC was defined as tumors originating anywhere from the distal rectum to the left colic flexure (splenic flexure). DAV was describe in cm measured by previous to surgery or treatment, colonoscopy, CT or MRI. Patients were divided for analysis purposes in two groups: Group A (tumors above 12cm from de anal verge), Group B (tumors below 12cm from the anal verge). Results: We retrospectively evaluated 29 patients with left metastatic colorectal cancer treated with anti-EGFR therapy as part of their treatment at the Paulistano Hospital -São Paulo from 2011 to 2018. Median population age 51.8 years (48.5-62.3). Median DAV 14.5 (4.6-25 cm). Median follow-up 12.8 months. No significant difference on stable and partial response rate was detected (Group A 43.7% vs Gropup B 56.3%), p=0.211. Long-rank test with a median pFS 8,5 meses and a PFS at 6 months of 66.7 vs 78,8 (Group A and Group B respectively ), p=0.901. Two-year OS was 58.4 % in Group A and 100% in Group B, p=0.17. Conclusions: Although no significant diferences were detected, responses rates were numerically higher in patients with tumors located below 12 cm from the anal verge. Further studies are needed to evaluate the association between response and DAV.
Prospective assessment of the risk for colorectal neoplasia in a Mexican population according to risk categories.
Authors: Camargo Vanessa Rosas , Martos Armendariz Edgar Omar , Rivera Aguilar Mauricio , Hernandez-Felix Jorge Humberto , Cordon Monica Lily , Rosales Sotomayor Angela , Meneses Medina Mónica Isabel , Huitzil Melendez Fidel David
Published: May 2019

e15158

Background: General population screening can reduce colorectal cancer (CRC) mortality. International guidelines recommend CRC screening for asymptomatic people over 50 years. There is no established national screening program in Mexico. Even in countries with low incidence of CRC such as Mexico, targeted screening of subjects at high risk could decrease resource utilization and cost. Our aim was to describe the distribution among an average-risk population based on risk for colorectal neoplasia (CRN). Methods: We performed a prospective assessment of the risk for CRN among asymptomatic people over 50 years at Instituto Nacional de Ciencias Médicas y Nutrición between 2017-2018. The inclusion was competitive consistent with our age-sex pyramid. We included workers, non-family attendants and patients (internal medicine consultation). Each subject answered a standardized questionnaire, which included information on their age, gender, family history of CRC, diabetes, body mass index (BMI), smoking status and drinking habits. In order to stratify the population according to their risk for CRN, we used the Asia-Pacific Colorectal Screening (APCS) score. Results: We included 256 subjects. Median age was 59 y/o (50-93), 52% were female. 5% had a first-degree relative with CRC. 44% were current or ex-smoker and 9% reported alcohol consumption. 21% had diabetes. The median BMI was 27.3 (17-51). According to the APCS score, 60% were assigned as average risk (AR) and 40% as high risk (HR) for CRN. We observed a higher proportion of HR compared to our previous retrospective data (Table). Conclusions: We prospectively confirmed that using basic clinical information (age, gender, smoking status, family history of CRC, BMI and diabetes), it is possible to identify a subset of asymptomatic subjects at high risk for CRN in whom screening strategies should be prioritized. In developing countries with limited resources, a focus on high risk groups could improve cost effectiveness of screening colonoscopy. Risk stratification based on APCS score. [Table: see text]
Exosomal microRNA-199b-5p as a potential circulating biomarker to predict response of preoperative chemoradiotherapy for locally advanced rectal cancer.
Authors: Baek Dong Won , Kim Kyung Hwa , Kang Byung Woog , Kim Hye Jin , Park Soo Yeon , Park Jun Seok , Choi Gyu Seog , Baek Jin Ho , Hur Keun , Kim Jong Gwang
Published: May 2019

e15161

Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision has become the standard treatment for locally advanced rectal cancer (LARC). However, the effect of CRT varies from complete response to complete resistance, and predicting response to CRT have not been well characterized yet. Previous studies have shown the potential of micro-RNA (miRNA) based approaches to enhance tumor radiation response. Accordingly, the present study attempted to identify biomarkers to predict response for preoperative CRT using comprehensive miRNA analysis in patients with LARC. Methods: This study included 65 rectal cancer tissues and 90 serum samples from patients who diagnosed with LACR and received preoperative CRT at Kyungpook National University Chilgok Hospital. Tissue specimens and serum samples were collected before CRT to evaluate the biologic differences between the good CRT response group and the poor CRT response group. For discovery of specific miRNAs, 800 miRNAs were analyzed using NanoString in 30 rectal cancer tissues. Thereafter, a total of 65 tissues, and 90 serum samples were investigated using real-time PCR for validation. Results: The median age was 59 years (range, 30-82), and the ratio of male to female was 3.05 to 1. The pathologic stages after preoperative CRT were as follows: pathologic complete response (n=13, 14.4%), pathologic stage I (n=13, 14.4%), pathologic stage II (n=27, 30.0%), pathologic stage III (n=28, 31.1%), and pathologic stage IV (n=9, 10.0%). In the discovery set, 16 target miRNAs were detected. In the validation set with tissue specimens, expression of 3 miRNAs (miR-199a/b-3p ( p=0.032), miR-199a-5p ( p=0.023), miR-199b-5p ( p=0.005)) was significantly upregulated which was associated with better response of CRT. Moreover, among the 3 candidate miRNAs, miR-199b-5p level was significantly upregulated in serum, and it was also found to be related with better response of CRT in LARC (pathologic stage 0/I versus II/III/IV, p=0.027). Conclusions: In the present study, high level of exosomal miR-199b-5p was associated with better response, suggesting it to be a promising non-invasive biomarker to predict response of CRT in patients with LARC. Accordingly, specific miRNAs can be predictive biomarker or therapeutic target to overcome radiotherapy resistance in LARC with a functional study.
Rectal admission of chemotherapeutic drugs in neoadjuvant treatment schemes of locally advanced rectal cancer.
Authors: Korytova Luiza
Published: May 2019

e15168

Background: High incidence and steady rise of rectal cancer morbidity, unsatisfactory treatment results, amount of disabling surgery, high rate of local recurrents advocate for searching for new methods of combined treatment of locally advanced rectal cancer. Methods: We had suggested to rectally install sterile hydrogel material based on sodium alginate with incorporated 5-FU for radio modification purposes during neoadjuvant chemo radiotherapy. 39 patients with histologically confirmed diagnosis were included into our study. 19 patients received preoperative radiotherapy with summary dose of 50-56 Gy and systemic chemotherapy with fluorpirimidines and rectally admitted hydrogel material with incorporated 5-FU twice per day. Control group consisted of 20 patients who had similar treatment, excluding rectal hydrogel installations. Results: There was no increase in early radiotherapy complications noticed. Three study group patients had complete response, 16 had partial response (versus 1 CR, 15 PR, 3 stabilization and 1 progression in control group). This allowed reduction of surgical assistance volume in seven patients - sphincter-preserving operations were performed. Grade 3-4 pathomorphosis by Dworak’s scale was identified in 17 out of 19 patients (13 out of 20 in control group). Conclusions: Use of hydrogel material based on sodium alginate with incorporated 5-FU does not increase amount and intensity of radiation induced complications, allows to improve patients quality of life and treatment results.
Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502).
Authors: Sinicrope Frank A. , Ou Fang-Shu , Zemla Tyler , Nixon Andrew B. , Mody Kabir , Levasseur Alexandra , Dueck Amylou C. , Dhanarajan Asha R. , Lieu Christopher Hanyoung , Cohen Deirdre Jill , Innocenti Federico , Behrens Robert J. , Peters Walter , Sommer Nicolas , O'Reilly Eileen Mary , Meyerhardt Jeffrey A.
Published: May 2019

e15169

Background: In metastatic colorectal cancer with deficient DNA mismatch repair (dMMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for cancers with proficient MMR. In an ongoing phase III randomized trial, we will determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR. By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that could serve as ‘immune priming'. Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR are randomized to modified FOLFOX6 for 6 months (12 cycles) alone (control arm) or combined with atezolizumab (840 mg IV q2 wk) with continuation of the antibody as monotherapy for an additional 6 months (total duration of 12 months) [experimental arm]. Patients will be stratified by T, N stage and tumor sidedness. Local testing for MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. One cycle of FOLFOX is allowed pre-registration. The targeted accrual goal of 700 patients and 165 disease-free survival (DFS) events will provide 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint of DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. Results: This study is being conducted by the Alliance for Clinical Trials in Oncology, was approved by NCI CTEP and activated in 09/2017. The study is actively accruing and, as of 02/11/2019, 152 patients are enrolled. We are actively exploring an international collaboration. Conclusions: This is a current clinical trial in progress. Clinical trial information: NCT02912559.
Patient reported outcome measures (PROMs) in patients (pts) with locally advanced rectal cancer (LARC) managed with a watch and wait (W&W) approach after a clinical complete response to chemoradiotherapy (CRT).
Authors: Vatandoust Sina , Chen Gang , Sposato Luigi , Wattchow David , Roy Amitesh Chandra , Klevansky Myron , de Fontgalland Dayan , Leung John , Koczwara Bogda , Hollington Paul , Wilson Carlene , Flight Ingrid , Ruminski-Smith Dania , Karapetis Christos Stelios
Published: May 2019

e15173

Background: PROMs have not been adequately studied in LARC pts who are managed with W&W after a clinical complete response to CRT. The objectives of this study were to evaluate: quality of life measures, bowel function, Fear of Cancer Recurrence (FCR) and survivors’ needs, in this population. Methods: Data were collected from the Flinders Medical Centre W&W prospective database. Questionnaires including Self-Administered Comorbidity (SCQ), EORTC QLQ-C30 and -CR29, EQ-5D-5L, MSKCC Bowel Function Instrument (MBFI), Low Anterior Resection Syndrome (LARS) score, Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF), Cancer Survivors’ Unmet Needs (CaSUN) and Response Efficacy Score (RES) were sent via mail to eligible pts according to a Tailored Design Method. Descriptive statistical analyses were conducted. Results: Of 40 eligible pts, 21 (52.5%) responded: 15 (71%) were male, median age at diagnosis was 66 years (34-81). 5 developed local re-growth (1 had local excision and 4 had ultra-low anterior resection). Median time from end of CRT to data collection was 39.8 months (6.0-77.5). The mean SCQ score was 5.7 (SD 5.5). Mean EQ-5D-5L utility score was 0.84 (SD 0.13), mean EQ-VAS score was 81.9 (SD 12.7) and mean EORTC QLQ global health status score was 76.2 (SD 19.2). The most common symptoms were fatigue (90%), pain (67%) and flatulence (67%). In pts without a re-growth (n = 16), the mean MBFI total score was 27.9 (SD 7.7); based on LARS score: 6 (38%) had no LARS, 5 (31%) had minor LARS and 5 (31%) had major LARS. Mean FCRI-SF score was 11.8 (SD 6.1), clinical level FCR was reported by 2 (9.5%) [cut-off 22] and 4 (19%) pts [cut-off 16]. 10 (47%) reported unmet needs: the most common area was Comprehensive Cancer Care n = 9 (42%). On RES, of 20 responders, 19 (95%) believed W&W was a worthwhile and effective strategy. Conclusions: The most commonly reported symptoms included fatigue, pain and flatulence. LARS was common: in the absence of surgery, LARS is due to CRT. Clinical FCR was uncommon. The majority believed W&W was worthwhile and effective. Larger comparative studies are needed in this group of pts.
Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.
Authors: Abdalla Ahmed , Aref Amr M. , Alame Amer , Ma Danny , Barawi Mohammed , Szpunar Susan , Lambert Karrah , Kafri Zyad
Published: May 2019

e15178

Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.
Utilization of surgery and its impact on survival in elderly patients with localized colon cancer in the United States.
Authors: Arjyal Lubina , Bista Amir , Ojelabi Michael Olayiwola
Published: May 2019

e15179

Background: For patients with localized colon cancer, surgical resection is the only curative treatment modality. Old age may be an independent factor associated with decreased receipt of surgery. We conducted this study to evaluate the utilization of surgery and its impact on survival in older patients with colon cancer in the United States. Methods: Surveillance, Epidemiology and End Results Database (SEER-18) was utilized to identify elderly patients (≥65 years) diagnosed from 2004-2013 with non-metastatic colon cancer (stage≤ III). Study population was divided into various cohorts based on race (Caucasian, African Americans, others), sex and age (< 80 years and ≥80 years), histology grade, tumor side, and stage. Multivariate logistic regression model was utilized to assess factors associated with receipt of surgery. Kaplan-Meier estimators with the log rank test was used to compare median overall survival (Md OS) between the surgery arm and non-surgery arm. Statistical significance was defined for p < 0.05. Results: Database identified 89,467 patients (54.7% female, 82.7% Caucasian; Median age 77 years). 94.6% (n = 84,656) of patients received surgery. On multivariate-analysis, left sided disease, lower grade tumor, lower stage, female gender, residents of lower median household income county, African Americans and age ≥80 years were less likely to receive surgery. The Md OS in the surgery arm was 87 months vs 69 months for non-surgery arm, p < 0.001. This benefit was seen in all the three stages (stage I: Md OS 104 vs 75 months; stage II: Md OS 88 vs 50 months; stage III: Md OS 74 vs 37 months, p < 0.001 for all comparisons). Additional analysis for octogenarians (age≥ 80 years) showed Md OS of 68 months in the surgery arm vs 48 months in the non-surgery arm, p < 0.001). Conclusions: Our study showed significant utilization of surgery (94.6%) in elderly patients with localized colon cancer. There is a clear survival benefit to surgery even in patients with age≥ 80 years. Surgical resection with curative intent should be strongly considered in patients with good performance status irrespective of age.
Role of tropomyosin 4 gene misregulation in colon epithelial cell tumorigenesis.
Authors: Son Mony Pheachnak , Papetti Michael
Published: May 2019

e15184

Background: Ordered migration of colon epithelial cells from the bottom to the top of the crypt is required for their differentiation. Because aberrant colon cell migration may contribute to early stages of colon tumorigenesis, elucidation of how this migration is regulated provides insight into how colon cancer can be prevented and treated before malignancy. Certain actin-binding tropomyosins, including tropomyosin 4 (TPM4), regulate cytoskeletal contractility and migration in many different cell types. Methods: To determine whether aberrant TPM4 regulation may be an early event in colon cell tumorigenesis, we measured TPM4 RNA expression in uninvolved, grossly normal colon tissue from 10 human familial adenomatous polyposis (FAP) patients genetically predisposed to colon cancer versus 7 patients not genetically predisposed (normal). We also examined TPM4 expression in a colon adenocarcinoma cell line (Caco2). These are highly proliferative, undifferentiated cells but can be induced to growth arrest and differentiate, thus acquiring many characteristics of normal absorptive colon epithelial cells. Reporter assays were used to identify sequences that regulate TPM4 gene expression in Caco2 cells. Results: Average TPM4 RNA expression is 2.59 fold higher in the FAP versus normal tissue. TPM4 RNA and protein are highly expressed in proliferating, undifferentiated Caco2 cells but are severely reduced in growth arrested, differentiated cells. Reporter assays have identified genetic regions, near the TPM4 transcriptional start site, that may regulate TPM4 gene expression in proliferating Caco2 cells. Conclusions: This data suggests that aberrantly upregulated TPM4 may be an early event in colon tumorigenesis and that normal TPM4 expression, by fostering ordered colon epithelial cell migration, may promote normal cell differentiation and mitigate adoption of a premalignant state.
Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.
Authors: Bossard Carine , Chiu Kevin , Chung Heekyung , Nguyen John Duc , Creger Emily , Eastman Brian , Mak Chi Ching , Do Long , Cho Shawn , KC Sunil , Phalen Timothy , Tambiah Jeyanesh , Cha Steven
Published: May 2019

e15185

Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P < .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P< .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).
Correlation of CHAF1A with adjuvant chemotherapy outcome and microsatellite instability in gastric cancer.
Authors: Wang Deqiang , Chen Deyu , Shen Bo , Chen Xiaofeng , Qi Martin , Li Xiaoqin , Shu Yongqian
Published: May 2019

e15511

Background: Clinical outcomes of adjuvant chemotherapy in gastric cancer (GC) have considerable stage-independent variability, which underscores the need for predictive molecular markers. Previous studies indicated that CHAF1A played a critical role in tumor growth, but whether it was associated with adjuvant chemotherapy in GC was still unknown. This retrospective study investigated the prognostic value of CHAF1A in adjuvant chemotherapy of GC. Methods: A total of 325 stage IB-III patients with fluoropyrimidines (FU)-based adjuvant chemotherapy after curative D2 gastrectomy meeting eligibility criteria were selected. CHAF1A protein expression was determined by immunohistochemical method. The primary outcomes were Overall survival (OS) and Disease-free survival (DFS). Kaplan-Meier method was used to estimate survival curve and Cox model for multifactor analysis. Results: CHAF1A mRNA was overexpressed in GC tissues and positive CHAF1A protein expression was not associated with OS and DFS in overall patients treated by FU-based chemotherapy ( P = 0.391 and 0.511, respectively). However, as stratified by tumor sites, positive CHAF1A expression was associated with poor OS and DFS in non-cardia cancer ( P = 0.009 and 0.007, respectively) but not in cardia cancer ( P = 0.229 and 0.112, respectively). Multivariate analysis indicated that CHAF1A expression level was still an independent predictor for both OS (HR = 2.42; 95% CI: 1.12-5.20; P = 0.024) and DFS (HR = 1.91; 95% CI: 1.03-3.54; P = 0.039) in non-cardia GC. Furthermore, CHAF1A was correlated with the status of microsatellite instability ( P = 0.025). Conclusions: CHAF1A might be a predictor for outcomes of FU-based adjuvant chemotherapy in patients with non-cardia GC, but needed further prospective studies to confirm.
Prognostic value and clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in resected gastric cancer: A meta-analysis.
Authors: Yu Shuixiu , Ning Jing , Ouyang Wei , Ding Lingzhi , Lin Kaisu , Qi Martin , Zhu Hong
Published: May 2019

e15512

Background: Programmed death ligand 1 (PD-L1) expression has become a promising biomarker in predicting the efficacy of immune checkpoint inhibitors in various advanced cancers, including gastric cancer (GC). However, the prognostic value and clinicopathological significance of PD-L1 in GC is still not clearly identified. Hence, we carried out a meta-analysis to investigate the potential role of PD-L1 in GC, expecting to provide new clues for the judgement of prognosis in resected gastric cancer. Methods: A literature search strategy was performed from the PubMed, Web of Science, EMBASE, and the Cochrane Library database as of December 1, 2018. Relevant data was rigorously extracted from the included literatures. Hazard ratios (HRs) and Odds ratios (ORs) along with 95% confidence intervals (95% CIs) were used to evaluate the prognostic value or clinicopathological significance of PD-L1 expression in GC. Results: A total of 21 studies containing 6021 patients fitted into our meta-analysis. The pooled HRs indicated that PD-L1 high-expression accompanied with a worse overall survival (OS) (HR=1.28, 95% CI: 1.01-1.62, P=0.04) in GC, while no correlation with disease-free survival (DFS) (HR=0.88, 95%CI: 0.53-1.45, P=0.61). Subgroup analysis showed that PD-L1 high-expression was negatively associated with distant metastasis groups (OR=0.66, 95%CI:0.48-0.89, P=0.01), but was positively related to elderly(OR=1.19, 95%CI: 1.01-1.40, P=0.04), lymph-node metastasis(OR=1.63, 95%CI: 1.08-2.46, P=0.02), deeper tumor infiltration(OR=1.73, 95%CI: 1.08-2.79, P=0.02), Epstein-Barr virus infection positive (EBV+) (OR=8.01, 95%CI: 3.10-20.72, P<0.0001), and MET positive (MET+) groups (OR=1.78, 95%CI: 1.05-3.00, P=0.03). Conclusions: Our meta-analysis found that the high-expression of PD-L1 accompanied with a poor OS. Moreover, PD-L1 high-expression was related to age, lymph-node metastasis, depth of infiltration, distant metastasis, EBV infection, and MET status.
Second-line treatment of metastatic gastric cancer in the era of predictive biomarkers: A cost-effectiveness analysis.
Authors: Lauren Brianna , Silver Elisabeth , Ingram Myles , Oh Aaron , Kumble Lindsay , Ostvar Sassan , Laszkowska Monika , Chu Jacqueline N. , Manji Gulam Abbas , Neugut Alfred I. , Hur Chin
Published: May 2019

e15517

Background: Gastric cancer is the third leading cause of cancer-related mortality, with only a 30% five-year survival rate. Patients who progress after one round of systemic therapy face an especially poor prognosis. The National Comprehensive Cancer Network guidelines include both pembrolizumab (PEM) and ramucirumab plus paclitaxel (RAM/PAC) as second-line (2L) therapy for gastric cancer based on data from the Phase II KEYNOTE-059 and Phase III RAINBOW trials, respectively. Recently, the Phase III KEYNOTE-061 trial reported on the effectiveness of PEM for patients with programmed death-ligand 1 (PD-L1) expression and high microsatellite instability (MSI-H). Given the high prices of targeted therapies, it is important to determine if cost-effectiveness is possible using personalized treatment strategies. The aim of this study was to assess the cost-effectiveness of these regimens in both the general patient population and specific biomarker populations. Methods: A decision-analytic (Markov) model was constructed using data from the KEYNOTE-059, KEYNOTE-061, RAINBOW, and REGARD trials. The analysis compared PEM and RAM/PAC for all patients, as well as PEM for patients based on MSI status or PD-L1 expression (combined positive score of 1% or 10%) in the 2L setting. Comparators were paclitaxel monotherapy (PAC) for all patients and best supportive care (BSC) for all patients. Costs (USD) and utility values were estimated from Medicare and the literature. The primary outcome was the incremental cost-effectiveness ratio (ICER) with a willingness-to-pay (WTP) threshold of $100,000. Results: The only cost-effective strategy was PAC monotherapy for all patients, with an ICER of $53,705/QALY. PEM for MSI-H patients and RAM/PAC for microsatellite stable patients was the most effective strategy (greatest QALYs), but was not cost-effective with an ICER of $1,074,620/QALY. Conclusions: Despite their effectiveness, PEM and RAM/PAC are not cost-effective as 2L treatments for metastatic gastric cancer. Although personalizing treatment based on biomarkers improved cost-effectiveness, the ICERs surpassed the WTP threshold at current drug prices.
Clinical efficacy and safety in gastric cancer patients treated with apatinib: A retrospective real-world study.
Authors: Li Ning , Du Yali , Deng Wenying , Ma Yijie , Yang Xinyi , Bie Liangyu , Wu Qiong , Yang Haiying , Luo Suxia
Published: May 2019

e15522

Background: This study aimed to explore the efficacy, safety of apatinib and analyze the effects of HER2 mutation status and treatment lines on gastric cancer (GC) patients (pts) treated with apatinib in real-world clinical practice. Methods: We retrospectively analyzed the study data from Linkdoc database with 270 pts who were pathologically or cytologically diagnosed GC and treated with apatinib during January 2015 to November 2018 in Henan Cancer Hospital. Survival was estimated by Kaplan-Meier method. Results: In this study, there were 180 (66.7%) male, with median age of 59 years. The vast majority of pts (259/95.9%) had adenocarcinoma and 86.3% of pts were in stage IV. HER2 was positive in 33.0% of 100 treated pts undergoing HER2 mutation testing. Apatinib was mainly used as second-line treatment (122/45.2%), followed by third-line (82/30.4%), first-line (56/20.7%), fourth- and further-line (22/8.1%), adjuvant (12/4.4%) and neoadjuvant treatment (1/0.4%). Pts received apatinib alone or combined with chemotherapy were 175 (64.8%) and 119 (44.1%), with 53.6% administered at an initial dose of 500 mg. Of all the 270 enrolled pts, the median progression free survival (mPFS) and median overall survival (mOS) were 4.3 months (95% CI: 3.5-5.0) and 6.1 months (95% CI: 5.1-8.4), respectively. For treatment lines subgroup, the mOS was 12.6 months (95% CI: 3.5-NE) in adjuvant treatment; 8.9 months (95% CI: 4.3-12.6) in first-line; 7.3 months (95% CI: 5.0-9.7) in second-line; 6.2 months (95% CI: 5.1-9.9) in third-line; 4.0 months (95% CI: 1.6-6.9) in fourth- and further-line treatment. For HER2-negative pts, the mOS was slightly longer than those of HER2-positive pts (5.7 months vs. 4.5 months), however, the difference was not statistically significant ( p = 0.5185). The most common adverse events were fatigue (25.9%), anemia (24.8%), hypertension (9.3%) and vomiting (9.3%). Conclusions: This real world study revealed that the clinical efficacy of apatinib in GC pts was satisfying and the toxicity was tolerable and controllable. Pts received apatinib in ≤ second-line treatment may gain better survival benefits, and little difference was found in survival outcomes between pts with or without HER2 mutations.
Distribution of urokinase-type plasminogen activator and its receptor in malignant tissues of gastric adenocarcinoma.
Authors: Kozlova Larisa S. , Kit Oleg I. , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S. , Kharagezov Dmitry A. , Milakin Anton G. , Gabrichidze Petr N.
Published: May 2019

e15530

Background: Peritoneal metastases are the most common recurrence of gastric cancer, even after radical surgery. Urokinase-type plasminogen activator (uPA) system, including its receptor uPAR, is crucial in the proteolysis activation for the cleavage of the extracellular matrix and basement membrane. The purpose of the study was to determine the antigen form uPA-Ag, active form uPA-act and the uPAR receptor in tissues of adenocarcinoma of the stomach, its perifocal tissues (PT), greater omentum and peritoneum in patients with stomach cancer T3-4аN0-3M1 and T3-4аN0-3M0. Methods: Tissues of patients with gastric adenocarcinoma T3-4аN0-3M1 (n = 21: 10 men, 11 women) and T3-4аN0-3M0 (n = 24: 15 men, 9 women) aged 61.23±4.8 years were studied. Controls: non-cancer patients aged 39.1±3.2 years (n = 17: 6 men, 11 women). Levels of uPA-act, uPA-Ag and uPAR were determined by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: In T3-4аN0-3M1, the highest uPAR levels were observed in tissues of the tumor, greater omentum and peritoneum, compared to T3-4аN0-3M0 and controls (p < 0.01). In PT of T3-4аN0-3M1, uPAR levels were lower than in tumor (p < 0.01) but higher than in resection line tissues. Tumor levels of uPA-act in T3-4аN0-3M1 and T3-4аN0-3M0 were similar and in both cases higher than in PT. In the greater omentum in T3-4аN0-3M1, uPA-act levels were similar to tumor levels and exceeded the values in T3-4аN0-3M0 (p < 0.01). Peritoneal uPA-act did not differ in T3-4аN0-3M1 and T3-4аN0-3M0 but was higher than in controls (p < 0.05). Tumor levels of uPA-Ag in T3-4аN0-3M1 exceeded the levels in T3-4аN0-3M0 and in both PT (p < 0.05). Levels of uPA-Ag in the greater omentum in T3-4аN0-3M1 were higher than in T3-4аN0-3M0 and lower than in controls (p < 0.01). Comparable uPA-Ag levels in T3-4аN0-3M1 and T3-4аN0-3M0 were lower than in controls (p < 0.01). Conclusions: Gastric adenocarcinoma secretes uPAR and uPA, and uPAR levels in the tumor are associated with omental or peritoneal metastases. Levels of uPAR and uPA-act in the greater omentum and peritoneum in T3-4аN0-3M1 are increased even higher than in T3-4аN0-3M0; uPAR can serve as a marker of a pre-metastatic niche in peritoneal tissues.
tPA and PAI-1 in malignant tissues of gastric adenocarcinoma can be tumor-associated.
Authors: Samoylenko Nikolay S. , Kit Oleg I. , Frantsiyants Elena M. , Kozlova Larisa S. , Soldatkina Natalya V. , Tumanyan Sergey V. , Gevorkyan Yuriy A. , Aleynov V. I. , Milakin Anton G. , Poluektov Sergey I. , Duritskiy Maksim N.
Published: May 2019

e15533

Background: Plasminogen regulator system is considered to be involved in migration, invasion and proliferation of malignant cells. The role of tissue plasminogen activator (tPA) and PAI-1 in cancer is still discussed. Our purpose was to study the antigen and active forms of tPA and PAI-1 (tPA-Ag, tPA-act and PAI-1-Ag, PAI-1-act) in tissues of gastric adenocarcinoma (GA), greater omentum and peritoneum with and without metastases (mts). Methods: We studied tissues of patients with GA T3-4аN0-3M1 (n = 21, 10 men, 11 women) and T3-4аN0-3M0 (n = 24, 15 men, 9 women) aged 61.23±4.8 years. Control group included 17 non-cancer patients aged 39.1±3.2 years (6 men, 11 women). Levels of tPA-act, tPA-Ag, PAI-1-act and PAI-1-Ag were measured by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: Levels of both forms of tPA and PAI-1 in GA with and without mts were 1-2 orders of magnitude higher than in resection line tissues. Levels of tPA-Ag and PAI-1-Ag in GA without mts were 1.7 and 2.5 times higher than in GA with mts, while levels of tPA-act and PAI-1-act were similar. In tissues of the greater omentum, levels of tPA-Ag with mts exceeded that in tissues without mts and in controls by 5.0 and 1.7 times, respectively; levels of tPA-act were similar to controls, while without mts they were 1.6 times lower than in controls. PAI-1-Ag with mts was 3.2 and 4.5 without mts and in controls, respectively; PAI-1-act with mts was 1.8 and 1.5 times higher than in controls and without mts, respectively. In tissues of the peritoneum, tPA-Ag with mts was 1.6 and 1.4 times higher than without mts and in controls, respectively; tPA-act with and without mts was 1.4 (p = 0.0412) and 1.5 times lower than in controls. PAI-1-Ag in the peritoneum with and without mts 1.4 times (p = 0.0428) exceeded control, and PAI-1-act was higher than in controls by 1.6 and 2.8 times, respectively. The results demonstrated that GA with and without mts secreted PAI-1 and tPA, and levels of tPA-Ag and both forms of PAI-1 were elevated in tissues of the peritoneum and omentum with and without mts. Conclusions: Levels of tPA-Ag and both forms of PAI-1 in the greater omentum and peritoneum without mts indicate possible formation of a pre-metastatic niche.
Prevalence of esophageal malignant and premalignant lesions in a Michigan cohort, 2013-2017.
Authors: Tatineni Shilpa , Nemakayala Divyesh Reddy , Enofe Ikponmwosa , Wang Ling , Laird-Fick Heather
Published: May 2019

e15541

Background: Esophageal cancer is diagnosed in roughly 4 per 100,000 US population. Older men are most frequently affected. Adenocarcinoma is most common and incidence is increasing. EGD with biopsy is important for diagnosis. Many patients present with metastases, limiting treatment options. EGD can identify Barrett’s esophagus, a precursor lesion for adenocarcinoma, but evaluation of biopsy specimens is difficult. This study describes findings from esophageal biopsies in a large community-based Michigan cohort. Methods: Patients aged ≥18 years undergoing EGD with esophageal biopsies in Sparrow Health System were identified. Pathology reports were abstracted for sociodemographics, procedure information, and pathologic findings. Only patients with complete data were included for analysis. Statistical comparisons were assessed by chi-square tests or Fisher’s exact test in contingency tables for categorical variables, or t-tests for continuous variables as appropriate. Results: 4,471 patients were included. 3,279 (73.3%) had benign findings, 1,117 (25%) premalignant changes, 69 (1.54%) malignancy including adenocarcinoma, poorly differentiated cancer or high-grade dysplasia, 1 (0.022%) squamous cell cancer, and 5 (0.11%) neuroendocrine tumors. The latter six were excluded from analyses.Most procedures were performed for inpatients (70.5% for benign, 72.5% malignant and 76.3% pre-malignant; p< 0.001 for all comparisons). Patients with malignancy were older than those with premalignancy [mean 69.8 (SD = 10.4) vs 62.6 (SD = 12.2) years; p< 0.001], who were older than those with benign findings [62.6 (SD = 12.2) vs 56.2 (SD = 14.7) years; p< 0.001]. Patients with premalignancy came from areas with higher average household incomes ($42,179 vs $41,247; p< 0.01). There were no other socioeconomic or sex differences between groups. Conclusions: In a community sample, esophageal malignancy was uncommon but premalignant changes common. Most procedures occurred during hospitalizations. Ensuring appropriate post-discharge follow up for premalignant changes could be challenging. Association between premalignant changes and higher average household income is intriguing and merits additional study.
The ratio of negative lymph node count inside the thoracic cavity to the positive lymph count is a prognostic factor in esophageal squamous cell carcinoma.
Authors: Zhang Jinling , Heng Xueyuan , Che Fengyuan
Published: May 2019

e15545

Background: It was reported that the number of positive lymph nodes (PLN) and negative lymph nodes (NLN) resected in lymphadenectomy were both independent prognostic factors in esophageal squamous cell carcinoma (ESCC). However, it is unclear which kind of combination of them would have a stronger impact on the prognosis of the ESCC patients. Methods: A total of 229 patients with ESCC were retrospectively investigated. The Cox Proportional Hazards Model was used to investigate the relationship between the PLN or NLN and the overall survival of patients. Survival analysis was performed using the Kaplan-Meier method, and the survival difference between sub-groups were explored with log-rank tests. The cut-off number of the ratio of NLN count to PLN count resulted in an improved outcome for patients was investigated by a series of log-rank tests. Results: The numbers of PLN and NLN were both independent prognostic factors, supported by the results of Cox regression model analysis (hazard ratio [HR], 1.12, P < 0.001 and HR, 0.97, P = 0.024, respectively).The survival differences among sub-groups from N0 to N3 stage were statistically significant (P < 0.001). Analysis using a Cox regression model revealed that the number of NLN inside the thoracic cavity had a stronger impact on the prognosis compared to the number of NLN outside the thoracic cavity (HR,0.959, P = 0.042 vs.HR, 0.973, P = 0.179). As a combination analysis consisting of the number of PLN and NLN, the log-rank test result demonstrated that patients with the ratio of NLN count inside thoracic cavity to the PLN count less than 8 could achieve a better survival. Conclusions: The ratio of NLN count inside thoracic cavity to the PLN count was a independent prognostic factor.