bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of adipose tissue distribution and metabolic activity in PET-CT images of patients with metastatic colorectal cancer.
Authors: Karacelik Tuba , Kaya Bugra , Karaagac Mustafa , Araz Murat , Karakurt Eryılmaz Melek , Bozcuk Hakan Sat , Artac Mehmet
Published: May 2020

e16038

Background: The metabolic activity in visceral and subcutaneous adipose tissue have different metabolic risk profiles for colorectal cancer. The aim of this study was to investigate the prognostic significance of adipose tıssue distribution and metabolic activity in PET-CT and predict the overall survival in patients with metastatic colorectal cancer (mCRC). Methods: A total of 83 patients diagnosed with mCRC between 2010-2018 were evaluated retrospectively. Pretreatment PET-CT images were reevaluated to determine adipose tissue distribution and metabolic activity. Volume and metabolic activity of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on FDG PET-CT images were measured. SAT volume, SAT density (HU), SAT ratio (SAT volume/ SAT density) were calculated. The maximum standardized uptake (SUV) of tumor tissue was measured. The relationship between adipose tissue and overall survival was examined. Results: 53 patients died during follow-up and the median overall survival was 33.76 months (95% CI: 28.185-39.349). According to univariate analysis results, tumor location (HR:2.5; 95% CI 1.27-4.98, p = 0.008) and SAT ratio (HR:0.5; 95% CI 0.34-1.00, p = 0.053) were the significant parameters for the OAS. VAT volume (p = 0.774), VAT density (p = 0.899), VAT suv mean (p = 0.831) and SAT volume (p = 0.423), SAT density (p = 0.353), SAT suv mean (p = 0.575), tumor suv max (p = 0.589) values were not correlated with OAS. In the multivariate analysis, SAT ratio (p = 0.011) and tumor location (p = 0.001) were correlated significantly with OAS. The median OAS for the patients with SAT ratio value < -1.1 and -1.1 were 38.5 (95% CI 31.54-45.58) and 24.5 (95% CI 14.13-34.93) months, respectively (p = 0.05). Conclusions: This study showed that SAT ratio was an independent prognostic factor for OAS in patients with mCRC. We need prospective studies for to observe the relationship between adipose tissue distribution and response to treatment in mCRC.
Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: A prospective, multicenter, open-label, single arm phase II study.
Authors: Kato Takeshi , Ikeda Masataka , Ikeda Atsuyo , Hasegawa Junichi , Ota Hirofumi , Shingai Tatsushi , Yasui Masayoshi , Fujii Hitoshi , Miyake Yasuhiro , Uemura Mamoru , Matsuda Chu , Satoh Taroh , Mizushima Tsunekazu , Doki Yuichiro , Eguchi Hidetoshi
Published: May 2020

e16039

Background: Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods: We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stages II and III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2,000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results: Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions: Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides good 3-year DFS prospects.And this is probably the first and last report in the world for such cases. Trial registration: This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.
Evaluation of molecular pathogenesis of colon cancer in Kerala using high-throughput expression, signaling pathways, and network analyses.
Authors: Ariyannur Prasanth , Keechilat Pavithran , Paulose Roopa , Vasudevan Damodaran M
Published: May 2020

e16065

Background: The molecular pathogenesis of colon adenocarcinoma (COAD) is attributed to large molecular changes such as Chromosomal Instability and high somatic copy number variation or defective DNA mismatch repair and consequent microsatellite instability (MSI). The prevalence of this type of cancer is increasing in the state of Kerala, India. A detailed study of the signaling pathways could lead to a better understanding of the central molecular pathological changes and potential biomarkers particular to this population. Methods: High throughput somatic expression analysis using Nanostring PanCancer pathway panel assay was performed. Differentially expressed (DE) genes were selected and KEGG pathway enrichment analysis was performed for assessment of canonical signaling pathways. Expression profiles were compared against the public database, Colon Adenocarcinoma cohort of the Cancer Genome Atlas (TCGA-COAD), using the Genome Expression Profiling Interactive Analysis (GEPIA). Protein-protein interaction network analysis was done using Cytoscape. DE genes were compared against immune cell infiltration in the TCGA-COAD from Tumor Immune Estimation Resource (TIMER) databases. Results: Nanostring assay was performed in 10 Tumor-Normal paired FFPE samples of stage II/III colon adenocarcinoma. Out of > 700 genes, significant difference in expression was found in 83 genes (FDR adjusted p -value < 0.01) with fold-change |fc(log2)| of at least one. Fold-change |fc(log2)| ≥ 2 was found in 19/83 genes. Network analysis clustered 13 out of 17 upregulated genes. Superimposition of the current data on TCGA study showed that among the three genes, four (MET, MCM2, ETV4 and MMP7), were common. DE Genes which were not significant in TCGA COAD study such as INHBA, COL1A1, COL11A1, COMP, SFRP4, SPP1, IL11, LIF, WT1 and DDIT4, were found to be significant in the current study. A few of the unique genes identified in the current study were found to have significant correlation with antigen presenting cells infiltration in the TCGA-COAD studies. Conclusions: Many DE genes from the study population were found to be different from previous large cohort studies in other population. This may suggest a different pathogenesis of COAD in this population, warranting a detailed study on the pathogenesis.
Hsa-miR-196a2 Rs 11614913 C>T polymorphism and CRC susceptibility: A case-control study.
Authors: Chen Li-zhu , Chen Yu , Tang Wei-feng , Chen Lin , Lin Jin , Guo Zeng-qing , Huang Yufang , Xia Xuefeng
Published: May 2020

e16066

Background: The incidence and mortality rate of Colorectal cancer (CRC) is high worldwide. Many genetic studies have suggested that single nucleotide polymorphisms (SNPS) in genes encoding small molecule RNAs were associated with CRC risk, but the results were different in different studies. In our study, we investigated the general demographic characteristics and the relationship of hsa-mir-196a2 rs11614913 C > T polymorphism and CRC susceptibility in Chinese CRC. Methods: Our study included 1,003 CRC patients and 1,303 controls. Restriction fragment length polymorphism (RFLP-PCR) method was used for genotyping and SAS version 9.4 software for statistical analysis. Results: The incidence of smoking status,alcohol use and BMI in the CRC group (25.82%,17.35%,66.80%) were much higher than that in the control subjects (20.34%,10.44%,52.80%) respectively(P < 0.05). After adjusting age and other factors, hsa-mir-196a2 rs11614913 C > T genotypes were not statistically correlated with CRC risk and tumor location.But the TT genotype in the hsa-mir-196a2 rs11614913 C > T polymorphism reduced the risk of CRC in women (OR = 0.64, 95 CI: 0.42-0.97, P = 0.036). Conclusions: Smoking status,alcohol use and BMI may be main risk factors for CRC development in our study population.The polymorphism of hsa-mir-196a2 rs11614913 C > T gene may affect the risk of CRC in women, which requires further investigation in a larger cohort in the future.
Rural and urban disparities based on zip code of residence: Analyses of 834 and 2,159 patients in NCCTG N9741 and CALGB 80405 (Alliance) trials respectively.
Authors: Malla Midhun , Huebner Lucas J. , Piawah Sorbarikor , Lenz Heinz-Josef , Blanke Charles David , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary , Shi Qian , Venook Alan P. , Goldberg Richard M.
Published: May 2020

e16076

Background: Median overall survival (mOS) of patients (pt) with metastatic colorectal cancer (mCRC) has improved steadily over the past two decades. However, epidemiological data suggest that cancer outcomes for rural compared to urban dwelling pts are worse. In this study, we retrospectively compared progression free survival (PFS) and OS among mCRC pts residing in urban versus rural areas enrolled in N9741 (1997-2004) and CALGB 80405 (2005-2012) clinical trials. Methods: Zip code data from the Centers for Disease Control (CDC) were used to classify pts into rural or urban dwellers. Chi-square and Kruskal Wallis analyses were used to compare the groups. Survival outcomes were evaluated using Kaplan-Meier estimates, compared by stratified log rank and cox proportional hazards models. Results: In N9741 and 80405 respectively, 217 (35%) and 521 (21%) pts resided in rural areas. Median age of mCRC pts at diagnosis was 60.5 yrs. (rural) compared to 58.6 yrs. (urban) in 80405 (P < 0.01) and 59.6 yrs. to 60.2 yrs. in N9741 (P = 0.4). In 80405, pts in rural areas were less likely to be female (35% vs 43%, P < 0.01) black (6.6% vs 15.1%, P < 0.01), unmarried (51% vs 62%, P < 0.01), and to have private insurance (PI) (45% vs 50%, P = 0.03) when compared to pts in urban areas. In N9741, gender (P = 0.8) and PI (P = 0.3) distribution was similar; pts in rural areas were less likely to be black (1.4% vs 9.1%, P < 0.01). Rural vs urban pt PFS was no different in either trial. MOS was worse in pts in rural areas when compared to urban dwellers in 80405 (Table). OS outcomes stratified based on the use of cetuximab based regimen in 80405 showed worse outcomes for pts in rural compared to urban dwellers (21.9 vs 26.3 mo. HR: 1.22 (1.03-1.44), P = 0.02). Conclusions: MCRC pts from rural areas had a significantly worse mOS when compared to pts in urban areas in 80405. Furthermore, mOS with cetuximab based regimens was 4.4 months shorter in rural pts. The observed rural vs urban dweller mOS disparities in 80405 pts justifies additional research searching for causal factors and the necessity to identify actionable approaches in order to improve pt outcomes in rural areas. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA180830; Pfizer, Sanofi, BMS, Genentech, https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00003594, NCT00265850. [Table: see text]
Correlation of LINE-1 hypomethylation with size and dysplasia in colorectal tubular adenomas, and risk for synchronous and metachronous CRC.
Authors: Jiang Alice , Sutherland Stephanie , Buckingham Lela , Melson Joshua
Published: May 2020

e16083

Background: Conventional adenomas (tubular or tubulovillous adenoma; TA) are frequently detected in patients undergoing average risk screening colonoscopy. Risk stratification of adenomas is currently limited to histologic features and size. Molecular features of TA could help further determine risk for development of CRC. Here, we report whether size of TA, high grade dysplasia, and synchronous or metachronous CRC associate with LINE-1 methylation. Methods: LINE-1 methylation was assessed by pyrosequencing of bisulfite-converted DNA. We compared LINE-1 methylation in TA among varying sizes, in the presence of high or low grade dysplasia, and between patients with synchronous and metachronous colorectal cancer. Results: LINE-1 methlyation was found to progressively decrease in TA of increasing size and with high grade dysplasia. TA < 5mm in size (n = 45) had higher LINE-1 methylation levels compared to TA 5-9mm in size (n = 42), and > = 10mm (n = 32) (72.31 ± 6.11 vs 67.50 ± 7.00 vs 66.75 ± 11.89, p = 0.013). TA with high grade dysplasia (n = 26) had lower LINE-1 methylation levels compared to low grade dysplasia (n = 135) (59.86±7.93 vs 67.16±9.20, p < 0.001). Tumor tissue (n = 36) had the lowest levels of LINE-1 methylation at 50.36±8.40. There were lower levels of LINE-1 methylation in TA of patients with synchronous CRC compared to those without (53.07+4.5 vs 59.95+5.4 vs, p < 0.001). LINE-1 methylation was lower in normal tissue from cancer patients compared to that from patients without any neoplasia (50.36 ± 8.40 vs 71.50 ±6.47, p < 0.001). LINE-1 methylation levels were higher in patients with initial low risk TA who developed metachronous high risk TA (n = 31) compared to those who did not (n = 35) (75.78±2.45 vs 64.84±4.58, p = 0.001). LINE-1 methylation levels were not different in patients with initial TA who developed metachronous CRC (n = 2) compared to those who did not (n = 89) (70.00±5.65 vs 66.85±8.20, p = 0.69). Conclusions: High-grade dysplasia and increasing size of conventional TA were associated with greater LINE-1 hypomethylation. This is supportive of a hypothesis that greater LINE-1 hypomethylation of tubular adenomas indicates advancement along the CRC tumorigenesis pathway. Greater LINE-1 hypomethylation in TA was also seen in patients with synchronous CRC compared to those without, though no difference was found in those who developed metachronous CRC. Higher LINE-1 methylation was seen in patients with initial low risk TA, who developed metachronous high risk TA compared to those who did not.
Outcomes of rectal cancer patients treated using Polish II neoadjuvant short course radiation therapy and chemotherapy approach in comprehensive cancer center.
Authors: Haff Stephen , Kazmi Syed Mohammad Ali , Sanford Nina Niu , Aguilera Todd Anthony , Beg Muhammad Shaalan , Farkas Linda , Anandam-Matthews Joselin , Salgado Pogacnik Javier , Cheedella Naga , Karri Sirisha , Kainthla Radhika , Jones Amy Little , Verma Udit , Sanjeevaiah Aravind , Folkert Michael Ryan
Published: May 2020

e16088

Background: Neoadjuvant short-course (SC) radiation (RT) followed by fluoropyrimidine based chemotherapy prior to surgery (Polish II approach) is a less utilized treatment in the United States for rectal cancer. Based on data suggesting equivalent or improved outcomes at lower cost compared to the long course neoadjuvant chemoradiation, our team started utilizing this approach for rectal cancer management at Simmons Comprehensive Cancer Center. We aim to document our experience with Polish II approach at NCI-designated comprehensive cancer center program. Methods: A retrospective review of stage I-IV rectal cancer patients, seen at an academic center or the Dallas County safety net hospital and treated at Simmons Comprehensive Cancer Center from Nov 2017 to Dec 2019. Patients were treated with neoadjuvant SC-RT followed by 3 cycles of FOLFOX prior to surgery and followed by adjuvant FOLFOX. Descriptive data for demographic, radiation, chemotherapy and surgery, hospitalizations, 30 day post-surgery admission, time to relapse, and laboratory parameters was collected. Results: Thirty-nine patients met the inclusion criteria (average age 58 years; 74% men/26% women). Forty-six percent of patients were Hispanic, 28.2% White, 15.4% African American and 7.7% Asian. The majority of patients had stage IIIB (46.2%), followed by IIIC (17.9%), IIA (12.8%), IIIA (7.7%), while rest were stage I, IVA or unknown (5.1%). All patients received 5 x 5 SC-RT, 100% completed 3 cycles of planned neoadjuvant FOLFOX (12.8% received 4-8 cycles) and 36/39 (92%) of patients underwent planned surgery. Median duration from SC-RT to chemotherapy was 12 days, and from chemotherapy to surgery was 37 days. Hospitalization occurred in 3 patients (7.7%) during neoadjuvant therapy, and in 8 patients (20.5%) within 30 days post-surgery. Complete pathological response was seen in 6 patients (16.6%) and near-complete pathological response in 3 patients (8.3%). Relapse occurred in 10.3% patients at time of data acquisition. Grade 3 and 4 neutropenia, anemia, and thrombocytopenia in neoadjuvant phase was observed in 8.6%, 25.7%, and 2.8% patients, respectively. Conclusions: In rectal cancer patients treated at a comprehensive cancer center, neoadjuvant Polish-II approach was feasible and well tolerated. Pathological response rates were comparable to historical data. SC-RT based neo-adjuvant therapy approach should be favored due to lower pelvic radiation dose, tolerance and convenience to patients.
Multigene mutation signatures in colorectal cancer patients: Predict for the diagnosis, pathological classification, staging and prognosis.
Authors: Zhuang Yan , Wang Hailong , Jiang Da , Li Ying , Tian Caijuan , Xu Zanmei , Su Meina , Wang Xiaowei , Zhang Jiangyan , Hu Yuanjing , Liu Pengfei
Published: May 2020

e16113

Background: Like most cancers, early diagnosis of colorectal cancer (CRC) contributes to a good prognosis. Recently, some studies indicated that mutation gene signatures have good performances in predicting the treatment and prognosis in CRC patients. However, incomplete understanding of the genotype is not conducive to proper treatment. The objective was to give further genetic insights into CRC and provide more comprehensive references for clinical practice. Methods: In the training group, the whole genome sequencing (WGS), clinical, and demographic data of 531 patients were downloaded from The Cancer Genome Atlas (TCGA). The validation group contained 53 patients, which were collected in Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) from April 2014 to November 2018. The fresh tissues collected within 24 hours after operation were used to extract genomic DNA, and then sequenced with targeted next-generation sequencing (NGS) technology to examine somatic mutations and analyze relevant gene concerning clinical indicators. The correlation between gene variation distribution and various indexes such as cancer species, stage, total survival period, sex, age and race were evaluated. Results: A total of 44 mutant genes with mutation frequencies above 5% were found in both TCGA cases and validated cases. Mutations of TP53, APC, KRAS, BRAF and ATM covered 97.55% of TCGA population and 83.02% validation patients, which were proved to be associated with the development of CRC and could be used as a diagnostic signature. Importantly, mutations of TP53, PIK3CA, FAT4, FMN2 and TRRAP had a remarkable difference between early (I/II) and advanced (III/IV) stage patients (P < 0.0001). Besides, we also confirmed that PIK3CA, LRP1B, FAT4 and ROS1 were a mutated gene signature for the prognosis, LRP1B portended to a higher of recurrence and shorter progression-free survival (PFS); mutation of FAT4 portended to a lower of recurrence and longer PFS, which could predict the recurrence and survival of CRC patients. Conclusions: We have indicated gene mutation signatures related to the diagnosis, pathological classification, staging and prognosis in CRC, which provides further insights into the study of CRC genotype. It is helpful to further improve the personalized diagnosis and treatment.
Prognostic value of De Ritis ratio (aspartate transaminase/alanine transaminase) in patients with non-metastatic colorectal carcinoma [izmir oncology group(IZOG) study].
Authors: Oflazoglu Utku , Insan Temmuz Gurdal , Kucukzeybek Yuksel , Varol Umut , Salman Tarik , Yildiz Yasar , Saray Seray , Butun Osman , Taskaynatan Halil , Bolat Kucukzeybek Betul , Alacacioglu Ahmet
Published: May 2020

e16114

Background: We aimed to assess the prognostic effect of preoperative De Ritis (aspartate aminotransaminase/Alanine aminotransaminase) ratio and pathological variables to find out whether it is an independent prognostic factor in patients with non-metastatic CRC. Methods: We retrospectively evaluated the patients who underwent curative surgery for non-metastatic CRC between 2006 and 2017. The potential prognostic value of De Ritis ratio was assessed by using a ROC curve analysis. The effect of the De Ritis ratio was analyzed by the Kaplan–Meier method and Cox regression hazard models for patients’ disease-free survival (DFS) and overall survival (OS). Results: We had 921 CRC patients in total. The univariate analysis demonstrated that low De-Ritis ratio and several well-established prognostic factors, including well-differentiated tumor,negative lymph node involvement, lymphatic invasion, perineural invasion and surgical margin, left tumor localization and early-stage tumor were good prognostic factors in terms of DFS and OS. On the multivariate analysis, De-Ritis ratio, lymph node involvement, perineural invasion status, surgical margin statusand tumor localization were independent prognostic factors for DFS [ De-Ritis ratio HR 0.468, 95% CI 0.358-0.613,p < 0.001]. We also found that De-Ritis ratio, degree of differentiation, lymphatic invasion status, perineural invasion statusand stage were independent prognostic factors for OS on multivariate analysis [ De-Ritis ratio HR 0.354, 95% CI 0.407-0.702, p < 0.001]. Conclusions: Our study first established a connection between the preoperative De-Ritis ratio and patients undergoing curative resection for non-metastatic colorectal cancer, suggesting that De-Ritis ratio was a simple, inexpensive, and easily measurable marker as a prognostic factor and may help to identify high-risk patients for treatment decisions.
Prognostic role of macrophage infiltration and monocyte-to-lymphocyte ratio in stage III colon cancer: The MIRROR study.
Authors: Basile Debora , Polano Maurizio , Buriolla Silvia , Gallois Claire , Cortiula Francesco , Corvaja Carla , de Scordilli Marco , Michelotti Anna , Parnofiello Annamaria , Gerratana Lorenzo , Ongaro Elena , Andreuzzi Eva , Toffoli Giuseppe , Buonadonna Angela , Mongiat Maurizio , Zaanan Aziz , Aprile Giuseppe , Canzonieri Vincenzo , Taieb Julien , Puglisi Fabio
Published: May 2020

e16118

Background: Changes in peripheral blood cells composition may reflect immune microenvironment and its role in cancer growth. High monocyte-to-lymphocyte ratio (MLR) could be a marker of tumor’s recruitment of suppressive cells, showing a prognostic role. This study aimed to assess the prognostic impact of macrophage infiltration and MLR in stage III colon cancer (CC) patients (pts). Methods: This multicentric study retrospectively analyzed a consecutive cohort of 423 CC pts treated between 2008-2019 at the Cancer Centre of Aviano (Italy) (n = 300) and at the European Georges Pompidou Hospital of Paris (France) (n = 123). The association of MLR with disease-free survival (DFS) and overall survival (OS) was evaluated with Cox regression analyses. Random Forrest was implemented on python using h2oai. Performance was assessed in terms of accuracy (ACC) and Matthews Coefficient (MCC). Analyses was adjusted on classical prognostic factors of stage III CC such as pT, pN, grade, location, ECOG PS. Results: Overall, 77% had pT1-3, 30% pN2 and 73% G1-2 tumors. Interestingly, 25% had a lymphatic and vascular invasion, 42/230 (18%) had MSI status, 69/152(45%) and 19/114 (13%) were KRAS and BRAF mutant. 56% had CEA > 5. Pts were treated with fluoropyrimidine and oxaliplatin as adjuvant therapy. Notably, 130 cases were analyzed according to lymphocytic and macrophage infiltration (CD163, CD68, CD3, CD8). Of them, 78% had a CD163/CD8 ratio ≤3 and 74% a CD8/CD3 ratio ≤1.5. At median follow-up of 57 months, median DFS and OS were not reached, 31% of pts relapsed and 23% dead. By multivariate analysis, including statistically significant prognostic variables, CD163/CD8 ratio (HR 1.15, p = 0.039, 95%C.I. 1.1-1.32) and MLR > 0.45 (HR 2.98, p = 0.008, 95%C.I. 1.33-6.67) were associated with worse DFS. By multivariate analysis for OS, including statistically significant confounding variables, MLR > 0.45 (HR4.32, P = 0.012, 95%C.I. 1.37-9) and BRAF mutation predicted worse OS. According random survival forest for OS, CD68/CD3 were the first variable of importance (0.06), followed by MLR (0.009) and CD8 (0.007). Interestingly, high MLR followed by CEA, MSI, KRAS were the features linked with organotropism on liver (ACC 0.6 ±0.3), while high MLR, KRAS, pN, pT were mainly linked with lung colonization (ACC 0.6 ±0.2). Conclusions: High pre-treatment levels of MLR and CD163/CD8 ratio in stage III CC are independently associated with worse prognosis. The present study paves the way to a prospective validation of these promising cost-effective biomarkers.
Metastatic lymph node ratio as better prognostic tool than TNM system in colorectal cancer.
Authors: Macedo Filipa , Sequeira Hugo , Ladeira Katia , Bonito Nuno , Viana Charlene , Martins Sandra
Published: May 2020

e16128

Background: Colorectal cancer (CRC) is the third leading cause of cancer death in the world. Lymph node metastasis is an important prognostic factor; however, the minimum number of lymph nodes that should be evaluated for adequately categorizing lymph node status is still a controversial theme. The TNM staging system has limitations in defining the pN category. The lymph node ratio (LNR) may be a better prognostic indicator. Objectives: Evaluate the impact on the prognosis of patients operated for CRC, comparing the LNR with the pN category of TNM system. Methods: We studied 1065 patients treated at a General Surgery Department from 01/01/2000 to 08/31/2012. The LNR was separated into 5 categories based on three previously calculated cut-off values: LNR0 (0), LNR1 (0.01-0.17), LNR2 (0.18- 0.41), LNR3 (0.42-0.69) and LNR4 (≥0.70). Results: The results of the univariate analysis indicated significant differences in survival according to age (p < 0.001), tumor size (p < 0.001), serosal invasion (p < 0.001), histological type (p = 0.002), differentiation (p < 0.001), pT (p < 0.001), pN (p < 0.001), LNR (p < 0.001), M (p = 0.001), TNM stage (p < 0.001), venous invasion (p < 0.001). Multivariate analysis confirmed the LRN, pN, age, venous invasion and pT as independent prognostic factors. The survival analysis showed significant differences between the categories of pN (p < .001) and LNR (p < .001). Spearman correlation analysis showed a significant correlation between the total number of dissected lymph nodes and the number of metastatic lymph nodes (rs = 0.167, p < 0.001). The total number of dissected lymph nodes is not significantly correlated with LNR (rs = -0.019, p = 0.550). Conclusions: In this study LNR seems to demonstrate a superior prognostic value when compared to the pN categories, in part due to its greater independence regarding the extent of lymphadenectomy.
Organ index of immunological and anti-tumor effect of intratumor injection of penicillin sodium combined with chemotherapy drug for tumor-bearing mice.
Authors: Fu Qiang , Han Yan , Li Bian , Zhang Jian , Chen Dong , Zhao Ming , Zheng Guoqin , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc.
Published: May 2020

e16134

Background: To observe the antitumor mechanism of penicillin combined with chemotherapy drugs in tumor-bearing mice. Methods: The H22 experimental tumors were randomly divided into groups when the longest diameter of the tumor reached about 4 to 7 mm. First and the second administration was performed every 7 days. Perform a skin test and observe the local response. There were 22 mice in each group, male and female. The No. 1 to No. 3 of each group of male and female are used for pharmacodynamic experiments and executed by cervical dislocation on the 13th day. The tumor tissue is removed, weighed, and the tumor growth inhibition rate is calculated. Thymus and spleen, calculate the thymus and spleen coefficients. The male and female Nos. 4 to 8 of each group was used for survival experiments. The death time of the mice was observed and recorded. And 9 to 11 mice from the male and female mice in each dose group of penicillin were taken for skin test, and the skin test response was recorded; the 4th day after the second administration (the 12th day of the experiment) the 9th to 11th of each group No. is used for the tumor formation time experiment of the contralateral tumor. The tumor formation time of the mice is observed and recorded. Results: (1) Comparison with body weight. Sustained-release chemotherapeutic agents of penicillin sustained-release medicines by hydrogen peroxide can cause less damage to mice. (2) Compared with tumor volume and tumor inhibition rate, the compound group (I-Ⅵ) could significantly inhibit tumor growth in mice after intratumoral injection, but penicillin and DNP had no obvious tumor inhibition after intratumoral injection. (3) The comparison of thymus coefficients shows that the adjuvant can obviously prevent the damage to the thymus caused by the drug and has a certain protective effect on the thymus which is very important organ for immune systems. Comparison of survival time, the survival rate and average survival time of the compound Ⅱ group were higher than those of other compound groups. Conclusions: Based on the efficacy and survival results, this intratumoral injection with penicillin could increase organ index for spleen and thymus and indicated it could increase immunological response to against whole body cancer cell.
Blockade of TRIM59 to enhance chemosensitivity of esophageal cancer cell to cisplatin by upregulating p53 expression.
Authors: Liu Rong Feng , Shi Jian , Duan Xiaoyang
Published: May 2020

e16509

Background: TRIM59 is the one of TRIM family characterized by an N-terminal really interesting new gene (RING)-finger domain, followed by two zinc-finger domains named B2 box and a coiled-coil (CC). Ubiquitination plays a vital role in the degradation of many kinds of proteins that function in the intracellular signaling pathway, cell cycle, DNA repair and transcriptional regulation. Because of the RING-finger domain, TRIM59 protein functions as E3 ubiquitin ligase activity and can selectively target ubiquitin-modified proteins for proteasomes or degradation. In additional, accumulating finding results have shown the TRIM proteins promote positively or negatively carcinogenesis. Here we focus on the TRIM59 protein: oncogenic activity in the promoting proliferation and metastasis of esophageal cancer cell. Methods: None. Results: Human esophageal cancer cells’ motility adopts various modes resulting in the HESC progression and poor survival of patients. We proved that TRIM59 is aberrantly up-regulated in metastatic human esophageal cancer (hESC) than adjacent normal esophageal tissue, which is on behalf of poor survival and advanced TNM state among the hESC patients. At the molecular level, we proved TRIM59 as an E3 putative ubiquitin ligase targets the p53 protein leading to the increased degradation of p53 resulting in the less chemotherapy sensitivity to cisplatin. TRIM59 knockdown in hESC cell lines reduced TRIM59 expression and promotes p53 protein level and decreased the proliferation, clone formation, migration. At the same time, hESC cell lines showed more sensitive to the cisplatin in the cell line treated with knockdown of TRIM59. These findings establish the relationship between TRIM59 and p53 and chemotherapy sensitivity of cisplatin and TRIM59 may be a promising prognostic indicator for esophageal squamous cell carcinoma (ESCA) patients. Conclusions: We have confirmed that the up-regulation of TRIM59 in human esophageal cancer tissues closely correlates with poor prognosis of patients and TRIM59 serves as an oncogene promoting the proliferation and metastasis of esophageal cancer. The study demonstrates that knockdown of TRIM59 inhibited the growth and invasion of Eca109 cancer cells and strengthened the chemosensitivity to cisplatin through the mechanism of increasing the p53 expression. These results suggest that combination of TRIM59 knockdown with cisplatin might provide a promising strategy to treat the patients with esophageal cancer.
Initial safety run-in findings with bavituximab plus pembrolizumab in patients with advanced gastric or gastroesophageal cancer.
Authors: Chau Ian , Park Haeseong , Lee Jeeyun , Rege Jessicca Martin , Culm-Merdek Kerry , Bendell Johanna C.
Published: May 2020

e16537

Background: Bavituximab, an investigational, chimeric monoclonal antibody designed to inhibit the immunosuppressive effects of phosphatidylserine (PS), is being evaluated in combination with pembrolizumab in patients with advanced gastric and gastroesophageal junction (GEJ) cancer. Bavituximab binds in a high-affinity complex with β2-glycoprotein and PS to reverse immunological non-responsiveness and activate multiple immune cell receptors. Post-hoc data from the Phase III Sunrise second-line lung cancer study indicated that patients who progressed on study treatment with bavituximab plus docetaxel and continued with a checkpoint inhibitor showed significantly improved overall survival. Cumulative data suggest that bavituximab may potentiate pembrolizumab-mediated checkpoint inhibition, potentially increasing overall clinical benefit. ONCG100 is a phase 2, multicenter, open-label, single-arm global study designed to assess the safety, tolerability and efficacy of bavituximab and pembrolizumab when administered in combination to advanced gastric or GEJ adenocarcinoma patients, regardless of PD-L1 status, who have progressed on or after at least one prior standard therapy (NCT04099641). Methods: The safety run-in phase of the trial evaluated the safety and tolerability of de-escalating doses of bavituximab when administered in combination with the approved dose and schedule of pembrolizumab (200mg, Q3W). Adverse events were evaluated by CTCAE v5.0. Results: Three patients enrolled and completed the safety-run in phase of the study where bavituximab was administered at the starting dose of 3 mg/kg QW in combination with pembrolizumab. There were no dose-limiting toxicities observed during the 21-day monitoring period. A total of 4 treatment emergent adverse events were observed; 2 of which were reported as related to treatment with bavituximab (arthralgia and fatigue, both grade 1). There was one treatment-unrelated SAE reported (chylous ascites, grade 2), which resolved allowing the patient to continue treatment. Conclusions: The 3 mg/kg dose of bavituximab was readily combined during the safety run-in phase of the study with the approved dose of pembrolizumab. The AE profiles for this combination were manageable and expected given the known profiles of each agent. Based upon these findings, the recommended dose for expansion for the combination was declared and the expansion phase of the study opened. Updated safety data from the study will be presented. Clinical trial information: NCT04099641 .
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated to systemic chemotherapy for gastric cancer with diffuse peritoneal metastases in a palliative setting.
Authors: Bonnot Pierre Emmanuel , Rabel Thomas , Lintis Alexandru , Laplace Nathalie , Bakrin Naoual , Kepenekian Vahan , Villeneuve Laurent , Chauvenet Marion , Bouarioua Nadia , Alyami Mohammad , Glehen Olivier
Published: May 2020

e16538

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is emerging as a new intraperitoneal laparoscopic delivery of chemotherapy to treat peritoneal metastasis (PM). First results from several malignancies appear promising in small series of patients. Prognosis of PM from gastric cancer (GC) is poor. Median survival is ranging from 3 to 13 months with systemic chemotherapy (SC) alone. Purpose: to evaluate the feasibility and potential benefits of PIPAC associated to SC in GC with PM in a palliative setting Methods: From a prospective database, we identified 91 consecutive patients considered with isolated unresectable PM from GC treated by an alternance of SC and PIPAC with low-dose cisplatin-doxorubicin (ratio 2/1) between January 2016 and January 2019 in our institution. End of follow-up was January 2020. Results: Median age was 56 years, 86% of patients had a signet ring cell adenocarcinoma with 86.7% of synchronous PMs.Median Peritoneal Cancer Index was 16 (3-39). A total of 346 PIPAC were performed with a median of 3 per patient (1-18). Median number of SC lines was 3 (2-3) resulting in a median number of SC cycles of 14 (11-20). After a median follow-up of X months, 21 patients were still alive. In the whole population, median OS from diagnosis was 15.1 months. PIPAC was introduced in association to first-line SC as maintenance or intensification therapy in 75 patients with a median survival from diagnosis of 14.7 months and a median PFS from PIPAC introduction of 6.3 months. For 16 patients, PIPAC was introduced due to progression after a first or second line of SC leading to a median OS of 20 months after diagnosis and 5.9 months after PIPAC introduction. Reasons to stop PIPAC were cancer progression, intraperitoneal access difficulties or PIPAC related morbidity, a cytoreductive surgery attempt in 61.7%, 19.8% and 18.5% respectively. A cytoreduction and HIPEC attempt was performed for 12 patients before 3 PIPAC and 3 after 3 PIPAC or more, leading to a median OS of 19 months for those patients. Twelve (13,2%) patients developed extra-peritoneal metastases during PIPAC. Conclusions: PIPAC appears safe and feasible showing promising results in control of PMs from gastric origin. Further randomized studies are required to document its benefits compared to SC alone.
Outcomes relative to paclitaxel dose-intensity when administered with ramucirumab in gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Allen Michael J , Suzuki Chihiro , Espin-Garcia Osvaldo , Ma Lucy Xiaolu , Honório Marta , Lyra-Gonzalez Ivan , Chen Eric Xueyu , Darling Gail Elizabeth , Yeung Jonathan , Kalimuthu Sangeetha , Wong Rebecca , Veit-Haibach Patrick , Jang Raymond Woo-Jun , Elimova Elena
Published: May 2020

e16539

Background: Combination paclitaxel (PTX) and ramucirumab (RAM) is standard second-line treatment for gastric and GEJ cancers. Peripheral neuropathy (PN) is considered a potential obstacle to administering a maximal dose of PTX, potentially limiting efficacy. We sought to determine the dose-intensity and outcomes for patients receiving this treatment. Methods: A retrospective analysis of gastric and GEJ cancer patients treated at Princess Margaret Cancer Centre (2012-2017) was performed identifying all patients who received PTX and RAM during their treatment course. The primary objective was to determine the dose-intensity of PTX administration. Secondary objectives included identification of the reason for dose-reduction (DR), and comparing progression-free survival (PFS) and overall survival (OS) in relation to PTX DR. Results: 45 patients were included in the study. Mean age was 57.2y, 34 (76%) were male, 7 (16%) were Asian, 5 (11%) patients were her2 positive. 42 (93%) patients received first-line treatment containing a potential neuro-toxic agent (cisplatin, oxaliplatin, docetaxel or paclitaxel). 22 (49%) subjects required PTX DR. The median number of cycles administered for subjects not requiring a DR and those with dose-reduced PTX was 3 v 6 (p < 0.001) respectively, with the median number of PTX doses administered 8 v 15 (p0.0022). The mean dose-intensity was 100 v 83% (p < 0.001). PN was the reason for DR in 32% (n = 7) of subjects, whilst neutropenia was 41% (n = 9). The reason for treatment cessation was disease progression in 91% of subjects, irrespective of whether they required a DR or not. Median PFS was 2.8m (95% CI 2.1-4.8) (100% dose PTX) and 5.5m (95% CI 4.8-8.6) in those requiring a DR (p0.0006). Median OS, measured from the initial diagnosis of incurable/metastatic disease was 16.4m (95% CI 13.7-22.9) and 18.5m (95% CI 14.9-47.5) respectively (p0.0953). Conclusions: Approximately half of the patients required a PTX DR, of whom a clinically significant 32% were DR due to PN, slightly less than those DR due to neutropenia. PFS was longer in those requiring a DR, which may reflect that those on treatment longer are more likely to experience toxicity and require a subsequent DR. PTX DR did not significantly affect OS, thus whilst PTX toxicity remains a clinical concern we did not identify that a DR resulted in an appreciable difference in treatment efficacy.
Concurrent docetaxel and S-1 compared with oxaliplatin and s-1 as first-line therapy for advanced gastric adenocarcinoma: A retrospective study.
Authors: Tan Siyi , Xie Jiaqi , Wei Jia , Liu Qin , Du Juan , Liu Baorui , Yang Yang
Published: May 2020

e16540

Background: The aim of this study was to compare the efficacy and safety between docetaxel plus S-1 with oxaliplatin plus S-1 therapy as first-line treatment for advanced gastric adenocarcinoma. Methods: Patients, who had received docetaxel plus S-1 or oxaliplatin plus S-1 as first-line chemotherapy for advanced gastric adenocarcinoma, were retrospectively reviewed. Kaplan–Meier curve and log-rank test were used to analyze the survival. Prognostic factors were estimated by Cox regression. Adverse events (AEs) were evaluated using CTCAE 4.0. Results: One hundred and twenty-nine patients received concurrent docetaxel plus S-1, whereas 130 received oxaliplatin plus S-1. The median progression-free survival (PFS) and overall survival (OS) in docetaxel and oxaliplatin groups were 6.0 and 8.2 months ( P= 0.025), 14.7 and 15.7 months ( P= 0.697), respectively. Multivariate Cox regression suggested that chemotherapy regimen (docetaxel vs oxaliplatin; HR = 1.535, 95% CI:1.092-2.156, P = 0.014), Eastern Cooperative Oncology Group performance status (ECOG PS 3-4 vs 0-2; HR = 4.213, 95% CI: 2.246–7.903, P< 0.001), Lauren type (Intestinal vs Diffuse, HR = 0.471, 95% CI: 0.307–0.725, P= 0.001, Mixed vs Diffuse, HR = 0.649, 95% CI: 0.442–0.953, P= 0.028), and number of metastases (HR = 2.097, 95% CI: 1.421–3.095, P< 0.001) had significant effects on PFS. Multivariate Cox regression suggested that pathologic types (signet-ring cell carcinoma vs adenocarcinoma; HR = 1.688, 95% CI:1.152-2.472, P = 0.007), Lauren type (Intestinal vs Diffuse, HR = 0.637, 95% CI: 0.414–0.982, P= 0.041), number of metastases (HR = 1.7, 95% CI: 1.154–2.504, P= 0.007) had significant effects on OS.The most common grade 3-4 adverse events were leukopenia (3.1% vs 7.8%), neutropenia (7.7 vs 12.3%), anemia (13.2% vs 14.6%), thrombocytopenia (2.3% vs 10.8%), peripheral neuropathy(0.8% vs 7.8%)and Nausea/vomiting/ anorexia (1.6% vs 3.8%). Conclusions: Concurrent oxaliplatin plus S-1 therapy appears to be effective as first-line treatment in advanced gastric and has an acceptable safety profile. For patients in good physical condition, we prefer to recommend oxaliplatin combined with S-1 for treatment.
Preliminary results of a phase II study of neoadjuvant immune checkpoint inhibitor IMC-001 (anti-PD-L1 monoclonal antibody) in patients with resectable gastrointestinal cancers (NeoChance Study).
Authors: Im Hyeon-Su , Song Joon Seon , Jo Woo Ri , Yoo Moon-Won , Kim Yong-Hee , Kim Hyeong Ryul , Song Ho June , Kim Do Hoon , Choi Kee Don , Lee Jeong Hoon , Ahn Ji Yong , Na Hee Kyong , Song Ki-won , Park Sook Ryun
Published: May 2020

e16542

Background: Immune checkpoint inhibitors have shown survival benefits in unresectable/metastatic gastric cancer (GC), esophageal cancer (EC), and hepatocellular carcinoma (HCC). Based on scientific rationale for neoadjuvant immunotherapy, including enhanced immune recognition, we initiated a phase II study of IMC-001, a novel PD-L1 targeting fully human monoclonal Ab in the neoadjuvant setting for resectable GC, EC, and HCC. Methods: This is a prospective, open-label, phase II study of neoadjuvant IMC-001 (20 mg/kg iv every 2 weeks for 2 cycles) across three cohorts of resectable gastrointestinal cancers (GC, EC, HCC). The primary endpoint is major pathologic response rate ( < 10% of viable tumor cells) and secondary endpoints include safety, feasibility, R0 resection rate, clinical tumor response rate/disease control rate (DCR), progression-free survival, relapse-free survival, and overall survival. Exploratory endpoints include immune monitoring and biomarker analysis in tumor tissues, blood, and stool. Results: From Sep. 2019 to Feb. 2020, 14 eligible patients (pts) (6 HCC; 5 GC; 3 EC) were enrolled; male (79%), median age = 63 yrs (range, 40-72), clinical stage (AJCC 8th) I (57%)/II (21%)/III (21%). 12 pts completed 2 cycles of neoadjuvant IMC-001 and one pt stopped after one cycle due to G3 autoimmune hepatitis, which was only G3 adverse event (AE) and resolved with steroid. Other AE included G2 hyperthyroidism (n = 1), G1 pruritus (n = 2), G1 rash (n = 1), G1 myalgia (n = 1), G1 arthralgia (n = 1), G1 diarrhea (n = 1), G1 cough (n = 1), G1 palate discomfort (n = 1), and G1 chest discomfort (n = 1). So far, 10 clinical response-evaluable pts showed a 100% DCR and underwent surgery, which was all R0 resection. Post-treatment surgery specimens showed various degrees of lymphocyte infiltration in intratumoral or peritumoral areas ranging from 10% to 90%, which was increased compared to pre-treatment biopsies. In HCC pts, adjacent hepatic parenchyma showed mild to moderate, diffuse portal inflammation regardless of Hepatitis B virus status and minimal and moderate fatty change. IHC for PD-L1 using 22C3, SP263 and SP142 clones showed similar results among three Abs with relatively low expression regardless of tumor types (range, 0-20%). Conclusions: Neoadjuvant IMC-001 seems to be well tolerated and have preliminary immune modulating activity in resectable GC, EC, and HCC pts. The study is ongoing and the updated clinical and immunologic results will be presented. Clinical trial information: NCT04196465 .