bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy-induced neuronal dysfunction in the absence of axon degeneration.
Authors: Housley Stephen Nick , Flores Ann Marie , Wang Allison B. , Perreault Eric J. , Nardelli Paul , Carrasco Dario , Matyunina Lilya , McDonald John F. , Cope Timothy C.
Published: May 2019

e15091

Background: Colorectal cancer is one of the three most prevalent cancers. Mortality rates have largely decreased due, in part, to advanced treatments such as platinum-based chemotherapy (e.g. oxaliplatin – OX). Unfortunately, OX induces severe off-target, neurotoxic side-effects in the sensory nervous system that can limit or end treatment and diminish patient quality of life for years. Patient symptoms are often attributed to dying-back degeneration of primary sensory axons despite the absence of conclusive evidence. We tested the hypothesis that proprioceptive disorders persisting after chemotherapy result solely from axon degeneration of muscle proprioceptors. Methods: We used a rat model to test our hypothesis. In a rodent model of OX clinical cancer treatment, one that exhibits sensorimotor deficits in a test of proprioceptive behavior, we performed single-neuron in vivo electrophysiological and immunohistological experiments. We then profiled transcriptomes of sensory neurons to gain unbiased insight into molecular evidence of degeneration. We compared the OX group of rats (n = 18) to healthy, control rats (n = 6) using hierarchical Bayesian analysis. Results: We found no evidence for sensory axon degeneration in electrophysiologic measures of axon conduction or in immunohistochemical analysis of the axon terminals of sensory neurons, OX and control rats were indistinguishable by these measures. Unbiased transcriptional profiling gave little evidence of neuronal degeneration, although genes related to axon transport showed signs of dysregulation. Structural degeneration was also ruled out by finding that all sensory neurons fired in response to stretch. Nonetheless, anomalous firing patterns were observed, e.g. decreased spike activity in response to mechanosensory stimulation, consistent with changes in ion channel physiology. Conclusions: Our findings reject the hypothesis that nerve degeneration is required to explain OX-related sensorimotor disorders. Our research suggests biological mechanisms that are alternative to axon degeneration in explaining sensorimotor changes due to OX.
The metabolic clinical risk score (mCRS) as a new prognostic model for surgical decision in patients with colorectal liver metastases.
Authors: Duran Derijckere Ivan , Levillain Hugo , Bohlok Ali , Mathey Celine , Nezri Jonathan , Muteganya Raoul , Lucidi Valerio , Bouazza Fikri , Van Simaeys Gaetan , Goldman Serge , Hendlisz Alain , Flamen Patrick , Donckier Vincent
Published: May 2019

e15094

Background: Selection for surgery in patients with colorectal liver metastases (CRLM) remains poorly accurate. We evaluated if baseline metabolic characteristics of CRLM, as assessed by [18]-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18FDG-PET/CT), may predict the postoperative outcome in patients operated for CRLM. Methods: In a series of 450 patients operated for CRLM, we retrospectively identified 2 groups: The long-term survival (LTS), as defined by postoperative recurrence-free survival (RFS)≥5 years, and the early relapse groups (ER), as defined by RFS < 1 year. Clinicopathologic characteristics, Clinical Risk Score (CRS) and baseline 18FDG-PET/CT metabolic parameters were analyzed. Baseline 18FDG-PET/CT was performed at the time of diagnosis of CRLM, before any preoperative treatment. Low and high-risk CRS were defined by scores of 0 to 2 and 3 to 5, respectively. Metabolic CRS (mCRS) was implemented, using 1 additional point to the standard CRS when the highest tumor standardized uptake value (SUVmax) and normal liver mean SUV (SUVmean(liver)) ratio was > 4.3. Low and high-risk mCRS were defined by scores of 0 to 2 and 3 to 6, respectively. Results: We analyzed 53 patients. No difference was observed between LTS (n = 23) and ER (n = 30) groups for clinicopathologic parameters related to the primary tumor and CRLM, CRS and rates of low/high risk CRS. All metabolic parameters analyzed, including SUVmax and SUVpeak, at the exception of metabolic tumor volume, were significantly increased in ER group. Median SUVmax/SUVmean(liver) ratio was significantly increased in the ER vs LTS, respectively of 4.2 and 2.8 (p = 0.008). mCRS was significantly higher in ER as compared to LTS patients (p = 0.024), while 61% of the LTS patients had a low-risk mCRS and 73% of the ER patients had a high-risk mCRS (p = 0.023). Conclusions: Baseline 18FDG-PET/CT characteristics demonstrate an increased tumor glucose uptake in patients who rapidly recur after curative-intent surgery for CRLM. The introduction of these data into clinical risk model may represent a new tool to improve selection for surgery in patients with CRLM.
The mutational landscape of circulating cell-free DNA to identify neoadjuvant chemotherapy response in colorectal cancer patients.
Authors: Liu Yanlong , Wei Xiaoli , Shi Xinying , Yang Ying , Fu Lili , Mao Beibei , Zhang Henghui , Cui Binbin
Published: May 2019

e15096

Background: The neoadjuvant chemotherapy plays an important role in the current treatment of colorectal cancer (CRC), even though parts of patients could not be benefit from it. This study was aimed to explore the specific mutational profile of plasma cell free DNA (cfDNA) in CRC patients with or without response to neoadjuvant chemotherapy. Methods: 16 eligible CRC patients were enrolled in this study from Harbin Medical University Cancer Hospital. These patients were divided into two groups: with response ( R, n = 8) and without response (NR, n = 8) to neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy and their baseline blood samples were collected. The cfDNA fragments were extracted for enrichment of a panel covering exon regions of 1,086 genes. Gene alterations were analyzed to investigate the relationship between genetic characterizations of cfDNA and response to neoadjuvant chemotherapy. Results: Principal component (PCA) analysis for copy number variation(CNV) of cfDNA differed significantly in two groups. In the R group, there were higher frequency CNV loss in ABL-1, ERBB3, SMO, IGF1R, AURKA, PDGFRA, IDH1, BRAF, PIK3CB, NRAS, NF1, MITF, PTCH1 genes, and CNV gain in MTRR, HSP90AA1, VHL, CREBBP, CHEK2, DDR2, MUTYH, NCOA1, XPC, FANCA genes. Regarding to the area under the ROC curve, CNV of these genes had a high value of 0.967, which implied that CNV of the candidate genes have predictive value for identifying response to neoadjuvant chemotherapy in CRC patients. Furthermore, the Copy Number Instability (CNI) value of R group was significantly higher than NR group(p = 0.0014). Conclusions: The candidate genes’ copy number variation and CNI value of baseline plasma cfDNA can identify the colorectal cancer patients with response or without response to neoadjuvant chemotherapy in this small cohort. The molecular profile of cfDNA in plasma may be a potential biomarker for predicting the response to neoadjuvant chemotherapy in colorectal cancer patients. These findings warrant further expanded prospective cohorts to validate.
Single center experience: Management of metastatic appendiceal cancer with peritoneal carcinomatosis.
Authors: Malapati Sindhu Janarthanam , Khan Uqba , Mouabbi Jason Aboudi , Kafri Zyad , Hadid Tarik H. , Berri Richard N. , Sakhi Ramen , Mazzara Paul , Szpunar Susan
Published: May 2019

e15103

Background: Appendiceal tumors constitute only 1% of intestinal malignancies with no established standard of care due to their relative rarity. Timing, preferred regimen and utility of chemotherapy in this malignancy are among the many questions that still remain unanswered. Methods: Retrospective chart review of patients treated for appendiceal carcinoma at our institution who had slides available for pathology review (96 patients met this criteria). Results: Mean age at diagnosis was 55.8 years. 84% were Caucasian and 13.8% were African American, 19.8% had a family history of colon cancer. Mucinous adenocarcinoma was the most frequent subtype (70.8%) followed by colonic (8.3%), signet ring, goblet cell and mixed. 63 had cytoreductive surgery, 63 had HIPEC, 23 had neo-adjuvant and 41 patients had adjuvant chemotherapy. 30 patients received bevacizumab with first line. 6 of 43 patient with CCR0, 0 of 10 patients with CCR1 and 1 of 10 patients with CCR2 died during follow-up. Eventually, 17 patients had second surgery (debulking in 6, debulking+HIPEC in 11). 52 patients had progression and this was most frequently diagnosed on surveillance imaging (73.1%.) Mean time to progression (TTP) was 39.3 months (8-432 months) and second progression was 62.4 months (21.5-177.6 months.) Median time from surgery to progression was 31.6 months (9.6-417.5 months). TTP and OS are not associated with age and although mean survival was numerically greater in women (303.9 months) than men (220.5 months), this was not statistically significant (p=0.903). Pathologic grade 1 had a longer time to progression compared to grade 2 and 3 (176.9 months versus 55.5 and 59.1 months, p= 0.001). There was a significant difference in TTP based on tumor differentiation (p=0.019) with 191.5 months, 45.3 months and 67.2 months in well, moderate and poorly differentiated respectively. Survival by pathologic grade approached significance (p=0.067), 336.3 months, 171.9 months, 129.1 months in grade 1, 2 and 3 respectively. Conclusions: 80% patients have peritoneal carcinomatosis at diagnosis and for every 1 increase in PCI, the risk of progression increases by 4.8% but this does not affect survival. FOLFOX/ Xelox in first line was associated with longer time to progression. [Table: see text]
Mutational signatures of early-onset colorectal cancer.
Authors: Marsoni Silvia , Zanardi Federica , Iannelli Fabio , Salviato Elisa , Ferrari Francesco , Luraghi Paolo , Lazzari Luca , Sartore-Bianchi Andrea , Siena Salvatore , Abrignani Sergio , Bodega Beatrice , Russo Antonio , Amirouchene-Angelozzi Nabil
Published: May 2019

e15113

Background: Despite a reduction of Colorectal Cancer (CRC) incidence in western countries in the past decades, Early-Onset CRCs (EO-CRC, patients diagnosed with CRC ≤ 40 years old) incidence has increased. Although frequently occurring in the context of familial syndromes, EO-CRCs are mainly sporadic cases and phenotipically enriched for distal localisation and advanced stage at diagnosis. Whether EO-sporadic CRCs pathogenesis differs from that of normal-onset (NO) CRC and how this might impact incidence rates is currently unknown. This had prompted us to ask if, at the genetic level, “traces” of peculiar pathogenic processes could be identified in EO-specific (or -enriched) genetic signatures (GS). Methods: The mutational signatures of 424 TCGA CRC patient samples (19 EO and 405 ≥ 50 years at diagnosis) were analyzed and the similarity between each mutational profile and COSMIC GS was calculated using Bioconductor R package Mutational Patterns (doi: 10.1186/s13073-018-0539-0). Unsupervised hierarchical clustering of the samples according to similarity to GS was performed in single cohort and pooled analysis. Association between age and individual GS was assessed through grouped and linear correlation analysis. Results: EO-CRC patients were grouped in three main clusters: Cluster1 exposing a major similarity with GS10 (associated with defects in polymerase proofreading activity), Cluster2 showing stronger similarities with GS6 (associated with mismatch repair deficiency), and GS1 (associated with 5-MeC deamination) and Cluster3 presenting similarity with multiple GSs, such as 3 (associated with homologous recombination deficiency) and 5 (pathogenesis unknown). Overall this clustering was maintained when EO-CRC samples were pooled with NO CRC. Grouped and correlation analysis revealed no significant association between age and individual GSs, including GS1 (associated with age). Conclusions: These preliminary analyses show that the relative contribution of known GS is similar in EO and NO cohorts of patients. Possible enrichment for EO-CRC in specific signature clusters will be analysed on a wider sample series.
The mutational landscape of MSI-H and MSS colorectal cancer.
Authors: LI Enxiao , Hu Ying , Han Wenbo , Liu Tianshu , Lv Fang , Zhao Lili , Liu Yang , Chen Yanhui , Zhang Henghui
Published: May 2019

e15122

Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.
Rates of genotyping for KRAS, NRAS, BRAF, microsatellite instability (MSI), and mismatch repair (MMR) in metastatic colon cancer patients: Gaps and implications.
Authors: Gutierrez Martin , Price Kristin Sedgwick , Lanman Richard B. , Nagy Rebecca , Shah Irfan , Mathura Shivam , Norden Andrew David , Goldberg Stuart L.
Published: May 2019

e15123

Background: Molecular genotyping is essential to optimal treatment selection in metastatic colon cancer (mCC) as mutations in exons 2,3,4 of KRAS and NRAS (expanded RAS) and BRAF V600E predict lack of response to anti-HER2 therapy, and microsatellite instability high (MSI-H) predicts positive response to immune checkpoint inhibitor (ICPI)s. The National Comprehensive Cancer Network (NCCN) first recommended molecular genotyping for mCC in 2009 and by 2016 recommended all pts with mCC have expanded RAS, BRAF, and mismatch repair deficiency (MMRd) testing. This study updates genotyping rates in metastatic colon cancer (mCC) in a real-world practice setting. Methods: We performed a retrospective review of genomic testing patterns from pts with mCC diagnosed between January 2013 and December 2017 from 22 academic and community health centers in the United States who contributed to COTA’s de-identified Real World Evidence database. Results: 563 pts with mCC were identified in the Cota database over the 5-year period. 341 (61%) pts with mCC had testing for KRAS, 130 (23%) for NRAS, 177 (31%) for BRAF, and 297 (53%) for MMRd. Testing rates for NRAS, BRAF and MMRd all increased from 2013 to 2017 but remained suboptimal with undergenotyping rates of 48%, 45% and 12% respectively by 2017. 33 (6%) pts received cetuximab and/or panitumumab without prior testing for both KRAS and NRAS, despite established lack of benefit. Between 2016 and 2017, when NCCN recommended testing for KRAS, NRAS, BRAF and MMRd, only 24% of mCC pts were tested for all biomarkers. Conclusions: Although molecular genotyping rates increased over the described 5-year period, since 2016, less than one quarter of all mCC pts in this cohort received guideline recommended genotyping. Approaches that may improve complete genotyping rates in mCC, such as plasma-based comprehensive genomic profiling, may improve optimal treatment selection and should be tested in prospective trials.
Risk of treatment-related death in carriers of pathogenic DPYD polymorphisms treated with fluoropyrimidine chemotherapy: A systematic review and patient-level analysis.
Authors: Rai Karan , Batukbhai Bhavina D O , Brooks Gabriel A.
Published: May 2019

e15132

Background: Polymorphisms of the DPYD gene are present in 3-5% of the population and are associated with increased risk for grade ≥3 toxicity during treatment with fluoropyrimidine (FP) chemotherapy. Fatal toxicities in carriers of DPYD polymorphisms have been described in published reports, however reliable estimates of the risk of treatment-related mortality are lacking. Methods: We conducted a systematic review of the MEDLINE database to identify relevant manuscripts published before January 28, 2018. We searched for published studies of patients receiving standard-dose FP chemotherapy (5-fluorouracil or capecitabine) who had pre-treatment testing for ≥1 of 4 pathogenic DPYD polymorphisms (c.1236G > A/HapB3, c.1679T > G, c.1905+1G > A/*2A, and c.2846A > T) and who were systematically assessed for treatment-related toxicities. In the case of retrospective studies, we required that the cohort be defined by pretreatment characteristics (e.g., patients were not included on the basis of observed toxicity). Two reviewers extracted study- and patient-level data, with discrepancies resolved by consensus. The pooled data were analyzed to estimate the risk of treatment-related mortality among polymorphism carriers. Results: Of the 1290 references screened, 37 publications were included in the final analysis. Patient-level data identified 485 of 14,377 patients (3.4%) with pathogenic DPYD polymorphisms. There were 12 deaths among polymorphism carriers, resulting in a 2.5% risk of treatment-related mortality (95% CI 1.3-4.4%). Only 2 treatment-related deaths were reported in 13,892 patients without identified polymorphisms. Risk of death by genotype is shown in the table; two decedents were compound heterozygotes. Conclusions: Patients with pathogenic DPYD polymorphisms who are treated with standard-dose FP chemotherapy are at significant risk of death and can be prospectively identified through pharmacogenetic testing. [Table: see text]
The association between female hormonal supplementation and molecular types in colorectal cancer.
Authors: Chung Seung Won , Overman Michael J. , Morris Van K. , Fogelman David R. , Kee Bryan K. , Dasari Arvind , Raghav Kanwal Pratap Singh , Shureiqi Imad , Jiang Zhi-Qin , Jensen-Loewe Patricia A. , Wolff Robert A. , Eng Cathy , Menter David , Kopetz Scott , Davis Jennifer S.
Published: May 2019

e15133

Background: In the US, colorectal cancer is the third most common malignancy in women. Postmenopausal hormone use has been associated with decrease in incidence of colorectal cancer however few studies have evaluated the relationship between hormone use and molecular profiles of advanced colorectal cancer. The aim of this study is to evaluate correlations between female hormonal supplementation use and colorectal cancer molecular, clinical, and pathologic features. Methods: We conducted a retrospective case-case study of female patients with metastatic or unresectable, locally advanced colorectal cancer on the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol from 2010 to 2017. Post-menopausal hormone use was self-reported in an environmental survey as part of the ATTACC protocol. Molecular, clinical, and pathologic features were obtained through medical record review. Results: Among 258 female patients, 163 (63%) patients reported ever use of female hormonal supplementation. Ever use was significantly associated with BRAF V600E mutant tumors (OR 2.63, p-value 0.04). There was no association with KRAS, NRAS, PIK3CA mutations, microsatellite instability, or CpG island methylation. The mean age at diagnosis of ever users was 54.4 and mean of no supplement was 56.5 (p-value 0.07), indicating no age difference between ever and never users. Conclusions: Despite the overall protective effects of postmenopausal hormone use on colorectal cancer incidence, among those who develop colorectal cancer, our data suggest an association between female hormonal supplementation and BRAF mutation. Further studies are needed to evaluate this relationship in additional cohorts, interrogate the biological basis, and identify whether there is an association with survival of patients with metastatic or locally advanced colorectal cancer with estrogen or progestin supplement use.
Defining an IBD-like subgroup in consensus molecular subgroups of colorectal cancer and transcriptomic biomarker development for at-risk patients.
Authors: Scanlon Enya , Murphy Seamus J , Kennedy Richard D. , Blayney Jaine K.
Published: May 2019

e15142

Background: Ulcerative colitis (UC), is a known risk-factor for colorectal cancer (CRC). 10% of UC-patients develop UC-specific CRC yet there are currently no biomarkers for early detection or understanding of drivers of disease. Unresolved inflammation is key in UC-CRC development, yet the aetiology is unclear. It is unknown if UC-CRC falls into a specific consensus molecular subgroup in the CMS classification (Guinney et al 2015). This bioinformatics approach aimed to identify patients at-risk of developing UC-CRC, whilst informing biological and clinical understanding of the disease. Methods: We used publicly available UC data and in-silico, cross platform, class label transfer (GECA) to determine mRNA similarity between UC/UC-CRC and sporadic CRC (sCRC) and to identify a UC-predominant CMS. Pathogenic mutations were identified for each CMS as well as gene set enrichment and survival analysis to determine UC-CRC behaviour comparative to sCRC. Transcriptional relationships were assessed via unsupervised and semi-supervised clustering by immune-signatures and scores to determine molecular patterns between phenotypes. We derived a gene list from UC data informed by clustering to stratify patients based on risk to UC-CRC progression. Results: UC-CRC featured predominantly in the NA group, with 3 attributed pathogenic mutations, an oxidative stress environment and neuroendocrine dysregulation. The subgroup had UC-like clinical features; younger age, distal tumour location and TP53 mutations along with the highest rate of cancer recurrence (~20%) and a unique cellular composition in CMS being highly immune and stromal. Importantly this immune signal was distinct from the interferon type signalling observed in CMS1 and was not associated with PD-L1 activation. Clustering revealed a loss of IFN-type gene expression in colon tissue as UC progressed to UC-CRC. Conclusions: The NA group was thought to be unclassifiable samples between CMS however, analysis shows UC-CRC enrichment with defined biological characteristics. We have identified novel biology that may inform the risk of developing UC-CRC and guide potential preventative and therapeutic approaches.
Characteristics of colorectal patients who discontinued oxaliplatin therapy.
Authors: Buchholz Alexander , Sahmoun Abe E , Kurniali Peter C.
Published: May 2019

e15155

Background: The 3rd generation platinum-based drug, Oxaliplatin, is indicated for treatment of stage II-IV colorectal cancer (CRC). Oxaliplatin combination with Fluorouracil and Leucovorin (FOLFOX) yields a 5-year disease free survival rate of 78%. Oxaliplatin use is limited by dose-limiting side effects such as neurotoxicity, peripheral neuropathy, and hepatotoxicity. Between 60 and 95% of Oxaliplatin treated patients experience neurotoxicity. The incidence of neuropathy varies between 4 and 98%, and of hepatotoxicity between 10 and 50%. There are few effective treatments to prevent or modulate neurotoxicity although infusions of calcium and magnesium may be beneficial. We sought to understand the factors that influence the discontinuation of Oxaliplatin. Objectives: 1) Determine the characteristics of CRC patients who discontinued chemotherapy involving Oxaliplatin; and 2) Examine metabolic panel monitoring among CRC patients. Methods: A retrospective chart review of newly-diagnosed adult patients with CRC stages II, III, and IV at Sanford Health. We used SAS v.9.4 to analyze demographic and clinical data. All P were two-sided, and P < .05 were considered significant. IRB approval was obtained from Sanford Health and the University of North Dakota. Results: Data for 197 patients who received chemotherapy involving Oxaliplatin were studied. The mean [SD] age at diagnosis was 58.4 [± 12.9]. The majority 117 (59%) were male and 188 (96%) were White. 48% of patients had stage III and 35% had stage IV disease. 167 (85%) of patients received FOLFOX therapy. 56 (30%) discontinued Oxaliplatin. The median [range] number of cycles of chemotherapy completed before discontinuing Oxaliplatin was 8 [1-16]. Relative to patients who did not discontinue, patients who discontinued were significantly more likely to have of the descending colon (46% vs. 38%; P=0.023). Discontinuers were significantly more likely to experience moderate to severe symptoms (42% vs. 25%; P=0.032). Only 25 (13%) of patients had serum magnesium measured prior to starting chemotherapy. However, the median [range] serum potassium was significantly lower among discontinuers prior to starting chemotherapy (3.9 [3.2-5.3] vs. 4.1 [2.8-8.1]; P=0.023). Among patients (92%) who developed some form of peripheral neuropathy, the mean [SD] serum calcium was significantly lower among discontinuers (9.22 ± 0.52 vs. 9.40 ± 0.49; P=0.044). Conclusions: This study showed that serum potassium and calcium were significantly lower among patients who discontinued Oxaliplatin. Magnesium was measured rarely.
Personalized T cell therapy for metastatic colon cancer.
Authors: Ravindranathan Sruthi , Jajja Mohammad Raheel , Waller Alexandra , Bommireddy Ramireddy , Petersen Christopher , Selvaraj Periasamy , Yang Lily , Lesinski Gregory B. , El-Rayes Bassel F. , Flynn Brianna , Waller Edmund K.
Published: May 2019

e15183

Background: Current immunotherapies fail to benefit patients with colon cancer, largely due to high molecular heterogeneity and low frequencies of tumor infiltrating lymphocytes. In this study, we are addressing this limitation via a novel technology to expand patient tumor specific T cells ex-vivo, using patient’s matched tumor and peripheral blood mononuclear cells (PBMCs). This technology utilizes tumor membrane vesicles (TMVs) made from excised tumor tissue, as a source of tumor associated antigens, and further modified to express IL-12 and B7-1 for ex-vivo expansion of tumor specific T cells. Additionally, the T cells are cultured with PI3K delta inhibitor (idelalisib) and vasoactive intestinal peptide antagonist (VIPhyb) to increase yield, polyfunctionality and in-vivo persistence. Methods: Matched tumor and blood were collected from consented colon cancer patients. TMVs were prepared from excised tumors by homogenizing and centrifuging the tumor over a sucrose gradient. TMVs were then made to express glycosyl phosphatidylinositol (GPI) linked IL-12 and B7-1 (decorated TMV) via a proprietary protein transfer technology. PBMCs isolated from matched blood were cultured in media with 10ug/ml decorated TMV with/without VIPhyb(3uM) and idelalisib (100nM) for 14 days. T cells were then phenotyped for percentage of IFN gamma secreting CD4+ and CD8+ T cells and injected into PDX mice bearing matched tumors (2 doses of 1 million and 4 million cells, 20 days apart). Results: 14 days after expansion, T cells expanded with decorated TMVs+VIPhyb+idelalisib (TMVs+drugs) resulted in significantly increased number of IFN gamma secreting CD8+ T cells (25% of T cells), when compared to T cells treated with decorated TMVs without VIPhyb and idelalisib (13% of T cells). Further, when injected to PDX mice bearing matched tumors, and followed for differences in tumor growth, we observed that on day 30 after T cell injection, while the tumor volumes increased 4.5-fold in the untreated group, the tumors in the TMVs+drugs group only increased 2.8-fold. Conclusions: In this study, we have thus developed a novel technology to expand patient tumor specific T cells ex-vivo, for adoptive T cell therapy against metastatic colon cancer.
Prognostic value of systemic immune-inflammation index in elderly patients with esophageal squamous cell cancer.
Authors: Ji Shengjun , Chen Qingqing
Published: May 2019

e15500

Background: The aim is to assess the value of systemic immune-infflammation index (SII) in elderly patients with esophageal squamous cell cancer after radiotherapy. Methods: Total 128 patients larger than 65 years were included. The optimal threshold of SII was determined by establishing a receiver operating characteristic (ROC) curve, and the relationship between SII and prognosis was analyzed. Results: The ROC curve showed that the optimal threshold of the pretherapeutic SII for predicting the efficacy of radiotherapy was 700.97. Univariate analysis showed that SII was significantly associated with radiotherapy (P<0.001). The OS of the low SII group was 83.5%, 62.0%, 48.1% for 1 year, 2 years, and 3 years, respectively. The OS of the high SII group was 75.5%, 30.6%, 24.5% for 1 year, 2 years, and 3 years, respectively. The differences were statistically significant (all P<0.001). Univariate analysis showed that SII, N stage, and TNM stage were all related to the OS (all P < 0.01). Cox multivariate analysis showed that SII were independent prognostic factors. Conclusions: SII is a predictive index for elderly patients with esophageal squamous cell cancer after radiotherapy.
Safety and efficacy of neoadjuvant chemotherapy with S-1 and oxaliplatin plus apatinib for locally advanced gastric cancer.
Authors: Zheng Ya'nan , Yang Xiao , Ni Zhentian , Zhu Zhenglun , Xu Wei , Yang Zhongyin , Liu Wentao , Yan Min , Zhu Zhenggang , Li Chen
Published: May 2019

e15503

Background: Locally advanced gastric cancer (LAGC) has a poor prognosis. Neoadjuvant chemotherapy can reduce tumor loading, degrade staging and increase possibility of complete resection, thus prolonging the survival of LAGC patients (pts). We conducted a phase II trial to assess the feasibility of SOX regimen in combination with apatinib (an anti-angiogenic agent) as neoadjuvant therapy in LAGC. Methods: This study recruited untreated LAGC pts with pathologically and/or cytologically confirmed adenocarcinoma. Treatment included three 21-day cycles of apatinib (oral, 500 mg qd; discontinued in the last cycle), S-1 (oral, 40-60 mg, bid, day 1-day 14) and oxaliplatin (iv, 130 mg/m2, day 1), followed by radical surgery after 4 weeks. The primary outcome was neoadjuvant therapy related toxicity, and the secondary outcomes included tumor response, R0 resection rate, postoperative pathological evaluation and surgical morbidity. Results: Between December 2, 2016 and August 1, 2018, 31 patients were enrolled. Total 29 patients were eligible for safety and efficacy analyses of SOXA as NAC. During NAC treatment, the incidence of adverse events (AEs, any grade) was 100%, and the incidence of grade 3/4 AEs was 34.48%. No treatment-related death. The ORR of 79.31% (95%CI, 60.28-92.01%) and DCR of 96.55% (95%CI, 82.24-99.91%) were achieved. One patient was evaluated as PD with hepatic metastasis after 3 cycles of preoperative chemotherapy, and this case was inoperable. Resection with curative intent was undertaken in 28 patients with R0 resection rate of 100%. Operative morbidity was observed in 12 of 28 patients including fever (9, 32.14%), anastomotic leakage (1, 3.57%), fat liquefaction of post-surgical incision (1, 3.57%), and gastroparesis (1, 3.57%). Additionally, after surgery 1 patient had pulmonary infection and 1 patient had pleural effusion. The median tumor regression was 90% on pathological findings after surgery. Conclusions: Neoadjuvant therapy with apatinib plus SOX for LAGC showed acceptable toxicity and promising efficacy.
Epigenetic alternate promoter utilization and association with PD-L1 expression in Epstein–Barr virus positive gastric cancer.
Authors: Sundar Raghav , Qamra Aditi , Tan Angie Lay Keng , Zhang Shenli , Ng Cedric Chuan Young , Teh Bin Tean , Lee Jeeyun , Kim Kyoung-Mee , Tan Patrick
Published: May 2019

e15509

Background: We recently elicited the role of epigenetic promoter alterations as a mechanism of immune-evasion and primary resistance to immune checkpoint inhibition in gastric cancer. High prevalence of epigenetic modifications are known to occur in Epstein-Barr virus associated gastric cancer (EBVaGC). EBVaGC has high response rates to anti-PD-1 immune checkpoint inhibitors and is associated with high levels of PD-L1 expression. However, not all EBVaGC express PD-L1 and mechanisms that mediate these phenomena are unknown. Methods: We performed NanoString profiling and PD-L1 immunohistochemistry (using Dako PD-L1 IHC 22C3) on tissue from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. NanoString panel was designed for 90 recurrent somatic alternate promoter-related genes, and immune-related genes including PD-L1. EBV status was determined using EBV-encoded RNA in situ hybridization and categorized as EBVaGC and EBV-negative. Samples in the top-quartile of alternate promoter utilization were classified as APhigh and the remaining APlow. Results: A total of 272 samples (EBVaGC n = 79; EBV-negative n = 193) were included in this study. EBVaGC had significantly higher PD-L1 expression (p < 0.001) compared to EBV-negative samples. APhigh group (n = 67) consisted of 61 EBV-negative and 6 EBVaGC samples. EBVaGC APhigh tumors had significantly lower PD-L1 transcript expression compared to EBVaGC APlow tumors (p = 0.011, Wilcoxon-rank sum). Similar correlation was also found with PD-L1 IHC combined positive score (CPS)(median CPS score 1 vs 8, p = 0.047). There was a trend towards poorer survival for EBVaGC APhigh tumors (vs EBVaGC APlow; HR 0.23, 95% CI: 0.046 – 1.23, p = 0.087). EBV-negative APhigh tumors also had lower PD-L1 expression (vs EBV-negative APlow; p = 0.046, Wilcoxon-rank sum). Conclusions: Increased utilization of epigenetic alternate promoter isoforms correlates with lower transcriptomic and protein expression of PD-L1 in EBVaGC. Here we describe a potential mechanism of immune-evasion to explain low immune-infiltration and PD-L1 expression that occurs in a group of EBVaGC that is traditionally considered highly immunogenic.
The ctDNA in peritoneal effusion of advanced gastric cancer for auxiliary diagnosis of peritoneal metastasis.
Authors: QI Changsong , Li Pansong , Hu Yanting , Chang Lianpeng , Wu Yi , Gong Yuhua , Gao Jing , Guan Yanfang , Zhang Xiaotian , Xia Xuefeng , Yi Xin , Shen Lin
Published: May 2019

e15516

Background: Peritoneal metastasis (PM) is the most frequent mode of distant metastasis in advanced gastric cancer (GC). Most PM could cause peritoneal effusion. However, the cytological examination of cancer cells in peritoneal effusion is less sensitive to the identification of PM early; the specificity of serum biomarkers in peritoneal effusion is poor. It is necessary to assess the feasibility of peritoneal effusion circulating tumor DNA (ctDNA) for the PM diagnosis. Methods: 22 GCs with clinically confirmed PM as positive subjects and 11 non-cancers without PM as negative control were recruited. GC tissues were collected from 16 positive subjects. Peritoneal effusion supernatant (AS), peritoneal effusion cells (AC), and plasma were collected from each subject. Next generation sequencing (NGS) was performed using a 1021-gene panel. Sensitivity and specificity for the diagnosis of GC with PM were assessed. Results: Median age of 22 GCs with PM was 57 yrs. 12 patients were male. Diffused and mixed-type accounted for 73%. For 45% of patients, primary tumor was found in gastric body. In tissue samples, recurrent genes were TP53 (63%), CDH1 (50%), RHOA (19%), TGFBR1 (19%), KRAS (13%), and PIK3CA (13%). Private and tumor-derived mutations were found in the AS, AC, and plasma. 95% of (21/22), 82% (18/22), and 77% (17/22) of AS, AC, and plasma samples carried mutations, respectively. AS had more mutations than AC and plasma (Wilcoxon’s matched-pairs signed-ranked test, AS vs AC, p= 0.006; AS vs plasma, p = 0.013). 98% of the AC and 80% plasma mutations were contained in AS, Variant allele frequency (VAF) in AS was higher than others (Mann Whitney test, AS vs AC, p= 0.038; AS vs plasma, p< 0.001). In 22 GCs with PM, 3 were identified with no cancer cells in AS using cytological examination. Of these, 3 were detected with mutations in AS, one with mutations in AC. Mutations were detected in only one negative control AS and AC. Receiver operating characteristic (ROC) curve showed the number of mutations was related to PM (AS: AUC 0.93, 95% CI 0.82-1.00, p< 0.001; AC: AUC 0.85, 95% CI 0.70-1.00, p= 0.001). When the threshold was determined with one mutation, the sensitivity and specificity were 95% and 91% in AS, 82% and 91% in AC, respectively. Conclusions: Peritoneal effusion ctDNA contained tumor-derived and specific mutations. Peritoneal effusion ctDNA can be used for the auxiliary diagnosis of PM.
The prognostic factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma.
Authors: Iwatsuki Masaaki , Harada Kazuto , Wang Xuemei , Bhutani Manoop S. , Weston Brian , Lee Jeffrey H , Nguyen Quynh , Hofstetter Wayne Lewis , Thomas Irene , Rogers Jane E. , Baba Hideo , Ajani Jaffer A.
Published: May 2019

e15523

Background: Patients with gastrointestinal cancer are increasingly being diagnosed with oligometastatic disease due to the development of sensitive imaging. Oligometastases (OLM) represent a clinical and anatomical manifestation of resistant localized cancer and/or metastases. However, oligometastatic disease is complicated by the lack of uniformity due to the heterogeneity of cancer, therefore, differing prognoses. The aim of this study is to identify the factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma (EAC). Methods: Between 2002 and 2016, of 1400 patients with EAC (esophagus and Siewert types I and II) treated at our institute, 233 patients initially diagnosed with stage IVB were enrolled. OLM was defined as only metastasized to one organ and less than 5 metastases. We retrospectively analyzed the association between clinicopathological factors and prognosis, especially focused on the pattern of metastases. Results: Eighty-five patients (36.5%) had OLM, and 148 (63.5%) had non-oligometastais (Non-OLM). The patients in OLM had significantly better overall survival (OS) than the patients in Non-OLM (p = 0.0001). Univariate analysis showed pattern of metastases (lymphatic OLM) and treatment method (consolidative local radiotherapy: CLT) were significantly associated with prognosis (p = 0.04 and 0.01, respectively). Multivariate analysis revealed that lymph node metastases (cN0-N1), number of metastasis (solitary) and treatment (CLT) were independent predictors for OS of patients with OLM. (p = 0.03, 0.01 and 0.001, respectively). In OLM patients, the patients with lymphatic OLM who received CLT had more favorable prognosis (5-years survival rate 25%). Conclusions: This study suggests that CLT is one of the promising modalities for oligometastatic patients with EAC, especially the patients with lymphatic OLM.
Tissue plasminogen activator in gastrointestinal adenocarcinoma: What is its role?
Authors: Maslov Andrey A. , Kit Oleg I. , Frantsiyants Elena M. , Kozlova Larisa S. , Dzhenkova Elena A. , Soldatkina Natalya V. , Tishchenko Irina S. , Tumanyan Sergey V. , Gevorkyan Yuriy A. , Samoylenko Nikolay S. , Aleynov V. I. , Milakin Anton G. , Poluektov Sergey I. , Gabrichidze Petr N.
Published: May 2019

e15532

Background: The aim of the study was a comparative analysis of the tissue plasminogen activator activity (tPA-Ag and tPA-act) in adenocarcinoma of the esophagus (EA), stomach (SA), pancreatic head (PHA), sigmoid colon (SCA) and rectum (RA). Methods: Tissues of tumors, perifocal area (PA) and resection line tissues were studied by ELISA in 143 patients (38-74 years) with EC (n = 12, G2, T2-3N0-1M0), SC (n = 28, G2, T2-3N0-1M0), PHC (n = 46, G2, Т2-4N0M0), SCC (n = 31, G2, T2-3N0-1M0) and RC (n = 26, G2, T2-3N0-1M0). Statistical analysis was performed using the Statistica 10 program. Results: Tumor levels of tPA-Ag were the highest in SA: SA˃RA˃SCA˃EA˃PHA, but in EA, SCA and RA were lower than in the resection line (p < 0.01). Tumor levels of tPA-Ag in SA were similar to the values in PA, and were 3.1-213 times higher than in other tumors. Perifocal levels of tPA-Ag were the highest in SA: SA˃SCA and RA˃EA˃PHA, but in EA and PHA they were lower than in the resection line tissues (p < 0.01), in SCA and RA – similar, in SA – exceeded the levels in all samples by 1-2 orders of magnitude (p < 0.0001). Levels of tPA-Ag were similar in resection line tissues in SCA and RA, being 2.5-128 times higher than in other tumors. The highest tPA-act was observed in perifocal and tumor tissues in SA (p < 0.0001, compared to other tumors): SA˃SCA˃RA˃EA˃PHA (p < 0.01). tPA-act in PHA tumors was 1.3 times higher (p < 0.05) than in resection line tissues and 40.5 times lower than in PA. In SCA, tPA-act was similar in tumor and PA, but was 1.3 times lower (p < 0.05) than in resection line tissues. In RA, tPA-act decreased from the resection line to the tumor by 1.3 and 2.3 times, respectively. Conclusions: The role of tPA in gastrointestinal adenocarcinomas differs: in EA, SCA and RA it has protective functions, as its levels in the tumor are lower than in the resection line. SA was accompanied by an enhanced secretion of tPA-Ag and the formation of tPA-act in tumors, with their subsequent evasion into PA. In PHA, the tPA distribution was similar, but the high rate of tPA activation led to the depletion of both forms of tPA, while still retaining their advantage in the tumor and PA, compared with the resection line.
Prevalence of gastric cancer and premalignant changes in a Michigan cohort, 2013-2017.
Authors: Nemakayala Divyesh Reddy , Tatineni Shilpa , Enofe Ikponmwosa , Wang Ling , Laird-Fick Heather
Published: May 2019

e15539

Background: Gastric cancer (GC) is uncommon in the US. Incidence varies by geography, race/ethnicity, sex, age, and socioeconomic status (SES). H. pylori is a risk factor for premalignant lesions and GC. Prior studies estimate risk of progression from premalignant to GC at 0.1-0.5% per year. US prevalence of premalignant lesions is unclear. This study describes the prevalence of premalignant lesions and GC in a large community-based sample. Methods: Patients aged ≥18 years undergoing EGD with gastric biopsy 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: 4,111 patients were included for analysis. 3,783 (92.04%) had benign findings, 119 (2.90%) premalignant changes, and 31 (0.75%) gastric malignancies. 177 (4.31%) were H. pylori positive. Patients with benign (72.2%), premalignant (69.8%) and H. pylori-positive (69.5%) findings were often inpatients ( p< 0.001 for all comparisons), but not patients with GC (58%, p= 0.37). Benign findings and H. pylori were more common in females (69.3%, p< 0.001 and 59.9%, p< 0.001, respectively). There were no sex differences for premalignant or malignant lesions. Patients with premalignancy and malignancy were older than those with benign findings (mean age 61.6 (SD = 14.8) vs 54.9 (SD = 16.1) years, p< 0.001, and 69.9 (SD = 14.2) vs 54.9 (SD = 16.1) years, p< 0.001, respectively). There was no age difference between patients with benign changes or H. pylori (mean age 54.9 (SD = 16.1) vs 56.4 (SD = 14.4) years, p= 0.24). There were no differences in SES by histological subtype. Conclusions: In a community sample, premalignant lesions and GC were uncommon and did not vary by sex or income. H. pylori infection was also uncommon and varied by sex. This may reflect actual burden of infection or protocols for testing biopsy specimens. Understanding local prevalence of premalignant changes could inform resource planning and surveillance strategies.
Survival analysis and clinical characteristics of forty-eight patients with alpha-fetoprotein-positive gastric cancer treated by integrated Chinese and western medicine.
Authors: He Wenting , Zhang Tong , Xuan Yanhong , Zhang Hongliang
Published: May 2019

e15550

Background: Alpha-fetoprotein-producing gastric carcinoma (AFPGC) is a special type of gastric cancer, which has characteristics of strong invasiveness, prone to liver and lymphnode metastasis, easy misdiagnosis and worse prognosis. According to the literature, the survival of AFPGC was 4-14 months (m). There is no report about integrated Chinese and Western Medicine on the AFPGC patients. This study is to explore the effect of integrated Chinese and Western Medicine on the survival and clinical characteristics of patients with AFPGC. Methods: 398 consecutive patients with gastric cancer admitted to Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine from Jan 2012 to Jun 2018 were retrospectively collected. All patients were diagnosed by pathology. And on the basis treatment of conventional Western Medicine combined with Chinese Medicine for more than 3 m. Follow-up up to Dec 31th 2018. The median follow-up time was 11.1 m. According to the results of serum alpha-fetoprotein chemiluminescence assay, AFPGC was found in 48 out of 398 patients. The median overall survival (mOS) and clinical characteristics of AFPGC patients were analyzed. Results: Among 48 patients with AFPGC, 1 case (2.1%) in stage Ⅰ, 1 case (2.1%) in stage Ⅱ, 8 cases (16.7%) in stage Ⅲ, 36 cases (75.0%) in stage Ⅳ, and 2 cases with unknown stages; 35 cases (72.9%) received chemotherapy, 22 cases (45.8%) received local treatment, including palliative radiotherapy and hepatic artery chemoembolization, and 4 cases (8.3%) received targeted therapy. At the end of follow-up, 40 patients died, with the mOS of 16 m, 27.5 m in stage Ⅰ-Ⅲ and 14 m in stage Ⅳ, which was significantly longer than reported in the literature. Compared with non-AFPGC patients, tumor metastasis and serosal invasion of higher incidence ( 75.0% vs 38.9, x2= 22.3, p < 0.0001; 75.0% vs 38.9%, x2= 17.5, p = 0.0015 ). The incidence of liver and/or lymph node metastasis is higher (52.1% vs 17.4%, x2= 25.1, p < 0.0001; 33.3% vs 15.7%, x2= 7.7, p = 0.0054 ). The incidence of pleuroperitoneal and omental metastasis is higher (33.3% vs 11.7%, x2= 13.0, p = 0.0003 ). Conclusions: Integrated Chinese and Western Medicine can significantly prolong the survival of patients with AFPGC. AFPGC seem to be more prone to tumour metastasis, serosal invasion, liver metastasis, lymph node metastasis, pleuroperitoneal and omental metastasis. However, limited by the sample size, whether the above factors are independent prognostic factors for AFPGC is still not conclusive.