bluuebunny/crossref_metadata_2025 huggingface dataset:
A multi-gene colorectal cancer liquid biopsy with >90% accuracy in diagnosis and assessment of disease status.
Authors: Modlin Irvin Mark , Kidd Mark S. , Kitz Alexandra , Drozdov Ignat A. , Malczewska Anna , Kusnierz Katarzyna , Aslanian Harry
Published: May 2020

e16079

Background: There are few blood-based biomarkers for colorectal cancer (CRC). We report a 13-gene colon cancer circulating-free mRNA to diagnose CRC. Clinical utility was assessed in surgical and chemotherapy patients. Methods: Gene identification/validation: Publicly available colon cancer transcriptomes (E-MTAB-57) to identify candidate markers using gene co-expression network enrichment, differential expression and functional enrichment analyses. Cell line/tumor tissue gene expression: Candidate gene expression was evaluated in 3 CRC cell-lines (LOVO, LS-180 and COLO320DM) and surgical resection samples (CRC adenocarcinomas: n= 33) and biomarkers validated in the TCGA-COAD database ( n= 261 adenocarcinomas, 41 mucinous adenocarcinomas). Blood gene expression: CRC set (cancers: n= 312, controls n= 117) and a CRC artificial intelligence model constructed. Normalized gene expression algorithmically scored (0-100). Matched tumor/ blood samples were available in 33 patients. RECIST criteria Clinical score assessment: Score utility was assessed in surgical and treated cohorts: Surgical: n= 37, follow>7 days. Chemotherapy: n= 75; stable disease (SD): n= 20, progressive disease (PD): n= 55). The relationship to CEA and CA-19-9 were assessed. Statistics: Non-parametric (Mann-Whitney), Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis: Thirteen candidate CRC genes blood were identified. Cell lines and tumor tissue: Expression levels were significantly elevated ( p< 0.001, 20-100-fold) in cell lines and CRC tumors. All 13 markers were confirmed in TCGA-COAD samples (average TPM ranged from 692-4405). Blood gene expression: All 13 CRC marker genes were identified in CRC blood. Levels were 54.4±1.5 ( p< 0.0001) compared to controls (9.5±1.7); AUROC:0.91±0.02, accuracy 90.5% (sensitivity 93.1%, specificity 81.2%). The matched tissue/blood correlation was r = 0.80 ( p= 0.002). Clinical Utility: In the surgical cohort, accuracy was 100% vs CEA (35%) or CA-19-9 (17%) (both p< 0.0001). Resection (R0–92%) significantly decreased levels (47±2) at follow-up ( p< 0.006). In the treated cohort, levels were elevated in PD (63±4.1) vs SD (30±3.2, p< 0.0001). Conclusions: A CRC gene marker panel in blood identified colon cancer with a diagnostic accuracy of 91%. This was significantly greater than CEA or CA-19 in CRCs. Surgical resection decreased levels. CRC score was elevated in progressive vs stable disease. A colorectal cancer liquid biopsy will facilitate image-based management.
Patient characteristics and outcomes of colorectal cancer (CRC) at Butaro Cancer Center of Excellence (BCCOE): Results from a retrospective cohort.
Authors: Fadelu Temidayo , Sebahungu Fidel , Diasti Kevin , Nguyen Cam , Yeh Tiffany , Shyirambere Cyprien , Nkusi Eugene , Nsabimana Nicaise , Ruhangaza Deogratias , DeBoer Rebecca Jane , Chamberlin Mary D. , Mpunga Tharcisse , Shulman Lawrence N.
Published: May 2020

e16081

Background: There are few studies on CRC in sub-Saharan Africa. BCCOE in Rwanda provides patients with CRC access to chemotherapy, surgery and radiotherapy referrals. Here, we describe patient characteristics, treatments delivered and outcomes. Methods: This retrospective observational study included 136 patients with CRC who presented between July 2012 and June 2018. We abstracted patient characteristics, diagnostic and treatment data, and outcomes from electronic and paper records. We compared baseline and treatment characteristics for colon cancer (CC) versus (vs.) rectal cancer (RC) patients. For patients treated with curative intent, we plotted Kaplan Meier estimation of disease free survival (DFS), defined as time from presentation to cancer recurrence, progression or death. Log-rank test was used to examine subgroup differences. Results: The mean age was 52.5, and 71 (52.2%) were female. 101 (74.2%) patients had RC. Compared to CC, patients with RC were older 54.5 vs. 46.9 (p = 0.0084), and more likely female 59.4 vs. 31.4 (p = 0.0043). All provinces in Rwanda were represented including 14 (10.3%) from outside Rwanda; 79 (58.1%) patients lived in rural areas. Median duration of symptoms prior to presentation was 12 months, and 57 (41.9%) had used traditional medicine prior to presentation. 72 (52.9%) patients were non-metastatic, 46 (33.8%) de novo metastatic, 4 (2.9%) recurrent, and 14 (10.2%) had indeterminate stage. Of the patients treated with curative intent, 54 (65.1%) had neoadjuvant and/or adjuvant chemotherapy, while only 34 (41.0%) had curative surgery. 40 (48.2%) patients received a permanent colostomy. 18 (27.7%) patients with RC received concurrent chemoradiation. Over the follow up period, 49 (36%) patients died or were referred for end of life care, 13 (9.3%) remain in surveillance, while 65 (47.8%) were lost to follow up. Median DFS for patients with non-metastatic disease was 22.2 months. On exploratory analyses, there were no statistically significant differences in DFS by cancer type, gender, or performance status, though these analyses were underpowered and follow-up short. Conclusions: CRC treatment requires multidisciplinary care, which is a challenge in low-resource settings. Our results highlight gaps in CRC care delivery and suboptimal patient outcomes; most striking gaps were the low rates of surgery and radiation, and high loss to follow up rates. Rigorous research is needed to understand the underlying causes, and to develop interventions to address these gaps.
Exosomal marker CD63 expression pattern using immunohistochemistry (IHC) in patients with rectal adenocarcinoma in comparison with left-sided colon cancer.
Authors: Prodduturvar Pranitha , McCormick Ben , Mneimneh Wadad , Dal Zotto Valeria , Escobar Daisy E , Manne Ashish , Grimm Leander , Rider Paul , Hunter John , Iliff Greire , Singh Ajay Pratap , Patel Girijesh Kumar , Alkharabsheh Omar , Khushman Moh'd M.
Published: May 2020

e16096

Background: Adenocarcinomas arising from the distal one third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum are often grouped together due to their hindgut embryologic origin and referred to as left-sided colorectal cancer (CRC). Rectal cancer represents a subset of CRC that has distinct differences in anatomical location, clinical behavior, prognosis and molecular background. In patients with left sided colon cancer (LSCC), the expression of exosomal marker CD63 was reported to be higher in the adjacent normal mucosa (ANM) compared to the tumor (224 vs 154, p = 0.0001). Here, we explored the pattern of CD63 expression using immunohistochemistry in patients with rectal cancer in comparison with patients with LSCC. Methods: Between 2015 and 2018, 53 patients underwent rectal cancer biopsy/resection and had available tissues for CD63 IHC staining. Two pathologists independently scored CD63 expression in the tumor and ANM. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Paired t test was used for statistical analysis. Results: Median age was 60 (range 34-80). Females represented 26%. Caucasians and African Americans represented 74% and 26%, respectively. In patients with rectal cancer, the mean CD63 expression was higher in ANM compared to their expression in the tumor (147 vs 113, p = 0.0012). Compared to patients with LSCC (N = 30), the mean CD63 expression in patients with rectal cancer was lower in the ANM (224 vs 147, p < 0.0001) and in the tumor (154 vs 113, p = 0.01). Conclusions: In our cohort of patients with rectal cancer, exosomal marker CD63 expression was lower in tumor compared to ANM. This observation was similar to our previously reported findings in patients with LSCC. Compared to patients with LSCC, patients with rectal cancer had lower expression of CD63 in the tumor and ANM. To our knowledge, this is the first study to explore exosomal marker CD63 expression using IHC in patients with rectal cancer.
Treatment of colorectal cancer in Armenia: A retrospective hospital-based study from a developing world.
Authors: Bardakhchyan Samvel , Mkhitaryan Sergo , Zohrabyan Davit , Safaryan Liana , Avagyan Armen , Harutyunyan Lilit , Arakelyan Jemma , Tamamyan Gevorg , Tananyan Armen
Published: May 2020

e16099

Background: In Armenia colorectal cancer (CRC) is on the third place by incidence. Every year around 700 new cases are diagnosed with 60% diagnosed in 3rd and 4th stages. Methods: For this retrospective hospital-based study we have collected data from two main oncology centers in Armenia: National Oncology Center and Muratsan Hospital Complex of Yerevan state medical university. The information about patients with CRC who were treated at these two centers during 01/01/2010 - 07/01/2018 period was collected from the medical records. Results: 602 patients with CRC treated during mentioned period in these two hospitals were involved in final analysis. From them 51.8% were female. Median age at diagnosis was 58. Median follow up time was 37 months (range 3-207). 26.1% had right sided, 30.9% left sided and 43.0% rectum cancer. 8.6% of patients had stage 1, 32.9% stage 2, 38.0% stage 3, 17.6% stage 4 CRC and for 2.7% patients stage was unknown. The median survival was not reached for the entire cohort ( > 37 months). Median survival was > 66.5 months for 1st, > 48.5 months for 2nd, > 35 months for 3rd and 19 months for 4th stages. Tumor stage, grade and histology were the main independent prognostic factors by univariate and multivariate Cox regression analysis. For stage 2 CRC patients (198) we found significant difference regarding overall survival (OS) (p = 0.024) and disease free survival (DFS) (p = 0.006) for those who received adjuvant chemotherapy after surgery compared to those who didn’t receive adjuvant chemotherapy. For stage 2 and 3 rectum cancer patients, our study failed to show OS (2nd stage: p = 0.961; 3rd stage: p = 0.348) or DFS (2nd stage: p = 0.719; 3rd stage: p = 0.983) advantage for those who received radiotherapy (RT) compared with those who didn’t receive RT. In our study population 28.3% of stage 4 patients received chemotherapy combined with Bevacizumab while 70% were treated with chemotherapy only. Median OS between these two groups wasn’t significantly different (21 months in Chemo+Bevacizumab group and 18.5 months in chemo only group (p = 0.382)). 3 and 5-year survival rates were 62.9% and 51.8% for all stages combined and 79.7% and 68.5% for stages 1-2, 62.5% and 48.4% for stage 3, 24.4% and 17% for stage 4 respectively. Conclusions: As seen from our results our survival rates are inferior compared to that of developed world. The reasons for that could be compromise in surgery and RT, poor pathological assessment, unavailability of some molecular markers, poor availability of new targeted drugs and absence of national treatment guidelines.
The clinical impact of MicroRNA-21 in low rectal cancers treated with curative radiotherapy in the organ preserving setting.
Authors: Hansen Torben , Thomsen Caroline Brenner , Andersen Rikke Fredslund , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller
Published: May 2020

e16120

Background: Neoadjuvant chemoradiotherapy (CRT) in curatively intended doses may result in clinical complete response (cCR) in selected patients, allowing for non-surgical management (NSM) of patients with low rectal cancers. MicroRNA-21-5p (miR-21), ubiquitous upregulated in cancer, has been associated with treatment response in rectal cancers treated with standard preoperative CRT. The aim of the present study was to investigate this association in low rectal cancers treated in the NSM setting. Methods: Forty eight patients from our single-arm phase II trial (NCT00952926) were available for analyses. All patients had resectable, T2 or T3, N0–N1, low adenocarcinomas and received 65Gy (intensity-modulated radiotherapy plus brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, magnetic-resonance imaging and biopsy) were referred to observation and followed closely. The miR expression, in the diagnostic biopsies, was measured by qPCR in 20 µl reactions using TaqMan MicroRNA Assays. The protocol using custom RT and preamplification pools was followed. The miR-193a-5p, -27a and –let7g were used for normalization based on previous recommendations from our group. The relationship between miR-21 expression and cCR was assessed using the Wilcoxon rank-sum tests. Results: Thirty-eight patients achieved cCR after treatment and were followed in observation while 10 patients proceeded to surgery due to a non-cCR. MicroRNA-21 was successfully analyzed in all samples. The median tumor expression of miR-21 in patients proceeding to surgery was significantly higher compared to patients achieving cCR, 24.3 (95% confidence interval (CI) 17.1-36.8) and 16.6 (95% CI 13.9-21.1), p = 0.02, respectively. Conclusions: The present results support a clinical impact of miR-21 in rectal cancer treated with CRT, comparable with results seen in patients treated in the standard preoperative setting, and may assist in the selection of patients for an organ preserving approach.
Phase II trial of induction chemotherapy plus chemoradiotherapy with aspirin or placebo in high-risk rectal cancer (ICAR).
Authors: Souza Juliana , Araujo Rodrigo Otavio , Valadão Marcus , Santos Victor Marcondes Lopes , Gonzaga Jamille , Padoan Monica Luciana Agostinho , Barbosa Monique Alvares , Torres Claudia , Guimarães Raquel , Carvalho Juliana , Gil Roberto de Almeida , Small Isabele , Ferreira Maria Aparecida , Correa João Pedro Araujo Simões , Oliveira Ivanir Martins , Mello Eduardo Linhares Rielo , Melo Andreia Cristina De , Araujo Luiz H.
Published: May 2020

e16131

Background: Induction chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in locally-advanced, high-risk rectal cancer. Additionally, aspirin has shown potential to lower recurrence rate in colorectal cancer, and improve outcomes alongside CRT in rectal cancer, with higher rate of tumor downstaging. Methods: Randomized, double-blind phase 2 trial to evaluate induction treatment with XELOX, followed by capecitabine-based chemoradiotherapy with aspirin or placebo in a high risk population selected by MRI. The aim of this study was to evaluate MRI response after total neoadjuvant treatment with aspirin or placebo. Results: Of the 25 pts who started treatment between January 2018 and March 2019, 4 pts did not complete (1 pt grade 5 diarrhea; 1pt treatment adherence). Median age was 55yo (32.9 - 73.6), 8 pts (32%) were women, and 80% had 3 or more high-risk criteria. 20 pts (80%) showed symptom improvement in the first cycle of IC. Of the 21 patients who finished treatment until interim analysis, 11 pts received aspirin (2 pts had MRI complete response (CR), 3 pts had minor/no response, and 3 pts had progression disease (PD)). 10 pts received placebo (4 MRI CR, 3 pts had minor/no response, and no PD). Conclusions: Aspirin added to chemoradiotherapy was safe but did not improve response to total neoadjuvant treatment. The study was closed due absence of benefit. Clinical trial information: NCT03170115 .
Circulating mitochondrial DNA (mtDNA) variants to predict metastatic progression of rectal cancer.
Authors: Ree Anne Hansen , Bousquet Paula A , Bjørnetrø Tonje , Fuglestad Anniken Jørlo , Lüders Torben , Esbensen Ying , Johansen Christin , Juul Hedvig V , Inderberg Else Marit , Kersten Christian , Redalen Kathrine Røe , Meltzer Sebastian
Published: May 2020

e16132

Background: High rates of systemic failure after curative-intent therapy in locally advanced rectal cancer (LARC) call for new diagnostic tools to improve risk-based treatment stratification. We hypothesized that blood mtDNA polymorphisms, generated by the high mtDNA mutation rate when the mitochondrial biogenesis is mobilized during clonal immune cell activation, correlate with systemic immune control of LARC dissemination and thus can be used as diagnostic marker. Methods: 41 LARC patients given neoadjuvant (chemo)radiotherapy had DNA extracted from whole blood (WB) sampled at the time of diagnosis, for high-throughput full-length mtDNA sequencing followed by annotation of mtDNA variants using the curated reference genome (mitomap.org). The composition of peripheral blood mononuclear cell (PBMC) subpopulations was analyzed by high-dimensional single-cell mass cytometry. Metastatic events were recorded over 24-60 months of follow-up after completion of the multimodal treatment. Results: The total number of WB-mtDNA variants was strikingly different across the study cases but without correlation to patient’s age, body mass index, or metformin use, which may affect mitochondrial function, or to the disease extension at presentation or the local tumor response to the neoadjuvant therapy. All patients had microsatellite-stable tumor. The higher the number of variants in MT-RNR2, encoding one of the two ribosomal subunits of mitochondria, the better distant metastasis-free survival (DMFS). For each patient, two MT-RNR2 sites were homoplasmic for either the normal or a deletion (3105AC > A, 3106CN > C) variant, categorizing the patients into two groups that comprised the same cases for both mtDNA sites. Nine of a total of 10 DMFS events occurred during the 18 first months of follow-up in one of the patient groups ( n = 23). The single event in the other group ( n = 18) appeared in a patient who had declined primary tumor surgery. In the former group, a low number of variants in the ribosomal subunit MT-RNR1 identified all patients who had metastatic progression. These patients had reduced PBMC frequency of CD8+ (cytolytic) T cells that were positive for CXCR4 ( p = 0.001), a chemokine receptor that promotes their homing to tumor sites. Conclusions: The WB-ribosomal mtDNA polymorphisms reflected systemic immune cells endowed with cytolytic and tumor-homing properties. The actual mtDNA variants were single-base alterations and might thus be analyzed by PCR and developed as a feasible assay for metastatic risk assessment in rectal cancer. Clinical trial information: 01816607 .
A prospective pilot study of pharmacogenetic-based dosing of 5-fluouracil (5-FU) and irinotecan (IRI) in patients (pts) with gastrointestinal (GI) malignancies.
Authors: Chi Jeffrey , Hakim Nausheen , Rehman Hasan , Moriarty Linda , Maloney Antonia , Smith Melissa H , Jose Jyothi , Saif Wasif M.
Published: May 2020

e16138

Background: 5-FU and IRI are core components of chemotherapies for GI malignancies. Previous studies have shown that mutations in DPYP and TYMS predispose the pts to 5-FU toxicities. Mutations in UGT1A1 predispose pts to increased IRI toxicities. Retrospective data suggest that these mutations may have implications in selecting dosage and/or schedule of 5-FU and IRI. We present here a prospective study of upfront pharmacogenetic testing with tailored dose of respective drugs in pts with these mutations. Methods: Pts with GI malignancies were tested for DPYD, TYMS and UGT1A1 mutations before initiating 5-FU and/or IRI. Mutation analyses were performed at Quest Diagnostics Nichols Institute. Pts were dosed at 50% if DPYD was abnormal and 25% dose reduction if indicated by TYMS or UGT1A1 * 28 (homozygous) abnormality. Adverse events (AEs) were graded according to CTCAE v.5.0. We compared AEs to our previously collected data in DPYD, TYMS deficient pts who underwent genetic testing due to toxicity to 5-FU. Results: Of 226 pts screened, 5 pts had DPYP mutations with genotypes (3: c.1905+1G/A; 1: c.2846A/T; 1: c.557A/G). TYMS mutations were identified in 24 pts. For 3'-UTR, distributions were: intermediate expression genotype 4: INS/DEL, low expression genotype 5: DEL/DEL. For 5'TSER, distributions were: low expression genotypes (6:2R/2R; 3:2R/3RC; 4: 3RC/3RC) and high expression genotypes (2: 2R/3RG, 2: 3RG/3RC, 1: 3RG/3RG). UGT1A1*28 mutation was identified in 53 pts – 19 homozygous and 34 heterozygous. No grade ≥3 neutropenia was observed with reduced dose of IRI in UGT1A 1 variant pts compared to 33% reported in pts not tested. For TYMS and DPYD variants, no grade ≥3 AEs were seen. Comparison of AEs in pts with post treatment genetic testing is listed in Table. Conclusions: Pharmacogenetic based dosing of 5-FU and IRI led to less frequent, less severe toxicities and no death related to AEs was observed in our pts. This can improve pts’ quality of life and lessen economic burden of managing severe AEs. Currently, there are no formal guidelines regarding testing for DPYD, TYMS and UGT1A1. Although non-randomized, this study advocates for systemic screening of pharmacogenetic testing in pts with GI malignancies. [Table: see text]
Prospective evaluation of current RAS mutation testing practices in newly diagnosed metastatic colorectal cancer: Middle East and North Africa Registry (MORE-RAS) Study.
Authors: Oukkal Mohammed , Kamel Bouzid , Bounedjar Adda , Alnajjar Abdelsalam , Abu-Taleb Fouad , Alsharm Abdullah , Mahfouf Hassen , Blaha Larbaoui , Elsaid Amr A. , Ouamer Assia , Basir Linah
Published: May 2020

e16141

Background: RAS testing is essential for treatment selection in metastatic colorectal cancer (mCRC), as anti-EGFR treatment is indicated only in patients with wild-type (WT) RAS. MORE-RAS was a multicenter, multicountry, observational, ambispective (retrospective + prospective) study designed to evaluate RAS mutation status among patients with mCRC in the Middle East and North Africa (MENA) region. Results of the retrospective study over a prior 2-year period have been previously presented. Here, we report on the prospective evaluation of testing practices in newly diagnosed patients from the same centers. Methods: Five countries (Algeria, Egypt, KSA, Kuwait, Lebanon) enrolled patients between Dec 2014 and Feb 2019. Patients with a new diagnosis of histologically proven mCRC, at least 1 measurable lesion per RECIST criteria, and tissue availability for biomarker analysis were included; those with co-existing malignancies or life expectancy < 6 months were excluded. The primary endpoint was evaluation of the rate of RAS mutation in newly diagnosed patients. Follow-up was for 2 years. Results: 500 patients (mean age 54.6 years; 58% female) were included; 96.4% had Stage 4 disease. Primary tumor sites were sigmoidal colon: 33.4%; rectum: 29.6%; ascending colon: 18.4%; descending colon: 11.4%; transverse colon: 5.2%; and unknown: 1.4%. Most frequent sites of metastasis were liver: 43.4%, lung: 16.0%, and peritoneum: 10.1%. Overall, 407 pts (81.4%; 95% CI, 78%–85%) received prescription for RAS testing. RAS WT was found in 58.4% and mutant in 41.6%; the test was inconclusive in 1 pt. Non-prescription was attributed to test unavailability and medical or financial reasons. The distribution of mutations was KRAS: 85%, NRAS: 4.9%, and not available: 10.1%. Predictors of RAS testing prescription were older age, primary tumor localization in ascending colon, and high tumor grade. Knowledge of RAS status resulted in the addition of bevacizumab or anti-EGFR therapy in 20.4% and 21.2% of pts, respectively at Visit 1 (baseline). Conclusions: RAS testing is now routinely prescribed for newly diagnosed mCRC in the MENA region and can change therapy patterns. The RAS mutation rate in this region differs from that in Western countries.
Serum-based multiplex protein assay for early detection of colorectal cancer and precancerous lesions in a FIT positive population.
Authors: Fritsche Herbert A. , Liggett Jason Lee , Zhang Hong , Ferm Linnea , Christensen Ib Jarle , Nielsen Hans J.
Published: May 2020

e16145

Background: Colorectal cancer (CRC) is the second leading cancer worldwide in terms of incidence, 5-year prevalence and mortality for both women and men ages 45 years old and up. The current screening method for many countries with organized screening programs is the FIT test for fecal occult blood; however, this test can result in false positive rates as high as 65%. A FIT reflex test could reduce unnecessary colonoscopies while reducing wait times for those patients that need confirmatory colonoscopies the most. Methods: Danish FIT positive colonoscopy confirmed serum samples (n = 1,499) were divided into training and validation sets maintaining approximately equivalent percentages of clean colonoscopy (40%), low risk adenomas (16%), medium risk adenomas (19%), high risk adenomas (13%), stage I CRC (5%), stage II CRC (2%), stage III CRC (4%), and stage IV CRC (0.5%). Proteins were quantified by custom 16-plex immunoassays utilizing the Luminex xMAP platform. A support vector machine supervised machine learning algorithm was trained with the 16 biomarkers plus age and FIT concentration using 1,291 samples for the outcome medium risk adenoma, high risk adenoma, and CRC. Then this algorithm was tested on a blind 208 sample validation set. Results: The training set was 90% sensitive and 27% specific (AUC = 0.68) and the validation set was 93% sensitive and 21% specific (AUC = 0.63). The sensitivities of the validation by risk/stage was as follows: medium risk adenoma 91%, high risk adenomas 92%, stage I CRC 100%, stage II CRC 100%, stage III CRC 100%, stage IV CRC 93%. Conclusions: This study demonstrates feasibility of a novel blood-based multiplex protein immunoassay for use as a reflex to FIT positive results in population wide screening. It detected nearly all adenomas and carcinomas while reducing FIT false positives and thus unnecessary colonoscopies by more than 20%. A FIT reflex test could alleviate endoscopy burden experienced in countries with organized cancer screening programs, while providing better patient outcomes by detecting polyps and early-stage CRC with high sensitivity.
Genetic landscape of 43 patients with dMMR gastric cancer and its clinical implications.
Authors: Wang Dongliang , Hu Nana , Xu Quan , Meng Erhong , Li Zhongwu , Shen Lin
Published: May 2020

e16501

Background: The FDA has approved immune checkpoint inhibitors for dMMR/MSI-H patients with solid tumors, but the efficacy varies greatly, so that more molecular biomarkers are needed to guide the clinical practice. Methods: In this study, the gene status of tumor tissues of 43 patients with dMMR gastric cancer previously identified by immunohistochemistry (IHC) was measured using TSO500, and the gene profile was preliminarily determined. Results: The genetic landscape is different between these 43 dMMR gastric cancer and TCGA as well as 200 cases of ordinary gastric cancer in China. The top five mutational genes in patients with dMMR gastric cancer were LRP1B (65.12%), RNF43 (62.79%), TP53 (58.14%), ARID1A (58.14%), BRCA2 (44.19%). In TCGA, the top five mutational genes were TP53 (48.1%), MUC16 (41.8%), SYNE1(32.1%), ARIDIA (31.4%) and LRP1B (30.7%). In 200 cases of patients with ordinary gastric cancer in China, the top five mutational genes were MUC6 (86.6%), MUC16 (84.6%), MACF1 (68.7%), DST (66.2%) and ZFHX4 (65.7%). The frequently abnormal signaling pathways in patients with dMMR gastric cancer were RTK/RAS (84%), P53 (77%), PI3K (74%), Notch (74%), Wnt (70%), Myc (47%),TGF-β(40%) signaling pathway. In addition, it was found that 40% of patients with dMMR gastric cancer were microsatellite-stable (MSS). Among the four dMMR biomarkers, 91.11% MLH1 negative or 86.67% MSH6 negative patients with dMMR gastric cancer were microsatellite-instable(MSI)–H, while only 11.11% MSH2 negative or 6.67% MSH6 negative patients with dMMR were MSI-H. Conclusions: This study provided important novel insight into the biology of dMMR gastric cancer and identified clinically genetic features for the future improvement management of patients with dMMR gastric cancer. It also suggested that in clinical practice, IHC is only suitable for preliminary screening. [Table: see text]
Hepatic arterial infusion oxaliplatin plus oral S-1 chemotherapy to improve prognosis for gastric cancer with multiple liver metastases.
Authors: Wang Kangxin , Yang Yang
Published: May 2020

e16508

Background: Gastric cancer with multiple liver metastases (GCLM) is associated with a high disease burden with synchronous or metachronous tumour invasions of other organs. In order to improve patient outcome, this study combined hepatic artery infusion (HAI) oxaliplatin with oral S-1 chemotherapy as a first-line palliative therapy. The aim is to assess efficacy and safety of this combination mode. Methods: We reviewed the records of ten patients with GCLM who received HAI oxaliplatin (70-80 mg/m2 2h d1,15) administered via a port-catheter system and S-1 with oral (35-40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically. Results: Until the 4th cycle response evaluation, the local effective rate and control rate was 60% and 90% respectively, only one patient developed progression. HAI oxaliplatin plus oral S-1 chemotherapy had a better local control against hepatic metastases (median progression-free survival: hepatic, 9.0 months vs. extrahepatic, 6.5 months), which showed potential benefit of the combination regimen in gaining local tumour control, maintaining function and improving life quality. Conclusions: HAI oxaliplatin plus oral S-1 chemotherapy can be regarded as an optimized treatment strategy for GCLM, which is also a crucial way for controlling of extrahepatic lesions without much systemic toxicity.
Esophageal cancer, five years of experience in a regional oncologic reference center in Mexico.
Authors: Alcorta-Garza Adelina , Cessa-Zanatta José Carlos , Alcorta-Nuñez Fernando , Muñoz-Ayala Juan Manuel , Hernández-Barajas David , Gonzalez Guerrero Juan Francisco , Vidal-Gutiérrez Oscar
Published: May 2020

e16515

Background: Esophageal cancer is a highly lethal entity. Within this group of tumors, squamous cell carcinoma (SCC) and esophageal adenocarcinoma (ACE) represent 95% of the total. For most of the twentieth century, the SCC predominated throughout the world, however, this trend has changed dramatically in Western countries, including ours. Mexican patients with esophageal cancer are diagnosed at later stages of the disease and have worse therapeutic outcomes than reported in the world literature. Methods: Retrospective, observational and descriptive study. The research subjects were obtained from the population of patients who attended the service of the Centro Universitario Contra el Cancer of the University Hospital "Dr. José Eleuterio González” between 2012 and 2017 (sample size calculated n = 120).The clinical and demographic characteristics of patients with esophageal cancer in our population were described. The results from international guides (AIMS65, New International Score, Glasgow-Blatchford scale and Rockall pre-endoscopic) were used to compare cut-off points with our population and their correlation with mortality. Results: A total of 179 research subjects were included in the study. The average age was 55 years, 62% male and 38% female. Various demographic characteristics such as in-hospital mortality (n = 42, 23.5%), 30-day mortality (n = 36, 20.1%), re-bleeding (n = 49, 27.4%) and transfusions (n = 99, 55.3%) were studied as incidence of positive cases to the event. We also studied the mean days of hospital stay (4.6 days), systolic blood pressure (108 mmHg) and diastolic blood pressure (66mmHg), hemoglobin (8.9 g / dL), among others. The type of bleeding was variceal in 122 subjects, and non-variceal in 57. In total, 117 subjects were treated with endoscopic treatment and 53, without endoscopic treatment. The Glasgow Blatchford scale obtained a higher discriminative score (AUROC 0.73) to predict in-hospital mortality in our subjects, compared to ASA (0.72 p < 0.001), New International score (0.76 p < 0.001) and AIMS65 (0.66 p < 0.001). Conclusions: The used scales had no positive predictive value for bleeding risk. The Glasgow Blatchford scale was the only score that showed an AUROC of 0.65 p < 0.001 to predict the efficiency of transfusion in patients compared to the other scores that showed no significant value. ASA was the predictive discriminative score (AUROC 0.73) for a 30-day in-hospital mortality (p < 0.001), followed by the Glasgow Blatchford scale (0.61 p < 0.04).
Identification and expression distribution of esophageal carcinoma autoantigens.
Authors: Si Fuchun
Published: May 2020

e16520

Background: To identify the autoantigen protein molecules with autoserum in the tissues from the esophageal carcinoma (EC) patients, analyze autoantigen expression distribution in EC tissues, so as to provide basis for the molecular pathogenesis and clinical medication of EC. Methods: 69 cases of EC patients tissues and serum and 81 cases of healthy people serum were collected, serological proteome analysis (SERPA) was modified with sequential extraction of subcellular protein fractions to identify esophageal oncopathgensis stages autoantigen with autoserum in the tissues from the EC patients. Another 93 cases of EC patients tissue were collected, immunohistochemical and western blot method were used to detect expression distribution of EC autoantigens in esophageal carcinoma tissue, para-carcinoma tissue and normal tissue. Results: Autoantigens CK13, CK16, CaD, ACTG2, tumor rejection antigen (gp96) 1 variant, heat shock protein gp96 precursor were identified, among wihich, CK16, CaD, ACTG2, tumor rejection antigen (gp96)1 variant, heat shock protein gp96 precursor were firstly reported as EC autoantigens. Expression of autoantigens CK16, CaD, ACTG2 were increased in EC carcinoma tissue than para-carcinoma tissue and normal tissue, while CK13 were decreased. Positive expression level of CK16 in normal tissue, para-carcinoma tissue and cancer tissue of EC patients was 0.0076±0.0033, 0.0158±0.0065, 0.0356±0.0165 respectively, CaD was 0.0085±0.0048, 0.0107±0.0056, 0.0177±0.0103 respectively, ACTG2 was 0.0091±0.0039, 0.0136±0.0043, 0.0214±0.0110 respectively, and CK13 was 0.2053±0.0311, 0.1633±0.0280, 0.0412±0.0239 respectively. Conclusions: 6 EC autoantigens were identified, and 5 were first reported. Autoantigens CK13, CK16, CaD and ACTG2 were expressed in EC patients carcinoma tissue, which can be the potential biomarkers of esophageal carcinoma. This study provides new basis for the EC molecular mechanism and development of molecular drugs.
Camrelizumab (Camre) plus taxane-based chemotherapy (CT): Clinical outcomes and dynamic monitoring of CEA as a predictive biomarker of response in patients with recurrent or advanced esophageal squamous cell carcinoma (ESCC).
Authors: Kong Cheng , Xu Jianhua , Jiang Ming , Zhu Xiangzhi , Ye Jinjun , Yu Shaorong , Zhu Jun
Published: May 2020

e16524

Background: Keynote-181 study reported anti-PD-1 antibody pembrolizumab as monotherapy had shown superior efficacy compared to CT for previously treated patients (pts) with advanced ESCC. The combination of anti-PD-1 antibody and CT may be a feasible approach to provide antitumor activity superior to either agent alone. However, the available data about the combination strategy is limited. Methods: We retrospectively reviewed the records of pts treated at our center to identify pts seen between 7/2019 and 12/2019 with recurrent or metastatic ESCC who received treatment with Camre (anti-PD-1 antibody) plus taxane-based CT. The primary endpoints were objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Secondary endpoint included toxicity. The carcinoembryonic-antigen (CEA) dynamics and clinical associations were also evaluated in the selected pts. Results: A total of 14 pts were identified. The median age was 66 years (44-80). Most pts were male (12/14, 85.7%) with metastatic disease (10/14, 71.4%). The CT regimens contained nab-paclitaxel in 4 pts, nab-paclitaxel plus nedaplatin in 2, liposomal paclitaxel in 2, liposomal paclitaxel plus nedaplatin in 6. Camre in combination with CT were repeated every 3 to 4 weeks for up to 4 cycles. Two pts also received maintenance therapy of Camre for 4 and 6 cycles. Five pts (35.7%) exhibited a best overall response of PR, 6 (42.9%) SD, and 3 (21.4%) PD. The ORR and DCR were 35.7% (5/14) and 78.6% (11/14), respectively. All the SD determination as the best response met the minimum interval of 8 weeks from baseline. Toxicity profile was mild with mainly grade 1, expected toxicities. The most common grade 3/4 adverse events were leucopenia (2/14, 14.3%) and neutropenia (2/14, 14.3%). CEA baseline levels were normal in 6 cases, elevated in 8. It was observed that CEA levels closely paralleled overall measurable tumor burdens in all the CEA-elevated pts. A patient with equivocal radiographic pseudoprogression even had CEA dynamics that correlated with eventual clinical outcome. Conclusions: We identified a group of pts of recurrent or metastatic ESCC treated with Camre plus taxane-based CT and achieving a favorable DCR to therapy with a tolerable toxicity profile. This combination regimen warrants further exploration in a prospective clinical trial. CEA dynamics may be a useful tool to monitor disease evolution in this setting.
Study of efficacy and tolerability of paclitaxel and carboplatin as a concurrent chemotherapeutic radiation sensitizer regimen in patients of esophageal cancer: Prospective observational study from tertiary center in northern India.
Authors: Goyal Pankaj. , Chaudhari Krushna A. , Batra Ullas , Jain Parveen , Agrawal Chaturbhuj , Talwar Vineet , Goyal Sumit , Bothra Sneha , Domadia Kshitij , Babu Venkata Pradeep , Doval Dinesh Chandra
Published: May 2020

e16526

Background: Neo-adjuvant chemotherapy followed by surgery is the standard of care in non metastatic oesophageal cancers. After the overall survival benefit observed in Cross trial, Paclitaxel and Carboplatin based neo-adjuvant chemoradiation has become the preferred treatment modality. There is paucity of data of its efficacy and tolerability in Indian patients. So this prospective study was done to assess the same. Methods: We enrolled 64 patients aged 18-75 years with histologically confirmed, potentially resectable squamous-cell carcinoma of the esophagus or esophagogastric junction from Aug 2017 to Jan 2019. On days 1, 8, 15, 22, and 29, carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously and a total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy each by external-beam radiation. Pathological complete response rate, Clinical response based on PET-CT scan and tolerability of paclitaxel and carboplatin as a concurrent chemotherapeutic radiation sensitizer regimen was studied. Results: 23 out 64 patients underwent surgery while others were either lost to follow up or they refused for surgery. Of these 23, 87.5% could complete all 5 planned cycles of chemotherapy. Complete pathological response was found in 73.9% patients. Statistically significant correlation was found between pathological and PET-CT based response (p-0.044). 4 patients showed distant progression on PET-CT based evaluation after neoadjuvant chemo radiotherapy before surgery. The most common major hematologic toxic effects were leukopenia (14%) and neutropenia (12.5%). Febrile neutropenia and grade 3 anemia was observed 2 and 4 patients respectively. The most common major non-hematologic toxic effects were vomiting (4.6%), nausea (3.1%), bronchoesophageal fistula(3.1%). Post operative mortality was seen in 1(4.3%) patient. Grade 3 pulmonary complications, atrial fibrillation and anastomotic leak was observed in 1 patient each. Conclusions: Concurrent chemoradiotherpy with weekly paclitaxel and caboplatin is well tolerated in Indian patients. High complete resection rate and PCR rate can be achieved with this regime with manageable adverse effect profile. Response evaluation with PET-CT after completion of preoperative therapy has correlation with pathological complete response.
Does radical surgery for gastric cancer after 70 years prolong survival?
Authors: Chanez Brice , Guiramand Jérome , Niziers Vincent , Dermeche Slimane , Rochigneux Philippe , Ries Pauline , Rousseau Fréderique , Loir Elika , Gilabert Marine
Published: May 2020

e16527

Background: Gastric cancer (GC) occurs in 50% of case after 70 years old (y/o). Radical surgery or perioperative treatments have to be balanced with safety management in those potential frail patients. Methods: We perfomed a retrospective review of our single institution database to address the outcome of patient (pts) > 70y/o who underwent radical surgery for GC with or without neoadjuvant and adjuvant treatment. Results: From 2005 to 2019, 60 eligible patients (pts) have undergone radical surgery for resectable GC. Median age at diagnosis was 74.2y/o [70.3-92.8] and 82% were male. Initial echoendoscopy staged 12% of T1/T2 tumor versus 70% of T3/T4, whereas 60% were found with lymph node spreading (N+). 80% of pts were given neoadjuvant treatment: chemoradiation (58%), chemotherapy (45%) or radiation alone (1%). 1/4 pt received perioperative chemotherapy. Only one patient had post-operative radiation with FOLFOX and none had adjuvant radiation alone. Surgery procedure was total (27%) or sub-total (5%) gastrectomy, polar-oesogastrectomy with thoracotomy (18%) or without thoracotomy (50%). Post-operative mortality within 3 months was 5% (n = 3) including 2 pts in the first 30 days. For the global cohort, median overall survival (mOS) was 44.75 months and median progression free survival (mPFS) was 21.2 months. Patients who frontly underwent radical surgery (n = 15, 25%) had small disease with 13% pT0 and 60% of pT1 on final pathology. Only 27% had pT2/T3 but all had vascular and/or peri-nervous emboli. Two of them (13%) were pN+. The mOS was 60 months and mPFS 60 months in this cohort and 33% of pts end/was lost of follow up. Only one metastatic relapse was identifies and no local relapse. Six pts died (40%): 2 in the 30-days post surgery (13%), 3 (30%) from other cause than GC and 1 (7.5%) because of GC distant relapse. The cohort treated with neoadjuvant chemotherapy (n = 45, 75%) was given platinum and anthracycline-based regimen in 73% and 16% of cases, respectively. 1% received fluoropyrimidine +/- irinotecan. 53% associated radiation to neoadjuvant chemotherapy. After neoadjuvant treatment completion, 47% of downstaging (including 18% of pCR), 33% of stable stage and 15.5% of upstaging was observed and 40% of initial usN+ was pN0. After perioperative treatment, mOS was 31 months and mPFS was 18.9 months. Overall 44% experienced local and/or distant relapse. Conclusions: Age above 70y/o should not systematically exclude patient from neoadjuvant or perioperative treatment and radical surgery, which is feasible in selected population displaying long term result in focal and distant disease control.
Effects of alkaline water intake on gastritis and miRNA expression (miR-7, miR-155, miR-135b and miR-29c) in the Amazon population.
Authors: Chaves Juliana Ramos , de Souza Carolina Rosal Teixeira , Modesto Antonio André Conde , Moreira Fabiano Cordeiro , Teixeira Eliel Barbosa , Sarraf Jonathan Souza , Allen Thaís Suellen Ramos , Araújo Taíssa Maíra Thomaz , Khayat Andre Salim , Werneck De Carvalho Luis Eduardo
Published: May 2020

e16544

Background: It is known that abnormal expression of miRNAs in the gastric cancer (GC) contributes to its carcinogenesis. Therefore, ingestion of commercial (usual) water on a daily basis may be a contributing factor for the occurrence of alterations in the gastric mucosal. In this study, it was evaluated the expression of the miRNAs miR-29c, miR-7, miR-155, and miR-135b in the gastric tissue of patients with gastritis before and after the consumption of alkaline water (pH range from 8.0 to 10.0), as well as the clinic pathological characteristics. Methods: 50 subjects from the Amazon region, diagnosed with gastritis that routinely used commercial (usual) water with a pH lower than 5.0, were enrolled to change the consume water to a pH of 8.5 to 10.0 for 5 months. Results: Endoscopic findings of gastritis were such different (less severe disease), p = 0.024; in 43% diagnosed with moderate gastritis upfront esophagogastroduodenoscopy (EGD) presented mild gastritis after the consumption of alkaline water, according to study methods; there were no worsening gastritis and there were a significant increase in the expression of miR-135b (p = 0.039) and miR-29c (p = 0.039). Conclusions: Modified pH range water (from 8.0 to 10.0) ingested for 5 months was able lead to a less severe gastritis according to the Sidney classification system, suggesting that this lifestyle change represented a clinical benefit in patients with gastritis on the Amazon region. In addition, higher expression of miR-135b and miR-29c was observed after the consumption of alkaline water for 5 months. [Table: see text]
Knockdown of KREMEN2 inhibits tumor proliferation and metastasis in gastric cancer.
Authors: Chen Beibei , Wang Saiqi , Huang Jinxi , Li Jitian , Zhang Jianying , Xu Weifeng , Lv Huifang , Nie Caiyun , Wang Jianzheng , Liu Yingjun , Chen Xiaobing
Published: May 2020

e16555

Background: KREMEN2 is an important regulator of classical Wnt/β-catenin signaling pathway. However, the relationship between KREMEN2 and gastric cancer is not clear. The aim of this study was to explore the regulatory role of KREMEN2 in the tumorigenesis and metastasis of gastric cancer. Methods: We measured the protein level of KREMEN2 in 156 gastric adenocarcinoma, 40 metastatic gastric adenocarcinoma, 8 marginal and 4 normal tissues using tissue microarray. The differences in KREMEN2 expression were tested with Mann-Whitney U test. The relationship between KREMEN2 expression and pathologic data was determined with Pearson’s correlation analysis. The mRNA and protein level in cultured cell lines were detected by qRT-PCR and western blotting, respectively. Lentivirus was transfected by repressing KREMEN2. Cell viability was determined by the MTT assay. Apoptosis and cell cycle distribution were detected using flow cytometry. The cell migration was investigated by wound healing and transwell assay. Antibody array was performed to explore the underlying molecule mechanism. In vivo, Xenograft assay was established using nude mice to explore the role of KREMEN2 in gastric cancer cell and bioluminescence was observed via an in vivo imaging system. Results: It was demonstrated that, compared to para-cancerous tissues, KREMEN2 was significantly up-regulated in gastric cancer tissues, and was positively correlated with the pathological grade of gastric cancer patients. Given that KREMEN2 is abundantly expressed in most tested gastric cancer cell lines, KREMEN2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down KREMEN2, the proliferation of gastric cancer cells was inhibited both in vivo and in vitro. At the same time, knockdown of KREMEN2 induced apoptosis, cell cycle arrest at G2/M phase and inhibition of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of KREMEN2 suppressed PI3K/Akt pathway. Conclusions: Therefore, we revealed that the overexpression of KREMEN2 in gastric cancer may promote the carcinogenesis and metastasis of gastric cancer by activating the PI3K/Akt pathway.