bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational profiles of sporadic synchronous colorectal cancer.
Authors: Yang Lu-Ping , Jiang Teng-Jia , He Ming-ming , Zhao Qi , Ling Yihong , Wang Zi-xian , Wu Hao-Xiang , Jin Ying , Zhang Zhen , Xu Rui-hua , Wang Feng
Published: June 2022

e15555

Background: Synchronous colorectal cancer (SCRC) refers to a special group of CRC with at least two primary tumors detected simultaneously in one patient, with 90% being sporadic. Although the systemic treatments of late-stage SCRC are mainly based on the molecular testing of one primary lesion, this might not be representable of the other tumors and metastatic lesions. This study aimed to investigate the molecular features and genetic heterogeneity of sporadic SCRC in order to guide clinical practice. Methods: We retrospectively collected all the primary tumor samples of 51 patients with sporadic SCRC, profiled 103 samples with whole-exome sequencing, and analyzed their molecular landscape and genomic profiles. We conducted comparative analyses between tumor pairs in one patient, and as well as between SCRC and solitary CRC. The evolutionary dynamics of SCRC tumors was also analyzed. Results: Most gene mutations and copy number variations were inconsistent in paired tumors except for early driving genes APC, TP53 and KRAS. No pathogenic germline variants of familial CRC-related genes were observed . Clonal composition analysis showed that tumors in 94.2% (48/51) of patients with SCRC were genetically heterogeneous. Only 7.8% (4/51) of patients harbored origin-shared tumors. Inconsistent MSI and TMB status were observed in 11.8% (6/51) of patients. For actionable RAS/ BRAF gene loci, 43.1% (22/51) of patients harbored tumor pairs sharing the same wild or mutant status. When compared with solitary CRC, SCRC had higher prevalence of MSI-H (29.4% vs. 12.0-17.0%) or TMB-H (33.3% vs. 10.0-16.0%) and lower mutational frequencies in the RTK/RAS (51.5% vs. 76.1%), PI3K (26.2% vs. 43.4%) and cell-cycle (2.9% vs. 10.2%) oncogenic signaling pathways. Moreover, neutral evolution analysis showed that 84.3% (43/51) of patients had at least one neutral tumor and 45.1% (23/51) of patients had tumors evolving differently. Conclusions: Sporadic SCRC was a special subclass of CRC, featured by prominent TMB-H, dMMR-related signatures, and intertumoral genetic heterogeneity. The tumors from the same SCRC patient tended to have different origins and evolved differently. Thus, clinical treatment strategies for sporadic SCRC should be re-evaluated accordingly.
Landscape of DNA damage response gene mutations in microsatellite-stable colorectal carcinoma.
Authors: Zhong Zhaoyang , Jiang Nan , Zhou Jinming , Shen Lu , Chen Rongrong
Published: June 2022

e15558

Background: Colorectal carcinoma (CRC) is one of the most frequent and lethal cancers in the world. Important therapeutic progress of immune checkpoint inhibitors (ICIs) is limited to molecular niche of CRC with microsatellite-stable(MSS). The identification of genomic alterations in the DNA damage response (DDR) pathway have been recognized as pathogenic factors in hereditary cancer predisposition. Few studies showed the effects of ICIs on DDR pathway in patients with MSS CRC. Some reports suggested that DDR could reshape tumor immune microenvironment by regulating tissue repair and local immune response. Here we evaluated the molecular roles of DDR pathway and the immune microenvironment in efficacy of immunotherapy in MSS CRC. Methods: A total of 67 patients with MSS CRC were enrolled into the study. All samples were collected and detected by using NGS with a 1021 gene panel which containing 56 DDR genes (Supplementary table 1). Furthermore, comprehensive bioinformatics analysis were performed by the TCGA and MSK data. We defined pathway alteration as at least one gene in DDR pathway mutated. Results: In our results, three DDR pathway alteration showed poor prognosis (P = 0.0167) compared with DDR wild type in TCGA data (Figure 1A). The MSK data demonstrated that three DDR pathway alteration were associated with a better prognosis in MSS CRC patients through ICIs therapy (P = 0.0416, P = 0.00627, respectively, Figure 1B). The clinical data suggested the patient with DDR pathway alteration had longer OS (354.7 ± 134.0 days, PR) than the others with DDR wild type (247.1± 258.4 days, PD/SD) after PD-1-targeted therapies (P = 1.587e-08). Moreover, the patient with DDR pathway alteration showed significant longer PFS (312.3 ± 179.2 days, PR) compared with DDR wild type (163.3 ± 157.7 days, PD/SD) through immune therapies (P = 4.249e-10). Moreover, significant results of immune infiltrate deconvolution revealed resting memory CD4+ T cells were the most prevalent population between DDR pathway alteration and DDR wild type using CIBERSORT analysis (P = 0.0295, Figure 1C). The activated memory CD4+ T cells in DDR pathway alteration were lower than DDR wild type (P = 0.00858, Figure 1C-D) in patients with MSS CRC. The effects of DDR pathway alteration on immune microenvironment was also necessary for effective PD-1-targeted therapy in future study. Our results suggest that two or more DDR pathways and CD4 + T cells may serve as immunotherapy markers for advanced MSS colorectal cancer. Conclusions: Mutations in DDR pathway may serve as a biomarker for PD-1-targeted therapy through memory CD4+ T cells for MSS CRC patients, which warrants further studies.
EPHB1 mutation predicts survival from treatment with immune checkpoint inhibitors and correlated with higher TMB and immune infiltrates in mCRC.
Authors: Cai Jinlin , Fan Dandan , Chen Yaoxu , Huang Mengli
Published: June 2022

e15559

Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, the research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that EPHB1 mutation in the NK cell-related pathway involved in the anti-cancer immune response and associated with survival of NSCLC patients, suggested that EPHB1 may be related to immune microenvironment and tumor immunity. However, the association between EPHB1 mutation and TMB or survival in metastatic Colorectal Cancer (mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs was retrieved from publicly accessible data(Pancancer.Samstein2018.NGS.1661),the association between EPHB1 mutation and overall survival(OS) was analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between EPHB1 mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, genome and immune cell infiltration data of 149 patients with Colon Adenocarcinoma (COAD) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and EPHB1 mutation status was further analyzed by CIBERSORT-ABS. Statistical significance was set at p = 0.05. Results: 7.3%(8/109) patients in the clinical cohort harbored EPHB1 mutation. Survival analysis in the public cohort demonstrated that EPHB1 mutation resulted in significantly longer OS (14 vs 8 months; HR, 0; p = 0.03) in mCRC patients treated with ICIs. Moreover, EPHB1 mutation was associated with higher TMB in public cohort (p = 0.0004). Furthermore, the correlation analysis between immune infiltration and EPHB1 mutation status in mCRC showed that CD8+T cells, activated memorial CD4+T Cell, M1 macrophages increased significantly in EPHB1 mutation patients(p = 0.023, p = 0.0079, p = 0.034). Conclusions: EPHB1 mutation may serve as a potential positive biomarker of ICIs in mCRC since it relatively correlated with higher TMB. In addition, the up regulation of CD8+T cells, activated Memorial CD4+T Cell as well as the M1 macrophages may be a potential mechanism for the better efficacy of ICIs in patients with EPHB1 mutation.
A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.
Authors: Chuang Jeremy , Gong Jun , Li Sierra , Wang Chongkai , Fakih Marwan
Published: June 2022

e15579

Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.
The professional seniority affects the clinical application of total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Şenocak Taşçi Elif , Aytac Erman , Ajredini Mırac , Mutlu Arda Ulaş , Yildiz Ibrahim , Ozer Leyla
Published: June 2022

e15590

Background: Total neoadjuvant therapy (TNT) integrates whole planned systemic chemotherapy within standard neoadjuvant protocols either before or after radiotherapy for locally advanced rectal cancer (LARC). Preference of neoadjuvant treatment type may vary among the medical oncologists. This study aimed to evaluate impact of professional seniority on TNT approach for LARC. Methods: A 20-item questionnaire was presented to medical oncologists as a cross-sectional survey during a national oncology congress via tablets. The evaluation was stratified by position; early-career oncologists (ECOs) and seniors. 2 questions were about experience regarding rectal cancer treatment. 5 questions were about physicians’ choice of screening and treatment in LARC and the factors affecting their treatment choices. 13 questions were about TNT approach (the sequencing of treatment, denominators of sequencing, chemotherapy choice, treatment response evaluation, operation preferences, adjuvant treatment and its denominators). Results: 189 medical oncologists were included (62.4% (n = 118) ECOs). An endorectal ultrasound was significantly preferred by the seniors (p = 0.039) in addition to conventional staging tools. 65.6% (n = 124) of the participants preferred long-course chemoradiation as their favorite neoadjuvant treatment approach. External sphincter invasion, threatened circumferential resection margin (CRM) and clinical stage were the most common denominators of TNT regardless of experience. ECOs favored short-course RT (p = 0.009) while the seniors chose long-course chemoradiotherapy (p = 0.041) as the index step of TNT. 57% (n = 108) of the physicians preferred to monitor treatment response for TNT at 8-weeks periods. Almost half of the participants (47.1%) reported pathological complete response (pCR) rates between 25-50% with TNT in their clinical practice. The physicians who prefer to give adjuvant treatment after completion of TNT make individualized decisions when surgical pathology reveals non-pCR, CRM and lymph node involvement. There was a significant difference between the ECOs and seniors (63.6 vs 45.1%, p = 0.013) in terms of choosing the adjuvant chemotherapy based on CRM positivity. Majority of the senior medical oncologists (88%) and ECOs (76.3%) agree that TNT should be the standardized neoadjuvant treatment approach for LARC. The preferred adjuvant chemotherapy after TNT was capecitabine-oxaliplatin (51.1%) or capecitabine alone (46%). Conclusions: TNT for LARC is well accepted among the medical oncologists and the professional seniority seems to affect its clinical application.
Evaluation of circulating tumor cells in stage III colorectal cancer patients under three or six months of adjuvant therapy.
Authors: Messaritakis Ippokratis , Koulouridi Asimina , Sfakianaki Maria , Vogiatzoglou Konstantinos , Gouvas Nikolaos , Tsiaousis Ioannis , Athanasakis Elias , Xynos Evangelos , Sougklakos Ioannis , Boukovinas Ioannis
Published: June 2022

e15601

Background: The duration of adjuvant oxaliplatin-combination treatment in stage III colorectal cancer (CRC) patients is still debatable. Circulating Tumor Cells (CTCs) have been proposed as a potential markers for detection of micrometastatic disease. The aim was to compare the elimination rate of CTCs in patients treated with three- and six-months treatment with FOLFOX or CAPOX, in stage III CRC patients. Methods: Peripheral blood samples were collected from 132 patients at baseline, after three (for all patients) and after six months (for those under six months treatment). Surgical specimens were collected from all patients for the evaluation of their genetic profiling using Sanger sequencing (Ras/Raf) and fragment analysis (microsatellite instability status). The detection and number of circulating tumor cells (CTCs) were evaluated using double immunofluorescence and a real time-polymerase chain reaction assay, at all three time points. Results: Median age of the patients was 62 years, 59.8% were males, 92.7% had a colon/sigmoid tumor location, 24.4% had tumor on the right colon and 99.2% had a good performance status (PS). Of all patients, 44.3% and 55.7% were treated with FOLFOX and CAPOX, respectively; patients received treatment for three and six months, were equally distributed. KRAS, NRAS and BRAFmutations were detected in 41.5%, 2.1% and 12.8%, respectively; whereas MSI-High status was detected in 9.8% of the patients. CTCs were detected in 43.2%, 42.4% and 54.2% of the patients, at baseline, after three and six months of treatment, respectively. Both positivity rate ( p< 0.001) and absolute number of CTCs ( p= 0.022) were decreased between baseline and three months of treatment. Moreover, a significant increase was observed both on the positivity rate ( p= 0.053) and absolute number of CTCs ( p< 0.001) between three and six months of treatment. Following Cox regression analysis, BRAF status and the detection of CTCs are significantly correlated with decreased time to progression. Conclusions: To conclude, the current study indicates that 3 months of adjuvant treatment is at least as efficacious as 6 months in eliminating CTCs. However, the increase of both the rate and number of positive CTCs after three months of treatment might highlight the emergence of resistant cancer cell clones.
Single-agent neoadjuvant immunotherapy of PD-1 antibody in resectable mismatch repair-deficient/microsatellite instability-high colorectal cancer.
Authors: Huang Jun , Pei Fengyun , Wu Jingjing , Zhao Yandong , He Wan , Shi Tianhao , Huang Meijin
Published: June 2022

e15605

Background: PD-1 blockade has been recommended as first-line therapy for non-resectable or metastatic mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, the safety and efficacy of neoadjuvant immunotherapy of PD-1 blockade for resectable dMMR/MSI-H CRC remains unclear. Methods: From June 2020 and March 2021, eight resectable dMMR/MSI-H CRC patients treated in the 6th Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were enrolled. All patients accepted 6 doses (200mg/dose, every 3 weeks) of Sintilimab injection (Innovent, LTD) before radical laparoscopic resections. The clinical and pathological data of the 8 patients was analyzed retrospectively. Results: All patients were confirmed dMMR by immunohistochemistry (IHC). However, 87.5% (7/8) of the patients were confirmed MSI-H and 12.5% (1/8) was confirmed microsatellite stable (MSS) by NGS. After 6 doses of neoadjuvant anti-PD-1 therapy, 87.5% (7/8) of the patients achieved pathological complete response (pCR), and the 7 patients were confirmed both dMMR and MSI-H. The rest 12.5% (1/8) who achieved major pathological response (mPR), with residual tumor <1%, was dMMR but MSS. None of the patients had immunotherapy-related adverse events (irAE) of grade 3 or above (CTCAE; version 5.0). 75.0% (6/8) of the patients had grade 1/2 irAE. No operational mortality or complications were found within 30 days after surgery. Conclusions: Single-agent neoadjuvant immunotherapy of PD-1 antibody was safe and effective in resectable dMMR/MSI-H CRC. Double confirmation of both dMMR and MSI-H status was necessary before PD-1 blockade therapy in dMMR/MSI-H CRC patients.
First-line therapy for gastric cancer with bone marrow metastasis and disseminated intravascular coagulation with infusional fluorouracil and weekly docetaxel: A multicenter, phase II clinical trail.
Authors: Zhai Xiaohui , Cao Taiyuan , Li Shanshan , Lin Xiaoru , Xiao Jian
Published: June 2022

e16004

Background: Gastric cancer (GC) with bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) is a special subtype of gastric cancer which has highly aggressive characteristic and extremely poor prognosis. Case reports showed chemotherapy achieved survival benefit but prospective trial is still urgently needed. Methods: This is a multi-center phase II clinical trial. Infusional fluorouracil of 200mg/m2/day, D1-21 (LD-FU) with docetaxel 25mg/m2, D1,D8,D15 will be administered to chemo-naïve metastatic GC with BMM and DIC every four weeks. The primary endpoint is the hematology response rate (HeRR) defined as the rate of platelet count restored to 100X109/L or higher. The secondary endpoints are time to HeR, duration of HeR, one-month mortality, overall survival, toxicity and the quality of life. Results: Until Feb 1, 2022, 11 gastric cancer patients with BM and DIC were enrolled in this trail and 8 patients reached the hematology response. The HeRR is 72.72%(8/11) and the media time to HeR is 13.5 days (11-20days). The rate of grade 1or to oral mucositis is 36.36%(4/11) and there is no grade 3 or 4 treatment toxicity. Conclusions: This is the first prospective clinical trail to evaluate the safety and efficacy of chemotherapy for advanced GC patients with BMM and DIC and will provide high level evidence to guide clinical practice. Clinical trial information: NCT04547153.
Safety and efficacy of anti-VEGF antibodies in the treatment of advanced gastric carcinomas.
Authors: Vorla Mounica , Akbar Usman Ali , Sheikh Daniya , Masthan Shameera Shaik , Pusa Mounika , Bamboria Aditya , Barham Saman , Dab Ammar Yaser , Qazi Shaheryar , Khan Adil , Anwer Rana Usman , Akinti Oluwasegun , Anwer Faiz
Published: June 2022

e16005

Background: The prognosis of gastric cancer remains poor despite advances in diagnostic techniques, neoadjuvant chemo radiotherapy and surgery. This led to the development of Anti-Vascular Endothelial Growth Factor inhibitors (Anti-VEGF), which inhibit angiogenesis, inducing a state of dormancy in the tumors. In this review, we studied the safety and efficacy of Ramucirumab (RAM) and Bevacizumab (BVZ). Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase & clinicaltrials.gov. A total of 311 articles were screened, and 4 studies were included. Results: When compared to placebo, in the two Phase III trials enrolling 1020 participants,RAM enhanced overall survival (OS) and progression-free survival (PFS). RAM treatment was associated with fewer hematological adverse effects, such as anemia. In addition, when administered in conjunction with CTx, bevacizumab (BVZ) improved OS (12.1m Vs 10.1m in one trial), but more clinical studies are needed to consolidate these findings. In both phase III studies with BVZ, anemia and neutropenia were shown to be less common, as shown in the table. Conclusions: Anti-VEGF inhibitors have shown to be effective in treating advanced or relapsed GC or GE CAs with minimal adverse effects. However, high-quality large prospective randomized clinical studies are still needed.[Table: see text]
ScRNA-seq based copy number variations (CNVs) detection identified TPSB2 and TPSAB1 as prognostic biomarkers in Gastric Cancer(GC).
Authors: Wang Tao , Zheng Liuqing , Wang Qian , Xiao Shanshan ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e16021

Background: Gastric Cancer (GC) is the third leading cause of cancer-related mortality around the world, with a relatively poor prognosis. Single-cell RNA-sequencing (scRNA-seq) is a powerful tool to analyze tumor microenvironment at a comprehensive resolution, revealing previously uncharacterized molecular complexities. CNVs detection based on scRNA-seq data can reveal genome heterogeneity, therefore identify prognostic biomarkers at the single cell level. Methods: ScRNA-seq data from publicly available dataset (Anuja S et.al, CCR 2020) with 3 gastric cancer tissues, and 3 paired adjacent normal tissues was used. We inferred CNVsusing non-malignant cells as reference to estimate the mutations of malignant cells based on InferCNV package. Survival analysis was made by Kaplan-Meier method on TCGA-STAD (Stomach adenocarcinoma) cohort to identify the CNV genes with prognostic ability. To further explore these genes, their correlations with CD8+T cells marker ( CD8A) and malignant marker ( EPCAM) were analyzed based on the Spearman Correlation Method. Results: From a total of 11,459 cells, comprising 3 gastric cancer tissues (7,634 cells), and 3 paired adjacent normal tissues (3,825 cells), we identified 23 clusters that belonged to different types of cells including Endothelial, Epithelial, Fibroblast, B cells, Myeloid cells, T cells and NK cells. InferCNV analysis predicted 5 CNV regions and 209 CNV genes according to the heterogeneity between malignant and non-malignant cells. Survival analysis based on RNA-seq data from TCGA-STAD cohort, enabled us to narrow down the list of candidate biomarkers to 22 genes with prognostic ability. Among them, the specific functions of TPSB2 and TPSAB1 in GC, especially in their prognosis value, remain unclear. Downregulations of these 2 genes were both associated with longer progression-free survival (PFS). More specifically, expression profiles of gene TPSB2 and TPSAB1 were positively correlated with Epithelial marker genes (p = 0.02 and 0.03 respectively) but negatively correlated with CD8+ T lymphocytes (p = 0.02 and 0.11 respectively). Conclusions: Our analysis suggested that the high expressions of gene TPSB2 and TPSAB1 are associated with poor prognosis in GC patients. And these two genes are correlated with low T lymphocyte infiltration and an immune-suppressive environment, which could be possible prognosis biomarkers to identify patients with a more aggressive tumor evolution.
Greater expression of THBS2 and VACN in gastric carcinoma compared to gastritis.
Authors: Fan Zhisong , Feng Li , Liu Linnan , Li Dan , Liu Jiayin , Zuo Jing , Wang Yudong , Han Jing , Zhang Xue , Wang Long
Published: June 2022

e16026

Background: Gastric carcinoma (GC) is one of the most common cancers with the lowest survival rate in the world. The development from gastritis to GC may be related to genetic factors, but the specific molecular mechanism is not clear. The present study aimed to explore the gene difference between GC and gastritis. Methods: Two gene expression profiles including GC and gastritis were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between GC and gastritis were explored. Through pathway enrichment of DEGs, hub genes were identified. The prognosis significances of hub genes for GC patients were analyzed by overall survival (OS) analysis. Animal models of gastritis and GC were constructed and immunofluorescence and RT-PCR were used to verify the distinct expression of hub genes between the two diseases. Finally, the correlations between hub genes and GC were understood based on BP neural network. Results: A total of 62 DEGs was identified between GC and gastritis. Eight hub genes were identified, including MSLN, FGA, SPP1, THBS2, SPARC, FN1, IGFBP7 and VCAN. Except SPP1, the high expression of the other seven hub genes predicted poor OS for GC patients. In mouse model, the mRNA expression of SPP1, FN1, IGFBP7, THBS2 and VCAN were significantly higher in GC group than that in gastritis group. No matter in mouse model or in Human Protein Atlas, the protein expression of THBS2 and VCAN in GC was higher than that in gastritis. Based on the strong correlation among THBS2, VACN and GC suggested by BP neural network, it was speculated that the expression levels of THBS2 and VACN may be a predictor of GC. Conclusions: Compared with gastritis, THBS2 and VACN are highly expressed in GC. THBS2 and VACN may be potential biomarkers and therapeutic targets for GC.
Outcomes of neoadjuvant and definitive CROSS (carboplatin and paclitaxel chemoradiotherapy) in oesophageal cancer.
Authors: Iqbal Samreen , Atkinson Victoria , Arneil Melissa , Andelkovic Vladimir , Roberts Kate Elizabeth
Published: June 2022

e16033

Background: This is a retrospective analysis of outcomes in patients with oesophageal cancer treated with either neoadjuvant or definitive CROSS chemoradiotherapy (CRT) at the Princess Alexandra Hospital between 2016-2020. Methods: Data was collected from a single centre using the electronic medical records system. Patient demographics, oesophageal cancer characteristics, treatments and outcomes were recorded. Results: 90 patients were identified–75% were male and the average age at diagnosis was 64 years. Higher tumour grade, nodal stage or grade of oesophageal cancer was associated with lower average overall survival (OS). 68% had oesophageal adenocarcinoma (Adeno) and 31% had oesophageal squamous cell carcinoma (SCC). Of those with Adeno, 69% received neoadjuvant CROSS and 31% definitive CROSS. 32% of those with SCC received neoadjuvant CROSS with 64% receiving definitive CROSS therapy. Routine adjuvant chemotherapy was not delivered post CRT. 81% of those with Adeno treated with neoadjuvant CROSS proceeded to surgery compared to 100% of those with SCC treated similarly. Only 19% of patients did not complete CRT however 67% of patients experienced some toxicity and 43% required hospitalisation during the course of therapy. Average weight loss during therapy was 6.4kg. 27% of patients required enteral nutrition and they had a lower OS (20 months) compared to those that did not require nutritional support (25 months). Of those with Adeno, 50% of patients who received neoadjuvant CROSS experienced relapse compared to 74% in patients who received definitive CROSS. For the SCC cohort, 22% of those who received neoadjuvant CROSS relapsed compared to 44% who received definitive CROSS. Average time to relapse (from end of CRT) was greatest for those with SCC receiving neoadjuvant CROSS (16 months) and worst for those with SCC receiving definitive CROSS (7 months). Average OS for patients with Adeno who received definitive CROSS was 18 months compared to 27 months for those who received neoadjuvant CROSS. For patients with SCC, the average OS for those who received definitive CROSS was 18 months compared to 29 months for those treated with neoadjuvant CROSS. Of those with Adeno, 63% of those treated with definitive CROSS and 38% of those treated with neoadjuvant CROSS died secondary to their disease. For patients with SCC, 44% of those treated with definitive CROSS died whilst everyone who received neoadjuvant CROSS was alive at study conclusion. Conclusions: The best outcomes were seen in patients with SCC treated with neoadjuvant CROSS; this group had the highest OS (29 months), the lowest relapse rate (22%) and all patients were alive at the end of the study. The pivotal CROSS study by Shapiro et al. also demonstrated better outcomes in the SCC cohort, with this analysis further comparing definitive vs neoadjuvant CROSS. A limitation however is the comparatively shorter follow up period.
Systematic genomics-based approach for developing new therapeutics and diagnostics for esophageal cancer.
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke
Published: June 2022

e16034

Background: As the prognosis of advanced esophageal cancer patients is still poor after standard therapies, development of new molecular therapies with minimum risk of adverse events and cancer biomarkers for companion diagnostics is eagerly awaited. Methods: We have been screening new therapeutic target molecules and biomarkers for esophageal cancers as follows; i) To identify highly expressed genes in esophageal cancers by gene expression microarray analysis, ii) To verify the target molecules for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To confirm their function for the growth and/or invasive ability of esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected ESOC1 (esophageal cancer-associated oncoprotein 1) that has a methyltransferase domain. We first confirmed its in vitro methyltransferase activity. Immunohistochemical analysis showed that ESOC1 positivity was detected in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 positivity was an independent prognostic factor for patients with esophageal cancer. Knockdown of ESOC1 expression by siRNAs suppressed growth of esophageal cancer cells. Exogenous expression of ESOC1 increased the growth of mammalian cells. Therefore, ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Systematic genomics-based approach could be useful for the selection of novel candidate cancer biomarkers and therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.
Microbiome associations between esophageal adenocarcinoma and esophageal squamous cell carcinoma.
Authors: Wang Qian , Liu Yang , Xiao Shanshan , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e16050

Background: Microbiomes in tumor environment are thought to be associated with outcomes of precision therapy. Esophageal squamous cell carcinoma (ESCC) and Eophageal adenocarcinoma (EA) are the two subtypes of esophageal cancer. Although gene mutation and expression profiles have been well characterized, the microbial set between them are poorly studied. Methods: The microbial dataset of the identified species and their relative abundance using whole genome sequencing (WGS) and whole exome sequencing (WES) was obtained from TCMA database, which includes 17 EA samples and 32 ESCC samples. To investigate the microbial difference between EA and ESCC, The alpha diversity (Shanno and Simpson index) and beta diversity (PCoA, NMDS, Adonis) were calculated using the identified species to examine the overall difference between the two subtypes. The student's t-test were used to examine the relative abundance of single species Using the identified differential abundant microbial species, correlation analysis were performed to investigate whether synergistic effects exist for some species between the two subtypes. Moreover, taxonomy set enrichment analysis was used to find out whether the differential genus between EA and ESCC were associated with cancers. Finally, cox regression was used to investigated differential species between EA and ESCC affected the survival rate of EA group or ESCC group. Results: Through alpha and beta diversities, we didn’t find overall difference between EA and ESCC both in WGS and WES datasets. However, seventeen and two differential abundance species were found using Student’s t-test in WGS and WES datasets, respectively. The relative abundances of the differential species were mostly higher in ESCC than in EA. Correlation analyses showed that prevotella sp. HMSC069G02 and prevotella sp. HMSC077E08 were highly correlated. There were eight differential species ( prevotella aurantiaca, prevotella dentalis, prevotella marshii, etc.) were found in WGS and two species ( prevotella sp. C561, prevotella pleuritidis) in WES, respectively. The ten species all belong to prevotella genus, and taxon set enrichment analysis showed prevotella genus was associated with esophageal cancer, implies the identified differential species may be different in ESCC and EA patients. Among them, prevotella dentalis and prevotella buccae were found to be potentially risk factors in ESCC after Cox regression. Conclusions: This study investigated the microbiome difference between EA and ESCC cancers. Although we didn’t find the overall difference between the two subtypes, our preliminary results showed there exist some differential species between two subtypes. We found prevotella dentalis and prevotella buccae were the potential risk factors in ESCC, and the results can help further understand the therapy outcome differences between EA and ESCC from the microbial aspect.
Systematic literature review and meta-analysis of clinical outcomes for previously treated patients with advanced gastric or gastroesophageal junction cancer.
Authors: Abderhalden Lauren , Frederickson Andrew , Lang Brain M , Mojebi Ali , Wu Ping , Gozman Alexander , Malbecq William , Jin Fan , Amonkar Mayur
Published: June 2022

e16054

Background: Standard of care treatment in advanced (unresectable and/or metastatic) gastric or gastroesophageal junction (GEJ) cancer includes chemotherapies with or without targeted therapies. While there have been many studies undertaken in this patient population, there exists uncertainty around the efficacy of these treatments. A systematic literature review and meta-analysis were conducted to assess clinical outcomes of chemotherapies with or without targeted therapies. Methods: A systematic literature review was conducted through mid-2021 to identify relevant studies using Embase, MEDLINE, and Cochrane Central Register of Controlled trials (January 1, 2000–July 6, 2021) with additional searches of recent annual ASCO and ESMO conferences. Eligible studies included randomized controlled trials (RCTs), controlled clinical trials, and non-randomized clinical trials of any pharmacologic treatments licensed by the FDA or EMA among patients (≥18 years age, Eastern Cooperative Oncology Group performance score 0 or 1) previously treated for advanced gastric or GEJ cancer and who had progressed on prior treatment (i.e., ≥2L). A meta-analysis of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were conducted among RCTs of relevant therapies for ≥2L gastric cancers. The ORR meta-analysis was performed using the Freeman-Tukey double arcsine transformation. For time-to-event outcomes, published Kaplan-Meier curves for OS and PFS were digitized to create pseudo- individual patient data. A meta-analysis of the resulting pooled survival curves for OS and PFS were conducted following the methodology of Combescure et al. (2014). Results: Of the 214 studies identified, 42 RCTs (77 trial arms) evaluating relevant therapies including 7,256 participants were included in the meta-analysis of ORR. The random effects pooled estimate of ORR was 15.0% (95% confidence interval [CI]: 12.7-17.5%). Median PFS (32 studies; 61 survival curves) was 3.5 months (95% CI: 3.2-3.7) with PFS rates at 6, 12, and 24 months of 25.8% (95% CI: 23.1-28.8%), 7.3% (95% CI: 6.0-8.9%), and 0.7% (95% CI: 0.4-1.0%), respectively. Median OS (34 studies; 64 survival curves) was 7.9 months (95% CI: 7.4-8.5) with OS rates at 6, 12, and 24 months of 62.5% (95% CI: 59.0-66.2%), 30.4% (95% CI: 27.7-33.3%), and 6.7% (95% CI: 5.4-8.4%), respectively. Conclusions: The standard treatments have demonstrated limited efficacy in previously treated patients with advanced gastric or GEJ cancers. Newer treatments (e.g., immunotherapies) to address this unmet medical need should be thoroughly investigated and evaluated.
Elevated serum alpha-fetoprotein is a significant prognostic factor for gastric cancer patients: Results based on a large-scale retrospective study.
Authors: Zhan Zhouwei
Published: June 2022

e16059

Background: To study the clinicopathological features and prognostic factors of serum alpha-fetoprotein (AFP) positive gastric cancer (GC). Methods: A cohort study including 2318 GC patients who underwent radical surgery from January 2008 to December 2015 was retrospectively analyzed. Patients were divided into two groups according to preoperative serum AFP values: 191 patients with AFP-positive GC (AFP > 20ng/mL, 8.24%) and 2127 patients with AFP-negative GC (AFP≤20ng/mL, 91.76%). The clinicopathological features and prognostic factors were explored. Results: Compared with AFP-negative GC, AFP-positive GC had higher rates of liver metastasis, lymph node metastasis, venous invasion, and nerve invasion (all P< 0.05). The 5-year OS, DFS and mLMFS of AFP-positive GC were shorter than AFP-negative GC (55.00% vs. 45.04%, P< 0.001; 39.79% vs. 34.03%, P< 0.001; 13.80 months vs. 16.25 months, P = 0.002). In whole cohort, multivariate analysis found serum AFP levels (positive vs negative), pT stage, pN stage, nerve invasion (yes or no), venous invasion (yes or no) were independent prognostic factors. Serum AFP levels (20-300 ng/mL vs. 300-1000 ng/mL vs. > 1000 ng/mL), pT stage, pN stage, venous invasion (yes or no) were independent prognostic factors in AFP-positive GC. Conclusions: Liver metastases and venous invasion are more likely to occur in AFP-positive GC and lead to poor prognosis. Serum AFP level is an independent prognostic factor in GC patients. As the level of AFP increases, the prognosis becomes worse.
Demographic differences in the treatment of gastric cancer.
Authors: LaPelusa Michael Brian , Shen Chan , Gibson Michael K. , Gillaspie Erin Alexis , Lambright Eric , Chakravarthy Anuradha Bapsi , Eng Cathy
Published: June 2022

e16078

Background: Globally, as of 2020, gastric cancer is the 5th most common cancer and the 4th common cause of cancer-related death. Our objective is to determine how gender/sex, race, treatment location, and socioeconomic factors contribute to the treatment of patients (pts) with gastric cancer. Methods: 233,479 pts were identified from the National Cancer Database (NCDB) between 2004 and 2018. Pts were divided into 3 age-based subgroups. The <=45 y/o (N=14,481) group was designated early-onset gastric cancer (EOGC). The 46 - 70 y/o (N=118,756) group was termed average-onset gastric cancer (AOGC). The >70 y/o (N=100,242) group was termed late-onset gastric cancer (LOGC). Overall 114,117 (48.9%) received surgery; 112,953 (48.4%) received chemotherapy; and 55,024 (23.6%) received radiation therapy. Unfortunately, data were not available on the receipt of bimodal or trimodal therapy. We used chi-square tests and a logistic regression model to examine factors associated with treatment patterns. Factors considered in the model included: age, gender/sex, race/ethnicity, cancer stage, facility type, year of diagnosis, insurance status, and location of residence. Results: Females represented a higher proportion of EOGC pts (47%) compared to AOGC pts (34.5%) and LOGC pts (41%). A greater amount of EOGC pts were Hispanic (24.9%) compared to AOGC pts (10.4%) and LOGC pts (7.1%). EOGC pts were often treated at academic centers (65.8%) compared to AOGC pts (60.9%) and LOGC pts (54.4%). A larger percentage of EOGC pts were uninsured (11.7%) vs AOGC pts (5.4%) and LOGC pts (0.9%). The table outlines differences in treatment by age, sex, race/ethnicity, facility type, year of diagnosis, insurance, and location of residence (after adjusting for stage). Conclusions: EOGC pts display unique demographic characteristics. After adjusting for stage, significant differences exist in how pts with gastric cancer are treated. Further work is needed to delineate the impact of gastric cancer in young pts and determine which factors play a role in treatment for pts of all ages from both the patient and oncologist perspective.[Table: see text]
Relationship between tumor infiltrating lymphocytes and clinicopathological features in Peruvian gastric cancer.
Authors: Castaneda Altamirano Carlos Arturo , Castillo Garcia Miluska , Bernabe Luis A. , Sanchez Joselyn , Fassan Matteo , Tello Katherine , Chávez Iván , Ruiz Eloy , Barreda Fernando , Valdivia Daniel , Bazan Yaqueline , Abad Milagros , Poquioma Ebert , Montenegro Paola Catherine , Taxa Luis
Published: June 2022

e16080

Background: Role of tumor-infiltrating lymphocytes (TIL) over clinicopathological features including Mismatch Repair (MMR), HER2 status, Epstein Barr Virus (EBV) and Helicobacter pylori (HP) infection is not well understood in gastric cancer (GC). Methods: TIL level and HP infection was also evaluated in H&E from 503 Peruvian GC patients who underwent surgery. Density of CD3+ T cells, CD8+ cytotoxic T cells, CD163 M2 macrophages, as well as MMR and HER2 status were determined by immunohistochemistry. HP and EBV infection was also detected by qPCR in a 234 cases subset. Results: Median age was 62 years and 50.1% were female, most tumors were grade 3 (59.1%), intestinal subtype (44.8%) and stage III (59.8%). MMR loss was found in 29.4% and HER2+ in 4.7%. HP+ was detected by H&E in 55.7% and by qPCR in 63.7%. EBV+ by qPCR was found in 20.5% and co-infection along with HP in 9.4% (22/234). Stage (p < 0.001), intestinal histology (IH) (p = 0.019), grade (p = 0.006) and lymphovascular invasion (p < 0.001) were associated with longer survival. Median TIL was higher in invasive border (IB) and stromal (ST) than intratumoral (IT) compartment but there were significantly correlated (p < 0.001). High IT TIL was associated with absence of HP H&E (p = 0.009). High ST TIL was associated with older age (p < 0.001), IH (p < 0.001), grade 1 (p = 0.009), lower stage (p = 002), MMR loss (p = 0.019) and EBV+ (p = 0.001). Density of CD3 and CD8 were significantly correlated in IT and ST compartments (p < 0.001). High CD3 density in IT compartment was associated with grade 3 (p = 0.001) and HP- (p = 0.02), and in ST was associated with IH (p = 0.005), grade 1- 2 (p = 0.002) and MMR loss (p = 0.04). High IT CD8 was associated with HER2- (p = 0.016), HP- (p = 0.014) and EBV+ (p = 0.012). High ST CD8/CD3 ratio was associated with diffuse histology (p = 0.034), grade 3 (p = 0.013), more advanced stage (p = 0.022) and recurrence (p = 0.014). High ratio of IT CD8/CD3 was associated with MMR loss (p = 0.007). High ST TIL was associated with longer DFS (p = 0.007). Lower ratio of CD8/CD3 was associated with longer OS (p = 0.024) and DFS (p = 0.02). Conclusions: TIL levels and infiltrating immune subpopulations differs by clinicopathological features in GC including MMR loss, HER2 expression EBV and HP infection. ST CD8/CD3 was associated with recurrence and shorter DFS.
Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC, RATIONALE 302): Impact on health-related quality of life (HRQoL).
Authors: Van Cutsem Eric , Kato Ken , Ajani Jaffer A. , Shen Lin , Xia Tianyu , Ding Ningning , Zhan Lin , Barnes Gisoo , Kim Sung-Bae
Published: June 2022

e16095

Background: RATIONALE 302 was a global phase 3 study (NCT03430843) that investigated tislelizumab (TIS) compared with investigator-chosen chemotherapy (ICC) as second-line treatment for patients (pts) with advanced or metastatic ESCC, in which TIS demonstrated a significant and clinically meaningful improvement in overall survival hazard ratio (HR = 0.70 [95% CI 0.57–0.85], P=0.0001), and a favorable safety profile compared with ICC. Here we assess the HRQoL of pts receiving TIS vs ICC in a pt population that usually experiences HRQoL deterioration. Methods: Adults with advanced or metastatic ESCC whose disease progressed following prior systemic therapy were randomized 1:1 to either TIS 200 mg IV every 3 weeks or ICC (paclitaxel, docetaxel, or irinotecan). HRQoL was measured using the global health status/quality of life (GHS/QoL), physical functioning, and fatigue scores from EORTC QLQ-C30 and the dysphagia, reflux, eating, and pain scores from the EORTC QLQ-OES18 from screening through Cycle 6 or until treatment discontinuation (whichever occurs first). Least-squares mean score change from baseline to Cycles 4 and 6 in HRQoL scores was assessed using a mixed model for repeated measurements. Time to deterioration (TTD) for the GHS/QoL score and the symptom scales of the QLQ-OES18 was examined using the Kaplan-Meier method. Results: Overall, 512 pts (median age 62) were randomized to TIS (n=256) or ICC (n=256). Compared with ICC, TIS-treated pts had stable GHS/QoL and fatigue scores as well as less decline in physical functioning at Cycles 4 and 6 (table). Except for pain, the TIS arm experienced less OES18 symptoms relative to baseline than the ICC arm. TTD analysis showed pts in TIS arm were at lower risk of worsening dysphagia (HR = 0.76 [95% CI 0.53, 1.07], P=0.0562) compared with ICC. Conclusions: The analysis showed that ESCC pts treated with TIS in the second line had a longer maintenance of HRQoL compared to pts treated with ICC. These results, along with improved survival and favorable safety profile, suggest TIS represents a potential new second-line treatment option for pts with advanced or metastatic ESCC. Clinical trial information: NCT03430843. [Table: see text]