bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel blood-based biomarker candidates in screening for colorectal cancer.
Authors: Liggett Jason Lee , Petersen Mathias M , Kleif Jakob , Rasmussen Morten , Jørgensen Lars Nannestad , Seidelin Jakob Benedict , Madsen Mogens R. , Vilandt Jesper , Gotschalck Kåre Andersson , Andersen Lars M. , Khalid Ali , Andersen Berit , Christensen Ib Jarle , Fritsche Herbert A. , Mayer Eric S. , Therkildsen Christina
Published: January 2023

244

Background: Colorectal cancer (CRC) is the third most common cancer worldwide motivating national screening strategies utilizing fecal immunochemical tests (FIT). Blood-based biomarkers could be an alternative method to increase compliance in population-based screening programs for early detection of CRC. We aimed to identify new blood-based biomarkers that could be potential candidates for use in colorectal cancer screening. Methods: In a nested cohort study of 1967 FIT positive participants of the Danish CRC screening program serum levels of GDF-15, hepsin, IL-8, keratin1-10, L1CAM, MIA, monocyte MCP-1, NSE and OPG were measured using the Luminex xMAP immunoassay platform. Main outcomes were CRC vs non-CRC and CRC, high-risk adenomas (HRA) or medium-risk adenomas (MRA) vs low-risk adenomas (LRA) or clean colorectum. Odds ratios for associations between biomarker expressions and outcomes were calculated using logistic regression models and visualized by area under the receiver operating characteristic (ROC) curve (AUC). Analyses were made on the Luminex biomarkers alone and with addition of clinical and demographic information. Results: FIT-induced colonoscopies detected 240 CRCs and 625 HRA or MRA. Multivariate analyses using all biomarkers and age found hepsin, IL-8 and OPG significantly (p<0.001) associated in relation to the main outcome (CRC vs non-CRC) with odds ratios of 0.74 [0.59-0.92], 2.59 [2.12-3.15] and 0.90 [0.82-0.99], respectively. The full model using all biomarkers and age presented an AUC of 0.73 [0.70-0.77]. Conclusions: Changed serum levels of nine novel biomarkers seem to be potential predictors for early detection of CRC, especially hepsin, IL-8 and OPG. [Table: see text]
Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.
Authors: Viñal David , Rueda-Lara Antonio , Martinez-Perez Daniel , Zwisler Patricia , Garcia-Leal Andrea , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Peña-Lopez Jesus , Alameda-Guijarro Maria , Martin-Montalvo Gema , Perez-Wert Pablo , Martínez-Recio Sergio , Palacios Maria Elena , Ghanem Ismael , Custodio Ana B. , Gutiérrez-Sainz Laura , Feliu Jaime , Rodriguez Salas Nuria
Published: January 2023

247

Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P <0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P < 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.
Predictive biomarkers for response to immunotherapy in patients with deficient DNA mismatch repair metastatic colorectal cancer.
Authors: Stemmer Amos , Strauss Gal , Halpern Naama , Beller Tamar , Golan Talya , Margalit Ofer , Shacham-Shmueli Einat , Boursi Ben
Published: January 2023

254

Background: Deficient DNA mismatch repair (MMRD) accounts for approximately 3% of metastatic colorectal cancers (mCRC). Treatment with Immune checkpoint inhibitors (ICI) in this patient population achieve an overall response rate (ORR) of up to 55%. However, to date there are no predictive biomarkers for response. Methods: A retrospective analysis of all MMRD mCRC patients that were treated with either Pembrolizumab, or Ipilimumab and Nivolumab in a large tertiary medical center between 2015-2022. The primary outcome was response to treatment and was assessed at first imaging following treatment initiation. Exposure variables included age, sex, ECOG performance status, metastatic sites (liver, peritoneum, lung, bone and brain) and CEA levels at treatment initiation. CEA below 5 mcg/l was treated as low and above as high CEA levels. Predictive biomarkers were assessed using cox hazard regression and Kaplan Meier analysis. Results: A total of 33 prospective MMRD mCRC patients were included in the study. Of them, 24 (72.7%) responded and 9 (27.3%) did not respond to immunotherapy. Median age was 70 (IQR 66-77) and 64 (IQR 51-75) for responders and non-responders respectively. Site of metastasis was an important predictor for response. Thirteen patients had liver metastasis, of them 6 (46%) responded (HR = 7.16; 95% CI = 1.47-35; p = 0.015). Five patients had single site metastasis in the liver, of them one (20%) responded (HR = 12.7; 95% CI = 2.99-53.8; p < 0.001). Fifteen patients had peritoneal metastasis, of them 13 (87%) responded to treatment (HR = 0.24; 95% CI = 0.05-1.19; p = 0.081). Median CEA at treatment initiation was 2 (IQR 1-4) in responders compared to 32 (IQR 1-70) for non-responders (HR = 5.27; 95% CI = 1.31-21.2; p = 0.019). There was no statistically significant difference between the groups in age, sex and ECOG performance status. Conclusions: Liver metastasis predict poor response to immunotherapy in MMRD mCRC patients while peritoneal metastasis and low CEA level predict response to immunotherapy.
Lack of hierarchical survival prognosis in AJCC staging for colon cancer: Implications for future summary stage classification.
Authors: Bhutiani Neal , Hu Chung-Yuan , Palis Bryan E. , Cotler Joseph , Shi Qian , Goldberg Richard M. , Washington Mary Kay , Nelson Heidi , Steele Scott , Chang George J.
Published: January 2023

256

Background: Current staging for colon cancer utilizing the American Joint Committee on Cancer TNM framework stratifies disease into groups according to how advanced the disease is and provides important standardized, individual prognostic information. Ideally, staging systems should exhibit hierarchical logic, with increasing stage reflecting worse prognosis. We sought to evaluate hierarchy within the 8th edition AJCC staging system for colon cancer. Methods: All patients with primary colon (including rectosigmoid) cancer diagnosed 2010-2017 were identified from the National Cancer Database (NCDB). Patients were only included if they carried a histologic diagnosis of invasive primary (non-recurrent) cancer, underwent radical surgery, and had complete pathologic staging data (T, N, M category data). Patients with missing follow-up data were excluded. Kaplan-Meier curves were used to assess overall survival by AJCC 8th edition pathologic summary stage group to determine whether staging was hierarchical for colon cancer. Multivariable modeling and log likelihood ratio test was then used to identify relative contributions of T and N variables to overall survival. Results: Among 270,584 colon cancer patients, pathologic staging was noted to be hierarchical by T category alone and by N category alone. However, summary staging was non-hierarchical in both instances. Multivariable modeling confirmed the AJCC non-hierarchy issue (colon HRs: 1, 1.54, 2.62, 2.60, 1.02, 2.15, and 4.38 for stage 1 as reference, 2a, 2b, 2c, 3a, 3b, 3c respectively). Multivariable modeling demonstrated that high T category (T4a, T4b) conferred the greatest risk of mortality based on hazard ratio (T4a HR 2.76, T4b HR 3.04), while high T category as well as high N category (N2a, N2b) contributed substantially to the survival model based on z-score. Further modeling assessing the predictive power of T and N category with respect to overall survival demonstrated that T category more strongly predicted overall survival than N category in colon cancer (likelihood chi-square test statistic pT:7009 vs pN:3586). Conclusions: Hierarchy in survival based on AJCC summary stage was not observed for patients with stage II-III colon cancer resulting in a paradoxical better observed survival with some stage III cancer subgroups compared to stage II cancer subgroups. High T category appears to more significantly impact survival than N category for patients with N0-N1 disease, while high N category appears more important for patients with T1-3 disease. Future revisions of the AJCC staging system should account for the differential impact of T and N category identified herein to more accurately confer prognostic information.
HERIZON: A phase 2 study of HER-Vaxx (IMU-131), a HER2-targeting peptide vaccine, plus standard of care chemotherapy in patients with HER2-overexpressing metastatic or advanced gastric/GEJ adenocarcinoma— Overall survival analysis.
Authors: Maglakelidze Marina , Ryspayeva Dinara E. , Andric Zoran , Petrovic Zoran , Bulat Iurie , Nikolic Ivan , Nagarkar Rajnish , Wiedermann Ursula , Blumenstein Brent A. , Chong Leslie Mi Ok , Ede Nicholas , Nixon Bonnie , Yavrom Sharon , Selvaggi Giovanni , Good Anthony J. , Chawla Tanuj
Published: January 2023

289

Background: Active immunization with the B-lymphocyte stimulating HER2 vaccine, HER-Vaxx (IMU-131), has shown clinical response correlated with HER2-specific antibodies (Wiedermann et. al., Clinical Cancer Research, 2021). The HER-Vaxx HERIZON study is based on the landmark ToGA study (Bang et. al., The Lancet, 2010) and included patients with HER2/neu over-expressing metastatic or advanced gastric/GEJ adenocarcinoma who were naïve to HER2 therapy. Methods: Thirty-six patients were randomized to either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint was overall survival (OS). HER-Vaxx plus chemotherapy treated patients received 50 µg dose of HER-Vaxx by intra-muscular injection at Days 0, 14, 35, 77 and every 63 days until disease progression. Both groups received chemotherapy starting at Day 0 and then every 21 days for a maximum of 6 cycles or until disease progression. Standard chemotherapy consisted of cisplatin + 5FU or capecitabine, or oxaliplatin + capecitabine. Statistical analysis pre-specified a 1-sided false positive probability of 0.10. Results: Of 36 patients randomized (19 treated with HER-Vaxx plus chemotherapy and 17 with chemotherapy alone), 32 patients had a survival event (15 and 17 respectively) at the time of final analysis. All patients received oxaliplatin + capecitabine chemotherapy. Analysis showed a 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy compared to chemotherapy alone. This translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927) with a statistically significant p-value of 0.066. The median OS for patients receiving HER-Vaxx plus chemotherapy was 13.9 (7.5, 14.3) months, compared to 8.3 (6.0, 9.6) months in patients treated with chemotherapy alone. Median duration of response was 30 vs 19 weeks in favor of the HER-Vaxx arm. There was no difference in safety between the two treatment arms, indicating HER-Vaxx does not add toxicity to standard chemotherapy. HER-Vaxx induced persistent HER2 specific antibodies which correlated with clinical response. Additional response parameters including DOR and biomarker data will be presented at the meeting. Conclusions: These data demonstrate that in patients with HER2 over-expressing gastric/GEJ cancer active HER2 immunization with HER-Vaxx is safe and provides relevant clinical benefit over standard of care chemotherapy. Clinical trial information: NCT02795988 .
Survival and clinical characteristics of patients with colorectal cancer and brain metastases.
Authors: Gordon Caroline , Cecchini Michael , Lacy Jill
Published: January 2023

29

Background: Brain metastases (BM) are rare in colorectal cancer (CRC) with 1-3% of patients developing BM over their lifetime. There are no screening recommendations for BM in patients with CRC and most are diagnosed after a patient develops symptoms. Identifying the clinical characteristics for patients with CRC and BM may aid clinicians to consider BM early in symptom onset and potentially screen appropriate patients. Methods: We performed a retrospective chart review of patients >18 years diagnosed with CRC and BM at Yale New Haven Hospital from 1/2012-9/2021. Clinical characteristics were analyzed by descriptive statistics, time intervals were compared using the Mann-Whitney test, and survival analysis was done using the Kaplan-Meier method. Results: We identified 93 patients with CRC and BM. Median age at diagnosis was 56 years, 55% were male, 75% of patients had a left sided primary tumor and 47% were rectal primary. At initial diagnosis, 38% and 39% were stage III and IV respectively. RAS/RAF mutations were present in 45% of patients and all were mismatch repair proficient. The median time from CRC diagnosis to BM was 3.81 years (95% CI 3.09, 4.41) and median time from metastatic CRC to BM was 2.21 years (95% CI 1.48, 2.75). Median overall survival after developing BM was 0.49 years (95% CI 0.24, 0.70). Patients with RAS/RAF mutations had a decreased median time from CRC diagnosis to BM of 3.33 years (95% CI 2.69, 4.37) compared to RAS/RAF wildtype at 5.09 years (95% CI 4.44, 7.97) (p 0.0028). Median time to BM from CRC diagnosis was also decreased in females (p 0.01). The location of primary tumor did not significantly decrease time to BM. Prior to BM diagnosis, 76% of patients had lung metastasis. 84% of patients received treatment for BM while 14% had no BM treatment and 2% were unknown. For treatment 50% had Gamma Knife Radiosurgery, 22% underwent surgical excision +/- adjuvant radiation, and 12% underwent whole brain radiotherapy. After BM treatment, 43% of patients received additional chemotherapy. Conclusions: Although BM in CRC is uncommon, early diagnosis in those at risk is critical given the urgent nature of BM. Patients with CRC that develop BM frequently have tumors that originate in the left side of the colon and preexisting lung metastasis. In patients with CRC and BM, the majority develop BM > 3 years after initial CRC diagnosis, and BM onset is significantly shorter in females and patients with tumors harboring a RAS/RAF mutation. After BM diagnosis and treatment, less than half of patients are able to receive subsequent therapy, and median survival is < 6 months. [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648.
Authors: Kato Ken , Ajani Jaffer A. , Doki Yuichiro , Xu Jianming , Wyrwicz Lucjan , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez Freitas Melro , Holtved Eva , Blum Murphy Mariela A. , Patel Apurva , Hu Nan , Matsumura Yasuhiro , Chau Ian , Kitagawa Yuko
Published: January 2023

290

Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]
A multiplex DNA methylation assay for noninvasive early detection of gastric cancer.
Authors: Ruan Weimei , Lei Xiaotian , Sha Weihong , Li Bin , Wang Hong , Xia Yuying , Shen Junran , Kong Lingchen , Ma Juan , Chen Zhiwei , Bibikova Marina , Cui Chunhui , Fan Jian-Bing
Published: January 2023

300

Background: Gastric cancer (GC) is the fifth leading cancer that ranked fourth in cancer mortality worldwide. Early screening and detection can significantly improve patients’ prognosis and survival. Although in standard GC diagnosis, gastroscopy provides sufficient diagnostic power for identifying GC in early stages, the invasive and costly procedure is not suitable for screening and has low compliance in countries with high GC incidence and large populations. Furthermore, the serum-based GC related biomarkers and non-invasive tests (serum pepsinogen I and II, gastrin-17, and anti-Helicobacter pylori IgG antibody tests) showed insufficient evidence as cost-effective GC screening approaches. A non-invasive DNA methylation assay with high sensitivity was aimed to develop and validate as a potential alternative for GC early detection. Methods: A multiplex quantitative PCR (qPCR) assay for detecting GC-specific DNA methylation markers in plasma was developed, in which the markers were further optimized from a reported seven-marker panel based on a pilot case-control study with 63 GC and 130 non-GC samples. The GC detection model of the assay was developed and locked down in the first cohort consisting of 54 GC and 79 non-GC samples. The second validation cohort with 117 GC and 309 non-GC samples was used to evaluate the assay performance. All plasma samples used in the two cohorts were prospectively collected from patients diagnosed with GC or other gastrointestinal diseases or from healthy donors. Results: The multiplex DNA methylation assay showed an overall sensitivity and specificity of 80% (95% CI: 77–83%) and 65% (95% CI: 63–66%) in the model development cohort, respectively, with a sensitivity of 80% (95% CI: 65–95%, n=10) in the detection of stage I GC. The assay revealed similar performance characteristics in the validation cohort, with an overall sensitivity of 82% (95% CI: 80–83%), a specificity of 69% (95% CI: 68–69%), and a sensitivity of 78% (95% CI: 74–82%, n=41) for the stage I GC detection. The DNA methylation assay outperformed the reported serum-based GC related biomarkers and non-invasive tests (sensitivity of 69.6-70.7% and specificity of 66.8-67.8%) with higher sensitivity, particularly in the stage I GC with a comparable specificity. Conclusions: The multiplex DNA methylation assay provides a potential cost-effective tool that features high sensitivity for GC early detection.
Short-term safety of adjuvant nivolumab therapy after neoadjuvant docetaxel plus cisplatin and 5-FU therapy for locally advanced esophageal squamous cell carcinoma.
Authors: Hirose Toshiharu , Yamamoto Shun , Kadono Toru , Ikeda Go , Ohara Akihiro , Itoyama Mai , Yokoyama Kazuki , Honma Yoshitaka , Ishiyama Koshiro , Oguma Junya , Daiko Hiroyuki , Kato Ken
Published: January 2023

312

Background: CheckMate 577 trial demonstrated efficacy of adjuvant nivolumab (Ad-Nivo) therapy in locally advanced esophageal cancer patients (pts) who underwent surgery after neoadjuvant chemoradiotherapy and did not achieve pathologic complete response. In Japan, neoadjuvant docetaxel plus cisplatin, 5-FU (NeoDCF) therapy is the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. The efficacy and safety of Ad-Nivo therapy after NeoDCF therapy were unknown, so guidelines recommendations have not been determined. Methods: The subjects of this retrospective study were pts with histologically confirmed resectable locally advanced ESCC who received Ad-Nivo (480mg/body, every 4 weeks for 12 times) after NeoDCF in our hospital from Jan 2022 to Sep 2022. We evaluated safety as adverse events during treatments and clinical outcomes. Results: Twenty pts were selected in this study. Characteristics were median age (range) 65 (51–75) years, male/female 70/30%, PS 0/1 85/15%, Ce/Ut/Mt/Lt 5/15/50/30%, clinical stage II/III/IVA/IVB (supraclavicular lymph node) 10/70/0/20%, pathological stage IIB/IIIA/IIIB/IVA/IVB 30/5/40/10/15%. The pathological response according to Japanese Classification of Esophageal Cancer was Grade 0/1a/1b/2/3 5/20/20/40/15%. Median time (range) from surgery to Ad-Nivo was 9 weeks (4-20 weeks). The adverse events included fatigue (30%), increase AST (30%), increase ALT (15%), pruritus (15%), hyperthyroidism (15%), diarrhea (10%), decreased appetite (10%), and pneumonitis (10%). Grade >3 adverse events were not observed. Recurrence was observed in three pts (15%), which site was regional lymph node (2 pts of pathological stage III and IVB) and anastomosis (1pt of pathological stage IVA). Three pts with recurrence received definitive chemoradiotherapy, and still continue the treatment. Conclusions: The short-term toxicity of Ad-Nivo after NeoDCF was well-tolerated and acceptable.
Lower risk of depression after smoking cessation and alcohol abstinence in patients with gastric cancer who underwent gastrectomy: A population-based nationwide cohort study.
Authors: Kim Bokyung , Han Kyungdo , Chung Hyunsoo , Kim Sang Gyun , Cho Soo-Jeong
Published: January 2023

314

Background: Although depression is associated with poor treatment outcomes and lower quality of life in cancer patients, little is known about whether lifestyle modifications could help prevent depression in these patients. This study aimed to identify the effect of lifestyle modifications such as smoking cessation, alcohol abstinence, and starting exercise on depression development in gastric cancer patients who underwent gastrectomy. Methods: Using the Korean National Health Insurance Service database, we identified gastric cancer patients who underwent gastrectomy between 2010 and 2017. Self-reported lifestyle behaviors within two years before and after gastrectomy were analyzed using health examination database. We classified the patients according to changes in lifestyle behaviors and compared their risk of developing depression. Results: Among 18,902 patients who underwent gastrectomy, 2,302 (12.19%) developed depression (26.00 per 1000 person-years). Smoking cessation (Hazard ratio (HR) = 0.77, 95% confidence interval (CI): 0.66-0.91) and alcohol abstinence (HR = 0.79, 95% CI: 0.69-0.90) were associated with reduced risk of depression development compared to persistent smoking and persistent drinking, respectively. Starting exercise was not associated with risk of depression. When lifestyle behaviors after gastrectomy were scored from 0 to 3 points (one point each for not smoking, not drinking, and being physically active), the risk of depression showed a decreasing tendency as lifestyle scores increased from 0 (reference) to 1 (HR = 0.69, 95% CI: 0.55-0.83), 2 (HR = 0.60, 95% CI: 0.50-0.76), and 3 (HR = 0.55, 95% CI: 0.45-0.68) points. Conclusions: Smoking cessation and alcohol abstinence can reduce the risk of depression in gastric cancer patients who undergo gastrectomy. [Table: see text]
Impact of chemotherapy on COVID-19 vaccination in patients with gastrointestinal cancer.
Authors: Suenaga Mitsukuni , Yamauchi Shinichi , Sato Yuya , Noji Rika , Morikawa Ryo , Kano Yoshihito , Tokunaga Masanori , Kinugasa Yusuke
Published: January 2023

32

Background: Multiple doses of vaccine against COVID-19 provide cancer patients with the opportunity to continue their cancer treatment. We previously reported the results that COVID-19 vaccination are tolerable, and treatment schedule changes could be minimized in gastrointestinal (GI) cancer patients receiving chemotherapy. In the present study, we investigated the differences in the occurrence of vaccine-related adverse events (AEs) in patients receiving chemotherapy and those not receiving chemotherapy. Methods: 141 patients with GI cancer who had two doses of mRNA COVID-19 vaccine (Pfizer-BioNTech or Moderna) between May 2021 and April 2022 with sufficient data on vaccination were included in this retrospective observational study at the Tokyo Medical and Dental University hospital. This study combined two different cohorts: an evaluation cohort of 89 patients (median age 70 years, male 57.8%) receiving chemotherapy; and a control cohort of 52 patients under follow-up after radical surgery (median age 68.5 years, male 69.2%). All patients had no history of COVID-19 infection. Treatment- and vaccine-related AEs were recorded by outpatient interviews and self-reports. Results: Patient characteristics of the two cohorts were similar except for the location of primary tumor: colorectal (80.9% vs 7.7%) and gastric (15.7% vs 88.5%). There were no significant differences in comorbidities between the cohorts (67.4% vs 55.8%). In the evaluation cohorts, 65 patients (73.0%) had vaccine-related AEs: injection site pain (68.5%), fever (9.0%), fatigue (6.7%), headache (3.4%), gastrointestinal symptoms (2.2%), redness (1.1%) and sleepiness (1.1%) after the first dose; and 66 patients (74.2%) had vaccine-related AEs with increased rate of fever (32.6%) and fatigue (19.1%) after the second dose. In the control cohort, vaccine-related AEs occurred in 28 (53.8%) after the first dose and 37 (71.2%) patients after the second doses, and similarly, fever and fatigue increased after the second dose. There were no significant differences in the number of vaccine-related AEs and their changes between cohorts. There was no treatment- and vaccine-related deaths. Conclusions: The results of this study suggest that systemic chemotherapy in patients with GI cancer does not have a marked negative effect on COVID-19 vaccination.
Integrating patient-reported-outcomes into prognostication in gastroesophageal cancer: Results of a population-based retrospective cohort analysis.
Authors: Megid Thais Baccili Cury , Sharma Divya , Ma Lucy Xiaolu , Wang Xin , Barron Carly C. , Jang Raymond Woo-Jun , Swallow Carol Jane , Mesci Aruz , Yeung Jonathan , Wong Rebecca KS , Chen Eric Xueyu , Brar Savtaj Singh , Veit-Haibach Patrick , Kim John , Bach Yvonne , Aoyama Hiroko , Elimova Elena
Published: January 2023

320

Background: Patient reported outcomes (PRO) measures are accurate self-reflections of an individual’s physical functioning and emotional well-being. The prognostic value is unknown in gastroesophageal (GE) cancer patients (pts). The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated 10-item PRO tool which uses a 0 to 10 rating of ten common symptoms (total rating 0-100). In this study, we examined the association between the ESAS score and overall survival (OS) in pts with localized and metastatic GE adenocarcinoma (GEA). Methods: This study is based on the retrospective cohort database of pts with localized (stage I-III) and metastatic GEA. We included pts who were diagnosed with GEA between 2011 and 2021 and completed at least 1 baseline ESAS prior to the treatment. Pts were grouped into 3 cohorts based as follows: High symptom burden (SB) ESAS score ≥ 26, Moderate SB (11-25) or low SB (0-10). OS was defined as time from the first visit date to death. OS was assessed using the Kaplan-Meier method and significance was set at 2-sided P < 0.05. Univariate statistical analyses were used to examine the relationships between OS and multiple variables in the presentation. Results: 233 pts met the inclusion criteria: median age was 60.8y [51.4, 69.4]; 58% of pts were ECOG PS 1; 81% were non-Asian and 18.9% Asian; 67.4% of pts were male and 32.6% female. In terms of tumor location, gastric represented 47.2% of pts, GEJ 40.8% and esophageal 12.0% primaries; 43.7% pts were stage I-III, while 56.3% were de-novo metastatic pts. Median OS in Low, Mod, High SB pts cohorts were 22.7m, 17.6mm, & 14.6m, respectively (p < 0.036). Although worse OS and worse ESAS levels were not statistically significant in the localized pts (p, 505) and metastatic subgroup (p 0,092), there was a numerical tendency, especially in the metastatic pts. In the univariate analysis, there was a significant association between OS and high-symptom burden (Hazard ratio [HR] = 1.64 (95% CI, 1.12-2.38; p = 0.0104), ECOG ≥2 (HR= 2.79 (95% CI, 1.62-4.79; p = 0.0002) and metastatic pts (HR= 3.50 (95% CI, 2.51-4.86, p<0.0001). Conclusions: Higher SB based on ESAS was associated with poorer OS among GEA pts. ESAS is a reliable tool that carries a prognostic significance that could be used in practice.[Table: see text]
Real-world effectiveness of drugs newly approved in Japan on survival in patients with advanced gastric cancer.
Authors: Kadono Toru , Iwasa Satoru , Hirano Hidekazu , Shoji Hirokazu , Okita Natsuko Okita , Takashima Atsuo , Kato Ken
Published: January 2023

322

Background: Ramucirumab (RAM), nivolumab (NIVO), and trifluridine/tipiracil (FTD/TPI) were approved for advanced gastric cancer (AGC) between 2010 and 2020 in Japan. However, the impact of these newly approved drugs on survival in the real-world clinical setting is not clear. Methods: This retrospective study investigated the effectiveness of RAM, NIVO, and FTD/TPI in patients with performance status (PS) 0 to 2 who received doublet or triplet chemotherapy including platinum agents in first-line (1L) for advanced gastric adenocarcinoma at our hospital between 2010 and 2020. Patients were divided into two groups before or after 2017 to compare the effectiveness. Results: From a total of 825 patients, 533 were assigned to the pre-2017 group and 292 to the post-2017 group. Baseline characteristics of the pre- and post-2017 groups were, respectively, as follows: median age, 64 (range, 20-83) and 65 (25-85) years; PS 0, 206 (39%) and 89 (31%), and PS 1-2, 327 (61%) and 202 (69%); peritoneal metastasis, 334 (63%) and 189 (65%); liver metastasis, 157 (30%) and 68 (23%); and HER2 positive, 82 (15%) and 57 (20%). There was no difference in the proportion of fluoropyrimidine and platinum agents between the two groups. For the pre- and post-2017 groups, 1L chemotherapy comprised fluoropyrimidine plus platinum agents (FP) for 71% and 68% of patients, FP plus taxanes for 15% and 1%, FP plus trastuzumab for 11% and 15%, and FP plus immune checkpoint inhibitors (ICIs) for 1% and 10%, respectively. Taxanes and irinotecan were used significantly more often in any treatment line in the pre-2017 group (taxanes, 74% vs. 64%, p<0.01; irinotecan, 32% vs. 7%, p<0.01), whereas RAM, ICIs, and FTD/TPI were used significantly more often in any line in the post-2017 group (RAM, 50% vs. 17%, p<0.01; ICIs, 48% vs. 9%, p<0.01; FTD/TPI, 6% vs. 0%, p<0.01). Overall survival was significantly longer in the post-2017 group than in the pre-2017 group (median, 16.9 months vs. 13.8 months, HR 0.74, p<0.01). Progression-free survival did not differ between the pre- and post-2017 groups in relation to 1L (median, 6.0 vs. 5.9 months, p=0.74); second-line treatment (median, 3.0 months [95%CI, 2.6-3.3] vs. 3.1 months [95%CI, 2.3-3.6]; HR 0.96 [95%CI, 0.82-1.14], p=0.57); third-line treatment (median, 2.1 months [95%CI, 1.8-2.5] vs. 1.8 months [95%CI, 1.4-2.1]; HR 1.03 [95%CI, 0.82-1.29], p=0.80); or fourth-line treatment (median, 1.9 months [95%CI, 1.7-2.5] vs. 1.8 months [95%CI, 1.5-2.8]; HR 0.85 [95%CI, 0.57-1.25], p=0.39). Rates of second-, third-, and fourth-line treatment in the pre- and post-2017 groups were 83% and 79% (p=0.23), 45% and 56% (p<0.01), 16% and 22% (p=0.07), respectively. Conclusions: Newly approved drugs in salvage-line treatment of AGC may have contributed to prolonged survival.
Multifocal early gastric neoplasms of three or more lesions versus single lesion without recurrence: A comparative study.
Authors: Pih Gyu Young , Yoon Ji Hoon
Published: January 2023

329

Background: As indication for endoscopic resection for gastric neoplasms have been expanded, patients receiving multiple times of endoscopic resection for metachronous or synchronous lesions have been increasing. We aimed to compare clinicopathologic characteristics of patient with gastric neoplasm in a single location and multifocal lesions of three or more. Methods: From January 2006 to December 2021, 255 patients underwent endoscopic resection for three or more of multifocal lesions at tertiary medical institution were reviewed retrospectively and 8667 patient showed no recurrence after endoscopic resection for single lesion. The clinicopathologic characteristics of index gastric lesions were compared. Results: The male ratio was higher in multifocal lesions group than single lesion group (83.9% vs. 68.4%, P < 0.001). Diabetes mellitus was significantly more in multifocal lesions group than single lesion group (20.4% vs. 18.4%, P = 0.046), however hypertension, cardiovascular disease, kidney disease, and hepatitis showed no significant difference between the two groups. Smoking rate was significantly higher in the multifocal lesions group (current smoker 31.0% vs. 25.4%, and ex-smoker 24.7% vs. 24.8%, P = 0.028). In rapid urease test for Helicobacter pylori infection, the multifocal group showed significantly higher positives (54.9% vs. 40.8%, P < 0.001). Tumor depth, lymphovascular invasion, and perineural invasion showed no significant differences. Conclusions: Patients with multifocal early gastric neoplasms showed higher male ratio, higher rate of diabetes mellitus, and smoking rate compared with single lesion group. In addition, Helicobacter pylori infection was also significantly higher in patients with multifocal gastric neoplasm.
Short-term outcomes of robotic gastrectomy vs laparoscopic gastrectomy for patients with gastric cancer: A randomized clinical trial.
Authors: Ojima Toshiyasu , Hayata Keiji , Kitadani Junya , Goda Taro , Tominaga Shinta , Ohi Masaki , Yamaue Hiroki , Kawai Manabu
Published: January 2023

344

Background: Robotic gastrectomy (RG) procedure for gastric cancer (GC) patients may be associated with decreased incidence of intra-abdominal infectious complications. Prospective randomized controlled trials (RCTs) comparing laparoscopic gastrectomy (LG) and RG are required, however. We completed an RCT to compare short-term surgical outcomes of LG and RG for GC patients. Methods: This was a randomized, two-center clinical trial. All included patients are adults with primary carcinoma of the stomach, in whom the tumor is considered surgically resectable (cStage I-III). Included in this trial were 240 patients with GC. The primary endpoint was to assess the incidence of postoperative intra-abdominal infectious complications including pancreatic fistula, intra-abdominal abscess, and anastomotic leakage. Secondary endpoints included incidence of postoperative complications, surgical results, postoperative course, and oncological outcomes. Lymphadenectomy without touching the pancreas was basically performed during robotic gastrectomy using assisting articulating forceps. Results: A total of 241 patients were randomly assigned to the LG group (n = 122) or the RG group (n = 119), and 236 patients (LG119 RG117) were analyzed for ITT population. Overall incidence of intra-opereative infectious complications higher than Clavien-Dindo grade II were not significantly different (LG 8.4%, RG 6%). However, overall incidence of any complications higher than grade II were significantly lower in the RG group (19.3 vs 8.5% P = .019). In RG group, postoperative pancreatic fistula was not found. Amylase levels in drainage fluid on POD 1 were significantly lower in the RG group (893IU/L) than in the LG group (438 IU/L) ( P = 0.039). Conclusions: Regarding short-term surgical outcomes, RG is feasible, safe and ideal treatment procedure for GC. Our RG procedure without touching the pancreas may be associated with decreased incidence of postoperative pancreatic fistula. Clinical trial information: UMIN000031536 .
Phase 2 study of cabozantinib (cabo) and pembrolizumab (pembro) in metastatic gastric/gastroesophageal adenocarcinoma (mGEA) refractory to immune checkpoint inhibitors (ICIs).
Authors: Dayyani Farshid , Ghio Kristian , Lee Fa-Chyi , Cho May Thet , Chao Joseph , Taylor Thomas H , Neumann Kristen
Published: January 2023

345

Background: Most mGEA patients (pt) progress on therapy including ICI, with about 5% progression-free at 6mo (PFS-6) with single agent ICI in later lines of therapy. Alternative therapeutic approaches are needed. Cabo is a multi-tyrosine kinase inhibitor which might modulate immunosuppression in the tumor microenvironment. This study reports on safety and efficacy of the combination of Cabo+Pembro in mGEA refractory to ICI. Methods: Investigator-initiated, single‐arm, two-stage, single institution, phase 2 study in pts with mGEA after ≥1L of fluoropyrimidine and platinum-containing regimens. Additionally, pts with a PD-L1 CPS score ≥10% had also progressed on ICI. Cabo dose was 40mg p.o. daily on days 1 through 21 of a 21‐day cycle, with Pembro 200 mg i.v. on day 1. The primary endpoint was PFS-6, with H0=5%, Ha≥20%. Stage one results (n=19) exceeded the futility threshold. The complete design requires 27 evaluable pts and n≥4 pts with PFS-6 to reject H0 in favor of Ha. Results: 25 pts are currently enrolled. Because stage one did not signal futility, enrollment continues. Median age 58 years (24-75), female (n=13), ECOG 0/1= 13/12, GC/GEJ= 14/11, Caucasian/Hispanic/Asian/other = 7/7/8/3. After a median follow-up of 5.1mo (1.2-24.6), the median PFS and OS are 2.9mo (95% CI 2.1-4.6) and 9.5mo (95% CI 3.1-14.6), respectively. 11/25 had disease progression on or before the first imaging timepoint at 8 weeks, i.e. the clinical benefit rate is 56% (14/25). 13/20 pts had measurable disease by RECISTv1.1: PR 1(7.7%), SD 7(41.2%), PD 5(38.5%). The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (28%), fatigue (20%), and hypertension (16%). G3-4 TRAE were seen in n=3 pts (Hypertension, Thromboembolic event, esophageal perforation; each n=1). No G5 were reported. Conclusions: In this interim analysis of this ongoing study, the combination of Cabo+Pembro shows promising clinical benefit with an estimated OS of 9.5mo in mGEA pts resistant to prior ICI. Follow-up of the primary endpoint is ongoing. The regimen appears tolerable with no new safety signals. More mature data including the primary endpoint and correlative studies will be presented at the meeting. Clinical trial information: NCT04164979 .
Exploring demographic differences and outcomes in young-onset colorectal cancer.
Authors: Vadehra Deepak , Siromoni Beas , Groman Adrienne , Mukherjee Sarbajit
Published: January 2023

35

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States (1). The incidence of young-onset CRC is on the rise based on recent data (2). Previous research on other cancers has shown that patients living in rural areas have worse outcomes (3). This study aimed to investigate the geographic and socio-demographic disparities in young-onset CRC patients. Methods: We conducted a retrospective study on colorectal cancer patients between 1975 and 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariable analyses were performed to evaluate overall survival (OS) and disease-specific survival (DSS). Socio-demographic factors, including the location of residence [metro area (MA) or rural area (RA)], gender, race, insurance status, and marital status, were analyzed. Young-onset colorectal cancer (CRC) was defined as the age of diagnosis less than 50 years. The program used for analysis was SAS software 9.4 (SAS Institute Inc., Cary, NC, USA.) Univariate and multivariable models were analyzed using Cox proportional models. Demographic differences between urban and rural population were assessed using Wilcoxon Rank Sum test (continuous variable) and Chi-square test (categorical variables). Results: A total of 73,378 [RA, N = 7,636(10.6%); MA, N = 64,605(89.4%)] young-onset CRC patients were included. RA had more Caucasian patients compared to MA (80.5% vs 60%, p < 0.001). Patients living in RA were more likely to be uninsured (4.8% vs 3%, p < 0.001) than MA. During the study period, the incidence and mortality rates were consistently higher in RA vs. MA. Univariate and multivariable analysis showed that RA had worse OS (multivariate HR = 1.14; p < 0.01) and DSS (multivariate HR = 1.15; p < 0.001) compared to MA. Similarly, males, single and uninsured patients had worse OS and DSS compared to females, married, and insured patients, respectively. Conclusions: Our study identified social and demographic disparities in young-onset CRC incidence and outcomes. Potential causes may include access to healthcare, diet, health behavior, and environmental factors. Future research is needed to understand and attenuate such disparities.
Ramucirumab beyond progression plus TAS 102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab-based therapy: Final results of the phase II RE-ExPEL study.
Authors: Goetze Thorsten Oliver , Stein Alexander , Lorenzen Sylvie , Habibzada Timorshah , Goekkurt Eray , Herhaus Peter , Sookthai Disorn , Ihrig Kristina , Pauligk Claudia , Al-Batran Salah-Eddin
Published: January 2023

359

Background: Based on results of prior trials (TAGS, REGARD, RAINBOW), it seems promising to combine Ramucirumab (Ram) beyond progression (PD) with TAS-102 (trifluridine/tipiracil). The purpose of RE-ExPEL is to investigate the tolerability, safety and benefit of Ram beyond PD in combination with TAS-102 in advanced esophagogastric adenocarcinoma (EGA). Methods: This is a multicenter, non-randomized, open-label investigator initiated pilot trial. 20 ram-pretreated patients (pts) with advanced EGA were enrolled to a maximum of 4 cycles of ramucirumab 8mg/kg every two weeks (days 1, 15; qd28) plus TAS-102 35 mg/m2/p.o. bid (d1-5 and d8-12; qd28). Primary endpoint (EP) was tolerability and toxicity, defining a positive trial if SAE rate according (acc.) to CTCAE 5.0 will increase less than 30% (up to 55%) compared with results from TAGS (SAE-rate 43%). Secondary EPs are further safety data and efficacy data, OS, PFS and ORR. Results: 20 pts (20% female) were enrolled between Oct 2020 and Aug 2021, 20% gastric and 80% GEJ- cancers, 55% of pts with ECOG 0. Results of the final analysis showed that only 25% of pts had at least one SAE and the total no. of SAEs was 9, one with fatal outcome, all without relationship to systemic therapy and no SUSAR reported. RE-ExPEL was able to show a median OS of 9.07 mo (95% CI 5.42-10.09) and a DCR of 45%. 90% of pts got study medication in 3rd line whereas 10% were even further line pts. Conclusions: The safety data showed a favorable safety profile with a low rate of severe toxicity for ram+TAS-102, maybe due to the long disease stabilization and therefore less tumor associated symptoms. Regarding the primary safety endpoint, the trial was positive with even a numerically lower SAE rate compared with TAGS. Furthermore, RE-ExPEL was able to show very promising efficacy data for the combination ram plus TAS-102 with median OS of 9.07 mo. Ram+TAS-102 seems to be more effective than TAS-102 alone acc. to TAGS-trial respecting the limitation of the RE-ExPEL one arm study design with only 20pts. The combination needs further evaluation in a randomized phase III trial. Clinical trial information: NCT04517747 .
Sidedness and addition of chemotherapy associated with treatment outcomes of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Wu Tsung-Che , Liang Yi-Hsin , Chen Kuo-Hsing , Chuang Chien Huai , Shao Yu Yun
Published: January 2023

36

Background: Regorafenib is one of the options of salvage treatment for mCRC. We aimed to explore the prognostic factors of such regorafenib treatment. Methods: We searched the database of National Health Insurance, Taiwan for patients who initiated regorafenib treatment for mCRC from September 1, 2015, to December 31, 2018. Database interrogation of National Death Registry, Taiwan and Taiwan Cancer Registry was conducted for survival data and clinicopathological variables, respectively. Results: A total of 3,643 patients were included in the analysis. The median age was 61.2 years. The primary tumor was left-sided and KRAS mutant in 75.3% and 54.5% of patients, respectively; 28.9% of patients received chemotherapy simultaneously, with irinotecan as the most common companion. The median time to treatment discontinuation (TTD) was 2.3 months (95% confidence interval [CI]: 95% CI: 2.3-2.3), and the median overall survival (OS) was 7.2 months (95% CI: 6.9-7.4). Patients with left-sided primary tumors, compared with patients with right-sided tumors, exhibited significantly longer TTD (median, 2.4 vs. 2.1 months, p < 0.001) and OS (median, 7.6 vs. 6.1 months, p < 0.001). By contrast, TTD and OS of patients under regorafenib treatment were similar regardless the KRAS mutation status ( p = 0.415 and 0.643, respectively). Patients who received chemotherapy along with regorafenib, compared with patients who did not, also exhibited significantly longer TTD (median, 2.6 vs. 2.2 months, p < 0.001) and OS (median, 8.3 vs. 6.7 months, p < 0.001). In multivariate analysis adjusting age, sex, time from colorectal cancer diagnosis, hospital level, KRAS mutation, and initial regorafenib dose, left-sidedness of the primary tumor remained a predictor for better TTD (hazard ratio [HR]: 0.88, p = 0.002) and OS (HR: 0.92, p = 0.048), as well as addition of chemotherapy (for TTD, HR: 0.86, p < 0.001; for OS, HR: 0.76, p < 0.001). Due to the interaction between sidedness and KRAS mutation, we established separate Cox models and found that left-sided primary tumor was an independent predictor for better TTD and OS for KRAS wild-type tumors, but not for KRAS mutant tumors. Conclusions: In this population-wide cohort study, left-sided primary tumor and addition of chemotherapy were associated with better TTD and OS of regorafenib treatment for mCRC.