bluuebunny/crossref_metadata_2025 huggingface dataset:
A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.
Authors: Yoshinami Yuri , Osumi Hiroki , Takashima Atsuo , Sawada Ryoichi , Ouchi Kota , Wakatsuki Takeru , Ooki Akira , Nakayama Izuma , Fukuoka Shota , Ogura Mariko , Takahari Daisuke , Chin Keisho , Hirano Hidekazu , Shoji Hirokazu , Okita Natsuko Okita , Boku Narikazu , Kato Ken , Ishizuka Naoki , Yamaguchi Kensei , Shinozaki Eiji
Published: January 2023

206

Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001), and between two groups divided at the median: tumor diameter (> 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), carcinoembryonic antigen level (> 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (> 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.
Association of punctate TAK1 expression with mortality in patients with microsatellite-stable colorectal cancer.
Authors: Galbraith Norman James , Al-Badran Sara SF , Hatthakarnkul Phimmada , Pennel Kathryn AF , Quinn Jean A. , Loi Lynette , Maka Noori , Steele Colin William , Roxburgh Campbell SD , McMillan Donald C. , Horgan Paul G. , Edwards Joanne
Published: January 2023

220

Background: Microsatellite stable (MSS) colorectal cancer continues to have limited options for personalised therapeutic targets. The NFKB pathway is known to play an important role in inflammation-related carcinogenesis but has yet to be translated into therapies for the clinical patient. The aim of this study was to investigate the expression of cytoplasmic and punctate TAK1 (transforming growth factor β-activated protein kinase 1) in colorectal cancer and its relationship to immune checkpoint expression and prognosis. Methods: Patients undergoing primary colorectal cancer resection between 1997 and 2007 at Glasgow Royal Infirmary (UK) were studied for clinicopathological data and immunohistochemistry (IHC) performed on archival FFPE tissue from resected specimens. Antibodies for TAK1, PD-1, PD-L1, IKK alpha and other proteins were used for IHC, with digital analysis (QuPath) for quantification of cytoplasmic staining and punctate score for juxta-nuclear TAK1 assessment. Kaplan-Meier curves were created with log-rank test to determine survival. Cox-proportional hazards regression were used to determine multivariate hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 898 patients who underwent colorectal resection were identified. Higher TAK1 punctate expression was observed in left colon and rectal cancer, compared with right sided disease (p = 0.045). MMR proficient tumours had higher frequencies of high TAK1 punctate expression (p < 0.001). Both cytoplasmic and punctate TAK1 expression correlated with IKK expression (p < 0.050). High cytoplasmic TAK1 expression was associated with increased PD-1 and PD-L1 expression (p < 0.001). Punctate TAK1 expression was associated with worse survival (p = 0.037). These differences were accentuated in patients with MSS status (p = 0.016). On multivariate analysis, high punctate TAK1 expression remained a predictor of worse cancer-specific survival (HR 1.843, CI 1.129-2.956, p = 0.011). Conclusions: TAK1 expression was associated with MSI status, and higher TAK1 expression correlates with upregulated PD-1 and PD-L1 expression. High punctate TAK1 expression predicted cancer-specific survival. In subgroup analysis of MSS patients, high punctate TAK1 expression was associated with poor survival. Further interrogation into this pathway may identify inflammation-related therapeutic targets in MSS patients with colorectal cancer.
Serum trefoil factor family 3 as a biomarker for the detection of colorectal cancer.
Authors: Lee Hyun Seok
Published: January 2023

229

Background: Colorectal cancer is one of the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for timely diagnosis and effective treatment. Our aim in the present study was to detect the serum level of trefoil factor family 3 (TFF3) and evaluate the diagnostic accuracy of TFF3 in patients with colorectal cancer. Methods: We prospectively collected serum samples from 72 subjects (36 patients with colorectal cancer and 36 healthy controls) in the derivation cohort. The validation cohort prospectively included 70 subjects (35 patients with colorectal cancer and 35 healthy controls). The levels of serum TFF3 and carcinoembryonic antigen (CEA) were examined using enzyme-linked immunosorbent assay. Results: The serum levels of TFF3 in patients with colorectal cancer was significantly higher compared with that in the healthy controls (9.34±12.2 ng/mL vs. 3.60±1.58 ng/mL, P = 0.008) in the derivation cohort. Using a cutoff of 3.85 ng/mL in the derivation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of advanced colorectal cancer were 0.972, 0.611, and 0.875, respectively. The sensitivity of serum TFF3 for the detection of colorectal cancer was superior (97.2%) to that of CEA (36.1%) in the derivation cohort. In the validation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of colorectal cancer were 0.771, 0.486, and 0.751, respectively. Similarly, the sensitivity of serum TFF3 for the detection of colorectal cancer was also superior (77.1%) to that of CEA (22.9%) in the validation cohort. Conclusions: Serum TFF3 is a potential biomarker for the detection of colorectal cancer and is more effective compared with CEA.
Tumour radiomics as imaging biomarker of tumour response to chemo-radiotherapy in patients with adenocarcinoma of rectum.
Authors: Engineer Reena , Puppalwar Abhinav , Sastri Jayant , Jha Ashish , Kumar Suman , Saklani Avanish
Published: January 2023

243

Background: We aimed to study whether texture (Radiomic) features obtained from T2W MRI of patients with rectal cancer can be used as a surrogate imaging biomarker to predict response to NACTRT. We explored various machine learning tools to develop the best model to predict response to NACTRT. Methods: One hundred patients with stage II/III who underwent MRI before and after NACTRT and surgical treatment were enrolled. Patients were classified into complete response (pCR, n = 21) and partial and nonresponse (pPR + pNR, n = 53) on the basis of histopathological report (74 patients who underwent surgery) and clinico-radiological response (26 patients who did not undergo surgery). Tumor volumes (Region of interest) were manually selected in each tumour segment. There were sixty four first-order and higher-order radiomic features. Recursive feature elimination method was used for feature selection and 5 prediction models were tested using 10-fold cross validation for predicting tumour response to NACTRT. Results: Using prediction model assessment matrix (RFC, SVC, GBC, NBC, ABC), the best results for prediction response were obtained using the random forest model with AUC of 0.79 ± 0.15 (Mean ± Standard deviation) accuracy of 0.72 ±0.12, precision of 0.77 ± 0.10, sensitivity of 0.87 ± 0.07, f1 score- 0.81 ±0.07. By using random forest model, Texrad features obtained from pre and post NACTRT MRI could accurately predict pCR. To the best of our knowledge, apart for the added values of RF model to Texrad features, is the first study to demonstrate and compare RF, SVC, GBC, NBC, Adaboost models to the same cohort of patient with 10-fold validation. Conclusions: Our study shows that RFM was most accurate and stable for predicting tumour response. MRI based Radiomic features can be used as surrogate image biomarker to accurately predict the treatment response to NACTRT in patients with locally advanced rectal cancer. The prediction model can be used as a complementary non-invasive tool to identify patients eligible for organ preservation. [Table: see text]
Genomic analysis to elucidate similarities and differences between primary colorectal cancers and colorectal cancer liver metastases.
Authors: Buechler Steven Allen
Published: January 2023

25

Background: Whole transcriptome (WT) analysis of primary colorectal cancer (pCRC) has shown that the tumor microenvironment (TME) plays a critical role in disease progression and response to treatment. Colorectal cancer liver metastases (CRCLM) bear many genetic similarities to primary tumors, however differences in the microenvironment could effect drug response. Since 80% of metastatic CRC patients have liver metastases there is a critical need for further molecular analysis of CRCLM. Methods: Using a novel method to identify aberrant activity of signaling pathways, continuous scores (called pathway cluster scores, PCS) were derived from subsets of Hallmark gene sets of MSigDB. PCS scores that were prognostic in CRCLM were considered relevant to disease progression. Combined studies of such scores in CRCLM and pCRC were used to explore differing effects of the colon and liver TMEs. Analyses were performed on published WT datasets of pCRC (4 cohorts, n = 2,978) and CRCLM (3 cohorts, n = 498). Immune cell infiltration levels were estimated with Immunedeconv. Results: The most significantly prognostic PCS score in CRCLM cohort GSE159216 (n = 171) was one derived from a cluster of 28 KRAS signaling genes, called K-score (p = .0004). Subtypes K+ (good prognosis) and K- (poor prognosis) denote samples with K-score above, respectively below, the median. Gene set enrichment analysis showed that in all CRCLM cohorts, K- was enriched versus (v) K+ in proliferation-related pathways, e.g. E2F signaling and DNA Repair, while K+ was enriched v K- in multiple immune system pathways. In both CRCLM cohorts, K+ was enriched v K- in infiltration of neutrophils and CD4+ T cells, while infiltration levels of CD8+ T cell were not significantly different between K+ and K-. The T cell homing chemokines CXCL12, CCL19, CCL21 were elevated in K+ v K-. The aforementioned molecular features of K+ and K- also held in all pCRC cohorts; however in these cohorts, K+ was also enriched v K- in B cell and M2 macrophage infiltration. Also, in pCRC expression of the B cell attractor CXCL13 and biomarkers for tertiary lymphoid structures (TLS) were significantly elevated in K+ v K-. Of note, TLS have been associated with response to immune checkpoint inhibitors in multiple cancer types. In addition, in 18 pairs of matching pCRC and CRCLM samples (GSE49355), K-scores of pCRC samples were significantly correlated to K-scores of the matching CRCLM samples (p = .01). Chemokine expression levels differed in matching pairs: mean expression of CXCL12 was significantly higher in CRCLM than pCRC, while mean expression of CXCL13 was significantly higher in pCRC than CRCLM. Conclusions: In the study cohorts, K- tumors in both pCRC and CRCLM, were proliferative and lacked inflammation. However, while both pCRC and CRCLM K+ tumors were inflamed and enriched with CD4+ T cells, only pCRC K+ tumors were likely to contain TLS.
A multicenter, case-control study of a novel multi-target fecal DNA test for colorectal cancer detection.
Authors: Peng Jiaxi , Yin Meichen , Jiang Ruijingfang , Li Zhilong , Zhuo Duan , Qu Hongyue , Luo Mengxue , Liu Qian , Jiang Weijia , Sun Jianlong , Lin Jia , Wang Yuying
Published: January 2023

26

Background: Globally, colorectal cancer (CRC) is the fourth most frequently occurring cancer and is the second leading cause of cancer-related deaths. Early detection and diagnosis of pre-cancer lesions and CRCs at curable stages could prevent the disease or improve patient survival. Colonoscopy, the current gold-standard approach for CRC screening, is an invasive procedure, and novel non-invasive alternatives are needed. Methods: In present study, we developed a novel multi-target fecal DNA based assay, which integrates detection of two stool DNA (sDNA) methylation markers by quantitative methylation-specific PCR (qMSP) and immunochemical fecal occult blood test. We performed a multi-center case-control study to validate the diagnostic performance of this novel multi-target assay. Thus far, we collected stool specimens from a total of 784 subjects including CRC, advanced adenoma, nonadvanced neoplasms and individuals with negative findings on colonoscopy from six sites across China. All participants underwent colonoscopy; the stool specimens were tested with the multi-target fecal DNA test as well as a quantitative FIT test (OC FIT-CHEK, Eiken) in parallel in order to perform head-to-head comparison of the test performance of both assays. Results: The multi-target fecal DNA test demonstrated a higher sensitivity (96.1%) than FIT (85.3%) for CRCs (n=204). Meanwhile, 20 of 39 (51.3%) patients with advanced adenoma tested positive by the fecal DNA test, which was remarkably superior to FIT (7 of 39 tested positive, 17.9%). Among 541 participants with nonadvanced neoplasms or negative findings on colonoscopy, the specificity of the DNA test was 86.9%, compared with a specificity of 93.1% achieved by FIT. Within the control group, the DNA test and FIT yielded a specificity of 90.5% and 94.9% respectively for individuals with negative results on colonoscopy. Conclusions: The novel multi-target fecal DNA test exhibited notably superior sensitivity for both CRC and advanced adenoma cases than the commercially quantitative FIT test, while sacrificing some specificity. Our results suggest that this novel multi-target fecal based test may be used as an effective tool for early detection and pre-screening of CRC. Prospective study will be conducted to further evaluate the clinical performance and cost-effectiveness of this assay.
Differences in genomic profiles of gastric adenocarcinoma in the US and Japan.
Authors: Nakauchi Masaya , Court Colin , Walsh Henry S. , Chatila Walid Khaled , Shimada Shoji , Vardhana Santosha , Tang Laura H. , Coit Daniel G. , Janjigian Yelena Y. , Maron Steven Brad , Ku Geoffrey Yuyat , Ilson David H. , Schultz Nikolaus , Matsuoka Hiroshi , Tsukamoto Tetsuya , Uyama Ichiro , Susa Koichi , Strong Vivian E.
Published: January 2023

299

Background: Although epidemiological and clinical differences in gastric cancer (GC) between the US and Japan have been reported, genetic differences have not been clarified. We aimed to characterize molecular differences in GC between the two countries. Methods: We collected data between January 2010 and December 2019 from a prospectively maintained database of GC at our US and Japanese centers. After matching clinicopathological backgrounds, including age, sex, clinical T and N status, and tumor location, the genomic profiles of the primary site were compared for 58 patients in each group undergoing surgical resection and had MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets), a tumor-normal next generation sequencing assay that can detect alterations in exons and select introns of 505 genes. The MSI sensor algorithm was used to assess microsatellite instability. Genomic alterations were filtered for driver variants using OncoKB, and genes were consolidated into pathways using curated pathway templates from the Cancer Genome Atlas. Results: The clinicopathological characteristics were well matched between 58 patients in each cohort. In the entire cohort, the most commonly altered genes were: TP53 (45%), ARID1A (24%), and ERBB2 (17%) in the US cohort, and TP53 (50%), ARID1A (19%), and ERBB2 (17%) in the Japanese cohort. Although KMT2D was more frequently altered in the US cohort (19% vs. 2%), the two cohorts had no significant differences in other altered genes and gene pathways. The tumor with MSI high was found more frequently in the US cohort (22.4% vs. 5.2%, p = 0.01). Among the MSI-normal tumors, the tumor mutational burden (US: 3.5 muts/Mb and Japanese: 4.1 muts/Mb) and the fraction genome altered (US: 0.37 and Japanese: 0.28) did not significantly differ between the two groups. Additionally, no genes or pathways were significantly enriched in either group. Patterns of mutual exclusivity and co-occurrence amongst genes and pathways were also similar between the two groups. Conclusions: In this original genomic comparison of US and Japanese gastric cancers, matching clinicopathological backgrounds, Japanese and US gastric cancers are remarkably similar at the genomic level, with the possible exception of MSI-high tumor that appear to be more frequent in the US.
Agreement between FGFR2 immunohistochemistry assays and fluorescence in situ hybridization (FISH) in metastatic gastric cancer: A comparison study.
Authors: Raskin Grigory A. , Mukhina Marina S. , Kravtsova Elena D. , Tjulandin Sergei , Tsimafeyeu Ilya
Published: January 2023

301

Background: FGFR2 status of a patient with metastatic gastric adenocarcinoma could be an important factor in determining optimal treatment strategy with FGFR2 inhibitors and antibodies. The question remains how well different assays agree on the FGFR2 status of the same patient and whether one test can be substituted by another. Methods: Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8] and one FISH test. One hundred and nine formalin-fixed, paraffin embedded samples (including 64 primary tumors and 45 metastases of same patients) were obtained and were stained with FGFR2 IHC assays. Two trained pathologists independently evaluated the percentages of tumor staining and their intensity. FGFR2 FISH was performed as described previously [Su, BJC 2014]. The concordance analysis was performed to assess (1) correlation of FGFR2 expression/amplification between different assays in primary and metastases, (2) the predictive properties of one test of another. Results: After evaluating the expression in the first 19 patients, further study was carried out only using the Abсam assay due to pronounced nuclear staining with other IHC tests. FGFR2 any level expression was detected in 29 (47%) primary tumors and 18 (40%) metastases with concordance of 91%. The prevalence of FGFR2 amplification was 9.4% and intratumoral heterogeneity was observed in 33% of FGFR2 amplified cases. Pearson Correlation Coefficients (PCC) were: 0.89, 0.38 and 0.35 between IHC3+/FISH, IHC≥1% stained cells/FISH and IHC≥10%/FISH, respectively. The table represents how well one assay can predict the same outcome (positivity or negativity) of another assay. Conclusions: Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC. [Table: see text]
Adjuvant chemotherapy for older patients with stage II/III gastric cancer: A retrospective cohort study.
Authors: Shih Yu-Hsuan , Lin Hsin-Chen , Hsu Chiann-Yi
Published: January 2023

303

Background: Current clinical guidelines recommended adjuvant chemotherapy for stage II and stage III gastric cancer after operation. The older patients were underrepresented in clinical trials and the role of adjuvant chemotherapy for older patients is unclear. We aimed to investigate the benefit of adjuvant chemotherapy in older patients with stage II and stage III gastric cancer. Methods: We retrospectively reviewed the medical records of patients with stage II-III gastric adenocarcinoma and underwent curative surgery at Taichung Veterans General Hospital (Taichung, Taiwan) between January 2009 and June 2017. The clinical characteristics and outcomes of patients ≥70-year-old were compared between patients received adjuvant chemotherapy or not received adjuvant chemotherapy. Results: A total of 357 patients were analyzed and 164 patients were older or equal to 70 years old. Majority of the young patients received adjuvant chemotherapy but only two-thirds of the old patients received adjuvant chemotherapy (93.8% vs. 61%; P<0.001). Among older patients, receipt of adjuvant chemotherapy was associated with longer disease-free survival (DFS) (10-year DFS, 45.89% vs. 17.55%; P<0.001) and overall survival (OS) (10-year OS, 61.71% vs. 36.27%; P=0.023) compared with patients who did not receive adjuvant chemotherapy. The total gastrectomy (hazard ratio (HR): 2.26; P=0.015), more advanced stage (HR: 2.71; P=0.018), positive surgical margin (HR: 2.56; P=0.02), elevated baseline carcinoembryonic antigen (HR: 2.37; P=0.026) were independent prognostic factors for OS in patients ≥70-year-old. Notably, the benefit adjuvant chemotherapy in older patients was significant in univariate analysis (HR: 0.53; P=0.025) but was not confirmed in multivariate analysis (HR: 0.52; P=0.072). Conclusions: The benefit of adjuvant chemotherapy in older patients with stage II-III gastric cancer was controversial in this retrospective study. Further prospective studies are needed to investigate this issue.
Real-world representativeness of patient-reported outcome measures of patients with esophagogastric cancer.
Authors: Kuijper Steven C. , Besseling Joost , Klausch Thomas , Slingerland Marije , van der Zijden Charlène , Kouwenhoven Ewout , Beerepoot Laurens V. , Haj Mohammad Nadia , Klarenbeek Bastiaan , Verhoeven Rob , Van Laarhoven Hanneke W.M.
Published: January 2023

319

Background: The use of patient reported outcome measures (PROMs) is a popular method to obtain real-world patient data in oncological research. However, PROMs rely on voluntary and active participation of patients and are therefore prone to selection bias. To investigate the suitability of PROMs as real-world data, we investigated the real-world representativeness of the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) registry with respect to the Dutch population of patients with esophagogastric cancer. Methods: We identified 2,575 patients in the POCOP registry and 13,702 in the nationwide population-based Netherlands Cancer Registry (NCR) from 2016-2021. We used Representativeness-indicators (R-indicators) to investigate the degree to which the POCOP registry and clinically relevant subgroups thereof, were a representative sample with respect to the population. R-indicators express the representativeness between 0 (not representative) and 1 (perfect representativeness). Calibration methods using inverse propensity weighting were used to correct potential differences between POCOP and the population estimates. Subsequently, median and 5-year overall survival were calculated and compared between patients in the POCOP registry and in the population, to investigate the representativeness in terms of survival. Results: Representativeness of the entire POCOP registry was 0.73 (95% CI: 0.71-0.74). The overall representativeness of palliative patients was higher than that of potentially curable patients (0.89 (0.87-0.90) and 0.70 (0.68-0.71), respectively). Representativeness of most clinical subgroups stratified to treatment was good; R-indicators ranged between 0.8 to 1.0. Median survival of the NCR, POCOP and calibrated POCOP was 19, 32, and 23 months, respectively. The 5-year overall survival of patients in the NCR, POCOP and calibrated POCOP was 26%, 36%, and 27%, respectively. Conclusions: The real-world representativeness of patients who participated in PROMs was good when we accounted for treatment. This shows that in the analysis of PROMs stratification to treatment groups can lead to generalizable results to the population. Using complete non-stratified PROMs, real-world representativeness was lower and calibration methods could be used to correct differences between patients in the PROMs and the population.
Neoadjuvant chemoradiation in elderly Irish patients with esophageal cancer: A review of the clinical outcomes and toxicity.
Authors: Mc Laughlin Ronan Andrew , Almeraikhi Majid , Alkaabi Humaid , Bligh Fianait , Cluxton Christopher , Mcmahon David , Fitzpatrick Orla , Conroy Michael R , Hennessy Bryan T. , O'Neill Brian , Naidoo Jarushka , Breathnach Oscar S. , Grogan William , Murphy Adrian Gerard , Morris Patrick G.
Published: January 2023

335

Background: In locally advanced esophageal cancer, neoadjuvant chemo-radiotherapy improves survival compared with surgery alone. In the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), the median age was 60. However, 1/3 of patients diagnosed with esophageal cancer are over 70 years. The CROSS outcomes are therefore limited in its application to older patients. The objective of this study is to report and compare the outcomes and tolerability in elderly patients (≥70 years), who underwent neoadjuvant chemo-radiation for esophageal cancer with younger patients < 70 years. Methods: A retrospective analysis of patients treated with neoadjuvant chemo-radiation for esophageal cancer between 1st January 2015 and 1st January 2021 was completed. Baseline characteristics and haematological toxicities were reported. Pathological response was reported. Survival was estimated using the Kaplan-Meier method. Results: In total 105 patients were included; 35 (33%) were ≥ 70 years and 70 (67%) patients were < 70 years. In the elderly cohort, the median age was 75 (70-86) and the younger cohort median age was 60 (29-69). 73% of patients in each cohort were male. 31 (89%) of older adults experienced any grade of anaemia compared with 45 (64%) of the younger cohort. Only one patient experienced ≥ grade 3 anaemia in each cohort. 18(51%) and 33(47%) of older and younger patients respectively experienced any grade of neutropenia. 5(14%) older and 7(10%) younger patients experienced ≥ grade 3 neutropenia. 15(43%) and 43(61%) of older and younger patients experienced any grade of thrombocytopenia. No patients experienced ≥ grade 3 thrombocytopenia. 80% of the older and 86% of the younger cohort proceeded to surgery. 3(11%) and 17(29%) of the older and younger cohorts respectively who underwent surgery achieved a complete pathological response. There was no difference in overall survival (OS) between the cohorts (p=0.48). There was also no difference in progression free survival (PFS) between the cohorts. Conclusions: In conclusion, we confirm that neoadjuvant chemo-radiation is tolerable in patients ≥ 70 when compared with patients < 70 years. Both OS and PFS is similar in both cohorts. We recommend the use of neoadjuvant therapy in appropriately selected patients ≥ 70 years.
Esophagogastrostomy with fundoplication versus double-tract reconstruction after laparoscopic proximal gastrectomy for gastric cancer.
Authors: Tominaga Shinta , Ojima Toshiyasu , Hayata Keiji , Kitadani Junya , Yamaue Hiroki , Kawai Manabu
Published: January 2023

346

Background: Upper-third gastric cancer has been increasing in incidence worldwide and performance of laparoscopic proximal gastrectomy has become increasing common. Various reconstructive procedures after laparoscopic proximal gastrectomy have been reported, but the optimal reconstructive procedure is unclear. Methods: This single-center retrospective study included 53 consecutive patients with early gastric cancer in the upper third of the stomach who received laparoscopic proximal gastrectomy at our hospital between September 2013 and November 2019. Of these 53 patients, 39 underwent esophagogastrostomy with fundoplication. In the 14 patients requiring resection of the abdominal esophagus or where the size of the remnant stomach was 50% or less, we performed double-tract reconstruction. We compared the surgical and nutritional outcomes of patients who underwent esophagogastrostomy or double-tract reconstruction after laparoscopic proximal gastrectomy. Results: There was no significant difference between the two groups regarding blood loss, incidence of postoperative complications, occurrence of gastroesophageal reflux disease, food intake, reflux symptoms, or usage of proton pump inhibitors. There was no significant difference in the rate of body weight change at 6 or 12 months, or in biochemical markers (hemoglobin, total protein and albumin) at 12 months. However, eight patients (21%) in the esophagogastrostomy group had extreme body weight loss (≥20%) within 12 months. Conversely, in the double-tract reconstruction group, no patients had any extreme body weight loss ( P = 0.013). Conclusions: Double-tract reconstruction is useful after laparoscopic proximal gastrectomy, especially in terms of preventing extreme body weight loss.
Safety and efficacy from the phase 1 SURPASS trial of ADP-A2M4CD8, a next-generation T-cell receptor T-cell therapy, in patients with advanced esophageal, esophagogastric junction, or gastric cancer.
Authors: Blum Murphy Mariela A. , Ajani Jaffer A. , Van Tine Brian Andrew , Clarke Jeffrey Melson , Butler Marcus O. , Lawrence Donald P. , Johnson Melissa Lynne , Cervantes Andres , Moreno Victor , Hong David S. , Brophy Francine Elizabeth , Navenot Jean-Marc , Lin Quan , Saro Jose , Norry Elliot
Published: January 2023

349

Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated a favorable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients (pts) with unresectable or metastatic tumors positive for MAGE-A4 (Hong DS, et al. E-poster 540P: ESMO 2021; Virtual). Here we report updated clinical outcomes in pts with esophageal, esophagogastric junction (EGJ), or gastric cancer. Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the pts as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: As September 6, 2022, 13 pts (11 male, 2 female) with esophageal (3), EGJ (8), and gastric cancer (2) received ADP-A2M4CD8 (range: 1.02–9.9x109 transduced T-cells). All pts had adenocarcinoma, median age was 55 years (range: 31–71), median MAGE-A4 expression H-score was 245 (range: 160–300), and pts received median of 2 lines of prior therapy (range 1–5). Adverse events (AEs) were consistent with those typically associated with lymphodepleting chemotherapy, cellular therapy, and/or disease. One pt had a Grade 5 (fatal) AE of pancytopenia. Overall response rate per RECIST v1.1 by investigator review was 15% (2 partial response [PR]). Disease control rate was 77% (2 PR+8 stable disease). This trial is ongoing, and additional data will be presented. Conclusions: Results indicate an acceptable benefit to risk profile and encouraging anti-tumor activity of ADP-A2M4CD8. An additional treatment cohort has been included in the updated SURPASS trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. A Phase 2, open-label trial in advanced esophageal and EGJ cancers has been initiated (SURPASS-2; NCT04752358). Clinical trial information: NCT04044859 .
A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors.
Authors: Xu Rui-hua , Wei Xiaoli , Zhang Dongsheng , Qiu Miaozhen , Zhang Yang , Zhao Hongyun , Chen Bo , Yan Joy
Published: January 2023

352

Background: CMG901, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate, has demonstrated potent preclinical anti-cancer activity through monomethyl auristatin E (MMAE)-mediated cytotoxicity with bystander killing, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Methods: This Phase 1a trial uses a modified 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity in subjects (ages 18-75 years) with advanced gastric, gastroesophageal junction (GEJ), pancreatic cancers, and other solid tumors. Eligible subjects are refractory and/or intolerant to standard therapies. CLDN18.2 expression was not required for study entry, but was retrospectively tested by the central lab. CMG901 was administered intravenously on Day 1 in 3-week (Q3W) cycle at doses of 0.3, 0.6, 1.2, 1.8, 2.2, 2.6, 3.0, and 3.4 mg/kg. Primary endpoints include safety and tolerability. Major efficacy endpoints include objective response rate (ORR) and disease control rate (DCR) based on RECIST v1.1. Pharmacokinetics (PK) and immunogenicity are also assessed. Results: As of August 4, 2022, 27 subjects (13 gastric/GEJ cancer and 14 pancreatic cancer patients) received CMG901 at dose levels up to 3.4 mg/kg. The median prior lines of systemic therapy were 2 (range: 1 to 5). Drug-related grade ≥3 adverse events (AEs) occurred in 3/27 (11.1%) patients. No drug-related grade 4 or 5 AEs were reported. MTD was not reached. In CLDN18.2-positive gastric/GEJ cancer patients, ORR and DCR were 75.0% and 100%, respectively, with ORR of 100% in the 2.6, 3.0, and 3.4 mg/kg Q3W dose cohorts. Median progression-free survival (mPFS) and median overall survival (mOS) were not reached yet. PK data showed that patients had low systemic exposure to unconjugated MMAE. Subsequent results will be presented. Conclusions: CMG901 was well-tolerated with preliminary promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. The Phase 1b dose-expansion trial in gastric/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors is rapidly enrolling, with multiple pivotal (Phases 2 and 3) trials planned. Clinical trial information: NCT04805307 . [Table: see text]
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis with 3-year follow-up.
Authors: Shen Lin , Bai Yuxian , Lin Xiaoyan , Li Wei , Wang Jufeng , Zhang Xiaochun , Pan Hongming , Bai Chunmei , Bai Li , Cheng Ying , Zhang Jingdong , Zhong Haijun , Ba Yi , Hu Wenwei , Xu Rui-hua , Guo Weijian , Qin Shukui , Wang Rui , Sullivan Kendall , Liu Tianshu
Published: January 2023

353

Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. Results from CheckMate 649 led to approval of 1L NIVO + chemo in multiple countries, including China. We report 3-year follow-up results in Chinese pts. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2-positive GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 37 month (mo) minimum follow-up, NIVO + chemo continued to demonstrate clinically meaningful improvement in OS and PFS vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts. The 36-mo OS rate was 31% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 26% vs 9% in all randomized pts, respectively. Objective response rate (ORR) (95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56-79) with NIVO + chemo and 48% (36-60) with chemo, and in all randomized patients was 66% (55-76) and 45% (35-56), respectively. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, with median duration of response (mDOR) (95% CI) of 12.5 mo (7.2-23.4) vs 6.9 mo (3.9-8.5); in all randomized pts, mDOR was 12.5 mo (7.2-17.7) vs 5.6 mo (4.4-8.3), respectively. No new safety signals were identified. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and durable objective responses vs chemo in Chinese pts, with an acceptable safety profile, consistent with the overall study population with advanced GC/GEJC/EAC. These results further support NIVO + chemo as a 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
Relevance of adjuvant chemotherapy in elderly patients with low rectal tumors.
Authors: Adeleke Sola , Davies Aaron , Okoli Somto , Wang Kaiwen , Brown Nicholas Fraser , Galante Joao R , Elwes Flora , Choy Adrian , Karova Mariya , Dahal Luna , George Sneha , Durve Meeta , Mikropoulos Christos , Edwards Albert , Raman Rakesh , Clarke Amanda
Published: January 2023

37

Background: The balance between the benefits and toxicities of adjuvant systemic chemotherapy is crucial in the elderly, and often co-morbid patients who have undergone total mesorectal excision (TME) surgery for carcinomas of the lower rectum (1). Tumour distance from the anal verge is a known prognostic factor in rectal cancer (2, 3) and it may influence the effectiveness of adjuvant chemotherapy (AC) (4). This study evaluated the differences in the survival outcomes between patients on surveillance(S) and those who received AC in a multi-centre, real-world setting with a focus on the elderly cohort. Methods: Data was extracted from electronic patient records from 4 NHS trusts in Kent, UK. We retrospectively analysed records of patients between 1 Jan 2014 and 31 Dec 2019, who had neoadjuvant chemoradiotherapy, were down-staged and then offered either S or AC based on clinician’s judgement. The tumour distance from the anal verge was measured through high resolution MRI. The patients were downstaged following assessment as their pTNM staging was lower than their cTNM staging. Results: 589 patients treated for rectal cancer were identified. Of these, 168/589(28%) had non-metastatic disease, were later down-staged at TME and were offered S or AC. 95/168 (57%) of these patients received AC. Patients who received AC were younger (median age 63 vs 70 years, p< 0.001) and with additional poor prognostic factors such as extramural venous invasion EMVI+ (74 vs 39%, p= 0.001), circumferential resection margin CRM+ (89 vs 70% p = 0.001) and pathological nodal involvement (AJCC stage III disease) ( p< 0.001) (table) compared to those on S. Our findings did suggest that patients on surveillance with tumours < 5cm from the anal verge had a longer disease-free survival(DFS) than those who received chemotherapy; this was especially the case in the elderly patient cohort (HR 0.13 95% CI 0.02-0.99, p= 0.049).Our findings also showed that the DFS benefit for patients under surveillance increased with age. Surveillance was most effective in patients over 60 years old compared to those under 60. However, age or distance from anal verge did not have an impact on overall survival (HR 1.01 95% Cl 0.95-1.08 p= 0.70). Conclusions: Although patients treated with AC were younger than patients on S, their tumours had additional poor prognostic factors. Patients on surveillance with tumours <5cm from the anal verge enjoyed a longer DFS but no OS benefit. Elderly patients with tumours < 5cm from the anal verge with no poor prognostic features could derive a benefit from surveillance and avoid chemotherapy-related toxicity. However, our findings will need to be corroborated in prospective studies. [Table: see text]
Long-term survival outcome of multi-institutional prospective phase II trial of conversion surgery: CCOG1403.
Authors: Ito Seiji , Ito Yuichi , Kobayashi Daisuke , Matsushita Hidenobu , Tanaka Yuri , Kodera Yasuhiro ,   Chubu Clinical Oncology Group (CCOG)
Published: January 2023

380

Background: From the result of CONVO-GC-1, safety and efficacy of conversion surgery are shown. But there are few prospective studies about conversion surgery. We conducted multi-institutional prospective study of conversion surgery (CCOG1403). Methods: The patients (pts) with gastric cancer, who were initially regarded as non-curable and curably resectable after at least one course of chemotherapy, were enrolled. After diagnostic laparoscopy or laparotomy, pts were performed gastrectomy in case of curably resectable. The primary endpoint was 3-year survival from the start of first line chemotherapy. The planned sample size was 30, with one-sided alpha of 5%, power of 90%, expected 3-year survival rate of 27%, and threshold of 7%. Secondary endpoints were 5-year survival from the start of first line chemotherapy, the proportion of R0 resection, 3-year survival from the conversion surgery, pathological response, and adverse events. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000014251. Results: From April 2014 to March 2019, 30 pts were enrolled from 7 institutions. The mean age was 66.7. Non-curable factors were PER(11), LYM(9), HEP(6), T(4), CY(1), PUL(1), BRA(1), and other(1), respectively. Four pts had more than one non-curable factors. The categories of Yoshida’s classification were Cat.1(3), Cat.2(16), Cat.3(8), and Cat.4(2). Regimen of chemotherapy were SOX (11), SP (8), XP+HER (8), PTX ip containing regimen (6), and others (12). Clinical responses of preoperative chemotherapy were PR in 24 and SD in 6. Operative procedures were TG (18), DG (7), and PG (1). Median operative time was 278.5min. and median blood loss was 417.5ml. Twenty-four (80%) pts achieved R0 resection. Five pts suffered >= C-D Grade III postoperative complication but all pts recovered. The pathological finding revealed major response, defined as disappearance more than two third of the primary tumor, in 26.7% (8/30) pts. Twenty-seven (90%) pts received postoperative chemotherapy. Among 24 pts with R0 resection, 16 pts experienced recurrence in PER(5), LYM(4), HEP(4), PUL(3), BRA(1), and others(4). In 30 pts accrued, 19 (66.3% 43.9-80.1), 16 (55.3% 34.3-71.7) survived more than 3 years from the start of first line chemotherapy and the conversion surgery, respectively. Conclusions: Conversion surgery is effective and worth for testing in the following randomized trial. Clinical trial information: UMIN000014251 .
Clinical outcomes of endoscopic resection of gastric GIST.
Authors: Park Jong-Jae , Joo Moon Kyung , Lee Beom Jae , Kim Sunsuk , Chun Hoon Jai
Published: January 2023

383

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in stomach. We evaluated the long-term clinical outcomes of endoscopic treatment for gastric GISTs. Methods: This is a retrospective study that enrolled 135 cases of gastric subepithelial tumors (SETs) resected by endoscopic procedures and confirmed as GISTs by histopathology from 2005 to 2019. The immediate and long-term clinical outcomes were analyzed retrospectively. Results: The mean age was 57.9 years, and the mean tumor size was 2.1 cm. Of the tumors, 43.0% were located in the corpus, followed by the fundus (26.7%) and cardia (17.0%). Most tumors (85.2%) were resected by endoscopic submucosal dissection. Macroperforation occurred in 4.4% and microperforation in 6.7% of the cases. The R0 resection rate was 15.6%. However, complete resection by the endoscopic view was 90.4%, of which 54.8% were in the very-low-risk group, followed by the low (28.1%), intermediate (11.9%), and high-risk groups (5.2%). During 36.5 months of follow-up, recurrence was found in four (3.4%) of the 118 patients who were monitored for more than six months (low risk group:1/37, 2.7%; intermediate risk group: 2/11, 18.2%; high risk group: 1/6, 16.7%). Conclusions: Endoscopic treatment of a GIST appears to be a feasible procedure in selected cases, however, additional surgery should be considered if pathologic result is corresponding to intermediate or high risk group.