bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-hospital retrospective study comparing gastric adenocarcinoma in Hispanic versus non-Hispanic patients.
Authors: Zarrinkhoo Erfan , Klingbeil Kyle D. , Condamoor Shreya , Park Joon , Jackson Nicholas , Chiu Victor , Kadera Brian E.
Published: June 2023

e16027

Background: Gastric cancer is one of the most prevalent malignancies in the United States and carries a particularly high rate of mortality. In the United States, the overall gastric cancer rate continues to decline amongst Caucasian and African American patients; however, it remains static amongst Hispanic patients. While numerous studies have been conducted to better understand the underlying causes leading to the disproportionate incidence of gastric cancer among Hispanics, it is still not well understood. This retrospective study sought to compare the clinicopathological features and overall survival of Hispanic patients with gastric adenocarcinoma with non-Hispanic patients treated in three safety-net county hospitals in Southern California. Methods: This is a retrospective cohort study of 123 patients with newly diagnosed gastric adenocarcinoma who were treated at three safety-net county hospitals in Southern California between 2010 and 2022. The subjects were categorized as Hispanic and non-Hispanic. Clinical, pathological, and survival data were obtained from the patient chart and compared. Results: Of the 123 patients included in the study, 87 (71%) were Hispanic. At time of diagnosis, Hispanic patients were found to be significantly younger than non-Hispanics (55.4 +/- 13.5 vs 60.8 +/- 12.2, p-value 0.03). They were also more likely to be misdiagnosed (defined as greater than one prior encounter of misdiagnosis within six months) relative to non-Hispanics (26% vs 14%, p-value 0.007) despite no differences in insurance/PCP status. Hispanic patients were more likely to present with metastatic disease (65% vs 30%, p-value <0.001), and were found to have a higher rate of peritoneal carcinomatosis (30% vs 8%, p-value 0.01). Hispanics were also more likely to present with disease in the gastric antrum (47% vs 19%, p-value 0.004) and have a higher rate of diffuse subtype histology (32% vs 22%, p-value 0.05). Similar rates of Helicobacter pylori infection were found within the tissue biopsy sample using Warthin Starry stain amongst Hispanic and non-Hispanic patients (17% vs 17%). Lastly, the mortality rate was higher in Hispanics relative to non-Hispanics at time of last contact (65% vs 35%, p-value <0.001). Conclusions: Upon comparing clinicopathological features and mortality among gastric cancer patients who were treated in multiple safety net county hospitals, there were significant differences noticed in Hispanic American patients. Relative to non-Hispanics, Hispanic patients were more likely to be misdiagnosed, more likely to present with metastatic disease, and have higher rates of mortality despite no disparities in insurance and PCP status. Further investigation is warranted regarding possible risk factors including exposures to possible environmental triggers or if there is a genetic predisposition in Hispanic populations.
First-line envafolimab plus SOX chemotherapy for PD-L1 positive metastatic or recurrent gastric adenocarcinoma: A multi-centre, single-arm phase II clinical trial.
Authors: Liangjun Zhu
Published: June 2023

e16029

Background: Clinical evidence for PD-L1 positive metastatic or recurrent gastric adenocarcinoma patients were relatively limited in clinic, which limited the development of evidence-based medicine for these patients. Immune checkpoint inhibitor (ICI) therapy has been established as the standard treatment for advanced gastric carcinoma patients recently. Envafolimab is the first approved subcutaneous single-domain PD-L1 antibody, which has been commercialized in China for the treatment of MSI-H/dMMR advanced solid tumors. This study aimed to investigate the efficacy and safety of Envafolimab plus SOX chemotherapy for metastatic or recurrent gastric adenocarcinoma, aiming to provide further reference for clinical rational drug use for this population. Methods: This multi-centre, single-arm, open-label study was conducted to evaluate the efficacy and safety of Envafolimab in metastatic or recurrent gastric adenocarcinoma. A total of 38 patients with histologically confirmed advanced gastric adenocarcinoma were enrolled. Patients will receive Envafolimab (300 mg, s.c., day 1) plus chemotherapy (oxaliplatin 130 mg/m2, i.v., day 1, and S-1 40mg, BSA＜1.25 m2、50mg 1.25 m2＜BSA＜1.5 m2、60 mg BSA＞1.5m2, p.o., twice daily, days 1-14) every 3 weeks for 6 cycles, followed by maintenance treatment with Envafolimab plus S-1 until disease progression (PD), unacceptable toxicity, or patient refusal. Eligible patients must be histologically confirmed, advanced metastatic gastric adenocarcinoma or recurrent gastric adenocarcinoma after prior surgical treatment. Other key inclusion criteria were previously untreated, HER2-negative, PD-L1 positive (Combined Positive Score (CPS)≥1), ECOG performance status of 0 or 1, and adequate organ function. Patients with any prior ICI therapy, abnormal AFP elevation, or microsatellite-instability-high (MSI-H) status will be excluded. The primary endpoint was objective response rate (ORR) based on the RECIST version 1.1, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), etc. Adverse events were evaluated using the CTCAE v5.0 criteria. Results: Overall, thirteen patients were consecutively enrolled from March, 2022 to September 2022 and involved in this study. The median age was 62.7 years. At present, eight patients were included for efficacy analysis, and nine for safety evaluation. The ORR was 50%, and DCR was 87.5%, based on RECIST v1.1. Survival data are not mature at present. The most common TRAEs were elevated AST (75%), elevated ALT (65%) and leukopenia (42.5%). No treatment-related deaths occurred. Conclusions: Envafolimab plus chemotherapy is a promising and tolerable therapeutic regimen for patients with metastatic or recurrent gastric adenocarcinoma. Clinical trial information: NCT05237349 .
Artificial intelligence model for predicting the efficacy of sintilimab plus chemotherapy in treating patients with esophageal squamous cell carcinoma.
Authors: Wang Kefeng , Wu Duoguang , Wang Wenjian , Lei Kai , Liang Ruihao , Tan Binghua , Hu Xueting , Li Lin , Lyu Yingcheng , Wang Zhizheng , Zeng Yanwu , Pang Fei , Wang Kai , Lin Huayue , Wang Minghui
Published: June 2023

e16030

Background: Blockade of programmed cell death 1 (PD-1) could induce tumor regression in patients with advanced esophageal squamous cell carcinoma (ESCC), although little is known about the biomarker to guide immunochemotherapy. In this study, we sought to evaluate the efficacy and discover biomarkers and establish an artificial intelligence (AI) model to predict the efficacy of the combination of sintilimab and chemotherapy in the treatment of patients with ESCC. Methods: Fifty-nine (59) patients enrolled in our study received chemotherapy with sintilimab and follow-up data were available. Treatment outcomes were assessed using the Response Evaluation Criteria in Solid Tumors (v1.1). Eleven (11) clinicopathologic characteristics including age, albumin, HLA-1 evolutionary divergence (HED), TMB, body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelets, hemoglobin, stage, sex, leukocyte, lymphocyte and therapy were collected. Results: Thirty-four (34) patients with ESCC who received sintilimab as first-line chemotherapy had a median follow-up of 13.7 (range, 0.53-35.57) months. At the time of analysis, six (6, 17.6%) patients were still receiving treatment, 24 patients achieved PR, and the confirmed ORR was 67.65%. Four (4) patients had SD and the DCR was 79.41%. Median PFS (mPFS) was 10.06 months. Median overall survival (mOS) was 23.27 months. The mPFS of the PD-L1 positive population was significantly better than that of the PD-L1 negative population (19.23 months vs. 6.57 months, p = 0.046). There was no significant difference in mPFS and mOS between the high and low TMB groups. Patients were divided into response (CR or PR) and non-response (SD or PD) groups according to their response to combined immunotherapy. The response rate of patients with wild-type MET was higher than that of patients with MET mutation (75% vs. 25%, p=0.0889). Compared to patients with wild-type BRCA2, patients with mutant BRCA2 had a significantly shorter mPFS (4.2 months vs. 13.3 months, p=0.027). Based on the efficacy data and 11 additional clinicopathologic characteristics of the 59 patients who received sintilimab in combination with chemotherapy, a random forest AI model was constructed to predict response to immunochemotherapy. Patients were randomly divided into a training set and a test set in a 6:4 ratio. In the test set, the top three predictive biomarkers were HED, age, and BMI. The area under the curve of the predictive model in the test set was 0.82. Conclusions: Sintilimab combined with chemotherapy could be an effective treatment for advanced ESCC, and an AI model based on multiple clinical features at baseline could predict the efficacy of immunochemotherapy. Further studies with larger sample size are needed to validate our findings.
TQB2450 plus anlotinib combined with paclitaxel and cisplatin as first-line treatment of advanced esophageal squamous cell carcinoma (ESCC): Update results of a single-arm, multicenter phase Ⅱ trial.
Authors: Wang Junsheng , Li Ning , Guo Yanzhen , Cheng Yufeng , Li Baosheng , Luo Su-xia
Published: June 2023

e16034

Background: PD-1 inhibitors plus chemotherapy are the standard regimens of first-line treatment in advanced ESCC. Anlotinib, a multi-target TKI effectively inhibiting angiogenesis and improving tumor microenvironment, had been demonstrated to have promising efficacy and tolerable toxicity whether combined with chemotherapy as first-line treatment or monotherapy as second-line in advanced ESCC. TQB2450 is a novel humanized anti-PD-L1 monoclonal antibody. We have conducted a phase II trial to evaluate the efficacy and safety of anlotinib combined with TQB2450, cisplatin and paclitaxel as first-line therapy in advanced ESCC. Here is the update results with more enrolled patients and longer follow-up period. Methods: Eligible patients (pts) with previously untreated unresectable locally advanced or metastatic ESCC received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with paclitaxel (135mg/m2, iv, d1, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) for 4 - 6 cycles as initial therapy. Patients without progressive disease (PD) continued to receive same dose of anlotinib plus TQB2450 as maintenance therapy until PD or unacceptable toxicity. The primary endpoint was PFS (RECIST version 1.1). Secondary endpoints included iPFS (iRECIST), ORR (RECIST version 1.1), DCR, DOR and safety. Results: From September 2021 to August 2022, 50 pts were enrolled with a median age of 64 years (range 41-74), male (39/50, 78%) and ECOG PS 1 (39/50, 78%). At the data cutoff date of January 16, 2023, 45 pts were tumor response evaluable, among whom, 3 pts achieved complete response, 34 had partial response and 8 had stable disease. The ORR was 82.2% (95% CI: 68.0%, 92.0%) and the DCR was 100.0% (95% CI: 92.1%, 100.0%). Median PFS was not reached. The incidence of grade 3-4 treatment emergent adverse events (TEAEs) was 66% (33/50), mainly included neutropenia (34%, 17/50), leukopenia (20%, 10/50) and hypertension (20%, 10/50), platelet count decreased (6%, 3/50). There was no grade 5 TRAE. 17 pts (34%, 17/50) occurred treatment related serious AEs. Conclusions: TQB2450 plus anlotinib combined with paclitaxel and cisplatin showed significant efficacy and manageable safety profile as first-line treatment in advanced ESCC, which might provide a new treatment strategy for ESCC patients. Clinical trial information: NCT05013697 .
18F-FDG PET and CT identifiers of high-risk lesions in the stomach and esophagus.
Authors: EighaeiSedeh Ashkan , Kako Bashar , Deffler Caitlin , Ng Thomas , Catalano Onofrio Antonio , Mahmood Umar , Heidari Pedram , Abdar Esfahani Shadi
Published: June 2023

e16036

Background: Assessing the significance of incidentally found increased 18F-FDG uptake in the stomach and esophagus on PET/CT has long been a challenge. Currently, there is no clear guideline to assist clinicians with distinguishing malignant from benign uptake. This study aims to compare various PET and CT characteristics used separately and collectively, to identify high-risk foci of uptake. Methods: 18F-FDG PET/CT images from August 2018 to October 2022 were reviewed and patients who completed a follow up EGD due to incidentally found increased gastroesophageal uptake were included in this study. To identify high-risk foci, the following PET and CT characteristics were used: 1) uptake intensity, using lesion SUVmax relative to mediastinal blood pool and liver SUVmean values (≤ blood pool = 0, > blood pool but < liver = 1, ≥ liver = 2); 2) uptake pattern (diffuse = 0, segmental = 1, focal = 2); 3) eccentricity (circumferential= 0, eccentric = 1); and CT correlation score (normal = 0, thickening = 1, mass = 2). Cut-off values were determined using receiver operating characteristic (ROC) curves. Benign and malignant uptake were compared to histological findings using Pearson’s chi-square test. Results: Incidental uptake in the stomach and/or esophagus were noted in 473/7805 (6.1%) patients of which 89 (18.8%) had a follow up EGD and were included in this study. Uptake intensity did not differentiate benign and malignant as SUVmax was greater than background tissues in all cases (Score =2). Uptake pattern, eccentricity, and CT-correlation of PET were significantly different between benign and malignant foci ( p < 0.001, p < 0.001, and p < 0.001, Chi-square). Using cut-off scores from ROC curves, the predictive value of different PET/CT characteristics in identifying high-risk foci was reviewed. Conclusions: PET eccentricity along with anatomic CT correlative findings, offer similar value in predicting high-risk uptake foci to uptake pattern, eccentricity, and CT correlation combined. These are both, however, superior to other PET/CT characteristics used alone or in combination. [Table: see text]
Updated results of the phase 1 I-FLOAT trial: Safety and efficacy of combining genotype-guided irinotecan with 5FU, leucovorin, oxaliplatin and docetaxel (gFOLFOXIRITAX) in advanced upper GI cancers.
Authors: Paydary Koosha , Loew Colton , Desgardin Aurelie , Shergill Ardaman , Reizine Natalie Marie , Robinzine Chanelle , Racette Christine , Ignatiev Elena , Neerukonda Anu Radha , Ji Yuan , Polite Blase N. , Liao Chih-Yi
Published: June 2023

e16038

Background: 5FU, Oxaliplatin (ox), irinotecan (iri) and docetaxel (tax) are each active in upper GI cancers; however, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms may predispose to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of therapy (tx) among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. We report the updated results of the I-FLOAT trial. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and H risk groups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu & Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1) & ctDNA response (>50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-1/1/2023, 27 pts (11F, 16M) enrolled: median age 51 (range 21-76); 9 ECOG PS 1, UGT-L:I:H with 6:18:3 pts; 12 esophageal, 6 gastric, 8 pancreatic, and 1 bile duct cancer; 3 pts HER2+; 22 metastatic, 5 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.2-4.7) and 4.06 (1.89-27.6), respectively; 81% (22/27) of pts had a NLR > 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 5 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax), one G3 fatigue (UGT-I DL2/DL2 Iri/Tax) and one G3 diarrhea and neutropenic fever (UGT-L DL4/DL1 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, & UGT-L DL4/DL1. The most frequent any Gr tx related toxicities: diarrhea (78%), fatigue (74%), nausea (70%), neuropathy (67%), anorexia (52%), elevated LFT (48%), anemia (37%), vomiting (37%). Of evaluable pts across all cohorts, PR/CR was seen in 18/22 (82%) patients, with 2 (9%) SD and 2 (9%) PD for a disease control rate of 91%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX continues to demonstrate tolerability at initial DLs of Iri/Tax. Efficacy is promising and could be an aggressive approach in upper GI cancers with high relapse risk in curative-intent settings. Clinical trial information: NCT04361708 .
Paclitaxel + ramucirumab versus paclitaxel alone in patients with squamous-cell carcinoma of the esophagus, refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs: Final results from the randomized phase 2 IKF-S627/RAMOS trial of the AIO.
Authors: Scheck Magdalena , Goetze Thorsten Oliver , Ettrich Thomas Jens , Schmalenberg Harald , Clemens Michael , Mahlberg Rolf , Heeg Steffen , Kanzler Stephan , Hapke Gunnar , Thuss-Patience Peter C. , Kestler Angelika , Treschl Anne , Frost Gregg , Schiemer Moritz , Junge Sabine , Pauligk Claudia , Al-Batran Salah-Eddin , Lorenzen Sylvie
Published: June 2023

e16043

Background: Ramucirumab (Ram) in combination with docetaxel is an approved 2nd-line treatment in patients (pts) with squamous cell carcinomas (SCC) of the lung (REVEL study) and with paclitaxel for esophagogastric adenocarcinoma (RAINBOW study). In SCC of the esophagus, nivolumab is currently the only evidence-based 2nd-line treatment option. This study evaluates the safety and efficacy of the combination of Ram plus paclitaxel. Methods: This prospective, randomized, open-label, multicenter, phase II trial evaluated paclitaxel plus Ram (Ram 8 mg/kg d1 and d15 and paclitaxel 80 mg/m2 d1, 8, 15) Arm A vs. paclitaxel alone (80 mg/m2 d1, 8, 15) Arm B, both q4w. Primary endpoint was overall survival rate at 6months (mos) (OS@6), main secondary endpoints were OS, PFS, objective response rate (ORR) and safety. Results: From 3/2019 to 4/2021, 21/186 planned pts were treated within the study protocol (Arm A 11 pts; Arm B 10 pts) in 10 German centers. Due to slow accrual, the study was terminated prematurely. Median age was 63y, 71% were male and 86% had relevant concomitant disease. Pts. received a median of 9 and 10 cycles Arms A and B, respectively. The most common treatment related AEs in Arm A were leucopenia (54.5%), fatigue (27.3%) and peripheral sensory neuropathy (18.2%). Treatment related adverse events (AEs) ≥ grade 3 occurred in 27% in Arm A and 50% in Arm B with neutropenia being most frequent in Arm B (n=3; 30%). Serious adverse events (SAE) occurred in 36% and 50% in Arms A and B respectively. Median follow-up was 9 months (0.7 – 32.4 months). OS@6 in Arm A was 73% for Ram/paclitaxel and 50% for paclitaxel. However, the study design did not allow for statistical comparison of the arms. ORR (CR+PR 18% vs. 20%) and DCR (55% vs. 60%) were in the same range, as well as median PFS (3.8 vs. 3.5 mos) and OS (12.1 vs. 9.2 mos), for Arms A and B, respectively. Conclusions: Ram and Paclitaxel is considered to show an acceptable tolerability and numerically improved OS@6. Due to the small number of pts the current trial must be considered exploratory and more data are needed in this indication. Clinical trial information: NCT03762564 .
Co-occurrence of mutations and related signal pathway analysis of CCND1 amplification in esophageal squamous cell cancer.
Authors: Pang Qingsong , Zhang Wencheng , Zhang Tian , Chen Xi , Zhao Fangdong , Li Jiacheng , Dong Jie , Liu Yang , Wang Qian , Xiao Shanshan , Wang Tao
Published: June 2023

e16044

Background: Profiling molecular subtypes was usually necessary for cancer patients to facilitate better treatment strategy. Esophageal squamous cell cancer (ESCC) has four subtypes including cell cycle pathway activation (CCA), NRF2 oncogenic activation (NRFA), immune suppression (IS), and immune modulation (IM). CCND1 amplification is one of the important molecular biomarkers for CCA subtype. Previous research showed that CCND1 amplification was associated with immune resistance in ESCC. The co-occurred mutations and related signaling pathways are of great interest to study molecular mechanism in ESCC. Methods: This study enrolled 50 ESCC patient samples comprising 19 whole exome sequencing (WES) samples, 18 whole genome sequencing (WGS) samples and 13 NGS panel (667 genes) samples. To use all the samples, the minimal set of 667 genes was analyzed in detail for gene amplifications and mutations. Kaplan-Meier (KM) survival analysis was applied to study the prognosis associations with the frequently occurred amplifications including CCND1, FGF3, FGF4 and FGF19, etc. Gene expression profiles were then investigated by RNA-Seq sequencing on ESCC cell lines with CCND1 (K30-N) and without CCND1 gene (K30-S, knocked out). PCA analysis was applied to explore the differences between K30-S and K30-N, and KEGG and GO enrichment analysis were performed on the differential expressed genes (DEGs). All analyses were carried out through R4.1.0. Results: The mutational profiles showed that TP53, CCND1, FGF4, FGF19, FGF3, and CDKN2A/B were the most frequently mutated genes in ESCC patients, with the mutation frequencies of 62%, 58%, 56%, 50%, 48% and 40%, respectively. Among those genes, CCND1 and FGF3/4/19 co-occurred amplifications presented in almost all the samples and no other co-existent gene amplifications were identified. The CCND1 and FGF3/4/19 amplification patients were associated with worse prognosis. A total of 1494 differential expressed genes were identified between K30-N and K30-S cell lines, including 998 up-regulated genes and 496 down-regulated gene in K30-S cell line. KEGG enrichment analysis showed that these DEGs were mainly enriched in MAPK signaling pathway, p53 signaling pathway, mTOR signaling pathway and etc. GO enrichment analysis revealed that these differential genes are mainly enriched in cell growth, developmental cell growth, Ras protein signal transmission. Those results were consistent with CCA molecular subtype and highlighted the important role of CCND1 in ESCC subtype classification. Conclusions: This study demonstrated that CCND1 and FGF3/4/19 amplifications frequently co-occurred in ESCC and they were associated with worse prognosis. Signal pathway analysis showed CCND1 play important roles in subtype classification of ESCC.
Comparison of efficacy between immune checkpoint inhibitors and irinotecan-based chemotherapy as third-line treatment for patients with advanced gastric cancer: A Korean real-world multicenter study (KCSG ST22-06).
Authors: Lim Sung Hee , Kim Jae-Joon , Im Hyeon-Su , Han Hye Sook , Kim In-Ho , Koo Dong-Hoe , Cho Jang Ho , Maeng Chi Hoon , Lee Min-Young , Lee Hyo Jin , Kim Jwa Hoon , Park Sang Gon , Jung Joo Young , Shin Seong Hoon , Kim Ki Hyang , Lee Keun-Wook , Rha Sun Young
Published: June 2023

e16047

Background: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy are frequently used after paclitaxel plus ramucirumab as second-line treatment for patients with recurrent and/or metastatic gastric cancer (RMGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with RMGC. Methods: We retrospectively reviewed patients with RMGC, whose third-line treatment started between July 2019 and June 2021 at 17 centers in South Korea. The ICI group included patients who received nivolumab or pembrolizumab and the irinotecan-based chemotherapy group included those patients who received irinotecan or FOLFIRI. Results: A total of 363 patients (129 in the ICI group and 234 in the irinotecan-based chemotherapy group) were analyzed. The median progression-free survival (PFS) was 2.2 and 2.9 months in the ICI and irinotecan-based chemotherapy groups, respectively. The median overall survival (OS) was 5.5 months (95% CI, 3.6-7.4) in the ICI group and 6.0 months (95% CI, 4.8-7.0) in the irinotecan-based chemotherapy group [HR 0.97 (95% CI, 0.75-1.25); P=0.786]. Multivariable Cox-regression analysis showed that weight loss, peritoneal metastasis, low serum sodium, low serum albumin and short duration of second-line treatment were associated with inferior OS ( P<0.05), meanwhile microsatellite instability-high (MSI-H)/mismatch repair-deficient (MMR-D) tumor was an independent prognostic factor for superior OS. The ICI group showed significantly longer OS than the irinotecan-based chemotherapy group in patients without peritoneal metastasis [HR 0.54 (95% CI 0.30-0.99); P=0.047)]. Whereas the irinotecan-based chemotherapy group showed significantly longer OS in patients without PD-L1 expression [HR 1.62 (95% CI 1.03-2.55); P=0.037] than the ICI group. Conclusions: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for patients with RMGC. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression.
Phase I/II study of nab-paclitaxel combined with S-1 as adjuvant chemotherapy in diffuse type of stage III gastric or gastroesophageal junction adenocarcinoma.
Authors: Cui Yuehong , Wei Jia , Yu Yiyi , Xu Bei , Wu Jing , Xu Xiaojing , Liu Tianshu
Published: June 2023

e16064

Background: Diffuse type (Lauren's classification) of gastric adenocarcinoma (GAC) or gastroesophageal junction adenocarcinoma (GEJ) has a poorer prognosis than intestinal type of GAC or GEJ. Studies have shown that nab-paclitaxel combined with S-1 has a synergistic anti-tumor effect on advanced gastric cancer. We designed this trial to evaluate the efficacy and safety of nab-paclitaxel plus S-1 as adjuvant chemotherapy in diffuse type of stage III GAC or GEJ. Methods: This study was a multi-center, open-label, phase I/II study. The results of the phase I dose escalation study have already been reported, and the recommended phase II dose (RP2D) of nab-paclitaxel is 260mg/m2. Patients with stage III diffuse type GAC or GEJ after D2 dissection and achieved R0 resection were included in this study. S-1 monotherapy was used as adjuvant therapy in the first cycle. If absence of grade3/4 treatment-related adverse events (AEs) of S-1 monotherapy, nab-paclitaxel (260mg/m2, d1, q3w) and S-1 [body surface area (BSA) <1.25 m2, 80mg/d; BSA 1.25–1.5 m2, 100mg/d; BSA >1.5 m2, 120mg/d; d1-14, q3w] were administered for 6 cycles. Then patients still received S-1 monotherapy for 8 cycles. In phase II study, the primary endpoint was 1-year disease free survival (DFS) rate, and the secondary endpoints were 3-year DFS rate and safety. Results: From January 2021 to February 2023, a total of 42 patients were enrolled in this analysis (3 patients in nab-paclitaxel 260mg/m2 dose group in phase I and 39 patients in phase II). The median age (range) was 53 (29~69) years, 18 patients (42.86%) were stage IIIA, 10 patients (23.81%) were stage IIIB and 14 patients (33.33%) were stage IIIC. The median follow-up time was 13.26 months. As of January 2023, 12 patients experienced recurrence. The 1-year-DFS rate was 74.07%, median DFS and 3-year-DFS rate were not reached. The incidence of adverse effects (AEs) was 78.57% (33/42), and the rate of grade 3-4 AEs was 42.86% (18/42). The most common AEs were neutropenia and leukopenia. In addition, we performed next generation sequencing (NGS) for 5 relapsed patients, and 5 non-relapsed patients who were matched to the relapsed patients. The results showed that the mutant rates of tumor supressor gene CDH1, ARID1A, KMT2D, and TP53 in non-relapsed patients were higher than that in relapsed patients. The positive rate of ctDNA were 60% in relapsed patients, but no ctDNA was detected in non-relapsed patients. Conclusions: Adjuvant chemotherapy with nab-paclitaxel and S-1 followed by S-1 monotherapy exhibited promising clinical efficacy, with acceptable tolerability. This study deserves further investigation and follow up for diffuse type of GAC or GEJ. Clinical trial information: NCT03977220 .
Co-mutation-based subtyping of Chinese patients with gastric cancer.
Authors: Huang He , Wang Zhimin , Chen Hao , Cheng Yafei , Liu Hui , Bai Shaoxiong , Huo Yaoliang , Zeng Yanwu , Lu Leilei
Published: June 2023

e16070

Background: The incidence of gastric cancer is decreasing globally, in contrast, that of Chinese patients has been increased from 35.9% to 48.3%. In-depth investigation of the characteristic of Chinese gastric cancer patients could help to understand the disease mechanism and improve the treatment of gastric cancer. Methods: Tumor tissues were obtained from 96 Chinese gastric cancer patients and tested by high-coverage ( > 1000x) panel sequencing containing 624 cancer-related genes. Genomic mutations including substitutions, insertions, deletions, rearrangements, fusions, and copy number variations were called. Genes were clustered based on their co-mutation relationship in all samples. Patients with gene mutations in each cluster were classified into corresponding groups. The properties of each patient group were characterized, including genomic features, age, gender, stage, LAUREN type, and grade. Results: The most mutated genes were TP53, ERBB4, LRP1B, and CDH1 in our cohort. A higher proportion of female patients had TP53 mutations compared to male patients. Mutations in ALK, KMT2C, and LRP2 were positively associated with microsatellite-instable, and that in ERBB4 and PIK3CA were positively associated with high tumor mutation burden (TMB). Four gene clusters (1, 2, 3, and 4) were identified based on the co-mutation relationship between genes. Cluster 1 included FAT4, APC, OBSCN, and GATA3; Cluster 2 included FGF3, CCND1, FGF19, and GATA4; Cluster 3 included BLK, FAM135B, and DLC1; and Cluster 4 included ATRX, KMT2D, STAG2, and EGFR. Patients were classified into the four patient groups (I, II, III, and IV) accordingly when mutations in the corresponding gene cluster were found. Further association analysis indicated that: Group I was associated with adenocarcinoma subtype; Group II was negatively associated with LAUREN type 2; Group III was associated with high TMB; Cluster IV was associated with microsatellite-instable. Conclusions: This study utilized gene co-mutations to classify gastric cancer patients into subgroups with unique clinical characteristics. Further study on the etiology, treatment, and prognosis of these groups of patients is needed.
A propensity score–matched analysis to evaluate the benefit of adjuvant therapy on disease progression of esophageal squamous cell carcinoma after R0 esophagectomy.
Authors: Cao Yuqin , Hu Qingqing , Zhang Yajie , Li Chengqiang , Zhou Yuan , Zhang Yongjing , Qiu Hong , Li Hecheng
Published: June 2023

e16071

Background: The impact of adjuvant therapy (AT) on patients’ disease progression with esophageal squamous cell carcinoma (ESCC) after R0 resection remains controversial in clinical practice. The study aims to evaluate the benefits of AT on recurrence or death through propensity score (PS) matched analyses. Methods: A cohort of patients who have undergone R0 esophagectomy without neoadjuvant therapy for ESCC was identified at the tertiary hospital in China between 2013 and 2020. Patients’ demographic, clinical, surgical, pathological and follow-up data were retrieved from a prospectively maintained database. PS for each patient was calculated by the generalized linear regression model including all potential confounders (age, sex, body mass index, smoking history, alcohol consumption, Eastern Cooperative Oncology Group performance score, baseline comorbidities, hospitalization days, tumor location, size, pathological stage T, N and differentiation grade). PS was stratified into four groups (PS < 0.20, 0.20≤PS < 0.30, 0.30≤PS < 0.40, and PS≥0.40) based on distributions. Patients with and without AT were matched by the nearest neighbor PS with caliper 0.05 to evaluate rates of recurrence-free survival (RFS) for overall patients and patients across four PS groups. RFS was defined as the time from date of curative surgery to the time of recurrence or death. Results: In total, 523 patients were identified and 162 (30.9%) of those patients received AT. A total of 312 (60.0%) patients experienced recurrence or death with a median follow-up of 4.15 years (interquartile range: 2.92-4.73 years). Patients with younger ages, shorter hospitalization, larger tumor size, advanced pathological T and N stages, poorly differentiated tumors were more likely to receive AT (all p < 0.05). The mean PS was 0.39 (standard deviation [SD] 0.16) for AT group and 0.27 (SD 0.15) for non-AT group. A total of 274 patients (137 AT and 137 non-AT) were matched. Before matching, AT group tended to have a worse RFS compared with non-AT group (median RFS: 1.84 years vs 2.67 years, p = 0.06). However, after PS matching, AT group showed a significantly better RFS compared with non-AT group (median RFS: 2.41 vs. 1.89 years, p = 0.02). In the subgroup analyses, the benefits of AT were mostly consistent with the whole group, except for patients with PS < 0.20 where AT tended to have worse RFS. Moreover, for PS≥0.40 subgroup, a significantly better RFS was observed in AT group compared with non-AT group (median RFS: 3.52 vs. 1.53 years, p < 0.01). Conclusions: Adjuvant therapy had a benefit on delaying disease progression for Chinese patients with ESCC after R0 esophagectomy, especially for patients with a higher PS score.
Effect of reducing the number of neoadjuvant chemoimmunotherapy cycles on clinical efficacy in locally advanced PD-L1 positive gastric cancer: A single center phase 2 study.
Authors: Zhao Lingdi , Jiang Zhiqiang , Huang Jinxi , Li Zhimeng , Fu Qiang , Ren Yingkun , Zhao Yuzhou , Zhang Bin , Wan Xiangbin , Shang Chuang , Kong Ye , Liu Jialin , Li Zhi , Gao Quanli
Published: June 2023

e16074

Background: The standard therapeutic recommendation is neoadjuvant chemotherapy with FLOT regimen following radical resection in patients with locally advanced gastric cancer. It is not clear whether neoadjuvant anti-PD-1 antibody plus FLOT regimen could improve the pathological complete response (pCR) rate and how to combine anti-PD-1 antibody and FLOT regimen. We conduct this phase II study to explore this problem (NCT 04891016). Methods: This study is a prospective clinical study, patients are randomly enrolled into the experiment group and the control group according to the random number method. The patients in the experiment group receive standard dose of FLOT regimen plus toripalimab every three weeks, toripalimab is administered on third day in each cycle, after three cycles operation is performed. The patients in the control group receive standard dose of FLOT regimen plus toripalimab every two weeks, toripalimab is administered on the first day in each cycle, after four cycles operation is performed. The primary endpoint is pCR and the secondary endpoint is recurrence-free survival. Results: From June 2021 until present, 57 patients with locally advanced gastric cancer were enrolled in this study, including 28 patients in the experiment group and 29 in the control group. Three patients in the experiment group and two in the control group withdrew from the study as to the influence of COVID-19’s epidemic or personal reason. One patient in the experiment group postponed operation due to immune-related thrombocytopenia. The remaining 51 patients completed the prescribed chemotherapy plus toripalimab and operation, and all the operations were R0 resection. Among these 51 patients, pCR was got in 16 patients and the pCR rate was 31.4%, MPR rate was 66.7%. Further analysis according to the expression of PD-L1 is shown. The overall incidence of adverse events was 93%. The incidence and severity of myelosuppression in the experiment group were lower than those in the control group. Among all the patients received R0 resection, 6 patients experienced recurrence and the remaining are still kept in recurrence-free status. The recurrence-free survival is not available at present. Conclusions: 1) Neoadjuvant therapy with FLOT plus toripalimab is safe and effective in locally advanced gastric cancer. 2) Postponing the use of toripalimab when combined with FLOT as neoadjuvant regimen in locally advanced gastric cancer patients with PD-L1 CPS ≥1 could reduce the number of chemotherapy cycles and thus reduce the adverse events of chemotherapeutic drugs, while the dose intensity of chemotherapy is import in patients with PD-L1 CPS ＜1. Clinical trial information: NCT04891016 .[Table: see text]
Induction immunochemotherapy conversion rate and survival outcomes versus chemotherapy in initially unresectable esophageal squamous cell carcinoma.
Authors: Huang Shujie , Wang Sichao , Gao Zhen , Zeng Ruijie , Xu Wei , Tang Yong , Tang Jiming , Ben Xiaosong , Zhang Dongkun , Xie Liang , Zhou HaiYu , Chen Gang , Fu Junhui , Kong Feng-Ming Spring , Qiao Guibin
Published: June 2023

e16077

Background: Currently, no comparative study has been reported to elucidate whether the addition of immunotherapy in the induction setting could improve treatment efficacy and prolong the overall survival of initially-unresectable locally advanced esophageal squamous cell carcinoma (iuESCC). This study aimed to compare surgical conversion rate and short-term overall survival in induction chemotherapy (iC) and induction immunochemotherapy (iIC) for patients with iuESCC. Methods: In this multicenter retrospective cohort study, patients with the guideline-defined unresectable disease were included at four high-volume institutions. The primary endpoints were conversion surgical rate and overall survival (OS). Pathological complete response (pCR) was defined as the disappearance of tumor cells in the primary lesion site. Multivariate cox regression analysis was used to identify the independent significant prognostic factors associated with OS. The stabilized inverse probability of treatment weighting (IPTW) was applied to confirm the survival comparison between iIC and iC cohorts. Results: A total of 309 patients (150 in iIC and 159 in iC cohort) were included. A significantly higher conversion surgical rate was observed in iIC cohort (iIC vs. iC: 127/150, 84.7% vs. 79/159, 49.7%, P < 0.001). In terms of pathological response, the rates of pCR were 22.0% and 5.1% in the iIC and the iC cohort, respectively (P = 0.001). A significant difference in OS was observed between iIC (not reached) and iC cohorts (median [95% CI]: 36.3 [27.2 – 45.5] months). The stabilized IPTW yielded similar results. Regimen (iIC vs. iC, HR 0.215, 95% CI: 0.102 - 0.454, P < 0.001) and operation (Yes vs. No, HR 0.262, 95% CI: 0.161 - 0.427, P < 0.001) were the significant prognostic factors for OS. Further, subgroup analysis revealed that significantly higher OS was seen in iIC cohort than that in the iC cohort (P = 0.003) in patients who had non-pCR disease. Conclusions: Immunochemotherapy plus conversion surgery in the induction setting had higher pathological response rate and better OS in iuESCC patients. Moreover, this combined modality also contributed to improving OS in patients with residual tumor burden. This study provided evidence for future randomized control trial designs.
Outcomes of Helicobacter pylori (HP) infection in esophageal cancer (EC): A 5-year nationwide analysis.
Authors: Vikash Sindhu , Vikash Fnu , Mehta Ansh , Bteich Fernand , Al Hamed Rama , Neupane Karun , Bazarbachi Abdul-Hamid , Hammami M Bakri , Esagian Stepan M. , Narvel Hiba , Atalla Eleftheria , Vegivinti Charan Thej Reddy , Gor Rajvi , Shah Nishi , Shastri Aditi , Steidl Ulrich G , Verma Amit , Sica Alejandro R. , Kaubisch Andreas , Goel Sanjay
Published: June 2023

e16079

Background: EC is a fatal condition, and recent literature suggests the association of HP with esophageal adenocarcinoma. In this study, we elucidate the outcomes of HP infection in EC. Methods: This is a retrospective longitudinal study from 2016-2020, using the nationwide inpatient sample database in the United States (US). Patients with EC with and without HP infection were selected. The baseline characteristics were compared using a T-test and Chi-Square. Multivariate regression analysis was applied to estimate the outcomes (length of hospital stay (LOS), mortality, and morbidity) while adjusting for patient and hospital confounders. We used STATA Version 17.0 for data analysis. The p-value was set at p < 0.05 for statistical significance. Results: In total, 69,144 patients with esophageal cancer were identified; among them, 0.3% (n= 220) had an HP infection. The highest prevalence of cases was seen in the Southern US (35.7%). The average LOS was 3.39 days (p = 0.01), and reduced mortality (p = 0.002). The Charlson comorbidity index (CCI) score was 3 or more for 74.2% (p=0.005). With regards to outcomes, 16.4% (p< 0.05) had esophageal obstruction, 20.2% (p< 0.05) had anemia, and 8% (p < 0.01) underwent esophagectomy. However, no significant differences in the rates of hematemesis 4.4% (p=0.15), melena 2.5% (p=0.28), or esophageal perforation 1.2% (p=0.45) were reported (Table 1). When compared to patients with HP infection, no statistically significant difference was found in the outcomes. Conclusions: Our study indicates a significantly increased prevalence of EC in the southern regions of the US, which may be attributed to regional differences in lifestyle, diet, and access to healthcare. The study population was predominantly admitted with a CCI score of 3, highlighting the burden of comorbid conditions. EC patients had decreased LOS and mortality trends in the past 5 years. Moreover, EC was associated with higher rates of esophageal obstruction and anemia. However, no effect on hematemesis, melena, and esophageal perforation was appreciated, and no statistically significant difference was found in the outcomes of EC with HP infection.[Table: see text]
Circulating tumor DNA in individuals with stomach adenocarcinoma (STAD) to detect MMR-related gene alterations.
Authors: Zhang Shi , Wang Guoqiang , Zhong Beiping , Fang Name , Zhou Aiwei , Liang Minchao , Li Yingqiang , Jing Zhang , Cheng Shaochen
Published: June 2023

e16083

Background: Stomach adenocarcinoma (STAD) ranks as the second incidence rate in China. The MisMatch Repair (MMR), composed of MLH1, MSH2, MSH3, MSH6, and PMS2, is a critical mechanism for repairing DNA error. In case of microsatellite instability (MSI), the MMR system is capable of repairing the mismatches. MSI-high (MSI-H) is created as a result of deficient mismatch repair (dMMR). A numerous studies have established the clinical importance of both MSI and MMR for the diagnosis, prognosis, and treatment of STAD. Circulating tumor DNA (ctDNA) provides a non-invasive method for the diagnosis and prognosis of cancer. The examination of MMR-related gene mutations in STAD can serve as a means of evaluating the utility of ctDNA in detecting. Methods: MMR-related genes list was collected from relevant literature. The clinical and genetic mutation data of 441 STAD samples were obtained from cBioPortal. Kaplan-Meier survival analysis was used to evaluate the total survival rate (OS) of the published STAD data set. 680 STAD patients with TP53 mutation were screened and analyzed from the HapLab database. Results: An analysis of the TCGA data indicated that 356 patients had wild-type MMR genes and 85 had MMR mutations. MSH3 mutations accounted for 19.27% of the overall mutations and 42.35% of patients with MMR mutations, with a total of 36 patients. In terms of OS, patients with MMR gene mutations had a better prognosis compared to those with wild-type genes (log-rank test, p-value = 0.028). In the single-gene prognostic analysis, patients with MSH3 mutations had better prognosis (p-value 0.0004), while no statistical differences were found in other genes. In the monitoring of 680 HapLab STAD patients using ctDNA, 12.35% (84/680) had MMR mutations in their tumor tissue. After treatment, the proportion of TP53 mutations detected in patients was 11.91% (81/680), while the proportion of MMR mutations was 3.57% (3/84). Conclusions: The results of survival analysis showed a significant association between the mutation status of MMR and STAD. Monogenic MSH3 mutations was highly associated with the better survival, and circulating tumor DNA in blood highlight the importance of detecting MMR mutations in STAD patients. ctDNA provides a non-invasive method for the assessment of prognosis in STAD patients through the analysis of MMR gene mutations.
Efficacy and safety of perioperative chemotherapy combined with tislelizumab and trastuzumab for HER2-positive resectable gastric/gastroesophageal junction cancer (GC/EGJC): Preliminary results of a phase 2, single-arm trial.
Authors: Zhao Chunlin , Meng Xiangrui , Shan Zhengzheng , Jiang Jianwu , Liu Xinyu , Li Haohao , Sun Junfeng , Ding Chaohui , Xia Jin , Liu Zhiqiang , Wang Feng
Published: June 2023

e16084

Background: Recently, immunotherapy combined with trastuzumab and chemotherapy have been recommended by the clinical guidelines of many countries as the first-line treatment for advanced HER2-positive G/GEJ adenocarcinoma. Combining chemotherapy with tislelizumab and trastuzumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable HER2-positive GC/GEJC. Methods: This study is a multicenter, single-arm, open-label phase 2 study (NCT04819971). Patients with histologically confirmed cT2-4NxM0 or cTxN+M0, (TNM 8th edition), resectable gastric adenocarcinoma are eligible for this study. Neoadjuvant therapy will be administered for four cycles. The patients will receive tislelizumab and trastuzumab for 1 cycle (Q3W), followed by tislelizumab and trastuzumab combined with DOS (Docetaxel + Oxaliplatin + S-1) for 3 cycles (Q3W). Surgery is planned 4-6 weeks after preoperative treatment. Patients who have complete surgical resection will receive adjuvant therapy starting within 4–6 weeks after surgery for 6 cycles (three cycles of tislelizumab and trastuzumab combined with DOS regimen, followed by 6 weeks of tislelizumab and trastuzumab for 6 cycles. The primary endpoint was pathological complete response rate (pCR). Secondary endpoints included R0 resection rate, 1-year and 2-year event-free survival (EFS), overall survival (OS) and safety. Results: From September 13, 2021 to February 01, 2023, 12 patients were enrolled (58.0% male, median age 61 years old), and the median follow up time was 7.3 months (0.4-16.9). Seven patients completed surgery, and 5 patients were undergoing neoadjuvant therapy. The R0 resection rate was 100%, 3 patients (42.9%) achieved pCR, and 4 patients (57.1%) achieved major pathological remission (MPR). Postoperative pathology showed tumor downstaging in 5 cases after neoadjuvant therapy, with a decrease rate of 71.4%. Median OS and EFS have not been reached. The most common AEs (all grades, grade ≥3) were anemia in 1 (8.3%) and neutropenia in 1 case (8.3%). The immune-related adverse events were all grade 1 included 2 thyroid dysfunction (16.7%), 1 abnormal liver function (8.3%), and 1 of elevated blood sugar (8.3%). No grade 3 or higher immune-related AE was observed. No treatment related deaths were reported. Conclusions: According to the preliminary results, tislelizumab combined with trastuzumab and standard chemotherapy in the perioperative period of HER2-positive GC and EGJ have a good clinical benefit trend and controllable security. Clinical trial information: NCT04819971 .