Heli Liu

PURPOSE: Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC. METHODS: Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan at 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion at selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety. RESULTS: Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization–negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR). CONCLUSION: Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.

Objective: The clinicopathological features and outcome of gastrointestinal stromal tumors (GISTs) with lymph node metastasis remain controversial owing to their low incidence. A multicenter retrospective cohort study was conducted to compare the clinicopathological features and oncologic outcomes of GIST without metastasis, with lymph node metastasis, and with distant metastasis. Design: The medical records of patients with GISTs in 16 large medical centers in China from January 2014 to December 2022 were reviewed. Patients were divided into four groups: no metastasis (988 cases, 89.1%), lymph node metastasis without distant metastasis (75 cases, 6.8%), distant metastasis without lymph node metastasis (36 cases, 3.2%), and distant metastasis with lymph node metastasis group (10 cases, 0.9%). Propensity score matching (PSM) was performed to reduce confounding factors. Result: A total of 1109 cases of primary GIST were included in this study, comprising 607 males (54.7%) and 502 females (45.3%), with a mean age of 56.6 ± 11.9 years. Compared to that in GIST without lymph node metastasis, the proportion of nongastric GIST was higher in GIST with lymph node metastasis (52.9% vs 40.7%) with a larger tumor diameter (>10 cm: 36.5% vs 18.1%) and more patients with distant metastasis (11.8% vs 3.5%). Tumor location not in the stomach, the largest tumor diameter, and distant metastasis were independent risk factors for GIST with lymph node metastasis (all P < .05). After PSM, 96, 48, 24 patients comprised no metastasis, lymph node metastasis without distant metastasis, and distant metastasis without lymph node metastasis, respectively. The relapse-free survival (RFS) of the lymph node metastasis group was comparable to that of the distant metastasis group without lymph node metastasis (P = .368) and significantly inferior to that of no metastases (P = .042). Conclusions and Relevance: The RFS of patients with GIST with lymph node metastasis was comparable to those with distant metastasis and significantly worse than those without metastasis. Lymph node metastasis is an advanced event in GIST.

Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide, posing a serious threat to public health. Prognostication of overall survival (OS) in patients undergoing radical gastrectomy remains a clinical priority. Evidence suggests that preoperative nutritional and inflammatory status correlated with postoperative outcomes. This study aims to evaluate the prognostic value of the skeletal muscle index at the third lumbar vertebra (L3-SMI) as a trichotomous variable and to compare the performance of commonly used nutritional and inflammation-related indicators in predicting postoperative survival in GC patients. This retrospective study analyzed clinical data of patients who underwent radical gastrectomy with neoadjuvant chemotherapy between 2011 and 2018 at the Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University. L3-SMI was measured by preoperative CT, and 8 preoperative nutritional/inflammatory indices were calculated from the latest laboratory tests before surgery: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), albumin-globulin ratio (AGR), and prognostic nutritional index (PNI). L3-SMI was categorized into 3 groups using X-tiler software. ROC curves were used to determine optimal cut-off values for the other eight indices. Kaplan-Meier curves and univariate/multivariate Cox proportional hazards models were used to analyze the association between variables and OS. Concordance index (C-index) and subgroup analysis assessed predictive performance and consistency across patient subgroups. A total of 546 patients were included, with a minimum follow-up time of 36 months. Kaplan-Meier and univariate analysis showed that L3-SMI and the 8 indicators were significantly associated with OS (all PHR=0.676, 95% CI 0.523 to 0.872), AGR (HR=0.611, 95% CI 0.452 to 0.827), and PNI (HR=0.590, 95% CI 0.418 to 0.833) were independent predictors of OS. The full model confirmed the independent prognostic roles of L3-SMI, AGR, and PNI. Among all indicators, PNI had the highest C-index for 1-year OS prediction (0.632, 95% CI 0.568 to 0.695), while AGR showed the best performance at 3 years (0.585, 95% CI 0.548 to 0.622) and 5 years (0.578, 95% CI 0.542 to 0.613). Subgroup analysis indicated that higher L3-SMI, AGR, and PNI were associated with lower mortality risk in patients aged<65 years, with lower gastric tumors, poor differentiation, stage III pTNM, or who underwent subtotal gastrectomy. Compared with other indicators, preoperative nutritional markers such as L3-SMI, AGR, and PNI demonstrated superior prognostic value for OS in gastric cancer patients undergoing radical gastrectomy. Assessing these indices can help identify patients at high risk of poor prognosis, thereby guiding targeted nutritional interventions and potentially improving survival outcomes.

PURPOSE: This multicenter, randomized phase III trial evaluated the efficacy and safety of perioperative camrelizumab (an anti–PD-1 antibody) plus low-dose rivoceranib (a VEGFR-2 inhibitor) and S-1 and oxaliplatin (SOX) (SOXRC), high-dose rivoceranib plus SOX (SOXR), and SOX alone (SOX) for locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. METHODS: Patients with T3-4aN + M0 G/GEJ adenocarcinoma were randomly assigned (1:1:1) to receive perioperative treatment with SOXRC, SOXR, or SOX. The primary end points were pathologic complete response (pCR) and event-free survival. The Independent Data Monitoring Committee recommended stopping enrollment in the SOXR group on the basis of the safety data of the first 103 randomly assigned patients in the three groups. The patients were then randomly assigned 1:1 to the SOXRC or SOX groups. This report presents the pCR results obtained per protocol for the first 360 randomly assigned patients who had the opportunity for surgery in the SOXRC and SOX groups. RESULTS: In the SOXRC and SOX groups, of the 180 patients in each group, 99% and 98% of patients received neoadjuvant therapy, 91% and 94% completed planned neoadjuvant therapy, and 86% and 87% underwent surgery, respectively. The pCR was significantly higher in the SOXRC group at 18.3% (95% CI, 13.0 to 24.8) compared with 5.0% (95% CI, 2.3 to 9.3) in the SOX group (difference of 13.7%; 95% CI, 7.2 to 20.1; odds ratio of 4.5 [95% CI, 2.1 to 9.9]). The one-sided P value was <.0001, crossing the prespecified statistical significance threshold of P = .005. Surgical complications and grade ≥3 neoadjuvant treatment-related adverse events were 27% versus 33% and 34% versus 17% for SOXRC and SOX, respectively. CONCLUSION: The SOXRC regimen significantly improved pCR compared with SOX alone in patients with G/GEJ adenocarcinoma with a tolerable safety profile.

The NTRK fusion gene is a rare cancer driver and a typical representative "diamond mutation". Its unique role in tumor progression is highly important for the clinical diagnosis and treatment of patients with tumors. We searched for NTRK fusion-positive patients in our hospital. As of August 2022, a total of 8 patients were affected. We discovered that NTRK fusion was associated with enhanced tumor invasion and migration ability. Previous reports also support this finding, but its underlying mechanism has not been elucidated. We undertook a comprehensive exploration of the correlations between NTRK fusions and tumor invasion as well as migration by analysing clinical data, performing bioinformatics analysis via public databases, and conducting in vitro cell experiments. We ascertained that within the thyroid cancer (THCA) dataset and the pancancer dataset, ECM1 and NOVA1 were coexpressed with NTRKs. Additionally, they demonstrated a significant association with the activity of the epithelial‒mesenchymal transition (EMT) pathway. Furthermore, these genes are overexpressed in various cancers and are associated with advanced clinical stage and increased aggressiveness. Our in vitro study revealed that larolutinib potentially inhibited the invasion and metastasis ability of NTRK-fused cells. Interestingly, contrary to previous findings, the repression of ECM1 increased the migration and invasion ability of NTRK-fused tumor cells. NTRK fusion tumors present heightened migratory and invasive potential in clinical settings. Further experiments confirmed the significant inhibitory effects of TRK inhibitors on the migration and invasion abilities of these cells. There is a complex relationship between ECM1, NOVA1 and NTRK fusion; however, further research is needed to determine whether NTRK fusion promotes tumor metastasis through these two genes.

Non-invasive prediction for KIT/PDGFRA status in GIST is a challenging problem. This study aims to evaluate whether CT based sarcopenia could differentiate KIT/PDGFRA wild-type gastrointestinal stromal tumor (wt-GIST) from the mutant-type GIST (mu-GIST), and to evaluate genetic features of GIST. A total of 174 patients with GIST (wt-GIST = 52) were retrospectively identified between January 2011 to October 2019. A sarcopenia nomogram was constructed by multivariate logistic regression. The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Genomic data was obtained from our own specimens and also from the open databases cBioPortal. Data was analyzed by R version 3.6.1 and clusterProfiler (http://cbioportal.org/msk-impact). There were significantly higher incidence (75.0% vs. 48.4%) and more severe sarcopenia in patients with wt-GIST than in patients with mu-GIST. Multivariate logistic regression analysis showed that sarcopenia score (fitted based on age, gender and skeletal muscle index), and muscle fat index were independent predictors for higher risk of wt-GIST (P < 0.05 for both the training and validation cohorts). Our sarcopenia nomogram achieved a promising efficiency with an AUC of 0.879 for the training cohort, and 0.9099 for the validation cohort with a satisfying consistency in the calibration curve. Favorable clinical usefulness was observed using decision curve analysis. The additional gene sequencing analysis based on both our data and the external data demonstrated aberrant signal pathways being closely associated with sarcopenia in the wt-GIST. Our study supported the use of CT-based assessment of sarcopenia in differentiating the wt-GIST from the mu-GIST preoperatively.

OBJECTIVE: At present, there is still no definite conclusion on whether advanced gastric cancer (GC) requires additional para-aortic nodes dissection (PAND). The purpose of this study is to summarize current evidence on the potential benefits of the extended systemic lymphadenectomy (D2+) compared to D2 lymphadenectomy in the treatment of gastric cancer. MATERIALS AND METHODS: Systematic literature search was performed across PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP Database for Chinese Technical Periodicals, and China Biology Medicine disc using the following terms: gastric cancer, para-aortic lymphadenectomy, D2+ lymphadenectomy and D3 lymphadenectomy. RevMan 5.3 software was used for the meta-analysis. RESULTS: A total of 20 studies involving 5,643 patients were included, consisting of 6 randomized controlled trials (RCT) and 14 non-randomized controlled trials (nRCT). Compared with the D2 group, the operating time in the D2+ group was longer [mean difference (MD)=99.45 min, 95% confidence interval (CI) (48.93, 149.97), p<0.001], with more intra-operative blood loss [MD=262.14 mL, 95% CI (165.21, 359.07), p<0.001]. There were no significant differences in five-year overall survival (OS) [HR=1.09, 95% CI (0.95, 1.25), p=0.22] and post-operative mortality [RR=0.96, 95% CI (0.59, 1.57), p=0.88] between the two groups. The rate of post-operative complications in group D2+ was higher than that in group D2 [RR=1.42, 95% CI (1.11, 1.81), p<0.001]. CONCLUSIONS: Prophylactic D2+ surgery is not recommended, since D2+ surgery is associated with an increased rate of post-operative complications and does not improve the long-term survival rate of patients with advanced gastric cancer. However, D2+ surgery (especially D2+PAND) has certain survival advantages for specific patients, and D2+PAND surgery combined with chemotherapy may potentially improve long-term survival rate.

Background: The predictive role of sarcopenia in cancer prognosis is an area of increasing concern. However, the influence of sex difference on the predictive role of sarcopenia in cancer prognosis has not been clearly defined. This retrospective cohort study investigated the effect of preoperative sarcopenia on the long-term outcomes of patients with gastric cancer (GC) based on sexual dimorphism.Methods: Preoperative abdominal computed tomography (CT) scans from 379 GC patients who underwent radical gastrectomy were carefully analyzed. The patients were categorized into sarcopenia and non-sarcopenia groups according to the L3 skeletal muscle index (L3 SMI) measured on CT scans. Moreover, other indexes which can be used to evaluate the muscle area or the muscle quality, including skeletal muscle area (SMA), visceral fat area (VFA), subcutaneous fat area (SFA), skeletal muscle radiation attenuation (SM-RA), visceral fat index (VFI), subcutaneous fat index (SFI), and subcutaneous and visceral ratio (SV), were obtained from CT scans.Results: There were 254 men and 125 women included in our study. After calculation, we defined sex-specific SMI-related mortality cutoff as 39.73 and 32.97 cm²/m² for men and women. Univariable analysis showed that pathological tumor-node-metastasis (pTNM), depth of invasion, lymph node metastasis, differentiation degree, preoperative sarcopenia (for men), SMA (for men), L3 SMI, SFA (for women), SFI (for women), SV (for women), and SM-RA (especially for men) were significant independent predictors of overall survival (OS). Multivariable analysis showed that pTNM, depth of invasion, poor differentiation, and SM-RA were significantly associated with 5-year OS in GC patients. However, CT-determined sarcopenia was associated with significantly worse OS only in men, and SFA was significantly associated with 5-year OS only in women.Conclusion: SM-RA is a reliable prognostic factor in patients with GC after radical gastrectomy. The impact of indexes mentioned above on survival outcomes is dependent on sex. CT-determined preoperative sarcopenia, a muscle-related indicator, was associated with outcomes in men. Adipose-related indicator (SFA), instead, was associated with outcomes in women.

Lymph node metastasis (LNM) is considered to be one of the important factors in determining the optimal treatment for early gastric cancer (EGC). This study aimed to develop and validate a nomogram to predict LNM in patients with EGC. A total of 842 cases from the Surveillance, Epidemiology, and End Results (SEER) database were divided into training and testing sets with a ratio of 6 : 4 for model development. Clinical data (494 patients) from the hospital were used for external validation. Univariate and multivariate logistic regression analyses were used to identify the predictors using the training set. Logistic regression, LASSO regression, ridge regression, and elastic-net regression methods were used to construct the model. The performance of the model was quantified by calculating the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs). Results showed that T stage, tumor size, and tumor grade were independent predictors of LNM in EGC patients. The AUC of the logistic regression model was 0.766 (95% CI, 0.709–0.823), which was slightly higher than that of the other models. However, the AUC of the logistic regression model in external validation was 0.625 (95% CI, 0.537–0.678). A nomogram was drawn to predict LNM in EGC patients based on the logistic regression model. Further validation based on gender, age, and grade indicated that the logistic regression predictive model had good adaptability to the population with grade III tumors, with an AUC of 0.803 (95% CI, 0.606–0.999). Our nomogram showed a good predictive ability and may provide a tool for clinicians to predict LNM in EGC patients.