Neoadjuvant Immunotherapy With Ipilimumab Plus Nivolumab in Mismatch Repair Deficient/Microsatellite Instability-High Colorectal Cancer: A Preliminary Report of Case Series.

BACKGROUND: Although ipilimumab plus nivolumab have significantly improved the survival of metastatic colorectal cancer (CRC) with mismatch repair deficient (dMMR) /microsatellite instability-high (MSI-H), the data on neoadjuvant setting is limited. PATIENTS AND METHODS: We enrolled 11 patients with advanced dMMR/MSI-H CRC. 10 patients were locally advanced and 1 was metastatic. Ten patients were treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), and 1 patient was treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) with 2 cycles. All the patients underwent surgery after immunotherapy. The aim of the study was to evaluate the safety and short-term efficacy of this strategy. RESULTS: Pathologic responses were observed in 11/11 (100%) dMMR/MSI-H tumors, with 9/11 (81.8%) achieving complete responses. Among these 9 cases with complete responses, 1 achieved a radiological noncomplete response after treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), so another cycle of treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) was administered, followed by surgery. The postoperative pathological evaluation was a complete response. Seven patients (63.6%) developed grade I/II adverse events. No patients developed grade III/IV adverse events or postoperative complications. CONCLUSION: Neoadjuvant immunotherapy with ipilimumab plus nivolumab induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H CRC. Notably, patients do not achieve a complete response to neoadjuvant immunotherapy, additional neoadjuvant immunotherapy may offer benefits. Further research is needed to assess the long-term efficacy of this strategy.

SIRGs score may be a predictor of prognosis and immunotherapy response for esophagogastric junction adenocarcinoma.

Background: Esophagogastric junction adenocarcinoma (EGJA) is a special malignant tumor with unknown biological behavior. PD-1 checkpoint inhibitors have been recommended as first-line treatment for advanced EGJA patients. However, the biomarkers for predicting immunotherapy response remain controversial. Methods: We identified stromal immune-related genes (SIRGs) by ESTIMATE from the TCGA-EGJA dataset and constructed a signature score. In addition, survival analysis was performed in both the TCGA cohort and GEO cohort. Subsequently, we explored the differences in tumor-infiltrating immune cells, immune subtypes, immune-related functions, tumor mutation burden (TMB), immune checkpoint gene expression, immunophenoscore (IPS) between the high SIRGs score and low SIRGs score groups. Finally, two validation cohorts of patients who had accepted immunotherapy was used to verify the value of SIRGs score in predicting immunotherapy response. Results: Eight of the SIRGs were selected by LASSO regression to construct a signature score (SIRGs score). Univariate and multivariate analyses in the TCGA and GEO cohort suggested that SIRGs score was an independent risk factor for the overall survival (OS) and it could increase the accuracy of clinical prediction models for survival. However, in the high SIRGs score group, patients had more immune cell infiltration, more active immune-related functions, higher immune checkpoint gene expression and higher IPS-PD1 and IPS-PD1-CTLA4 scores, which indicate a better response to immunotherapy. The external validation illustrated that high SIRGs score was significantly associated with immunotherapy response and immune checkpoint inhibitors (ICIs) can improve OS in patients with high SIRGs score. Conclusion: The SIRGs score may be a predictor of the prognosis and immune-therapy response for esophagogastric junction adenocarcinoma.

Indications for Adjuvant Chemotherapy in Stage II Gastric Cancer After D2 Gastrectomy-A Chinese Multicenter Study.

BACKGROUND: The benefit of adjuvant chemotherapy (AC) for patients with stage II gastric cancer remains controversial. This study aimed to explore the indications for adjuvant chemotherapy in patients with stage II gastric cancer by constructing an individual prediction model. PATIENTS AND METHODS: In this Chinese multicenter study, a total of 1012 patients with stage II gastric cancer after D2 radical gastrectomy were retrospectively analyzed. All patients were randomly assigned to a training cohort (n = 674) or a validation cohort (n = 338). A nomogram was constructed according to the training cohort. Concordance index (C-index), the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA) were applied to evaluate the performance of the nomogram. ROC curves and stratified survival were used to determine the patients' cutoff score for a benefit from adjuvant chemotherapy. An additional 338 patients were used as a validation cohort to validate the feasibility of using this nomogram to guide individualized therapy for patients with stage II gastric cancer. RESULTS: Univariate and multivariate analyses illustrated that age, sex, tumor location, size, carcinoembryonic antigen (CEA), hemoglobin (HB), and T stage were independent prognostic factors for overall survival (OS), and they were used to establish a nomogram. The cutoff value was determined by ROC curve analysis, and patients were divided into a high-risk group (< 239 points) and a low-risk group (≥ 239 points). There was no significant difference in the OS of low-risk patients in either the training cohort or the validation cohort. However, the OS of high-risk patients in the AC group was better than that of patients in the surgery-only group. CONCLUSIONS: This prediction model can be applied to guide treatment of patients with stage II gastric cancer. High-risk patients (< 239 points) are likely to benefit from AC after D2 radical gastrectomy.

Survival analysis of stage II gastric cancer patients after D2 gastrectomy: a Chinese people-based research.

OBJECTIVE: The benefit of adjuvant chemotherapy is still controversial for stage II gastric cancer patients. This study aims to identify prognostic factors to guide individualized treatment for stage II gastric cancer patients. METHODS: We retrospectively reviewed 1121 stage II gastric cancer patients who underwent D2 radical gastrectomy from 2007 to 2017 in the Sixth Affiliated Hospital of Sun Yat-sen University, FuJian Medical School Affiliated Union Hospital and Sun Yat-sen University Cancer Center. Propensity score matching was used to ensure that the baseline data were balanced between the adjuvant chemotherapy group and surgery-only group. Kaplan-Meier survival and multivariate Cox regression analyses were carried out to identify independent prognostic factors. RESULTS: In univariate analysis, after propensity score matching, age, tumor location, tumor size, CEA, T stage and N stage were associated with overall survival (OS). Multivariate analysis illustrated that age ≥ 60 years old, linitis plastica and T4 were independent risk factors for OS, but lower location and adjuvant chemotherapy were protective factors. CONCLUSION: Stage II gastric cancer patients with adverse prognostic factors (age ≥ 60, linitis plastica and T4) have poor prognosis. Adjuvant chemotherapy may be more beneficial for these patients.

Retrieval of 30 Lymph Nodes Is Mandatory for Selected Stage II Gastric Cancer Patients.

BACKGROUND: According to the 8th edition AJCC staging manual, a least of 16 lymph nodes retrieval (LNRs) is the minimal requirement for lymph nodes (LNs) dissection of gastric cancer surgery. Previous studies have shown that increasing the number of LNRs (≥30) prolongs survival for selected patients. However, the necessity of retrieving 30 or more LN for stage II gastric cancer patients is still under debate. AIM: This study aims to explore the impact of retrieving 30 or more lymph nodes on the survival of stage II cancer patients. METHODS: A total of 1,177 patients diagnosed with stage II gastric cancer were enrolled in this study. The clinicopathological parameters and the impact of different LNRs (<30 or ≥30) and positive lymph node ratio (NR) on overall survival (OS) were retrospectively analyzed. RESULTS: The mean number of LNRs was 34 ± 15. A total of 44% (518/1,177) of patients had an LNRs <30, while 56% (659/1,177) of patients had an LNRs ≥30. The 5-year survival rate was 81% for all patients, 76% for the LNRs <30 group, and 86% for LNRs ≥30 group, respectively (P = 0.003). The survival benefit of retrieving 30 lymph nodes was significant in certain subgroups: age >60 years/male/underwent total gastrectomy/stage IIB. For N+ patients, higher NR was significantly correlated with poor survival. CONCLUSION: The survival benefit of retrieving 30 LNs varies in different subgroups. An LNRs of 30 is mandatory for selected stage II gastric cancer patients.

Near-infrared dye-loaded magnetic nanoparticles as photoacoustic contrast agent for enhanced tumor imaging.

Objective: Photoacoustic (PA) tomography (PAT) has attracted extensive interest because of its optical absorption contrast and ultrasonic detection. This study aims to develop a biocompatible and biodegradable PA contrast agent particularly promising for clinical applications in human body. Methods: In this study, we presented a PA contrast agent: 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy (polyethylene glycol)] (DSPE-PEG)-coated superparamagnetic iron oxide (SPIO) nanoparticles (NPs) loaded with indocyanine green (ICG). We used ICG and SPIO NPs because both drugs are approved by the U.S. Food and Drug Administration. Given the strong absorption of near-infrared laser pulses, SPIO@DSPE-PEG/ICG NPs with a uniform diameter of ~28 nm could significantly enhance PA signals. Results: We demonstrated the contrast enhancement of these NPs in phantom and animal experiments, in which the in vivo circulation time of SPIO@DSPE-PEG/ICG NPs was considerably longer than that of free ICG. These novel NPs also displayed a high efficiency of tumor targeting. Conclusions: SPIO@DSPE-PEG/ICG NPs are promising PAT contrast agents for clinical applications.

Imaging guided photothermal therapy using iron oxide loaded poly(lactic acid) microcapsules coated with graphene oxide.

A novel multifunctional theranostic agent has been successfully fabricated by loading iron oxide nanoparticles into poly(lactic acid) (PLA) microcapsules followed by surface functionalization with graphene oxide. Both in vitro and in vivo experiments proved that the resulting microcapsules could serve as contrast agents to simultaneously enhance ultrasound, magnetic resonance and photoacoustic imaging. The composite microcapsules show good biocompatibility and rapid response to magnetic fields. Due to the strong absorption of the near-infrared light, the composite microcapsules could efficiently kill cancer cells upon NIR laser irradiation. In addition, it was found that such a photothermal effect could be obviously enhanced by applying an external magnetic field. In a nutshell, this multifunctional microcapsule can be developed as a promising platform that integrates multimodality imaging and therapy capabilities for effective cancer theranostics.