Increased Levels of PD1 and Glycolysis in CD4+ T Cells Promote Lymph Node Metastasis in Oral Squamous Cell Carcinoma Patients

Background: Cervical lymph node metastasis is one of the poorest prognostic factors in oral squamous cell carcinoma (OSCC). Activated immune cells and cancer cells generally have metabolic similarities in tumor microenvironment. However, it is unknown whether abnormal glycolysis in T cells could facilitate metastatic lymph nodes in patients with OSCC. Methods: Flow cytometry and immunofluorescence staining were used to analyze the differences in CD4+ PD1+ T cells between metastatic and negative lymph nodes. RT-PCR was performed to detail the expression of immune checkpoints and glycolysis-related enzymes in metastatic and negative lymph nodes. Kruskal-Wallis, Mann-Whitney, or nonparametric paired tests (i.e., the Wilcoxon matched paired test) were used to analyze the non-parametric distribution of the samples. Results: The frequency of CD4+ T cells decreased in the metastatic lymph nodes (p = 0.0019). Immune checkpoints (PD1, PDL1, and CTLA4) of CD4+ T cells were detected in metastatic (LN+) and paired negative lymph nodes (LN-) of OSCC patients. The PD1 expression of LN+ increased markedly compared to that of LN- (p = 0.0205). Similarly, the PD1 of CD4+ T cells in LN+ increased significantly compared to that of LN-. Glycolysis-related enzyme levels in CD4+ T cells from LN+ were dramatically higher than those in LN-. Moreover, PD1 and Hk2 expressions in CD4+ T cells increased in metastatic lymph nodes of OSCC patients with prior surgical treatment compared to those without. Conclusions: These findings suggest that increased PD1 and glycolysis in CD4+ T cells may serve as pivotal regulators of OSCC metastatic lymph nodes, which are closely associated with elevated glycolysis.

O-OGC04 Peri-operative chemotherapy versus preoperative chemoradiotherapy in treatment of Esophago-gastric junctional adenocarcinomas: A 10-year cohort study

Background Esophago-gastric junctional (EGJ) cancers have been considered recently as distinct tumour entity with characteristic genetic profiles. However, the optimal multimodal therapy of advanced EGJ cancers is still debatable. In this comparative study, we analysed the outcomes of peri-operative chemotherapy (CT) versus pre-operative chemoradiotherapy (CRT) in treatment of advanced EGJ adenocarcinomas. Methods This study included patients with locally advanced but resectable EGJ adenocarcinomas who underwent surgical resection after oncological therapy between 2010 till 2019, at our institution. Follow up till May 2021 was done. The outcomes between CT and CRT groups were retrospectively analysed. The long-term follow up data was obtained via direct contact with the patients during our oncological clinics, cross-checked with our hospital/national patients’ electronic databases. Results 107 patients had EGJ cancers; 90 (84%) patients met our inclusion criteria. Peri-operative chemotherapy was received in 65 (72%) patients. Overall median survival rate was 2.2 years in CRT-group compared to 2.4 years in CT-group (p-value 0.29), with comparable recurrence rates (48% vs 36% respectively). R0-resections were higher in CRT-group (84%) compared to CT-group (71%), yet insignificant p-value 0.197. Preoperative chemoradiotherapy achieved higher complete pathological response (28% vs 6%, p-value 0.009) and negative lymph nodes rates (64% vs 37%, p-value 0.014) compared to CT-group. Short-term outcomes (postoperative complications, morbidity rates and length of hospital stay) were similar across both groups. Conclusions Preoperative chemoradiotherapy was associated with higher complete pathological response and negative lymph nodes rates for EGJ adenocarcinomas compared to peri-operative chemotherapy, without increase in postoperative complications or morbidity rates. However, it wasn’t associated with improved overall or disease-free survival rates. These findings supported the use of CRT in treatment of advanced EGJ adenocarcinomas.

Cervical Cancer and Fertility-Sparing Treatment

Radical hysterectomy with pelvic node dissection is the standard treatment for early-stage cervical cancer. However, the latter can be diagnosed at a young age when patients have not yet achieved their pregnancy plans. Dargent first described the vaginal radical trachelectomy for patients with tumors <2 cm. It has since been described a population of low risk of recurrence: patients with tumors <2 cm, without deep stromal infiltration, without lymphovascular invasion (LVSI), and with negative lymph nodes. These patients can benefit from a less radical surgery such as conization or simple trachelectomy with the evaluation of the pelvic node status. Tumors larger than 2 cm have a higher risk of recurrence and their treatment is a challenge. There are currently two options for these patients: abdominal radical trachelectomy or neoadjuvant chemotherapy (NACT), followed by fertility-sparing surgery. All patients who wish to preserve their fertility must be referred to expert centers.

Development and Validation of a Prognostic Nomogram Based on the Systemic Immune-Inflammation Index for Resectable Gallbladder Cancer to Predict Survival and Chemotherapy Benefit

ObjectivesTo investigate the prognostic significance of the systemic immune-inflammation index (SII) in patients after radical cholecystectomy for gallbladder cancer (GBC) using overall survival (OS) as the primary outcome measure.MethodsBased on data from a multi-institutional registry of patients with GBC, significant prognostic factors after radical cholecystectomy were identified by multivariate Cox proportional hazards model. A novel staging system was established, visualized as a nomogram. The response to adjuvant chemotherapy was compared between patients in different subgroups according to the novel staging system.ResultsOf the 1072 GBC patients enrolled, 691 was randomly selected in the discovery cohort and 381 in the validation cohort. SII&gt;510 was found to be an independent predictor of OS (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.42-2.54). Carbohydrate antigen 199(CA19-9), tumor differentiation, T stage, N stage, margin status and SII were involved in the nomogram. The nomogram showed a superior prediction compared with models without SII (1-, 3-, 5-year integrated discrimination improvement (IDI):2.4%, 4.1%, 5.4%, P&lt;0.001), and compared to TNM staging system (1-, 3-, 5-year integrated discrimination improvement (IDI):5.9%, 10.4%, 12.2%, P&lt;0.001). The C-index of the nomogram in predicting OS was 0.735 (95% CI 0.683-0.766). The novel staging system based on the nomogram showed good discriminative ability for patients with T2 or T3 staging and with negative lymph nodes after R0 resection. Adjuvant chemotherapy offered significant survival benefits to these patients with poor prognosis.ConclusionsSII was an independent predictor of OS in patients after radical cholecystectomy for GBC. The new staging system identified subgroups of patients with T2 or T3 GBC with negative lymph nodes who benefited from adjuvant chemotherapy.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT04140552).

The log odds of negative lymph nodes/T stage: a new prognostic and predictive tool for resected gastric cancer patients

Purpose When only the TNM classification is used to predict survival in gastric cancer (GC) patients, the impact of the degree of lymphadenectomy on the prognosis is neglected. This study aimed to establish a more effective nomogram based on the log odds of negative lymph nodes/T stage ratio (LONT) to predict survival in surgically treated GC patients. Methods The data of resected GC patients were extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database. Univariate and multivariate Cox regression analyses were used to identify the significant prognostic factors. The prognostic performance was assessed using a calibration plot, concordance index (C-index), and area under the (time-dependent receiver operating characteristic) curve (AUC) to compare the predicted survival probability based on the nomogram score groups. Results The results showed LONT as an independent prognostic factor for cancer-specific survival (CSS) and overall survival (OS), independent of clinicopathological factors. After removing potential redundancy, only LONT, T stage, N stage, location and age were used in the final nomogram model. The model had a higher C-index (0.736 ± 0.012) and AUC (0.798) than the TNM staging system (0.685 ± 0.012 and 0.744). The nomogram score could predict a significant survival difference between any two adjacent groups in terms of CSS and OS. Conclusion High LONT is associated with improved survival of gastric cancer patients, independent of other clinicopathological factors. The prognostic nomogram model based on LONT could effectively predict CSS and OS for resectable GC patients.

Prognostic value of the extent of lymphadenectomy for esophageal cancer-specific survival among T1 patients

Background Clinically, there are no clear guidelines on the extent of lymphadenectomy in patients with T1 esophageal cancer. Studying the minimum number of lymph nodes for resection may increase cancer-specific survival. Methods Patients who underwent esophagectomy and lymphadenectomy at T1 stage were selected from the Surveillance, Epidemiology and End Results Program (United States, 1998–2014). Maximally selected rank and Cox proportional hazard models were used to examine three variables: the number of lymph nodes examined, the number of negative lymph nodes and the lymph node ratio. Results Approximately 18% had lymph node metastases, where the median values were 10, 10 and 0 for the number of lymph nodes examined, the number of negative lymph nodes and the lymph node ratio, respectively. All three examined variables were statistically associated with cancer-specific survival probability. Dividing patients into two groups shows a clear difference in cancer-specific survival compared to four or five groups for all three variables: there was a 29% decrease in the risk of death with the number of lymph nodes examined ≥14 vs < 14 (hazard ratio 0.71, 95% confidence interval: 0.57–0.89), a 35% decrease in the risk of death with the number of negative lymph nodes ≥13 vs < 13 (hazard ratio 0.65, 95% confidence interval: 0.52–0.81), and an increase of 1.21 times in the risk of death (hazard ratio 2.21, 95% confidence interval: 1.76–2.77) for the lymph node ratio > 0.05 vs ≤ 0.05. Conclusions The extent of lymph node dissection is associated with cancer-specific survival, and the minimum number of lymph nodes that need to be removed is 14. The number of negative lymph nodes and the lymph node ratio also have prognostic value after lymphadenectomy among T1 stage patients.

Increased PD1 and Glycolysis in CD4+ T Cell Promotes Lymph Node Metastasis in Oral Squamous Cell Carcinoma Patients

Background: The presence of cervical lymph node metastasis is one of the poorest prognostic factors in oral squamous cell carcinoma (OSCC) with 50% reduction in survival of patients with lymph node positive involvement compared to those without. However, it is unknown whether immune checkpoint contributed to metastatic lymph nodes in OSCC patients. Methods: Flow cytometry and immunofluorescence staining were used to analyze the differences of CD4+ PD1+ T cells between metastatic and negative lymph nodes. RT-PCR was performed to clarify the expression of immune checkpoints and glycolysis related enzymes in metastatic and negative lymph nodes. Kruskal-Wallis tests, Mann-Whitney tests or nonparametric paired test (Wilcoxon matched paired test) were used to analyze the non-parametric distribution of samples. Results: We found that frequency of CD4+ T cells decreased in metastatic lymph nodes (p = 0.0019). In following experiments, immune checkpoints (PD1, PDL1 and CTLA4) of CD4+ T cells were detected in metastatic lymph node (LN+) and paired negative lymph node (LN-) of OSCC patients. The PD1 expression of LN+ was increased markedly compared to LN- (p = 0.0205). Similarly, the PD1 of CD4+ T cells in LN+ was increased significantly compared to LN-. We also found that glycolysis related enzymes levels in CD4+ T cells from LN+ were elevated dramatically compared to LN-. Moreover, PD1 and Hk2 expression of CD4+ T cells was increased in metastatic lymph nodes of OSCC patients with prior surgical treatment compared to those without. Conclusions: These findings suggested that increased PD1 and glycolysis in CD4+ T cell may serve as a pivotal regulator of OSCC metastatic lymph nodes via elevating glycolysis related enzymes level, especially in Hk2.

Isolated brachioradialis metastasis of gastric adenocarcinoma after R0 resection

BackgroundGastric cancer is the fifth most common cancer worldwide, with an incidence of 6.72 per 100,000 people. Thirty-two percent of gastric cancer patients will live 5 years after diagnosis. Single-site metastasis is noted in 26% of patients with gastric cancer, most commonly in the liver (48%), peritoneum (32%), lung (15%), and bone (12%). Here, a case is presented in which a single skeletal muscle metastasis appeared after appropriate resection and treatment.Case presentationA 63-year-old man underwent neoadjuvant chemotherapy and a multivisceral en bloc R0 resection. Final pathology showed no evidence of lymph node metastasis with 31 negative lymph nodes. Four months postoperatively, the patient was found to have a rapidly growing biopsy-proven extremity soft tissue gastric metastasis within the brachioradialis muscle. He subsequently underwent metastasectomy and immunotherapy.ConclusionThis case is a rare example of an isolated extremity metastasis of gastric adenocarcinoma in the setting of an R0 resection of the primary tumor and negative nodal disease on final pathology, suggestive of hematogenous spread. We review the biology, workup, and management of gastric cancer and highlight new advancements in the treatment of this aggressive cancer.