An automatically contamination-avoiding technique for intracorporeal esophagojejunostomy using a transorally inserted anvil during laparoscopic total gastrectomy for gastric cancer.

BACKGROUND: Intracorporeal Roux-en-Y esophagojejunostomy during laparoscopic total gastrectomy for gastric cancer remains a challenging manipulation due to the uncontrolled direction of the jejunal side or unintended embedded tissues, although several methods have been introduced. In this study, we simplified the procedure based on a surgical string fixing technique using a transorally inserted anvil (OrVil™; Covidien Ltd., Mansfield, MA, USA). METHODS: From March 2012 to September 2013, 14 consecutive patients underwent simplified intracorporeal Roux-en-Y esophagojejunostomy using OrVil™ during laparoscopic total gastrectomy for gastric cancer at our hospital. Clinicopathologic characteristics and surgical outcomes of these patients were retrospectively analyzed. RESULTS: All of the procedures were successful completed with no complication or conversion to open surgery. The mean overall operative time was 193.8 ± 41.8 min, whereas the mean reconstruction time was 32.6 ± 4.6 min. The mean estimated blood loss was 105.7 ± 65.4 ml. The mean diameter of anastomosis measured by upper gastrointestinal contrast X-ray test at 1 month after operation was 2.3 cm. During a median follow-up period of 12 months, neither local recurrence nor anastomosis-related morbidity was observed. CONCLUSIONS: Our preliminary results suggested that this automatically contamination-avoiding technique based on a surgical-string-fixing strategy using OrVil™ during laparoscopic total gastrectomy for gastric cancer might be feasible and safe and provide a simple solution for intracorporeal Roux-en-Y esophagojejunostomy.

Long-term combined blockade of CXCR4 and PD-L1 with in vivo reassembly for intensive tumor interference.

Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings.

Exploiting autophagy-regulative nanomaterials for activation of dendritic cells enables reinforced cancer immunotherapy.

Dendritic cells (DCs), as the most powerful antigen presenting cells, play a critical role in regulating immune response and anti-tumor process. However, the immunosuppressive cells and factors resided in the tumor microenvironment (TME) pose various challenges that can subvert competent DC function comprising antigen presentation and immune initiation. In this setting, developing potent strategies to improve the function of DCs is critically required for improving the efficacy of tumor immunotherapy. Autophagy is found to be closely associated to the various functions of DCs under physiological and pathological conditions. Especially, nanomaterials (NMs) can engage in the disorder and regularity of autophagy to modulate their metabolism and function of DCs. Reasonable design of nanomaterials with autophagy regulation is of great significance to activate DCs and enhance its immunological functions, provoking robust and durable antitumor immunity. In this review, we study the design and optimization of nanomaterials with the function of regulating DCs autophagy, discuss the main mechanism of DCs autophagy induced by nanomaterials and its application in tumor immunotherapy, promoting the progress and development of cancer immunotherapy strategies in the future.

MMP-responsive transformation nanomaterials with IAP antagonist to boost immune checkpoint therapy.

The clinical effect of immune checkpoint therapy is limited by the poor blocking efficiency of immune checkpoints and the insufficient infiltration of tumor-specific T cells. Here, we constructed enzyme-responsive PVA-peptide conjugates (PPCs) to achieve re-assembly with enhanced accumulation in the tumor region, enable enhanced PD-L1 occupancy and improve the blocking efficiency. The self-assembled PPC-1 nanoparticles can enter tumor environment, whereas the enzyme-cleavable peptide was digested under overgenerated matrix metalloproteinases (MMP). The accumulated PPC-1 simultaneously transformed into ß-sheet fibrous structures around the solid tumor and remained stable for over 96 h, which led to efficiently interrupting the PD-1/PD-L1 interaction. Upon introduction of the IAP antagonists, the non-classical NF-κB pathway of dendritic cells was activated and increased the infiltration of T cells in tumors. With the synergistic contribution of IAP antagonists from the substantial increase in expression of chemokines (CCL5 and CXCL9) and adequate T-cell infiltration in tumor sites, PPC-1 improved the biodistribution and accumulation of PD-L1 antagonists in tumor regions ultimately realizing higher-performance (P < 0.01) tumor growth inhibition efficiency (~80%) than PPC-2 group (~58%) in B16F10 tumor-bearing mice. The growth of the second tumor at the distal end was obviously inhibited (P < 0.01) after the resection of the primary tumor. The combined efficacy was similar to that observed in a Pan02 pancreatic cancer tumor model. This strategy aims to offer novel perspective for the development of locational assembly platforms in vivo and the optimal design of immune checkpoint combination therapy.

Hypoxia-modulatory nanomaterials to relieve tumor hypoxic microenvironment and enhance immunotherapy: Where do we stand?

The past several years have witnessed the blooming of emerging immunotherapy, as well as their therapeutic potential in remodeling the immune system. Nevertheless, with the development of biological mechanisms in oncology, it has been demonstrated that hypoxic tumor microenvironment (TME) seriously impairs the therapeutic outcomes of immunotherapy. Hypoxia, caused by Warburg effect and insufficient oxygen delivery, has been considered as a primary construction element of TME and drawn tremendous attention in cancer therapy. Multiple hypoxia-modulatory theranostic agents have been facing many obstacles and challenges while offering initial therapeutic effect. Inspired by versatile nanomaterials, great efforts have been devoted to design hypoxia-based nanoplatforms to preserve drug activity, reduce systemic toxicity, provide adequate oxygenation, and eventually ameliorate hypoxic-tumor management. Besides these, recently, some curative and innovative hypoxia-related nanoplatforms have been applied in synergistic immunotherapy, especially in combination with immune checkpoint blockade (ICB), immunomodulatory therapeutics, cancer vaccine therapy and immunogenic cell death (ICD) effect. Herein, the paramount impact of hypoxia on tumor immune escape was initially described and discussed, followed by a comprehensive overview on the design tactics of multimodal nanoplatforms based on hypoxia-enabled theranostic agents. A variety of nanocarriers for relieving tumor hypoxic microenvironment were also summarized. On this basis, we presented the latest progress in the use of hypoxia-modulatory nanomaterials for synergistic immunotherapy and highlighted current challenges and plausible promises in this area in the near future. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy, emerging as a novel treatment to eradicate malignant tumors, has achieved a measure of success in clinical popularity and transition. However, over the last decades, hypoxia-induced tumor immune escape has attracted enormous attention in cancer treatment. Limitations of free targeting agents have paved the path for the development of multiple nanomaterials with the hope of boosting immunotherapy. In this review, the innovative design tactics and multifunctional nanocarriers for hypoxia alleviation are summarized, and the smart nanomaterial-assisted hypoxia-modulatory therapeutics for synergistic immunotherapy and versatile biomedical applications are especially highlighted. In addition, the challenges and prospects of clinical transformation are further discussed.

Staging laparoscopy improves treatment decision-making for advanced gastric cancer.

AIM: To evaluate the clinical value of staging laparoscopy in treatment decision-making for advanced gastric cancer (GC). METHODS: Clinical data of 582 patients with advanced GC were retrospectively analyzed. All patients underwent staging laparoscopy. The strength of agreement between computed tomography (CT) stage, endoscopic ultrasound (EUS) stage, laparoscopic stage, and final stage were determined by weighted Kappa statistic (Kw). The number of patients with treatment decision-changes was counted. A χ(2) test was used to analyze the correlation between peritoneal metastasis or positive cytology and clinical characteristics. RESULTS: Among the 582 patients, the distributions of pathological T classifications were T2/3 (153, 26.3%), T4a (262, 45.0%), and T4b (167, 28.7%). Treatment plans for 211 (36.3%) patients were changed after staging laparoscopy was performed. Two (10.5%) of 19 patients in M1 regained the opportunity for potential radical resection by staging laparoscopy. Unnecessary laparotomy was avoided in 71 (12.2%) patients. The strength of agreement between preoperative T stage and final T stage was in almost perfect agreement (Kw = 0.838; 95% confidence interval (CI): 0.803-0.872; P < 0.05) for staging laparoscopy; compared with CT and EUS, which was in fair agreement. The strength of agreement between preoperative M stage and final M stage was in almost perfect agreement (Kw = 0.990; 95% CI: 0.977-1.000; P < 0.05) for staging laparoscopy; compared with CT, which was in slight agreement. Multivariate analysis revealed that tumor size (≥ 40 mm), depth of tumor invasion (T4b), and Borrmann type (III or IV) were significantly correlated with either peritoneal metastasis or positive cytology. The best performance in diagnosing P-positive was obtained when two or three risk factors existed. CONCLUSION: Staging laparoscopy can improve treatment decision-making for advanced GC and decrease unnecessary exploratory laparotomy.