Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma.

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.

Survival Profile and Prognostic Factors for Appendiceal Mixed Neuroendocrine Non-neuroendocrine Neoplasms: A SEER Population-Based Study.

INTRODUCTION: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare form of neuroendocrine neoplasms (NENs). The purpose of this study was to investigate the characteristics and survival profile of appendiceal MiNENs, with a view of providing robust clinical features of this rare disease. METHODS: Patients were selected from the Surveillance, Epidemiology, and End Results database (2004-2016). The prognosis of MiNEN (n = 315) was compared with other histological subtypes including neuroendocrine tumor (NETs) (n = 1734), neuroendocrine carcinoma (NECs) (n = 375), goblet cell carcinoid (GCC) (n = 968), signet ring cell carcinoma (n = 463), mucinous adenocarcinoma (MAC) (n = 2355), and non-mucinous adenocarcinoma (NMAC) (n = 1187) in the appendix. Age-adjusted incidence was calculated using Joinpoint regression. The Cox proportional hazards model and the Fine-Gray competing risk model were used to perform overall survival (OS) and cancer-specific mortality (CSM) analyses, respectively. RESULTS: The age-adjusted incidence of MiNENs increased from 0.01/100,000 person-years in 2004 to 0.07/100,000 person-years in 2016. The 3-, 5-, and 10-year OS rates for MiNENs were 69.5, 57.4, and 43.7%, respectively, and the corresponding CSM rates were 23.1, 36.4, and 45.1%, respectively. Multivariate analysis revealed that the prognosis of MiNENs was worse than that of NETs, NECs, GCC, and MAC but better than that of NMAC and signet ring cell carcinoma. Tumor extension was the only independent factor influencing the prognosis of MiNENs, but tumor size, grade, and surgical approaches were not. Moreover, when compared with local excision or appendectomy, extensive surgery such as hemicolectomy or colectomy did not prolong the survival of individuals with MiNENs. CONCLUSION: MiNEN is a rare but aggressive tumor with a poor prognosis differing from NENs, GCC and adenocarcinomas. To improve the prognosis of the disease, early diagnosis and comprehensive evaluation are necessary.

Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel.

Tumours with an immunosuppressive microenvironment respond poorly to therapy. Activation of the stimulator of interferon genes (STING) pathway can enhance intratumoural immune activation, but STING agonists are associated with high toxicity and degrade prematurely, which limits their effectiveness. Here, we show that the extended intratumoural release of the STING agonist cyclic di-AMP transforms the tumour microenvironment from immunosuppressive to immunostimulatory, increasing the efficacy of antitumour therapies. The STING agonist was electrostatically complexed with nanotubes comprising a peptide-drug conjugate (a peptide that binds to the protein neuropilin-1, which is highly expressed in tumours, and the chemotherapeutic agent camptothecin) that self-assemble in situ into a supramolecular hydrogel. In multiple mouse models of murine tumours, a single low dose of the STING agonist led to tumour regression and increased animal survival, and to long-term immunological memory and systemic immune surveillance, which protected the mice against tumour recurrence and the formation of metastases. Locally delivered STING agonists could help to reduce tumour immunosuppression and enhance the efficacy of a wide range of cancer therapies.

Resection of the primary tumor improves survival in patients with gastro-entero-pancreatic neuroendocrine neoplasms with liver metastases: A SEER-based analysis.

Patients who suffer from gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) often present with liver metastatic disease. The efficacy of primary tumor resection (PTR) for these patients remains controversial due to the relatively heterogeneous behavior of the primary tumor and the lack of clinical evidence. In this series, GEP-NEN patients with liver metastases (LM) were selected from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. A logistic regression model was used to analyze variables that were associated with PTR. A Cox proportional hazards model was used to identify independent prognostic risk factors. In total, 1547 patients were enrolled in our study, including 897 patients who underwent PTR. Resection of the primary tumor was associated with prolonged survival in all patients (5-year overall survival (OS) rates: 57.0% vs 15.4%, P < .001), and improved 5-year OS rates were observed in patients with gastric, small intestinal, colorectal, and pancreatic subtypes (39.7%, 73.3%, 24.6%, and 59.7%, respectively). On the multivariate analysis, PTR was an independent prognostic factor of prolonged OS (HR = 0.48, 95% CI: 0.39-0.59, P < .001). Patients with a young age (≤60 years), small intestinal or colorectal NENs, a large primary tumor, lymph node (LN) metastases, and high tumor differentiation were more likely to undergo PTR. However, patients with colorectal NENs or a large primary tumor (≥4 cm) were at an increased risk of death independently in the PTR subgroup. The risk factors for OS also included old age, gastric tumor location, and poor differentiation. In conclusion, although PTR prolonged OS in all GEP-NEN patients presenting with LM, surgical recipients should be considered carefully. Age, primary tumor site, size, and differentiation might help surgeons identify patients who could benefit from PTR.