Inhibition of Post-Surgery Tumour Recurrence via a Sprayable Chemoimmunotherapy Gel Releasing PD-L1 Antibody and Platelet-Derived Exosomes

Background: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods: Exosomes were isolated from platelets by differential centrifugation, and exosome-loaded doxorubicin (PexD) was prepared by mixing exosomes with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were coencapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion: Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence postsurgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

Cancer Stem Cell Biomarkers Predictive of Radiotherapy Response in Rectal Cancer: A Systematic Review

Background: Rectal cancer (RC) is one of the most commonly diagnosed and particularly challenging tumours to treat due to its location in the pelvis and close proximity to critical genitourinary organs. Radiotherapy (RT) is recognised as a key component of therapeutic strategy to treat RC, promoting the downsizing and downstaging of large RCs in neoadjuvant settings, although its therapeutic effect is limited due to radioresistance. Evidence from experimental and clinical studies indicates that the likelihood of achieving local tumour control by RT depends on the complete eradication of cancer stem cells (CSC), a minority subset of tumour cells with stemness properties. Methods: A systematic literature review was conducted by querying two scientific databases (Pubmed and Scopus). The search was restricted to papers published from 2009 to 2021. Results: After assessing the quality and the risk of bias, a total of 11 studies were selected as they mainly focused on biomarkers predictive of RT-response in CSCs isolated from patients affected by RC. Specifically these studies showed that elevated levels of CD133, CD44, ALDH1, Lgr5 and G9a are associated with RT-resistance and poor prognosis. Conclusions: This review aimed to provide an overview of the current scenario of in vitro and in vivo studies evaluating the biomarkers predictive of RT-response in CSCs derived from RC patients.

De novo and cell line models of human mammary cell transformation reveal an essential role for Yb-1 in multiple stages of human breast cancer

Breast cancer heterogeneity has made it challenging to identify mechanisms critical to the initial stages of their genesis in vivo. Here, we sought to interrogate the role of YB-1 in newly arising human breast cancers as well as in established cell lines. In a first series of experiments, we found that short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonising activity in immunodeficient mice. Conversely, upregulated expression of YB-1 enhanced the poor in vivo tumorigenicity of T47D cells. We then found that YB-1 knockdown also inhibits the initial generation in mice of invasive ductal carcinomas and ductal carcinomas in situ from freshly isolated human mammary cells transduced, respectively, with KRASG12D or myristoylated-AKT1. Interestingly, increased expression of HIF1α and G3BP1, two YB-1 translational targets and elements of a stress-adaptive programme, mirrored the levels of YB-1 in both transformed primary and established MDA-MB-231 breast cancer cells.

131I-radioisotope modified in PEGylation metal organic frameworks for sensitization in refractory differentiated thyroid cancer treatment

Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against refractory differentiated thyroid cancer. The nanoscale metal organic frameworks (NMOFs) have shown great potential in cancer diagnostic and treatment due to their advantages in the aspect of structural diversities, high intrinsic biodegradability and drug-loading capacities. Here, we provide that intratumoral injection, in mouse of refractory differentiated thyroid cancer. In this work, we used the therapeutic 131I radioisotope modified Zr-MOF (Zr-MOF@131I) with aim to enable long-term relief of tumour therapy, which has successfully eliminated tumour at ralatively low radioactivity doses. Polyethylene glycol (PEG) was coated into Zr-MOF and, as a result, circulation time was significantly improved by intratumoral injection. These findings therefore suggest that nanoparticles could be used in vivo combined therapy. On injection, while it is a highly effective drug for radioisotope, Zr-MOF with attenuation ability could apply for a radio-sensitizer to enhance inner radiotherapy (RT). The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments. These could be further combined with systemic therapeutic responses for the inhibition of refractory differentiated thyroid cancer and the prevention of tumour recurrence in patients.

High Rates of Treatment Stage Migration For Early Hepatocellular Carcinoma and Its Association With Adverse Impact On Outcomes: A Multicenter Study

Background & Aims:The rate of contraindications to percutaneous ablation (PA) for inoperable early HCC, and subsequent outcomes is not well described. We investigated the prevalence and outcomes of inoperable early HCC patients with contraindications to PA, resulting in treatment stage migration (TSM). Methods:BCLC 0/A patients diagnosed between September 2013 and September 2019 across five hospitals were identified. Primary endpoint was proportion of BCLC 0/A HCCs with contraindications to PA. Secondary endpoints included overall survival (OS), local tumour control (LTC) and recurrence-free survival (RFS). The causal effects of PA versus TSM were assessed using a potential outcome means (POM) framework in which the average treatment effects (ATE) of PA were estimated after accounting for potential selection bias and confounding.Results:245 patients with inoperable BCLC 0/A HCC were identified. 140 (57%) had contraindications to PA and received TSM therapy, 105 (43%) received PA. The main contraindication to PA was difficult tumour location (47%). Patients who received TSM therapy had lower median OS (2.1 versus 5.3years), LTC (1.0 versus 4.8years), and RFS (0.8 versus 2.7years); p<0.001 respectively, compared to PA. The ATE for PA versus TSM yielded an additional 1.02years (p=0.048), 2.87years (p<0.001) and 1.77years (p<0.001) for OS, LTC and RFS respectively. 3-year LTC after PA was suboptimal (63%).Conclusions:Our study highlights high rates of contraindication to PA in early HCCs, resulting in TSM and poorer outcomes. The local recurrence rate after PA was also high. Both findings support exploration of alternative ablative options for early HCCs.