Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Incidence and risk factors associated with the development of epilepsy in patients with intracranial alveolar echinococcosis.

Parasitic infection remains a critical health problem in Ganzi Tibetan Autonomous Prefecture of China. The association of epilepsy and intracranial alveolar echinococcosis (IAE) is still largely unclear. This study primarily aimed to assess both the incidence and possible risk factors of epilepsy in patients with IAE. According to the occurrence of seizures, patients were separated into two different groups consisting of patients with epilepsy and those without epilepsy. Univariate and multivariate logistic regression analysis was used to identify the potential risk factors associated with the development of epilepsy in patients with IAE. A total of 97 patients (42 women, 55 men; age 19-76 years) were enrolled. Epilepsy was observed in almost 20 % of patients with IAE. The use of anti-seizure medications was not standardized, as 83.3 % of female patients of childbearing age used sodium valproate. It was observed that cortical lesions (hazard ratio (HR) = 29.740, P = 0.006) were significantly associated with development of epilepsy. In addition, epilepsy had no significant effect on the overall survival rate of patients with IAE.

Linear and Core-Crosslinked Glycopolymer-Gadolinium Conjugates: Preparation and Their Behaviors as Nanoscale Magnetic Resonance Imaging Contrast Agents.

In this study, a linear glycopolymer-gadolinium conjugate (pGAEMA-DOTA-Gd) was prepared via the reversible addition fragmentation chain transfer (RAFT) polymerization. In addition, a crosslinked polymer-gadolinium conjugate (Crosslinked pGAEMA-DOTA-Gd) was prepared via a two-step RAFT polymerization approach, and its core was composed of the biodegradable oligopeptide GFLG. The features of the two glycopolymer-gadolinium conjugates as highly efficient and safe nanoscale contrast agents were discussed. These two glycopolymer-DOTA-Gd conjugates have aqueous dynamic particle sizes of 4.8 nm and 21.3 nm with neutral charges. Longitudinal relaxivity (r1) of these two glycopolymer-gadolinium conjugates were three to four times higher than that of clinical agent DTPA-Gd. Animal studies showed that pGAEMA-DOTA-Gd and Crosslinked pGAEMA-DOTA-Gd demonstrated higher signal intensity and the relative change in T1 value (ΔT1) in mouse liver and kidney, and prolonged blood circulation time compared to DTPA-Gd. Notably, the performance of the core-crosslinked glycopolymer conjugate was better than that of the linear polymer. Inductively coupled plasma mass spectrometry (ICP-MS) results showed that polymeric contrast agents, especially the crosslinked one, showed higher aggregation in mouse liver and kidney, and were mainly excreted through renal routes eventually. In vitro and in vivo toxicity studies in healthy mice including cytotoxicity, blood compatibility and systemic toxicity indicated the absence of significant toxicity. Therefore, the prepared glycopolymer-DOTA-Gd conjugates may have significant potential as highly efficient and safe nanoscale MRI contrast agents.