A new treatment approach of toripalimab in combination with concurrent platinum-based chemoradiotherapy for locally advanced cervical cancer: A phase II clinical trial.

This study investigated the efficacy and safety of toripalimab in combination with concurrent platinum-based chemoradiation in patients with untreated locally advanced cervical cancer. Eligible patients received toripalimab 240 mg once every 3 weeks in combination with concurrent platinum-based chemoradiotherapy, followed by the maintenance of toripalimab once every 6 weeks up to 1 year. The primary endpoint was objective response rate (ORR). Secondary endpoints included 2-year and 3-year progression-free survival (PFS) rates, 3-year overall survival (OS) rate, and safety. Biomarker analysis of PD-L1 expression and genomic mutational analysis by next-generation sequencing were conducted, as well as PD-L1 expression on tumor biopsies. A total of 82 patients were enrolled. The median follow-up was 21 months (range, 5.2-44.5 months). The ORR and disease control rate were both 87.8% among the 82 patients. Median PFS and OS were not reached. A trend toward longer PFS was observed in the populations with a PD-L1 combined positive score ≥10, low tumor mutation burden and loss of heterozygosity in human leukocyte antigen (HLA LOH) detected populations. A total of 37 patients experienced treatment-related adverse events, of which 17 (20.7%) patients experienced grade 3 or higher adverse events. Collectively, toripalimab plus concurrent platinum-based chemoradiotherapy showed promising antitumor efficacy with acceptable safety profiles in patients with untreated locally advanced cervical cancer.

Toripalimab combined with concurrent platinum-based Chemoradiotherapy in patients with locally advanced cervical Cancer: an open-label, single-arm, phase II trial.

BACKGROUND: Concurrent chemoradiotherapy is currently the standard of care for patients with locally advanced cervical cancer. However, even with the application of modern radiotherapy techniques, a considerable number of patients still develop distant metastases. PD-L1 inhibitors show good efficacy in cervical cancer. This single-arm phase II study aims to explore the efficacy and tolerability of combining PD-L1 inhibitor with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. METHODS/DESIGN: The primary endpoint of the study was the objective response rate assessed according to RECIST v1.1 criteria. The inclusion criteria were previously untreated patients aged 18-75 years with stage III-IVA (FIGO 2018 staging system) locally advanced cervical cancer. During concurrent chemoradiotherapy and consolidation chemotherapy, the enrolled patients will receive toripalimab (240 mg) every 3 weeks. After consolidation chemotherapy, the enrolled patients will be treated with toripalimab (240 mg) once every 6 weeks until the whole treatment cycle reaches 1 year. Intensity modulated radiotherapy was used for external beam radiation, and high-dose rate brachytherapy was delivered under image-guidance. Weekly DDP (40 mg/m2) was given concurrently with radiotherapy while 6 cycles of consolidated chemotherapy (paclitaxel plus DDP) were given after radiotherapy every three weeks. Secondary objectives included safety and tolerability, toxicity profile, progression-free survival, and overall survival. DISCUSSION: PD-L1 inhibitor has shown good efficacy in recurrent/metastatic cervical cancer. However, there is still a lack of evidence about its combination with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. The purpose of this study is to explore the efficacy and tolerance of this combination therapy, so as to lay the foundation for the future phase III randomized study. TRIAL REGISTRATION:  clinicaltrials.gov NCT05084677 . Retrospectively registered on Octorber 07, 2021.

Metal- and radical-free aerobic oxidation of heteroaromatic methanes: an efficient synthesis of heteroaromatic aldehydes.

A metal-free and radical-free synthesis of heteroaromatic aldehydes was developed through aerobic oxidation of methyl groups in an I2/DMSO/O2 catalytic system. Under the reaction conditions, various functional groups such as methoxy, aldehyde, ester, nitro, amide, and halo (F, Cl, Br) groups were well tolerated. The bioactive compounds like chlorchinaldin derivative and papaverine were also oxidized to the corresponding aldehydes and ketones. This reaction provided an efficient method for preparing the valuable heteroaromatic aldehydes.

Atomic-Level Insight into Optimizing the Hydrogen Evolution Pathway over a Co1 -N4 Single-Site Photocatalyst.

Knowledge of the photocatalytic H2 evolution mechanism is of great importance for designing active catalysts toward a sustainable energy supply. An atomic-level insight, design, and fabrication of single-site Co1 -N4 composite as a prototypical photocatalyst for efficient H2 production is reported. Correlated atomic characterizations verify that atomically dispersed Co atoms are successfully grafted by covalently forming a Co1 -N4 structure on g-C3 N4 nanosheets by atomic layer deposition. Different from the conventional homolytic or heterolytic pathway, theoretical investigations reveal that the coordinated donor nitrogen increases the electron density and lowers the formation barrier of key Co hydride intermediate, thereby accelerating H-H coupling to facilitate H2 generation. As a result, the composite photocatalyst exhibits a robust H2 production activity up to 10.8 µmol h-1 , 11 times higher than that of pristine counterpart.

Single-Site Active Cobalt-Based Photocatalyst with a Long Carrier Lifetime for Spontaneous Overall Water Splitting.

An active and stable photocatalyst to directly split water is desirable for solar-energy conversion. However, it is difficult to accomplish overall water splitting without sacrificial electron donors. Herein, we demonstrate a strategy via constructing a single site to simultaneously promote charge separation and catalytic activity for robust overall water splitting. A single Co1 -P4 site confined on g-C3 N4 nanosheets was prepared by a facile phosphidation method, and identified by electron microscopy and X-ray absorption spectroscopy. This coordinatively unsaturated Co site can effectively suppress charge recombination and prolong carrier lifetime by about 20 times relative to pristine g-C3 N4 , and boost water molecular adsorption and activation for oxygen evolution. This single-site photocatalyst exhibits steady and high water splitting activity with H2 evolution rate up to 410.3 µmol h-1 g-1 , and quantum efficiency as high as 2.2 % at 500 nm.

Development and validation of an automated Tomotherapy planning method for cervical cancer.

PURPOSE: This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness. MATERIALS AND METHODS: The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value < 0.05 indicating statistical significance. RESULTS: A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ < 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ < 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min. CONCLUSION: We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.

Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer.

BACKGROUND: As an unconventional subpopulation of T lymphocytes, γδ T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that γδ T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). γδ T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of γδ T cells in cervical cancer warrants further investigation. METHODS: We employed a multiomics strategy that integrated abundant data from single-cell and bulk transcriptome sequencing, whole exome sequencing, genotyping array, immunohistochemistry, and MRI. RESULTS: Heterogeneity was observed in the level of γδ T-cell infiltration in cervical cancer tissues, mainly associated with the tumor somatic mutational landscape. Definitely, γδ T cells play a beneficial role in the prognosis of patients with cervical cancer. First, γδ T cells exert direct cytotoxic effects in the tumor microenvironment of cervical cancer through the dynamic evolution of cellular states at both poles. Second, higher levels of γδ T-cell infiltration also shape the microenvironment of immune activation with cancer-suppressive properties. We found that these intricate features can be observed by MRI-based radiomics models to non-invasively assess γδ T-cell proportions in tumor tissues in patients. Importantly, patients with high infiltration levels of γδ T cells may be more amenable to immunotherapies including immune checkpoint inhibitors and autologous tumor-infiltrating lymphocyte therapies, than to chemoradiotherapy. CONCLUSIONS: γδ T cells play a beneficial role in antitumor immunity in cervical cancer. The abundance of γδ T cells in cervical cancerous tissue is associated with higher response rates to immunotherapy.

The relationship between the radiation dose of pelvic-bone marrow and lymphocytic toxicity in concurrent chemoradiotherapy for cervical cancer.

OBJECTIVE: The purpose of this study is to verify the correlation between medium and low radiation doses of the pelvic-bone marrow and the incidence of lymphocytic toxicity during concurrent chemoradiotherapy for cervical cancer. MATERIALS AND METHODS: This research included 117 cervical cancer patients, who received concurrent chemoradiotherapy. Radiotherapy included external-beam radiation therapy and brachytherapy. The dosimetry parameters include the Volume receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), 50 Gy (V50), and the mean dose (D mean) of the bone marrow. Lymphocytic toxicity was calculated from lowest lymphocytic count after two cycles of concurrent chemotherapy. RESULTS: During concurrent chemoradiotherapy, the incidence of lymphocytic toxicity is 94.88%. The incidence of grade 3-4 toxicity is 68.38%. Multivariate analysis findings show that the dosimetry parameters V5, V10, V20, and V30 are significantly correlated with lymphocytic toxicity. The patients are divided into small-volume subgroups and large-volume subgroups based on the cutoff values. The relative risk of both grade 1-4 and grade 3-4 lymphocytic toxicity is significantly lower in the small-volume subgroups than in the large-volume subgroups (P < 0.05). Kaplan-Meier analysis shows that the incidence of both grade 1-4 and grade 3-4 lymphocytic toxicity of the small-volume subgroups is significantly lower than that of the large-volume subgroups (P < 0.05). CONCLUSION: There is a significant correlation between a medium and low dose of pelvic-bone-marrow radiation and incidence of lymphocytic toxicity. Reducing the volume of medium and low radiation doses could effectively reduce incidence of lymphocytic toxicity.

Evaluation of mechanical accuracy for couch-based tracking system (CBTS).

This study evaluated the mechanical accuracy of an in-house-developed couch-based tracking system (CBTS) according to respiration data. The overall delay time of the CBTS was calculated, and the accuracy, reproducibility, and loading effect of the CBTS were evaluated according to the sinusoidal waveform and various respiratory motion data of real patients with and without a volunteer weighing 75kg. The root mean square (rms) error of the accuracy, the reproducibility, and the sagging measurements were calculated for the three axes (X, Y, and Z directions) of the CBTS. The overall delay time of the CBTS was 0.251 sec. The accuracy and reproducibility in the Z direction in real patient data were poor, as indicated by high rms errors. The results of the loading effect were within 1.0 mm in all directions. This novel CBTS has the potential for clinical application for tumor tracking in radiation therapy.

Timing of thoracic radiotherapy in the treatment of extensive-stage small-cell lung cancer: important or not?

BACKGROUND: This study evaluated the prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC) that may be associated with timing of thoracic radiotherapy (TRT). METHODS: ES-SCLC patients (n = 232) without progression were retrospectively analyzed after first-line induction chemotherapy. Patients in the TRT group were stratified as early-TRT (ERT; ≤3 cycles of induction chemotherapy received prior to TRT, n = 65) or late-TRT (LRT; >3 cycles, n = 122). To avoid selection bias, we conducted Propensity Score Matching (PSM) for patients. Overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRRFS) were assessed and compared. RESULTS: Overall, the median survival time, PFS, and LRRFS were 13.2, 8.7, and 14.6 months, respectively. After matching by PSM, there were 45 patients total in the TRT/non-TRT groups, and 56 patients total in the ERT/LRT groups. OS, PFS, and LRRFS were significantly longer in the TRT group than the non-TRT group (P < 0.001, all). However, between the ERT and LRT groups these survival parameters were similar (P > 0.05, all). CONCLUSION: For ES-SCLC patients without progression, the addition of TRT after first-line chemotherapy benefited survival greatly. Early TRT showed no significant benefit over late TRT.