Efficacy and optimal combination timing of chemotherapy combined with PD-1 inhibitor in advanced cervical cancer: a multicenter retrospective cohort study.

Background: This study aimed to investigate the efficacy and safety of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of advanced cervical cancer and the effect of optimal combination timing on prognosis. Methods: From March 2020 to December 2021, the clinical data of 116 patients with advanced cervical cancer who received PD-1 inhibitors combined with chemotherapy were collected. The clinical characteristics and adverse events of the patients were recorded until the cut-off date of follow-up. The primary endpoints were progression-free survival (PFS), the objective response rate (ORR), and safety; the secondary endpoints were the disease-control rate (DCR) and overall survival (OS). Multivariate Cox proportional hazards regression was used to analyze the prognostic factors affecting the PFS of patients and to assess the effect of the timing of combination therapies on PFS. Results: In total, 85 patients from 4 study centers were included in this study. The median PFS was 10.3 months [95% confidence interval (CI): 9.47-11.13 months], the ORR was 44.7%, the DCR was 75.3%, and the median OS was not reached. The multivariate Cox proportional hazards regression analysis showed that the early combination of chemotherapy with a PD-1 inhibitor provided better PFS than the late combination [hazard ratio (HR) 0.40, 95% CI: 0.24-0.67, P=0.001]. Lymph node metastasis (HR 2.04, 95% CI: 1.24-3.38, P=0.005), and previous treatment (HR 1.79, 95% CI: 1.09-3.00, P=0.023) were also independent risk factors for PFS. During the treatment and follow-up periods, the overall incidence of adverse events in this study was 56.5%, and that of grade ≥3 adverse events was 12.9%. Thrombocytopenia, neutropenia, anemia, and hypothyroidism were the main treatment-related adverse events, all of which were tolerated, and no serious adverse events leading to death were observed. There were no treatment-related deaths. Conclusions: PD-1 inhibitors combined with chemotherapy have good efficacy and controllable safety in patients with advanced cervical cancer. The early combination of PD-1 inhibitors and chemotherapy may provide better survival benefits than the late combination for patients.

[Expression and significance of P16INK4A and PTEN in high-risk human papillomavirus-related cervical cancer].

BACKGROUND & OBJECTIVE: High-risk human papillomavirus (HR-HPV) is the most important etiologic factor for cervical cancer. Recent studies have revealed that abnormal expression of tumor suppressor gene P16INK4A is closely associated with HR-HPV infection during carcinogenesis of cervical epithelium. Tumor suppressor gene PTEN is also involved in cervical tumorigenesis. This study was to investigate the correlations of HR-HPV infection to P16INK4A and PTEN expression and its clinical significance in the carcinogenesis of cervical epithelium. METHODS: The expression of P16INK4A and PTEN in 30 specimens of normal cervical tissues, 11 specimens of cancer in situ (CIS), and 24 specimens of invasive cervical carcinoma (ICC) was detected by SP immunohistochemistry; 13 types of HR-HPV DNA in these cases were detected by Hybrid Capture 2 (HC-2) assay. RESULTS: The positive rates of HR-HPV and P16INK4A were significantly higher in ICC and CIS than in normal tissues (91.7% and 90.9% vs. 30.0%, P<0.001; 87.5% and 81.8% vs. 6.7%, P<0.001). Both HR-HPV DNA and P16INK4A overexpression (moderate or strong expression) were observed simultaneously in 21 specimens of ICC and 9 specimens of CIS; they were simultaneously negative in 20 specimens of normal cervical tissues and 1 specimen of CIS and 2 specimens of ICC. Overexpression of P16INK4A was positively correlated to HR-HPV infection in cervical cancer (rs = 0.690, P<0.001). PTEN was moderately or strongly expressed in 26 specimens of normal cervical tissues. The positive rate of PTEN was significantly lower in ICC and CIS than in normal cervical tissues (37.5% and 36.4% vs. 83.3%, P<0.01). No obvious relationship between PTEN and HR-HPV was found (rs = -0.174, P = 0.167). CONCLUSIONS: P16INK4A is overexpressed in HR-HPV-infected cervical cancer, but its tumor suppressor action might be inhibited. In contrast, the functional down-regulation of PTEN contributes to cervical tumorigenesis through HR-HPV-independent mechanism.

Theoretical analyses of thermal stress of blood vessel during cryopreservation.

The infinite long hollow cylinder was selected as the model for studying the thermal stress inside the vascular wall during the common cryopreservation process (i.e. cooling-holding at a certain temperature-warming-holding at a second temperature). Transient distributions of temperature and stress were obtained; and effects of cooling rates, warming rates, the holding temperatures on this two distributions were analyzed. Coupled with the experimental results of other researchers, our theoretical predictions indicated that the appearance of the axial compressive stress during the initial period of cooling process was not the governing role that may cause the circumferential crack of the inner and outer vascular wall. Instead, it was the axial tensile stress during the initial period of the warming process that may cause the cracks. Furthermore, the stress history in the multi-steps warming methods was studied. Contrary to the common opinion, the results revealed that the multi-steps method could not decrease the maximal stress while it can change the temperature range containing the maximal stress from low temperature stage to relatively high temperature stage. As the flexibility of the blood vessel was partially recovered in the relative high temperature stage, it can bear the maximal stress that it cannot bear when still left in the low temperature stage, and the intrinsic feature of multi-steps warming method was revealed by this study. This paper provides a theoretical supplement to the study of Pegg et al. (1997) and Buján et al. (2001) published in the journal of Cryobiology.