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.

[Characteristics of membrane fouling and its control in membrane sequencing batch reactor process].

Characteristics of membrane fouling and its control were investigated using synthetic wastewater as feed in an anaerobic/aerobic membrane sequencing batch reactor (MSBR) for 300 days operational period. The experimental results showed that the sludge was in flocculent form, and the range of SVI was 64.6-110.6 mL x g(-1) during the initial 75 days operation. Membrane fouling occurred in a quick exponential growth, and the average growth rate of TMP was 0.309 kPa x d(-1). Membrane resistance was in the range of 0.393 x 10(11) - 1.298 x 10(11) m(-1) x d(-1) and specific membrane flux decreased from 4.4 L x (m2 x h x kPa) (-1) to 0.52 L x (m2 x h x kPa)(-1). The critical membrane flux was 20 L x (m2 x h)(-1) at 75th day. In 75-120 d operation, MSBR condition was regulated, and aerobic granular sludge in reactor appeared. SVI decreased steadily, and finally maintained approximately 40 mL x g(-1) from 170th day on. The sludge particle grew much gradually, and size distribution was mainly in diameter 500-1000 microm at 220th day. Membrane fouling developed very slowly. The average accumulating rate of TMP was only 0.062 kPa x d(-1) membrane resistance varied from 0.291 x 10(11) m(-1) x d(-1) to 0.404 x 10(11) m(-1) x d(-1), specific membrane flux decreased from 4.4 L x (m2 x h x kPa)(-1) to 1.4 L x (m2 x h x kPa) (-1) and critical membrane flux was 40 L x (m2 x h)(-1) at 220th day. These data clearly demonstrated that the formation of aerobic granular sludge was beneficial to cease the growth rate of membrane fouling. Specific membrane flux was the biggest at aeration strength of 100 m3 x (m2 x h)(-1) while membrane fouling rate was the lowest at aeration strength of 69 m3 x (m2 x h)(-1).

Calcium spatial distribution in aerobic granules and its effects on granule structure, strength and bioactivity.

Calcium-rich aerobic granules were cultivated after 3-month operation. The chemical form and spatial distribution of calcium in the granules and their physicochemical characteristics were explored. Examination with a scanning electron microscope combined energy dispersive X-ray detector (SEM-EDX) shows that Ca was mainly accumulated in the core of the granules. CaCO(3) was found to be the main calcium precipitate in the granules. The fluorescent in situ hybridization (FISH) analysis shows that the cells were crowded in the outer layer and gathered in clusters. Compared with the granules without Ca accumulation, the Ca-rich granules had more rigid structure and a higher strength. However, their specific oxygen uptake rate (SOUR) reduced after the Ca accumulation inside them. Comparison between the SOUR values of the granules with and without Ca accumulation suggests that Ca accumulated in the aerobic granules might have a negative effect on their bioactivity.

[Investigation of nitrogen removal performance with membrane sequencing batch reactor process].

Nitrogen removal performance was investigated using synthetic wastewater as feed without sludge discharge in an anaerobic/aerobic membrane sequencing batch reactor (MSBR) during 300 days operation. The results showed that MLSS in reactor was retained up to about 18 g x L(-1), sludge size larger than 100 microm was 96%, and aerobic granular sludge was developed. The bacterial community observation of AOB and NOB by FISH-CLSM for sludge revealed that they were existed in larger numbers. When influent NH(4+) -N concentration was about 50 mg x L(-1), effluent NH(4+) -N concentration was lower than to 1 mg x L(-1), and nitrification could complete in 180-210 min. There was a good correlation between nitrification reaction and aeration strength. When aeration strength was 100 m3 x (m2 x h)(-1), NH(4+) -N degradation rate 24.25 mg x (L x h)(-1), and nitrification reaction in MSBR was stable. The main factor determining nitrogen removal of the system was denitrification rate, which was optimal at aeration 69 m3 x (m2 x h)(-1), when the nitrification rate of NO(3-) -N 10.98 mg x (L x h)(-1), effluent NO(3-) -N 4.4 mg x L(-1), and NO(3-) -N in the beginning of anaerobic phase 3.5 mg x L(-1). The denitrification performance was not benefited by excessive aeration or deficient aeration. Bigger volumetric exchange ratio was helpful for nitrogen removal and the system treatment capacity. The C/N ratio 2 was suitable to good denitrification rate, while there was a NO(2-) -N accumulation if C/N ratio was larger than 2.