Efficacy and safety of anti-PD-1 inhibitor versus anti-PD-L1 inhibitor in first-line treatment of extensive-stage small cell lung cancer: a multicenter retrospective study.

BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice. METHODS: Patients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents. RESULTS: Of the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5-8.2 months) and 17.4 months (95% CI: 15.3-19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79-1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63-1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups. CONCLUSIONS: Anti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated.

Clinical Value Analysis of Serum TK1, SCC-Ag, and MUC-1 in the Diagnosis and Prognosis Evaluation of Cervical Cancer.

Objective: This study aims to analyze the diagnostic and prognostic value of serum thymidine kinase (TK1), squamous cell carcinoma antigen (SCC-Ag), and mucin-1 (MUC-1) in cervical cancer. Methods: This retrospective study included 85 cervical cancer patients as the experimental group treated at our hospital's obstetrics and gynecology department from January 2016 to January 2019. The benign group also consisted of 85 patients with benign lesions treated during the same period, and the comparison group comprised 85 patients with healthy physical examinations at the same time. Results: Serum levels of TK1, SCC-Ag, and MUC-1 were significantly higher in the experimental group than in the benign group and higher in the benign group than in the comparison group (P < .05). Additionally, serum TK1, SCC-Ag, and MUC-1 were higher in the lymph node metastasis group, infiltration depth > 1/2 group, tumor diameter ≥ 4 cm group, and stage III-IV group compared to the non-lymph node metastasis group, infiltration depth ≤ 1/2 group, tumor diameter <4 cm group, and stage I-II group (P < .05). No significant differences in serum TK1, SCC-Ag, and MUC-1 among different pathological types and age groups (P > .05). Moreover, serum TK1, SCC-Ag, and MUC-1 levels were higher in the deceased group compared to the survivor group (P < .05). These markers were negatively correlated with survival time (r value = -0.524, -0.428, -0.516), indicating that as the severity of cervical cancer increased, serum TK1, SCC-Ag, and MUC-1 concentrations also increased. The levels of these markers were significantly higher in deceased patients compared to survivors. Conclusions: Serum levels of TK1, SCC-Ag, and MUC-1 show promise as biomarkers for cervical cancer diagnosis and prognosis. TK1 and SCC-Ag are elevated, while MUC-1 is decreased in cervical cancer patients. Further research is warranted to confirm these findings and explore additional biomarkers.

Honokiol alleviates radiation-induced premature ovarian failure via enhancing Nrf2.

BACKGROUND: The ovary is highly sensitive to radiation, and patients receiving radiotherapy are at significant risk of premature ovarian failure (POF). This study aimed to explore the radioprotective effect of honokiol (HKL) on ionizing radiation (IR)-induced POF. METHODS: Female C57BL/6 mice were administered intraperitoneally with vehicle or HKL once daily for 7 days. On day 7, the mice in the IR and HKL+IR groups were exposed to 3.2 Gy whole-body radiation for one hour after the intraperitoneal injection and sacrificed 12 or 72 h after radiation exposure. The gonadosomatic index (GSI) was calculated. Blood samples were collected for enzyme-linked immunosorbent assay (ELISA). Ovaries were harvested for histological examination, immunohistochemistry, immunofluorescence, TUNEL, western blot, and qPCR. The fertility assessment was evaluated by calculating live offspring number. RESULTS: The optimum dose of HKL against radiation was 10 mg/kg via intraperitoneal injection. POF was induced 72 h after irradiation with significantly downregulated proliferating cell nuclear antigen (PCNA). The numbers of primordial and preantral follicles decreased significantly after irradiation (p < .001), whereas the number of atretic follicles increased (p < .001). The serum levels of estradiol (E2 ) and anti-Müllerian hormone (AMH) decreased to 50% of the control group after irradiation (p < .05). Moreover, the GSI after irradiation was 27% lower than in the control group (p < .05). The number of offspring in the IR group dropped by 50% compared with the control group (p < .05). HKL pretreatment protected the animals' fertility, GSI, PCNA, serum levels of E2 and AMH, and the number of primordial and preantral follicles. Significant upregulation of apoptosis-related proteins such as Pho-P53, Bax, Cyto C, C-caspase-3, C-PARP, and pyroptosis-related proteins such as Pho-NF-κB p65, NLRP3, caspase-1, IL-1ß, and IL-18 was observed after irradiation, while the expression of Bcl-2 decreased. HKL pretreatment prevented these changes. After irradiation, malondialdehyde (MDA), Nrf2, and HO-1 were upregulated. HKL treatment activated the expression of Nrf2 and HO-1 and promoted the nucleus translocation of Nrf2. Furthermore, HKL did not affect ovarian reserves under physiological conditions. CONCLUSIONS: HKL ameliorated IR-induced POF by inhibiting apoptosis and pyroptosis by enhancing Nrf2 expression and translocation.

Efficacy and safety of oral gonadotropin-releasing hormone antagonists in moderate-to-severe endometriosis-associated pain: a systematic review and network meta-analysis.

PURPOSE: The aim of this NMA is to comprehensively analyze evidence of oral GnRH antagonist in the treatment of moderate-to-severe endometriosis-associated pain. METHODS: Literature searching was performed to select eligible studies published prior to April 2022 in PubMed, Cochrane, Embase and Web of Science. Randomized controlled trials involving patients who suffered from moderate-to-severe endometriosis-associated pain and treated with oral nonpeptide GnRH antagonists or placebo were included. RESULTS: Elagolix 400 mg and ASP1707 15 mg were most efficient in reducing pelvic pain, dysmenorrhea and dyspareunia. Relugolix 40 mg was best in reducing the analgesics use. The rates of any TEAEs and TEAEs-related discontinuation were highest in relugolix 40 mg and elagolix 250 mg, respectively, while rates of hot flush and headache were highest in relugolix 40 mg and elagolix 150 mg. Significantly decreased spinal BMD was observed in elagolix 250 mg. CONCLUSION: Oral GnRH antagonists were effective in endometriosis-associated pain in 12w, and most of the efficiency and safety outcomes were expressed in a dose-dependent manner, but linzagolix 75 mg was an exception.

The effects of vasopressin injection technique on ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma: a retrospective cohort study.

OBJECTIVE: To evaluate the effects of vasopressin injection technique (VIT) on ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma. MATERIAL AND METHODS: A total of 122 patients with bilateral ovarian endometrioma undergoing laparoscopic cystectomy were assigned to control or the VIT group. Coagulation-event count and blood loss were recorded. Levels of serum anti-Müllerian hormone (AMH) were assessed at 1 day pre-operation, 1 month, 3 months, and 6 months post-operation. The follicles in the tissue sections were counted, and the maximum thickness of cyst wall was measured. RESULTS: Coagulation-event count and blood loss in the VIT group were statistically less than those in control group (P<0.05). In both groups, AMH levels at pre-operation were the highest among different time-points (P<0.05); a remarkable decrease of AMH level was observed at 1 month post-operation, and the values were the lowest among different time-points (P<0.05). At 3 months post-operation, AMH levels gradually increased to approximately 60% of those at pre-operation (P<0.05); at 6 months post-operation, AMH levels were significantly higher than those at 3 months post-operation in VIT group (P<0.05). AMH levels in VIT group were significantly higher than those in control group at each time-point post-operation (P<0.05). The cyst walls in control group were statistically thicker than those in VIT group (P<0.05). Consistent with results of cyst wall thickness, numbers of total follicle loss, primordial and primary follicles in VIT group were less than those of control group (P<0.05). CONCLUSION: VIT effectively protected ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma.

Real-World Efficacy and Safety of Anlotinib With and Without Immunotherapy in Advanced Non-Small Cell Lung Cancer.

AIMS: Combination of anti-angiogenesis therapy and immunotherapy has showed synergistic effects in non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate the efficacy and safety of anlotinib with and without immunotherapy in NSCLC. METHODS: Pathologically confirmed NSCLC patients (stage IIIB-IV) receiving anlotinib between November 2018 and February 2020 were enrolled for retrospective analysis. The outcomes and safety of overall patients were evaluated, and the efficacies of anlotinib plus immunotherapy and anlotinib alone was compared. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 80 patients (median age: 62 years, range: 29-86 years) were included. Overall median PFS was 4.3 months (95% confidence interval (CI): 2.7-5.9 months). In univariate analysis, patients without EGFR mutation, previous EGFR target therapy, and brain metastasis had significantly longer PFS. Cox regression analysis showed that only brain metastasis was an independent predictor of PFS. The median PFS of patients receiving anlotinib plus immunotherapy was slightly longer than that of patients receiving anlotinib alone (4.2 vs 3.1 months); however, the difference was not statistically significant. A tendency of longer median PFS was observed in patients with adenocarcinoma, EGFR wild type, stage IV, no liver metastasis, former smoker, ≥2 previous treatment lines, no previous VEGF or EGFR target therapies in anlotinib plus immunotherapy group. Treatments with anlotinib alone or anlotinib plus immunotherapy were well tolerable. The most common adverse events were fatigue, decreased hemoglobin count, hypertension, hand-foot syndrome, oral mucositis and hoarseness. CONCLUSION: Anlotinib is well tolerable and effective in advanced NSCLC patients. Brain metastasis is an independent predictor of PFS in NSCLC patients receiving anlotinib. Future prospective studies with larger sample size and extended follow-up are needed to confirm the clinical benefit in NSCLC patients treated with anlotinib combined with immunotherapy.

Response to first-line treatment predicts progression-free survival benefit of small-cell lung cancer patients treated with anlotinib.

BACKGROUND: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment. METHODS: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more. CONCLUSION: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity.

Retroperitoneal ectopic pregnancy: A case report and literature review.

Retroperitoneal ectopic pregnancy (REP) is a rare type of pregnancy with retroperitoneal implantation of the embryo. Herein, we report a case of a 29-year-old female with REP admitted in our department. Moreover, we review the literatures published previously reporting REP with the aim to improve the understanding of diagnosis and treatment of REP.

Post-treatment neutrophil-to-lymphocyte ratio (NLR) predicts response to anti-PD-1/PD-L1 antibody in SCLC patients at early phase.

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) have been identified as predictors of treatment response in a variety of cancers. We conducted a retrospective analysis to investigate the usefulness of NLR, PLR and SII at baseline and at 6 weeks post-treatment as predictors of response to anti-PD-1/PD-L1 antibody treatment in small cell lung cancer (SCLC). Data of 41 SCLC patients receiving immunotherapy as second- or later-line treatment were analyzed. The overall median progression-free survival (PFS) was 5.1 months (95% CI 3.2-6.2). The median PFS was significantly longer in patients with NLR < 5 than in patients with NLR ≥ 5 at 6 weeks post treatment (HR = 0.29, 95%CI 0.09-0.96, P = 0.04). However, median PFS was comparable between patients with NLR < 5 and patients with NLR ≥ 5 at baseline (HR = 0.75, 95% CI 0.24-2.26, P = 0.56). The median PFS was similar between patients with PLR < 169 and those with PLR ≥ 169 at baseline (HR = 0.67, 95% CI 0.25-1.80, P = 0.43) and at 6 weeks post treatment (HR = 0.69, 95% CI 0.25-1.86, P = 0.46). No statistically different PFS was found between patients with SII < 730 and those with SII ≥ 730 at baseline (HR = 0.70, 95% CI 0.26-1.89, P = 0.48) and at 6 weeks post treatment (HR = 0.38, 95% CI 0.013-1.09, P = 0.07). In conclusion, NLR at 6 weeks after start of treatment appears to be a biomarker of response in the early phase in SCLC patients treated with anti-PD-1/PD-L1 antibodies as second- or later-line treatment.

Proteomics study reveals that the dysregulation of focal adhesion and ribosome contribute to early pregnancy loss.

PURPOSE: Early pregnancy loss (EPL) affects 50-70% pregnant women in first trimester. The precise molecular mechanisms underlying EPL are far from being fully understood. Therefore, we aim to identify the molecular signaling pathways relating to EPL. EXPERIMENTAL DESIGN: We performed proteomics and bioinformatics analysis of the placental villi in women who have undergone EPL and in normal pregnant women. The proteomics data were validated by Western blot analysis. RESULTS: We identified a total of 5952 proteins in placental villi, of which 588 proteins were differentially expressed in the EPL women. Bioinformatics analysis revealed that these differentially expressed proteins participated in a variety of signaling pathways, including the focal adhesion pathway and ribosome pathway. Moreover, results of the Western blot confirmed that Desmin, Lamin A/C, MMP-9, and histone H4 were upregulated in EPL and the Lamin C/ Lamin A ratio decreased obviously in EPL. These proteins could be associated with the pathophysiology of EPL. The data have been deposited to the ProteomeXchange with identifier PXD002391. CONCLUSION AND CLINICAL RELEVANCE: Our study demonstrated that the focal adhesion pathway and ribosome pathway are involved in EPL, and these findings might contribute to unveil the pathophysiology of EPL.

Association between matrix metalloproteinase-2 and matrix metalloproteinase-9 polymorphisms and endometriosis: A systematic review and meta-analysis.

Matrix metalloproteinase-2 (MMP-2)-735C/T and MMP-9-1562C/T polymorphisms have been indicated in the predisposition to endometriosis. However, due to the small sample sizes of previous studies, the results remain inconclusive. The present meta-analysis was conducted to detect the association between the two genetic polymorphisms and the risk of endometriosis by pooling all the available data. Electronic databases, including PubMed, Embase, Web of Science and CNKI, were searched comprehensively for studies examining a link between MMP-2 and MMP-9 polymorphisms and endometriosis. The strength of the association was assessed based on the pooled odds ratio with a 95% confidence interval, which was calculated using either the fixed- or random-effect model. Following the inclusion criteria, 6 case-control studies were included. The total number of participants was 2,486 (558 cases and 797 controls concerning the MMP-9-1562C/T polymorphism, and 525 cases and 606 controls concerning the MMP-2-735C/T polymorphism). No significant association was identified between the MMP-2-735C/T or MMP-9-1562C/T polymorphism and endometriosis. In further stratified analysis, no significant association was identified between the MMP-9-1562C/T polymorphism and endometriosis. The present meta-analysis revealed no association between the MMP-2-735C/T and MMP-9-1562C/T polymorphisms and the risk of developing endometriosis. Considering the limitations of the meta-analysis, well-designed studies with larger sample sizes are required.

Proteomic study of different culture medium serum volume fractions on RANKL-dependent RAW264.7 cells differentiating into osteoclasts.

BACKGROUND: Cultivation of osteoclasts is a basic tool for investigating osteolytic bone diseases. Fetal bovine serum (FBS) is the standard supplement used for in vitro cell culture medium. Typically, the serum volume fraction used for osteoclast cultivation is 10%. In this study, we investigated the use of a low serum (1% FBS) model for culturing osteoclasts. RESULTS: To confirm the validity of this model for use in osteoclast research, we compared the capacity for osteoclastogenesis and bone resorption of RANKL-induced RAW 264.7 cells cultured in medium supplemented with 10% FBS and 1% FBS. Osteoclasts were successfully generated in medium supplemented with 1% FBS, and exhibited prolonged longevity and similar bone resorbing ability to those generated in medium supplemented with 10% FBS, although the osteoclasts were smaller in size. Proteomics and bioinformatics analyses were performed to assess the suitability of osteoclasts formed in low serum-containing medium for use in research focusing on osteoclast differentiation and function. Our study demonstrated that a total of 100 proteins were differentially expressed in cells cultured in medium containing 1% FBS, of which 29 proteins were upregulated, and 71 proteins were downregulated. Bioinformatics analysis showed that the electron transport chain and oxidative phosphorylation pathways were downregulated obviously; however, the osteoclast signaling pathway was unaffected. The data have been deposited to the ProteomeXchange with identifier PXD001935. CONCLUSION: Our study provides clear evidence of the validity of the low serum model for use in studying RANKL-dependent osteoclasts differentiation and bone resorption with the advantage of prolonged survival time.

Recombinant receptor activator of nuclear factor κB exhibits more marked inhibitory effects on osteoclasts compared with recombinant osteoprotegerin in vitro and in vivo.

The aim of the present study was to compare the osteoclast-inhibiting ability of recombinant osteoprotegerin (OPG) protein (rhOPG-Fc) and recombinant receptor activator of nuclear factor κB (rhRANK) in vitro and in vivo. Osteoclasts were cultured with either rhOPG-Fc or rhRANK for 9 days. The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and resorption pits in bone slices were then counted. In the in vivo investigation, female mice were bilaterally ovariectomized (OVX) and intraperitoneally injected with 3 mg/kg rhOPG-Fc or rhRANK for 12 weeks, respectively. Bone metabolism, bone mineral density and microstructure changes were then evaluated. The number of TRAP-positive cells and bone resorption pits decreased significantly following culture with either rhOPG-Fc or rhRANK, and this was more marked following culture with rhRANK compared with rhOPG-Fc. The levels of calcium and alkaline phosphatase in the serum were similar pre-OVX and after 12 weeks of treatment, while the levels of phosphorus in the serum were higher following treatment with rhRANK compared with rhOPG. The bone mineral density (BMD) of the whole body, femoral neck and L4 lumbar vertebral body in the mice treated with either rhOPG-Fc or rhRANK increased markedly. In addition, the mice treated with rhRANK exhibited significantly higher BMD in the femoral neck and lumbar vertebral body compared with those treated with rhOPG-Fc. Microcomputed tomography analysis demonstrated that the mice treated with rhRANK exhibited an increased bone volume and structure model index, and decreased trabecular spacing compared with those treated with rhOPG-Fc. rhRANK increased the inhibition of osteoclast differentiation and bone resorption, and rescued OVX-induced osteoporosis more effectively compared with rhOPG-Fc.

Association between calcitonin receptor AluI gene polymorphism and bone mineral density: A meta-analysis.

The association between calcitonin receptor (CTR) AluI gene polymorphism and bone mineral density (BMD) remains unclear. In order to elucidate this association, a meta-analysis was performed to provide a comprehensive assessment of the studies carried out to date. PubMed, the Cochrane Library, Web of Science and the China National Knowledge Infrastructure database were searched to identify eligible studies. The data were extracted independently by two authors using a standard form, the studies were meta-analyzed and disagreements were resolved through discussion. Fifteen eligible studies involving 3,093 females and 654 males were included for analysis. Overall, the male subjects with the CC genotype had non-statistically different lumbar spine and femoral neck BMD compared to subjects with the CT/TT and CT genotypes. The BMD of female subjects with the CC genotype was similar to that of patients with the CT or CT/TT genotypes. In Chinese male subjects, those with the CC genotype had almost the same BMD as those with the CT and CT/TT genotypes. The results also demonstrated that Chinese female subjects with the CC genotype had similar BMD at the lumbar spine and femoral neck to subjects with the CT and CT/TT genotypes. Furthermore, Southern Chinese subjects with CC genotypes did not have a different BMD at the lumbar spine and femoral neck compared to patients with CT and CT/TT genotypes. Notably, Northern Chinese subjects with the CC genotype had a higher BMD at the lumbar spine compared to subjects with CT/TT genotypes and a lower BMD at the femoral neck compared to subjects with CT/TT genotypes. Among Northern Chinese females, those with CC genotypes also had a higher BMD at the lumbar spine compared to those with CT/TT genotypes, while no difference was observed in the BMD of the lumbar spine and femoral neck between patients with CC and CT genotypes. In Southern Chinese females, no significant difference was found in the BMD at the lumbar spine and femoral neck between those with CC and those with CT or CT/TT genotypes. In conclusion, the AluI gene polymorphism may have an association with BMD in Northern Chinese subjects and the CC genotype may have a protective effect on spine BMD; however, the CC genotype may be a risk factor for low femoral neck BMD in Northern Chinese subjects. Further studies are required to fully investigate the potential association between AluI gene polymorphism and BMD.