Journal of the Chinese Medical Association

Programmed death-ligand 1 upregulation is associated with poor prognosis in patients with epithelial ovarian cancer

Background: The clinical significance of programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC), particularly its association with platinum resistance (PR) and prognosis, remains unclear. This study aimed to evaluate the relationship between PD-L1 expression and PR in EOC and investigate cisplatin-induced PD-L1 modulation using in vitro and in vivo models. Methods: We retrospectively analyzed 189 patients with EOC, treated between 2014 and 2020. Tumor PD-L1 expression was assessed by immunohistochemistry (IHC) using the combined positive score (CPS). Serum PD-L1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Cisplatin-induced PD-L1 regulation was examined in paired platinum-sensitive (PS: A2780 and ES2) and PR (A2780R and ES2R) cell lines and xenograft models. Results: High tumor PD-L1 expression (CPS ≥10) was more frequent in PR (38.5%) than in PS patients (19.0%, p < 0.01), and was associated with higher recurrence rates ( p < 0.001) and shorter overall survival ( p < 0.001). Serum PD-L1 concentrations were significantly elevated in patients with endometrioid and clear cell histologies compared with those in the control group ( p < 0.05). In vitro, PD-L1 expression was upregulated in PR cell lines compared with parental PS cell lines and was further increased following cisplatin exposure in a dose- and time-dependent manner. Xenograft models confirmed that cisplatin induces PD-L1 upregulation in both tumor tissue and serum, with more pronounced effects observed in PR tumors. Conclusion: PD-L1 upregulation (CPS ≥10) is associated with PR, disease recurrence, and poor prognosis in EOC. Endometrioid and clear cell histologic subtypes demonstrated higher baseline PD-L1 expression in our cohort. Cisplatin-induced PD-L1 upregulation represents a tumor-intrinsic response, particularly in PR tumor cells, highlighting PD-L1 as a histology-specific marker of poor prognosis and a potential therapeutic target in platinum-resistant EOC.

Immunology and ovarian cancers

The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery and multiagent chemotherapy with/without adding targeted therapy. After treatment, response rate is high and nearly all patients can achieve complete remission, even though they are advanced diseases; however, the majority of patients will relapse and subsequently die of diseases within several years after initial treatment. When treatment options are limited, there is the urgent need for new novel therapeutic approaches for precise cancer control. The development of chemoresistance and evading of the anticancer immune response may be one of the important causes contributing to the therapeutic failure, and therefore, it represents a paradigm shift in cancer research. An individual’s immune response and interaction with EOC cells might be one of the key factors for cancer treatment. There are many interventions, including targeting certain type immunogenic EOC-associated antigens, immune checkpoint blockade, and adoptive cellular therapy, which present a profound opportunity to revolutionize EOC treatment. This review will encompass the interaction between EOC and immune system and highlight recent data regarding the research of immunotherapy in EOC.

Aberrant sialylation in ovarian cancers

Sialylation (the covalent addition of sialic acid to the terminal end of glycoproteins or glycans), tightly regulated cell- and microenvironment-specific process and orchestrated by sialyltransferases and sialidases (neuraminidases) family, is one of the posttranslational modifications, which plays an important biological role in the maintenance of normal physiology and involves many pathological dysfunctions. Glycans have roles in all the cancer hallmarks, referring to capabilities acquired during all steps of cancer development to initiate malignant transformation (a driver of a malignant genotype), enable cancer cells to survive, proliferate, and metastasize (a consequence of a malignant phenotype), which includes sustaining proliferative signaling, evading growth suppressor, resisting cell apoptosis, enabling replicative immortality, inducing angiogenesis, reprogramming of energy metabolism, evading tumor destruction, accumulating inflammatory microenvironment, and activating invasion and accelerating metastases. Regarding the important role of altered sialylation of cancers, further knowledge about the initiation and the consequences of altered sialylation pattern in tumor cells is needed, because all may offer a better chance for developing novel therapeutic strategy. In this review, we would like to update alteration of sialylation in ovarian cancers.

Increased incidence of neurogenic bladder after radical hysterectomy for cervical cancer: A nationwide population-based cohort study

Background: The effect of radical hysterectomy for patients with cervical cancer on voiding function remains controversial. The purpose of this study was to examine the association between radical hysterectomy for patients with cervical cancer and the odds of developing neurogenic bladder by using data from the National Health Insurance Research Database (NHIRD) in Taiwan. Methods: We identified 17 936 patients who underwent radical hysterectomy for cervical cancer between 2000 and 2013 among inpatients registered in the Longitudinal Health Insurance Database in Taiwan. Of the patients, those diagnosed as having cervical cancer without radical hysterectomy were selected and compared as a matched control group. Patients diagnosed as having cervical cancer before the index date, those with neurogenic bladder dysfunction before tracking, and those aged <20 years were excluded. The hazard ratios (HRs) of neurogenic bladder and other variants of interest were further calculated using a multivariate Cox regression analysis. The cutoff p value of <0.05 was regarded as statistically significant. Results: The adjusted HR (aHR) of subsequent neurogenic bladder was higher in the hysterectomy group (aHR = 1.205; 95% CI, 1.086-1.440; p = 0.029) than in the control group during the follow-up period. As to the age subgroups, the patients aged 20 to 44 years (aHR = 3.321, p = 0.001) had a significantly increased risk of developing neurogenic bladder after radical hysterectomy as compared with those aged 45 to 64 years (aHR = 1.193, p = 0.012). Conclusion: Patients with cervical cancer undergoing radical hysterectomy have an increased risk of neurogenic bladder, which may result from nerve denervation caused by the operation. These patients should be informed of the potential risk of voiding dysfunction during discussion of the subsequent management for cervical cancer.

The relationship between serum CA-125 level and recurrence in surgical stage I endometrial cancer patients

Background: The majority of patients diagnosed with early stage endometrial cancer have a favorable prognosis; however, approximately 10% to 15% experience a recurrence. Therefore, the aim of the present study was to evaluate whether postoperative carbohydrate antigen 125 (CA-125) levels could be used to predict recurrence and recurrence-free survival (RFS) in patients with surgical stage I endometrial cancer. Methods: We enrolled a total of 518 patients with stage I endometrial cancer who underwent surgical treatment between January 2010 and March 2019. Serum CA-125 levels were measured prior to surgery, as well as 6 to 12 months after surgery. Subsequently, the correlations between the CA-125 levels, cancer recurrence, and RFS were analyzed. Results: Although the preoperative CA-125 level was not associated with the risk of cancer recurrence, the postoperative CA-125 level was found to be the only independent predictor of recurrence in both univariate and multivariate analyses. Additionally, we found that a postoperative CA-125 cutoff value of 13.75 U/mL yielded the best sensitivity and specificity for predicting cancer recurrence. Patients with a postoperative CA-125 level ≥13.75 U/mL, and those with a level <13.75 U/mL, had a median time to recurrence and a 5-year RFS rate of 35.5 vs 50.5 months and 84.7 vs 94.4%, respectively. Additionally, postoperative CA-125 levels were not found to be correlated with preoperative levels. Conclusion: In patients with stage I endometrial cancer, a postoperative CA-125 level ≥13.75 U/mL was found to be significantly correlated with a higher recurrence rate, as well as a shorter RFS. Therefore, obtaining a follow-up CA-125 level within 6 to 12 months after staging surgery may be a promising noninvasive biomarker for predicting recurrence.

Minimally invasive approach is preferred for clinical stage 1 endometrioid-type endometrial cancer

CA 125 for surgico-pathological stage 1 endometrial cancer

Long-term outcome of minimally invasive staging surgery for clinical stage I endometrial cancer: A single institute experience in Taiwan

Background: Endometrial cancer is the most common gynecological cancer in developed countries. With recent advances in equipment and knowledge, minimally invasive surgery (MIS) is widely accepted for the treatment of endometrial cancer. This study had the largest number of cases to date in Taiwan, comparing outcomes between MIS and laparotomy staging surgery using real-world data with long-term follow-up. Methods: We retrospectively reviewed patients with clinical stage 1 endometrial cancer from 2009 to 2020 in our institute. All patients underwent comprehensive surgical staging procedures by MIS or laparotomy. The safety, morbidity, progression-free survival (PFS), and overall survival (OS) rates of the two groups were compared. Clinical and pathologic factors were compared with Chi-square and Fisher Exact test. PFS and OS were estimated by the Kaplan-Meier method. Differences between survival curves were analyzed using the log-rank test. A p value of <0.05 was considered statistically significant. Using Cox proportional hazards models, all factors found to be significantly associated with risk of recurrence on univariate analyses were then assessed together through multivariable models, resulting in a final oncologic outcome between MIS and laparotomy. Results: A total of 665 cases (412 cases in MIS group and 253 cases in laparotomy group) were enrolled for data analysis. Median operation time was shorter in MIS group (244 and 265 minutes, p < 0.001). Median blood loss was also less (75 and 430 mL, p < 0.001). Median postoperative hospitalization duration was longer in the laparotomy group (2 and 7 days, p = 0.001). After adjusting presurgery risk factors, the PFS and OS were no significant difference in MIS and laparotomy groups. Conclusion: Using real-world data with long-term follow-up, we could confirm excellent PFS and OS in selective patients with clinical stage 1 endometrial carcinoma who received MIS, and the surgical time, hospital day, and blood loss were also less.

Comparison of clinical outcomes in women with surgically treated early primary cervical cancer: Lymphadenectomy vs sentinel lymph node biopsy

Background: The primary objective of this study was to elucidate the impact of sentinel lymph node (SLN) mapping and biopsy techniques on the clinical outcomes of women with early primary cervical cancer. Methods: All consecutive women with clinically determined stage I-IIA cervical cancer who underwent lymph node assessment with either SLN mapping or conventional pelvic/para-aortic lymphadenectomy were reviewed. Results: Women in the SLN group (n = 33) had fewer total dissected pelvic nodes (8.3 ± 5.9 vs 17.4 ± 7.7, p < 0.001), less intraoperative blood loss (513 ± 332 vs 1228 ± 1170 mL, p < 0.001), a shorter length of hospital stay (7.1 ± 2.4 vs 10.2 ± 6.1 days, p = 0.004) than women in the conventional lymphadenectomy group (n = 74). The rates of recurrence-free survival (3-year: 87.6% vs 82.9%) and overall survival (3-year: 100% vs 91.0%) did not differ between the SLN group and the conventional lymphadenectomy group (p = 0.846 and p = 0.254, respectively). Conclusion: SLN biopsy does not seem to be associated with an inferior survival outcome compared with conventional lymphadenectomy in women with early primary cervical cancer. In addition, it is associated with less blood loss and a shorter length of hospital stay.

WGCNA reveals a biomarker for cancer-associated fibroblasts to predict prognosis in cervical cancer

Background: Cancer-associated fibroblasts (CAFs) are crucial components of the cervical cancer tumor microenvironment, playing a significant role in cervical cancer progression, treatment resistance, and immune evasion, but whether the expression of CAF-related genes can predict clinical outcomes in cervical cancer is still unknown. In this study, we sought to analyze genes associated with CAFs through weighted gene co-expression network analysis (WGCNA) and to create a predictive model for CAFs in cervical cancer. Methods: We acquired transcriptome sequencing data and clinical information on cervical cancer patients from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. WGCNA was conducted to identify genes related to CAFs. We developed a prognostic model based on CAF genes in cervical cancer using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Single-cell sequencing data analysis and in vivo experiments for validation of hub genes in CAFs. Results: A prognostic model for cervical cancer was developed based on CAF genes including COL4A1, LAMC1, RAMP3, POSTN, and SERPINF1. Cervical cancer patients were divided into low- and high-risk groups based on the optimal cutoff value. Patients in the high-risk group had a significantly worse prognosis. Single-cell RNA sequencing data revealed that hub genes in the CAFs risk model were expressed mainly in fibroblasts. The real-time fluorescence quantitative polymerase chain reaction (PCR) results revealed a significant difference in the expression levels of COL4A1, LAMC1, POSTN, and SERPINF1 between the cancer group and the normal group (p < 0.05). Consistently, the results of the immunohistochemical tests exhibited notable variations in COL4A1, LAMC1, RAMP3, POSTN, and SERPINF1 expression between the cancer and normal groups (p < 0.001). Conclusion: The CAF risk model for cervical cancer constructed in this study can be used to predict prognosis, while the CAF hub genes can be utilized as crucial markers for cervical cancer prognosis.

The recent progress and therapy in endometriosis-associated ovarian cancer

Endometriosis-associated ovarian cancers (EAOCs) including endometrioid and clear cell ovarian carcinoma are subgroups of epithelial ovarian carcinomas (EOCs), which is generally acknowledged as the most lethal gynecological malignancy. Endometriosis (ES), a common clinical disease among women, presents with clinical symptoms of pelvic pain, infertility, or adnexal masses with the formation of endometrioma. It has long been considered to be a potential risk factor for developing EOCs, mainly of endometrioid and clear cell subtypes. Here, we compiled data from previous researches on deregulated molecular functions among ES and EOCs using gene set–based integrative analysis to decipher molecular and genetic relationships between ovarian ES and EOCs, especially EAOCs. We conclude that epidermal growth factor receptor (ERBB) and Phosphoinositide 3-kinases (PI3K)-related pathways are important in the carcinogenesis of type I EOCs, including clear cell, endometrioid, and mucinous ovarian carcinoma. Dysfunctional molecular pathways, such as deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response, and cell–cell signaling, played key roles in the malignant transformation of EAOCs. Nine genes related to inflammasome complex and inflammasome-related pathway were identified, indicating the importance of inflammation/immunity in EAOC transformation. We also collect progressive treatments of EAOC focused on targeted therapies and immunotherapy so far. This summarized information can contribute toward effective detection and treatment of EAOCs in the future.

Serum levels of alpha1-antitrypsin isoforms in patients with ovarian clear cell carcinoma: An exploratory study

Background: Ovarian clear cell carcinoma (OCCC) is frequently associated with endometriosis. Since serum levels of cancer antigen 125 (CA125) have limited diagnostic and prognostic value in this malignancy, there is an unmet need for reliable and specific biomarkers. Previous findings indicated that alpha 1-antitrypsin isoforms (isoAAT) are significantly increased in the peritoneal fluid of patients with endometriosis. This study was undertaken to examine whether serum isoAAT levels in patients with OCCC differ from those measured in women with endometriosis or benign ovarian tumors. We also investigated whether this biomarker may be useful for predicting survival in OCCC. Methods: Paired serum samples before and after debulking surgery were collected from 27 patients with OCCC. All sera from patients with endometriosis (n = 44) and benign ovarian tumors (n = 32) were obtained in the pretreatment phase. Serum isoAAT levels were assayed using a proprietary ELISA kit. Results: The highest levels of serum isoAAT (median, range) were identified in patients with OCCC (preoperative values: 160.9 ng/mL, range, 101.4−1098.8 ng/mL), followed by patients with endometriosis (125.0 and 83.4−473.2 ng/mL), and those with benign tumors (125.2 and 60.5−191.3 ng/mL). The differences in serum isoAAT levels between patients with OCCC and benign tumors were significant (p = 0.041). Debulking surgery of OCCC resulted in a significant decrease in serum isoAAT levels compared with the preoperative period (median, 160.9 versus 113.0 ng/mL, respectively, p = 0.012). As for prognostic prediction, we found that none of the nine patients with OCCC and serum isoAAT levels ≤130 ng/mL died of disease. Conclusion: Serum isoAAT levels may be diagnostically useful to distinguish OCCC from benign ovarian tumors and could also serve as a potential prognostic marker.

Is it possible to use the serum levels of alpha 1-antitrypsin as a serum biomarker to distinguish endometriosis and endometriosis-associated epithelial ovarian cancers?

Neurogenic bladder in patients with cervical cancer after treatment

Redefined complement C3c structures have significant increase in the plasma of ovarian cancer patients

Background: Ovarian cancer (OC) is the third most common gynecological cancer. Effective biomarkers are required for OC as in the case of other cancers. Therefore, here we explored whether plasma proteolytic products could serve as potential biomarkers. Methods: We devised a platform that incorporates CyDye labeling, macroporous reversed-phase liquid chromatography, reducing/nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAG), and fluorescence imaging. Paired preoperative and postoperative plasma samples from four patients were used to screen for possible proteolytic changes. For identified difference proteins, liquid chromatography-tandem mass spectrometry was used to analyze the protein digests using various proteases. Plasma samples from 33 healthy controls and 85 patients with OC were examined using an enzyme-linked immunosorbent assay. Results: Our analyses revealed that the circulating complement C3 derivative was present only in the diseased state. This 145-kDa species, under nonreducing conditions, could split into 72-, 39-, and 29-kDa fragments upon reduction, reminiscent of the C3c structure. While confirming the C3c identity, mass spectrometric analyses showed multiple C-terminal ends in the C3c α’1 fragment, which were utilized differently among patients with OC. Various ends were also observed in serum samples prepared using different complement activators, thus redefining C3c as a mixture of multiple molecular entities. Enzyme-linked immunosorbent assay (ELISA) targeting only canonical C3c demonstrated a strong correlation between increased plasma levels and the occurrence and progression of OC. Conclusion: Our findings suggest that plasma proteolysis during complement deactivation is explicitly involved in ovarian tumorigenesis and the associated protein changes may aid in developing next-generation cancer biomarkers.

Synergistic therapeutic effect of low-dose bevacizumab with cisplatin-based chemotherapy for advanced or recurrent cervical cancer

Background: Cisplatin-based chemotherapy (CBC) is highly efficacious for advanced cervical cancer; its efficacy can be enhanced by combining with 15 mg/kg (standard dose) bevacizumab (BEV). However, this standard dose is associated with various adverse events (AEs). Therefore, in this retrospective study, we analyzed the survival outcomes and AEs in patients with advanced or recurrent cervical cancer treated with CBC in combination with BEV 7.5 mg/kg. Methods: Registered patient data were retrieved between October 2014 and September 2019, and 64 patients with advanced or recurrent cervical cancer treated with CBC + BEV (n = 21) or CBC alone (n = 43) were analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were the frequency and severity of AEs. The Cox proportional-hazards model was applied to explore prognostic factors associated with PFS and OS. Results: The 1-, 2-, and 3-year PFS rates (95% CI) were 36.24% (22.0-50.5), 20.7% (9.8-34.2), and 17.7% (7.7-31.1) for the CBC group; and 71.4% (47.1-86.0), 51.0% (27.9-70.1), and 51.0% (27.9-70.1) for the CBC + BEV group, respectively. The 1-, 2-, and 3-year OS rates were 62.6% (46.4-75.18), 32.4% (18.8-46.9), and 23.2% (11.2-37.6) for the CBC group; and 85.7% (61.9-95.1), 66.6% (42.5-82.5), and 55.5% (27.1-76.7) for the CBC + BEV group, respectively. The CBC + BEV group presented higher PFS and OS rates, p = 0.003 and p = 0.005, respectively. Proteinuria (6 vs 9, p = 0.025) and hypertension (0 vs 10, p < 0.001) were less common, but anemia was more common in the CBC group (35 vs 11, p = 0.021). Conclusion: Overall, CBC + BEV significantly improved the PFS and OS compared with CBC alone. CBC + BEV also prevents severe AEs and hence is an efficacious and safe therapeutic option.