The Utility of Preoperative Serum CA125 Combined with HE4 to Predict Lymph Node Metastasis in Endometrial Cancer.

OBJECTIVES: To investigate the diagnostic performance of the serum cancer antigen 125 (CA125), human epididymis protein 4 (HE4), a combination of CA125 and HE4, and a risk of ovarian malignancy algorithm (ROMA) in the preoperative prediction of high-risk lymph node metastasis (LMN) in patients with early stage endometrial cancer (EC). DESIGNS: This is a cross-sectional study. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: A cross-sectional study of data for patients with early stage endometrioid EC treated surgically at Rajavithi Hospital between April 2020 and April 2021 was commenced. The preoperative serum levels of CA125 and HE4 were measured and analyzed. The ROC curves were generated to determine the optimal cutoff values of CA125, HE4, and ROMA with optimum sensitivity and specificity for predicting LMN. RESULTS: Eighty-six patients with surgically staged EC were identified. Lymph node involvement was detected in 9 patients (10.5%). The median serum CA125, HE4, and ROMA levels were significantly higher in EC patients having LMN than in those who did not (p < 0.05). Based on the ROC curve, both serum markers showed good discrimination for the prediction of LMN, with an optimal cutoff value of 35 U/mL for CA125 (AUC 0.789, 95% CI; 0.647-0.932), 200 pMol/L for HE4 (AUC 0.825, 95% CI; 0.700-0.950), and 60% for ROMA (AUC 0.856, 95% CI; 0.720-0.982). Additionally, HE4 showed the highest sensitivity, whereas the combination of CA125 and HE4 had the highest specificity. LIMITATIONS: The lack of ultra-staging might have been an important issue in underestimating the rate of nodal metastasis in low-risk patients and made the number of patients who developed LMN low (10.5%) in this study. CONCLUSIONS: The preoperative combined CA125 and HE4 levels are associated with an increased risk of having LMN in patients with early stage EC. This biomarker panel can guide identifying EC patients who might most benefit from lymphadenectomy.

Comparison of doses and injection sites of botulinum toxin for chronic anal fissure: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: There are no consensus guidelines on the optimal dose or injection site of botulinum toxin (BT) for chronic anal fissure (CAF). The objective of this study was to determine the appropriate dose and injection site of BT for CAF by comparing healing rate and adverse effects (incontinence and recurrence). METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Scopus were searched from inception through May 31, 2021. Randomized controlled trials evaluating healing and adverse effects of BT injection for CAF published in any language were selected. Multiple treatment comparisons and ranking were performed using a two-stage network meta-analysis, and results were graded by Confidence in Network Meta-Analysis tool. RESULTS: Twenty-seven trials involving 1880 patients were included. The results demonstrated that high-dose-BT had significantly higher short-term healing when injected out of the fissure (OF) site than each side of the fissure (SF) site, with a risk ratio (RR) of 2.12 (1.08, 4.15); low-dose-BT did not show any difference across OF and SF site with RR of 1.20 (0.85, 1.68). High-dose-BT at the OF site showed similar healing to low-dose-BT at the same site (RR of 1.02 (0.79, 1.31)) but with a higher risk of incontinence with RR of 3.54 (0.85, 14.76). In contrast, high-dose-BT at the SF site showed lower healing compared to low-dose-BT at the same site with RR of 0.57 (0.29, 1.14). Both high-dose-BT and low-dose-BT at the OF site had higher recurrence than high-dose-BT or low-dose-BT at the SF site with RR of 2.08 (0.33, 13.11) and 1.89 (0.60, 5.94), respectively. CONCLUSIONS: Given moderate level of evidence, low-dose BT is optimal; injection out of the fissure site improves short-term outcomes while injection each side of the fissure site tends to reduce recurrence in the longer term.

Association of Hormonal Contraceptive Use With Adverse Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies.

Importance: Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate. Objective: To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women. Data Sources: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. Evidence Review: The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing. Results: A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis. Conclusions And Relevance: The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.

Association of preoperative serum HE4 levels on the survival of patients with endometrial cancer.

PURPOSE: To evaluate the association between preoperative serum human epididymis protein 4 (HE4) levels and survival outcomes in endometrial cancer (EC) patients. METHODS: A retrospective cohort study was conducted of EC patients who were scheduled for surgery between September 2013 and May 2014 at Rajavithi Hospital. Association between preoperative serum HE4 levels and clinicopathological characteristics were evaluated. Cox proportional-hazards model was used to compare overall survival (OS) and recurrence-free survival (RFS) between EC patients who had high serum HE4 levels and those who did not. RESULTS: A total of 86 EC patients were enrolled. Serum HE4 levels was significantly associated with older age (p < 0.001), postmenopausal women (p = 0.001), large tumor size (p < 0.001), presence of lymphovascular invasion (p = 0.022), deep myometrial invasion (p = 0.001), lymph node metastasis (0.017), high-risk group (p < 0.001), and death status (p = 0.002). With a median follow-up of 53 months, the 3-years OS and PFS of EC patients who had high serum HE4 levels were significantly poorer than those who did not (71% vs 95.8%, and 67.7% vs 91.7%, respectively). A high serum HE4 level was a significant prognostic factor for OS and RFS from the univariate analysis. However, it was not a significant prognostic factor in the multivariate analysis. CONCLUSION: Preoperative high serum HE4 levels were significantly associated with the worse clinicopathological characteristic of EC patients and decreased OS and RFS. Although there was no strong independent prognostic factor for survival, serum HE4 levels could be used in an algorithm for stratifying high-risk EC patients with more proper management.

Prevention of venous thromboembolism in gynecological cancer patients undergoing major abdominopelvic surgery: A systematic review and network meta-analysis.

OBJECTIVE: Although thromboprophylaxis is recommended to reduce death and disability from venous thromboembolism (VTE), it remains underused due to a perceived risk of bleeding, especially in major abdominopelvic surgical patients. METHODS: We conducted a systematic literature review to identify all eligible randomized controlled trials (RCTs), searching MEDLINE and Scopus databases through November 25, 2020. RCTs published in any language were eligible if they studied in gynecological cancer patients undergoing major abdominopelvic surgery and assessed efficacy of mechanical and pharmacological interventions. Studies with insufficient data for pooling or those comparing different doses/schedules of interventions were excluded. Outcomes of interest were composite VTE (ie, deep vein thrombosis or pulmonary embolism) and major bleeding. Relevant data were extracted for direct and network meta-analyses. Risk ratios (RR) and 95% confidence interval (CI) were estimated and the best intervention probability calculated for each outcome. This study was registered with PROSPERO (CRD42019145508). RESULTS: We identified 1990 studies; 20 RCTs (4970 patients) were eligible. The overall risk of bias was of some concern. In direct meta-analyses, antithrombins were superior to unfractionated heparin in preventing composite VTE (RR 0.69; 95% CI 0.48-0.99), with no difference detected in the rate of major bleeding for any pairwise comparison. In network meta-analyses, graduated compression stockings plus low-molecular-weight heparin (LMWH) was top-ranked for prevention of composite VTE, whereas sequential compression devices (SCD) ranked second, after no treatment, for major bleeding. In a clustered ranking plot, SCD plus LMWH provided optimal balance between efficacy and safety. CONCLUSIONS: SCD plus LMWH might be safe and effective in VTE prevention following gynecological cancer surgery. However, the patient's bleeding risk should be considered to balance the risk and benefit of treatment.

Effect of Metformin For Decreasing Proliferative Marker in Women with Endometrial Cancer: A Randomized Double-blind Placebo-Controlled Trial.

OBJECTIVE: To compare the Ki-67 index of endometrial cancer cells before and after treatment between the metformin and placebo group in women with endometrial cancer (EC). METHODS: This study was a randomized, double-blind, placebo-controlled trial conducting in non-diabetic women who diagnosed with endometrioid EC and had a schedule for elective surgical staging at Rajavithi Hospital between August 2018 and June 2019. Tissue specimens were obtained via endometrial curettage at the time of initial diagnosis (pre-treatment) and hysterectomy (post-treatment) to assess the value of the Ki-67 index by immunochemistry. Patients were randomly assigned into 2 groups: metformin and placebo group. Metformin 850 mg or placebo 1 tab were administered once daily for at least 7 days, starting on the first morning after recruitment until one day before surgery. Baseline characteristics (e.g., age, body mass index, co-morbidities) including surgical and pathological characteristics were recorded. The metabolic effect of metformin was also evaluated by a recording of fasting blood sugar, HbA1C and potential adverse events including nausea, vomiting, dizziness, and hypoglycemic symptom. RESULTS: A total of 49 EC patients were included in this study. Twenty-five patients were assigned to the metformin group and 24 patients were assigned to the placebo group. Baseline demographic, surgical, and pathological characteristics between the 2 groups were similar. Metformin significantly changed the Ki-67 index relative to placebo, with a mean decrease of 23.3% (p=0.001) and a mean proportional decrease of 39.1% (p=0.006) before and after treatment. Additionally, no significant differences were detected in metabolic effects and adverse events between the metformin and the placebo groups. CONCLUSION: Short-term treatment with an oral metformin significantly reduced a proliferative marker Ki-67 index in women with endometrioid EC awaiting surgical staging. This study supports the biological effect of metformin in EC and potential applications in the adjuvant treatment in EC patients.

Effect of Chewing Gum on Gastrointestinal Function Recovery After Surgery of Gynecological Cancer Patients at Rajavithi Hospital: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of postoperative gum-chewing compare with routine postoperative care on the recovery of gastrointestinal function after comprehensive surgical staging for gynecological cancer. MATERIALS AND METHODS: A total of 82 patients who underwent comprehensive surgical staging for gynecological cancer at Rajavithi Hospital between October 1st, 2018 and June 30th, 2019 were randomly allocated into two groups: Gum-chewing group (n=40) and control group (n=42). In the gum-chewing group, patients were assigned to chew sugar-free gum for 30 minutes starting from the first postoperative morning then every 8 hours until the first passage of flatus. In the control group, patients have received routine postoperative care. The primary endpoint was time to first flatus after surgery. The secondary endpoints were time to first bowel sound, time to first defecation, time to first walk, postoperative analgesia and anti-emetic drug requirement, ileus symptoms, length of a hospital stay, and potential adverse events of gum-chewing, including dry mount, choking, and aspiration. RESULT: Chewing gum was statistically significant in reducing time to first flatus compared with routine postoperative care (median 24.7 (range 2.2-86.5) vs 35.4 (range 7.2-80.9) hours, p=0.025). The length of a hospital stay was also significantly shorter in the gum-chewing group (median 3.0 (range 1.0-8.8) vs 3.5 (range 1.8-50.0) days, p=0.023). There were no significant differences in time to first bowel sound, time to first defecation, time to first walk, postoperative analgesia and anti-emetic drug requirement, and ileus symptoms between both two groups. No adverse events related to postoperative gum-chewing were observed. CONCLUSION: Gum-chewing was associated with early recovery of gastrointestinal function in patients undergoing surgery for gynecological cancer. It is an inexpensive and physiologic intervention that appears to be reasonably safe and should be recommended as an adjunct in postoperative care of gynecological cancer surgery.

Therapeutic Use of Metformin in Diabetes and Survival Outcomes in Endometrial Cancer Patients with Diabetes

Objectives: To compare survival outcomes between endometrial cancer (EC) patients with diabetes who used metformin to those who did not use metformin. Materials and Methods: A retrospective cohort study was conducted of EC patients who were diabetes at the time of their cancer diagnosis and had been scheduled for elective surgery at Rajavithi Hospital between 1 January 2003 and 31 December 2013. The patients were excluded if they had type I diabetes mellitus and a history of other cancers. Results: Of 1,262 EC patients in the study period, there was 212 (16.8%) patients who met the inclusion criteria. Among them, 90 (42.5%) were non-metformin users and 122 (57.5%) were metformin users. With a median follow-up of 47 months, the 5-year overall survivals (76.4% vs 77.9%, p=0.959) and the 5-year progression-free survivals (92.6% vs 84.7%, p=0.091) did not significantly differ between the both groups. On Cox proportional-hazards regression analysis, independent prognostic factors for overall survival (OS) were FIGO stage, depth of myometrial invasion, and cervical involvement. Patients with non-endometrioid histology and advanced stage were found to have a significant effect on progression-free survival (PFS). However, metformin used did not predict either OS (HR, 0.99; 95%CI, 0.56-1.73; p=0.959) or PFS (HR, 2.19; 95%CI, 0.86-5.55; p=0.099). Conclusion: Overall, a significant effect of metformin on survival outcomes in EC patients with diabetes was not found in the current study. Larger studies with a prospective randomized control design are needed to clarify the benefit of metformin as a strategy for endometrial cancer prevention and treatment.