Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Blood-based biomarkers have been proposed as an alternative to liver biopsy for non-invasive liver disease assessment (NILDA) in chronic liver disease (CLD). Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4) and cirrhosis (F4), as compared to biopsy in CLD. APPROACH AND RESULTS: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in hepatitis B virus (HBV) and C virus (HCV), HIV-HCV/HBV co-infection, and nonalcoholic fatty liver disease (NAFLD). Positive (LR+) and negative (LR) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86 respectively; LR+ and LR for NAFLD F2-4, F3-4 and F4 were 2-65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15 respectively. Overall, proportional odds ratio indicated FIB-4 <1.45 was better than APRI <0.5 for F2-4. FIB-4 >3.25 was also better than APRI >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS: Blood-based biomarkers are associated with small-to-moderate change in pre-test probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV co-infection, and NAFLD, with limited comparative or combination studies for other CLD.

APOBEC3A/B deletion polymorphism and endometrial cancer risk.

BACKGROUND: A common 30 kb deletion affecting the APOBEC3A and APOBEC3B genes has been linked to increased APOBEC activity and APOBEC-related mutational signatures in human cancers. The role of this deletion as a cancer risk factor remains controversial. MATERIALS AND METHODS: We genotyped the APOBEC3A/B deletion in a sample of 1,470 Norwegian endometrial cancer cases and compared to 1,918 healthy controls. For assessment across Caucasian populations, we mined genotypes of the SNP rs12628403, which is in strong linkage disequilibrium with the deletion, in a GWAS dataset of 4,274 cases and 18,125 healthy controls, through the ECAC consortium. RESULTS: We found the APOBEC3A/B deletion variant to be significantly associated with reduced risk of endometrial cancer among Norwegian women (OR = 0.75; 95% CI = 0.62-0.91; p = 0.003; dominant model). Similar results were found in the subgroup of endometrioid endometrial cancer (OR = 0.64; 95% CI = 0.51-0.79; p = 3.6 × 10-5 ; dominant model). The observed risk reduction was particularly strong among individuals in the range of 50-60 years of age (OR = 0.51; 95% CI = 0.33-0.78; p = 0.002; dominant model). In the different populations included in the ECAC dataset, the ORs varied from 0.85 to 1.05. Although five out of six populations revealed ORs <1.0, the overall estimate was nonsignificant and, as such, did not formally validate the findings in the Norwegian cohort. CONCLUSION: The APOBEC3A/B deletion polymorphism is associated with a decreased risk of endometrial cancer in the Norwegian population.

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61-0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50-0.95; p = 0.018 and OR = 0.77; CI = 0.62-0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59-1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69-1.00).

Clinical and Genetic Investigation of Premature Ovarian Insufficiency Cases from Turkey.

OBJECTIVE: Premature ovarian insufficiency is a lack of ovarian functions in patients younger than 40 years old. Genetic causes leading to accelerated follicle depletion may result in premature ovarian insufficiency. We aimed to determine genetic etiology of nonsyndromic premature ovarian insufficiency cases from Turkey. MATERIALS AND METHODS: We analyzed 86 nonsyndromic premature ovarian insufficiency cases and 26 matched control female participants. Participants have been investigated in cytogenetic analysis followed by FMR1 repeat size expansions and search of variants for nine premature ovarian insufficiency-associated genes. RESULTS: Four cases had a structural cytogenetic abnormality. Two cases revealed with premutation size FMR1 triplet repeat expansion. Four cases carried variants in which two were very rare in FSHR and PDPK1, and three were novel in NR5A1, PDPK1, and POF1B genes. Six novel variants have been identified in NOBOX, NR5A1, POF1B, and PDPK1 in control population assigned to be benign alterations. CONCLUSION: Mosaicism of sex chromosomes was responsible in 4.6% and FMR1 premutation in 2.4% of premature ovarian insufficiency cases, while the association of premature ovarian insufficiency-related genes was found very subtle. Novel variants in NR5A1, PDPK1, and POF1B may necessitate further evaluation for their association with premature ovarian insufficiency via functional studies.

Gonadotropin-Releasing Hormone Analogs for Gonadal Protection During Gonadotoxic Chemotherapy: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis was conducted to investigate whether gonadotropin-releasing hormone analogs (GnRHa) have a protective role in women treated with alkylating agents. DATA SOURCES: Major databases (PubMED, EMBASE, Cochrane Central Register of Controlled Trials), systematic snowballing, and trial registries were screened from the inception dates until September 2017. METHODS AND STUDY SELECTION: Comparative studies involving reproductive-aged women undergoing chemotherapy with or without coadministration of GnRHa were included. Spontaneous menstrual resumption was assessed as a main outcome. Statistical analyses were performed with STATA 14.2 statistical software. Effect estimates were presented as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: The literature search yielded 25 436 citations and 84 papers were assessed in full text. Eighteen studies (11 randomized controlled trials [RCTs] and 7 cohort studies) published between 1987 and 2015 were included in the analysis, revealing a significant protective effect of GnRHa (n = 1043; RR:1.38; 95% CI: 1.18-1.63) although with high heterogeneity (I2 = 83.3%). Subgroup analyses revealed a significant benefit of GnRHa cotreatment both in RCTs and in cohort studies. Statistical significance was found in all subgroups by the underlying disease, that is, hematological malignancies, autoimmune diseases, and breast cancer. Sensitivity analyses in GnRH agonist-treated patients, in patients younger than 40 years old, and in patients without supradiaphragmatic radiotherapy also revealed a significant benefit of GnRHa cotreatment. CONCLUSION: Our results indicate that concurrent GnRHa administration is an effective method to decrease gonadotoxicity of alkylating agents. The presence of low-quality evidence favoring gonadoprotective effect requires a strong recommendation for offering GnRHa coadministration to young women who are to undergo gonadotoxic chemotherapy. CAPSULE: The present systematic review and meta-analysis shows a significant gonadoprotective effect of gonadotropin-releasing hormone analogs in women treated with alkylating agents.

Serum AMH levels and insulin resistance in women with PCOS.

OBJECTIVE: To compare the serum AMH levels between women with and without insulin resistance (IR) in polycystic ovary syndrome (PCOS). STUDY DESIGN: 293 women with PCOS according to the Rotterdam criteria were enrolled into our study. Insulin resistance was diagnosed according to the Homeostatic model assessment insulin resistant (HOMA-IR) formula and the cut-off point was set to more than 2.5. Women were grouped according to the presence of insulin resistance (IR) (HOMA-IR ≥ 2.5). Serum AMH and other hormones were compared between the IR (+) and IR (-) groups. Additionally, AMH percentiles were (<25, 25-75, >75) constructed; HOMA-IR and BMI values in women with/without IR were compared in different percentiles. Further, HOMA-IR, BMI and AMH values were measured across different PCOS phenotypes. RESULTS: The prevalence of IR was 45%. The prevalence of IR was 57% in women with BMI ≥ 25. Serum AMH levels were not significantly different among women with and without IR. Also, HOMA-IR values were not significant among different AMH percentiles. However, in each AMH percentile BMI were found to be higher in women with IR than in women without IR. The median HOMA-IR values were the highest in women with BMI ≥ 25 in both IR (+) and IR (-) groups. No significant difference was found among PCOS phenotypes in terms of HOMA-IR and BMI. Positive correlations were found between BMI, free testosterone and HOMA-IR. However, no correlation was found between AMH and HOMA-IR. CONCLUSION: The serum AMH levels between women with IR and without IR in PCOS were not significantly different. Also, we did not reveal a correlation between serum AMH levels and IR in women with PCOS. IR was not correlated with different PCOS phenotypes either. We found a positive correlation between BMI and IR. IR should be investigated in women with PCOS having a BMI ≥ 25, independent of their phenotype or AMH levels.

Comparison of antagonist mild and long agonist protocols in terms of follicular fluid total antioxidant capacity.

OBJECTIVE: A high dose of prolonged gonadotropins can yield higher numbers of oocytes and embryos. The high dose or prolonged regimens can be associated with ovarian hyperstimulation syndrome (OHSS), multiple gestations, emotional stress, economical burden and treatment dropout. In mild stimulation lower doses and shorter duration times of gonadotropin are used in contrast to the conventional long stimulation protocol in IVF. It has been proposed that supraphysiologic levels of hormones may adversely affect endometrium and oocyte/embryo. Also it has been proposed that oxidative stress (OS) may alter ovarian hormone dynamics and could be further affected by additional exogenous hormonal stimulation. Therefore our aim was to compare follicular fluid total antioxidant capacity (TAC) in antagonist mild and long agonist stimulations. MATERIALS AND METHODS: Forty patients received antagonist mild stimulation, starting on the 5th day of their cycle and forty patients received long agonist treatment. Seventy-five patients undergoing their first IVF cycle were included in the final analysis. Follicular fluid (FF) samples were analyzed for estradiol (E2), antimullerian hormone (AMH) and TAC. RESULTS: FF-Total antioxidant capacity (TAC) levels were higher in the long agonist group as opposed to the antagonist group [1.07 ± 0.04 mmol Trolox equivalent/L vs 1 ± 0.13 mmol Trolox equivalent/L] (Fig. 1). Pregnancy rates were not significantly different between the two treatments. The FF-TAC levels were not different among infertility etiologies (Fig. 3). FF-TAC levels did not have a direct correlation with pregnancy but a positive correlation with the total gonadotropin dose was observed. CONCLUSION: Patients with good ovarian reserves and under the age of 35 effectively responded to mild stimulation treatment. Using lower amounts of gonadotropin, yielded less FF-TAC levels in patients who underwent antagonist mild protocol. In patients under the age of 35, antagonist mild stimulation is a patient friendly and effective procedure when undergoing their first IVF cycle.

Ykl-40 and cancer antigen 72-4 as new and promising diagnostic and prognostic markers for endometrial cancer.

OBJECTIVE: To determine the predictive role of serum levels of YKL-40 and cancer antigen (CA) 72-4 in the diagnosis of endometrial cancer (EC). MATERIALS AND METHODS: Forty-one patients with EC and 21 women with uterine polyps were evaluated between January and December 2015 in a prospective study. RESULTS: Age, body mass index, preoperative serum YKL-40 and CA 72-4 levels were significantly higher in the malignant group compared with the control group. Serum YKL-40 levels were significantly higher in patients with superficial myometrial invasion and no lymph node involvement (p=0.042; p=0.004). No relationship between clinicopathologic factors and serum CA 72-4 levels was found. CONCLUSION: Serum CA 72-4 and YKL-40 levels are increased in women with EC compared with uterine polyps. Preoperative serum YKL-40 levels may be associated with favorable prognostic factors. The determination of YKL-40 before surgery may be helpful in the evaluation of the regional lymph nodes.

Does telomerase activity have an effect on infertility in patients with endometriosis?

OBJECTIVE: This study aimed to investigate the role of telomerase activity in the development of endometriosis-related infertility by evaluation of the serum telomerase in eutopic and ectopic endometrial tissue. STUDY DESIGN: Eutopic endometrium, cystic wall/ovarian cortex, and venous blood were assessed in forty-seven patients. The following groups of patients were identified: females with endometriosis requiring surgical intervention and healthy control females. Patients with histopathologically confirmed endometriosis were further subdivided in the infertile (n=14) and fertile (n=17) groups. Patients who underwent hysterectomy and oophorectomy for benign gynecological conditions were enrolled in the healthy control group (n=16). Telomerase activity was evaluated with three-group, endometriosis-based and fertility-based designs. Analyses were performed regardless the menstrual cycle phase (Phase G), in proliferative (Phase P) (n=22) and secretory phases (Phase S) (n=25). Telomeric Repeat Amplification Protocol PCR was applied for telomerase activity assessment. All statistical analyses were performed with STATA 14.2, GraphPad Prisma 7.01. RESULTS: In analyses of the eutopic endometrium, with three-group design, a significant difference was not found in Phase G and P (p=0.58 and p=0.33, respectively). However, a statistical difference was shown in Phase S (p=0.008). A significant difference was not established in Phase G, P and S of endometriosis-based design (p=0.35, p=1.0, p=0.13, respectively). No difference was detected in Phase G and P of fertility-based design (p=0.66 and p=0.14, respectively), whereas in secretory phase difference was approved (p=0,049). Telomerase activity was not established in ectopic endometrium and in serum assessment. CONCLUSIONS: Telomerase activity is useless as a biomarker in peripheric blood analysis. The absence of activity in cystic wall approves the high differentiation of endometriosis tissue, what is the possible reason of low malignancy risk. The high rate of telomerase activity in the eutopic endometrium of the infertile group may be considered as a cause of endometriosis-related infertility.

ASSERT trial - How to assess the safety and efficacy of a high frequency rTMS in postpartum depression ? A multicenter, double blinded, randomized, placebo-controlled clinical trial.

BACKGROUND: Postpartum Depression affects a considerable number of women worldwide. This condition inflicts severe consequences to mother and child health. Thus far, available treatments have low response and high relapse rates. We designed this trial to evaluate a safe and more efficacious innovative therapy. AIMS: To report a feasible and ethical study design to assess the safety and efficacy of a high frequency repetitive Transcranial Magnetic Stimulation 10 Hz (rTMS) compared to sham rTMS in women with moderate to severe Post-Partum Depression using standard treatment (sertraline).To conduct an ancillary, exploratory, randomized, active controlled, double blind study with a hypothesis to assess the safety and efficacy of 10 Hz rTMS compared to sertraline. METHODS: A multicenter, parallel arm, randomized, placebo-controlled, double-blind design to assess safety and efficacy of 10 Hz rTMS compared to sham.An ancillary study will be conducted with parallel arm, randomized, active controlled and double dummy design to assess safety and efficacy of 10 Hz rTMS compared to sertraline.

Is serum level of nestin useful in detecting epithelial ovarian cancer?

AIM: The aim of the present study was to evaluate the usefulness of nestin as a discriminative marker between benign and malignant ovarian tumors. METHODS: During the 1 year from January 2015 through December 2015, a nonconsecutive series of 80 patients (40 malignant, 40 benign) who underwent surgery for an adnexal mass were enrolled in the study. Intraoperative frozen section evaluation was performed if there was a suspicion in diagnosis. Statistical analyses were performed using spss ver. 16.0, while clinicopathological variables, including the categorical data, were analyzed using the χ2 -test or Fisher's exact test. A P-value < 0.05 was defined as statistically significant. RESULTS: Preoperative serum carbohydrate antigen (CA)-125, CA-15-3, and nestin levels were significantly higher in the malignant group compared to patients with benign ovarian tumors (P < 0.001, respectively). Serum nestin levels did not differ significantly on the basis of histologic subtypes. Serum nestin levels had specificity of 89.7%, which demonstrates nestin's sufficiency to distinguish benign from malignant epithelial ovarian tumors. The positive likelihood ratio of nestin was found to be superior to that of CA-125 and CA-15-3. CONCLUSION: The results obtained from our study suggest that measurement of nestin level, alongside physical examination, transvaginal ultrasound, and serum CA-125 and CA-15-3 levels, can help differentiate benign ovarian tumors from malignant epithelial ovarian tumors. The findings of our study need to be supported with additional studies.

Risk factors for recurrence of borderline ovarian tumours: A tertiary centre experience.

The aim of this study was to evaluate the risk factors for recurrence of borderline ovarian tumours. This study investigated 127 women who were finally diagnosed with borderline epithelial ovarian tumours. Most of them were diagnosed in stage I (83.4%). With a median follow-up of 81.8 months (range: 14-205), the median time to recurrence was 22.4 months (range: 3-74). Five-year recurrence-free survival (RFS) and overall survival (OS) rates were 85.8% and 97.6%, respectively. In multivariate analysis, invasive implants and fertility-sparing surgery were found to be independent prognostic factors for 5-year RFS. Overall, 20 patients (15.7%) experienced relapse within the observation period. Although there is no consensus about high-risk category of borderline ovarian tumours, invasive implants and conservative surgery were closely related to the recurrence. Patients presenting these risk factors should undergo closer follow-up.

Tertiary Cytoreduction for Recurrent Epithelial Ovarian Cancer: a Multicenter Study in Turkey.

BACKGROUND: The purpose of this study was to determine the benefit of tertiary cytoreductive surgery (TC) for secondary recurrent epithelial ovarian cancer (EOC), focusing on whether optimal cytoreduction has an impact on disease-free survival, and whether certain patient characteristics could identify ideal candidates for TC. MATERIALS AND METHODS: Retrospective analysis of secondary recurrent EOC patients undergoing TC at three Turkish tertiary institutions from May 1997 to July 2014 was performed. All patients had previously received primary cytoreduction followed by intravenous platinum-based chemotherapy and secondary cytoreduction for first recurrence. Clinical and pathological data were obtained from the patients' medical records. Survival analysis was caried out using the Kaplan Meier method. Actuarial curves were compared by the two tailed Logrank test with a statistical significance level of 0.05. RESULTS: Median age of the patients was 49.6 years (range, 30-67) and thirty-eight (72%) had stage III-IV disease at initial diagnosis. Twenty six (49%) had optimal and 27 (51%) suboptimal cytoreduction during tertiary debulking surgery . Optimal initial cytoreduction, time to first recurrence, optimal secondary cytoreduction, time interval between secondary cytoreduction and secondary recurrence, size of recurrence, disease status at last follow-up were found to be significant risk factors to predict optimal TC. Optimal cytoreduction in initial and tertiary surgery and serum CA-125 level prior to TC were independent prognostic factors on univariate analysis. CONCLUSIONS: Our results and a literature review clearly showed that maximal surgical effort should be made in TC, since patients undergoing optimal TC have a better survival. Thus, patients with secondary recurrent EOC in whom optimal cytoreduction can be achieved should be actively selected.

Surgical Treatment of Metastatic Ovarian Tumors From Extragenital Primary Sites.

OBJECTIVE: The purpose of this study was to investigate the outcomes and prognostic factors of metastasectomy in patients with metastatic ovarian tumors from extragenital primary sites. MATERIALS AND METHODS: All patients with pathologically confirmed metastatic ovarian tumors between January 1997 and June 2015 were included in this study. A total of 131 patients were identified. The data were obtained from the patients' medical records. Clinicopathological features were evaluated by both univariate and multivariate analyses. RESULTS: The primary sites were colorectal region (53.4%), stomach (26%), and breast (13%). Preoperative serum CA 125 and CA 19-9 levels were elevated in 29.4% and 39.8% of the patients, respectively. Cytoreductive surgery was performed in 41.2% of the patients. Seventy-three (55.7%) patients had no residual disease after surgery. Sixty-six (49.6%) patients had combined metastases at the time of the surgery to sites including the liver, pancreas, lung, bone, lymph nodes, bladder, or the intestine. With a median follow-up of 33 months, the median survival time was 22 months. The estimated 5-year survival probability is 0.26. On univariate analysis, primary cancer site, combined metastasis outside the ovaries, residual disease, preoperative serum CA 125 and CA 19-9 levels, and histologic type were significant parameters for overall survival. Furthermore, residual disease, preoperative serum CA 19-9 level, and primary cancer site were found to be independent prognostic factors on multivariate analysis. CONCLUSIONS: The most common primary sites for ovarian metastasis are gastrointestinal tract. Metastasectomy may have beneficial effects on survival, especially if the residual disease is less than 5 mm. Prospective studies warranted to evaluate the value of metastasectomy in patients with ovarian metastasis.

Expression of PTEN and ß-Catenin and Their Relationship With Clinicopathological and Prognostic Factors in Endometrioid Type Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate rates of expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10) and ß-catenin and their relationship with clinicopathological and prognostic factors in endometrioid type endometrial cancer (EC). METHODS AND MATERIALS: PTEN and ß-catenin expressions of 59 operated patients with EC between January 2000 and December 2008 and followed-up until December 2014 in Cerrahpasa School of Medicine, Gynecologic Oncology Division, were evaluated retrospectively. Clinical data were obtained from patient files, and pathological data were obtained from pathology records. Each patient had 4 paraffin sections of tumoral tissue. These sections were stained by immunohistochemical methods. Clinical features and postoperative histopathologic findings were analyzed using Fisher exact test or the χ(2) test as appropriate. The Kaplan-Meier method was used to generate the survival curves. RESULTS: During median follow-up of 102 months, tumor recurrence and disease-related mortality were observed in 10 (16.9%) and 7 (11.9%) cases, respectively. Immunohistochemical staining of PTEN and ß-catenin were positive in 61% and 69.5% of all cases, respectively. Positive staining of PTEN was positively correlated with myometrial invasion (P= 0.02). There was no correlation between ß-catenin and clinicopathological factors. PTEN or ß-catenin positivity were not significant prognostic factors for 5-year overall survival (P = 0.37, P = 0.62, respectively) and 5-year disease-free survival (P = 0.28, P = 0.58, respectively). CONCLUSIONS: PTEN and ß-catenin expressions cannot be used to determine prognosis in patients with EC as PTEN and ß-catenin staining status were found to have no significant effect on 5-year overall survival and disease-free survival. Positive staining of PTEN may be associated with increased myometrial invasion. Meta-analyses and broader studies are needed to evaluate the prognostic value of PTEN and ß-catenin in EC.

Serum YKL-40 levels are altered in endometriosis.

Endometriosis is traditionally defined as the presence of endometrial glands and stroma in ectopic locations, especially the pelvic peritoneum, ovaries and rectovaginal septum. YKL-40, a new biomarker of inflammation, is secreted by activated macrophages and neutrophils in different tissues with inflammation. Serum concentrations of YKL-40 are elevated in patients with diseases characterized by inflammation. We aimed to investigate the possible association between serum YKL-40 levels and endometriosis. A total number of 88 women were recruited for this case-control study. About 53 patients with surgically proven endometriosis were included, while 35 patients without endometriosis comprised the control group. Patients were classified as having minimal, mild, moderate and severe disease in accordance with the severity. Two new groups were formed by combining patients with minimal and mild disease (Stage 1-2) and with moderate and severe disease (Stage 3-4). Serum YKL-40 levels were statistically higher in the endometriotic group compared to control group (p:0.001). YKL-40 levels were significantly higher in Stage 3-4 group compared to Stage 1-2 group (p values 0.001) as well. Correlation analysis revealed a positive correlation between serum YKL-40 levels and the stage of the disease. YKL-40 may be utilized as a marker for determining the severity of endometriosis.