Efficacy, safety, and patient-reported outcome of immune checkpoint inhibitor in gynecologic cancers: A systematic review and meta-analysis of randomized controlled trials.

Over the past decades, immune checkpoint inhibitors (ICIs) have shown dramatic efficacy in improving survival rates in multiple malignancies. Recently, gynecological cancer patients also showed to respond favorably to ICI treatment. This study aimed to evaluate the efficacy, safety, and patient-reported outcomes of ICI therapy in gynecological cancers. We conducted a systematic review and meta-analysis by retrieving literature from multiple electronic databases, such as MEDLINE, ScienceDirect, EBSCO, ProQuest, and Google Scholar. The protocol used in this study has been registered in PROSPERO (CRD42022369529). We included a total of 12 trials involving 8 therapies and 8,034 patients. ICI group demonstrated a longer OS (HR: 0.807; 95% CI: 0.719, 0.907; p = 0.000) and greater PFS improvement (HR: 0.809; 95% CI: 0.673, 0.973; p = 0.024) compared to the control group. There was no significant difference in the incidence of treatment-related adverse events [RR: 0.968; 95%CI: 0.936, 1.001; p = 0.061], but a higher incidence of immune-related adverse events (IRAEs) was observed in the ICI group (RR: 3.093; 95%CI: 1.933, 4.798; p = 0.000). Although the mean changes of QOL score from baseline was not significantly different between both groups (SMD: 0.048; 95% CI: -0.106, 0.202; p = 0.542), the time to definitive QOL deterioration was longer in the ICI group (HR: 0.508; 95% CI: 0.461, 0.560; p = 0.000). Despite having a higher incidence of IRAE, ICI was shown to improve survival rates and QOL of patients. Thus, it should be considered as a new standard of care for gynecologic cancers, especially in advanced stages.

Role of CD44 and CD24 Expression on 2-years Disease Free Survival in Patients with Advanced Epithelial Ovarian Carcinoma.

OBJECTIVE: Ovarian cancer is one of the most common cancers with a high mortality rate worldwide. Despite optimal surgical therapy and chemotherapy, recurrence is still common. Cancer stem cells expressing CD44 and CD24 are thought to be contributing factors in recurrence. METHODS: A cohort retrospective study with survival analysis was carried out on advanced ovarian cancer patients who underwent optimal debulking surgery followed by 6 cycles of chemotherapy at Cipto Mangunkusumo General Hospital and Fatmawati General Hospital from January 2019 to March 2023. Immunohistochemical examination was performed on tumor tissue with CD44 and CD24 expression were assessed using the H-Score method then determined the cut off-point expression level using the ROC curve. Furthermore, the relationship between these expression levels with the disease-free survival was assessed using the survival curve. RESULTS: There were 48 subjects who were included in the study. There were high expression levels of CD44 in 47.9% and CD24 in 50% of cases. High CD44 expression had mean and median survival of 13.2 ± 1.8 and 11 months (HR 5.05, 95% CI 1.84- 13.85). High CD24 expression had mean and median survival of 13.5 ± 2.4 and 7 months (HR 7.73, 95% CI 2.58 - 23.15). The combination of the two high expressions had mean and median survival of 10.44 ± 1.88 and 7 months. CONCLUSION: High expression of CD44 and CD24 will shorten the disease-free survival of patients with advanced ovarian cancer.

High ALDH-1 Expression Predicts Non-Complete Response of Radiotherapy in Stage III Squamous Cell Cervical Carcinoma Patients.

BACKGROUND: ALDH1 is a cervical cancer stem cell marker that has radioresistance profile. Recurrence and metastasis following radiotherapy are still being problems of most patients. This study aimed to determine the correlation between ALDH1 and radiotherapy response in stage III squamous cell cervical carcinoma (SCCC) of the cervix. METHODS: A total 58 of 360 patients of stage III SCCC who received external beem radiation and brachytherapy (2016-2021) at Cipto Mangunkusumo Hospital met the eligibility criteria of this study. Pre- and post-irradiation MRI examinations and ALDH expression with immunohistochemistry (Santa Cruz®) were performed on formalin-fixed paraffin-embedded of pre-treatment cervical tissue biopsy taken from RSCM pathological anatomy laboratory. Patients were divided into two groups, complete responders vs non-complete responders. ALDH-1 scores were compared between two groups to assess ALDH-1 expression. The statistical analyses were carried out by SPSS 24. RESULTS: The optimal ALDH-1 score cut-off point on the radiation response was 166.05 pg/mL which was obtained from the analysis of the ROC curve. The AUC value was 0.682 with sensitivity and specificity, 63,6% and 64%, respectively. ALDH score ≥166.05 increased the risk by 3.127 times for not achieving complete response (adj OR 3.127, 95% CI 1.034 - 9.456, p = 0.043). Pre-radiation tumor size (p = 0.593), degree of differentiation (p = 0.161), renal abnormalities (p = 0.114), and keratinization (p = 0.477) were not associated with radiation response. CONCLUSIONS: High ALDH expression was associated with non-complete radiation response in stage III squamous cell cervical carcinoma. 
.

Is there any difference in insulin resistance status between cases of benign and malignant ovarian neoplasms? A study on surrogate markers of insulin resistance in Indonesian non-diabetic women.

The association between insulin resistance (IR) and ovarian neoplasm is little known. The present study attempted to investigate the difference in clinicopathological characteristics, metabolic parameters, and IR prevalence between benign and malignant ovarian neoplasms. The cross-sectional study involved 52 non-diabetic women with benign (n=27) and malignant (n=25) diagnoses in a tertiary hospital in Indonesia. Fasting insulin level (FIL), homeostatic model assessment of IR and ß-cell dysfunction (HOMA-IR and HOMA-ß), fasting IR index (FIRI), and quantitative insulin sensitivity check index (QUICKI) were used as surrogate markers to evaluate IR. Parametric and nonparametric statistical tests were employed to analyze the different parameters between the two groups. Pearson or Spearman's rank test assessed the correlation between markers and clinical variables. Results revealed that patients with benign neoplasms were younger than those with malignant neoplasms (38.63 vs. 47.40 years; P=0.003) and had a higher median body mass index (BMI) than their counterparts (22.98 vs. 18.61 kg/m2; P=0.014). Different characteristics between benign and malignant neoplasm cases were found in menopausal status, ovary side affected, systolic blood pressure, and BMI classes. Endometrial cysts and mucinous carcinoma were the most often diagnosed benign and malignant neoplasms. Malignant neoplasms had a lower median HOMA-ß score than benign neoplasms (49.33 vs. 75.79; P=0.011), indicating more severe ß-cell dysfunction. No significant difference was observed in the prevalence of IR between benign and malignant ovarian neoplasms for the following values of each marker: FIL (25.9% vs. 12.0%), HOMA-IR (37.0% vs. 28.0%), FIRI (51.9% vs. 48.0%) and QUICKI (81.5% vs. 92.0%). The indicators of FIL, HOMA-IR, HOMA-ß, FIRI, and QUICKI correlated with each other and confirmed the reliability of these surrogate markers for measuring IR status in ovarian neoplasms. In brief, benign ovarian neoplasms tended to have more IR when compared with malignant ovarian neoplasms. However, this difference was not statistically significant.

Establishment of Epithelial Cell Culture from Ovarian Cancer Tissues: A Method Comparison Study.

OBJECTIVE: This study aimed to determine the most effective method in establishing primary cell culture from epithelial serous ovarian cancer tissues with the highest yield of cells and percentage of epithelial cells. METHODS: Primary and metastasis tissues from three serous ovarian cancer patients were processed using 18 different combinations of methods based on different factors: the source of tissue (primary site or metastasis site), the cell suspension method (explant method, enzymatic methods, or the addition of Percoll), and the alternatives of three different media. We compared the total count of cells, the percentage of epithelial cells, and the estimated number of epithelial cells per observation field. The calculation of cells from primary tissues were compared to metastasis tissues, and the difference was statistically analyzed using Mann Whitney-U test on SPSS software. RESULT: The groups that were processed using dispase and trypsin resulted higher number of cells and higher percentage of epithelial cells when compared to the explant method. Among all media, we found that DMEM:F12 and McCoy's 5A media as equally useful in isolating and culturing epithelial cells. Statistically, the metastasis tissue derived more epithelial cells when compared to the primary tissue (102.32±82.65 vs 22.6±23.81, p=0.001). CONCLUSION: The use of metastasis tissue processed with trypsin or dispase and cultured in DMEM:F12 or McCoy's 5A media was found to be the most efficient way to produce the highest amount of cells with high percentage of epithelial cells.

Histopathological discrepancy and variation of surgical management in mucinous ovarian cystadenoma and pseudomyxoma peritonei.

INTRODUCTION AND IMPORTANCE: Mucinous cystadenoma occurs in 10-15% of all ovarian tumors. Diagnosis and treatment should be decided precisely as it has a chance to develop into pseudomyxoma peritonei (PMP). Management of PMP might be challenging especially when repeated surgery is needed. CASE PRESENTATION: The first case, a 22-year-old lady with recurrent stomach enlargement for seven months. She had history of laparotomy surgery due to an ovarian tumor. Whole abdomen contrast CT scan showed a large cyst with mucinous fluid. We decided to do re-laparotomy and found a left ovarian cyst. Histological examination results confirm ovarian mucinous cystadenoma. The second case was, 55-year-old woman, with abdominal enlargement for six months. She had a history of laparotomy and chemotherapy due to pseudomyxoma peritonei. Post chemotherapy MRI showed persistent pseudomyxoma and two multilocular cysts from both adnexa. Debulking laparotomy was then conducted. We obtained 8 L of mucinous pseudomyxoma along with mucinous cyst from both ovaries. The final diagnosis concluded as a pseudomyxoma and we decide to close the follow-up of the patient. CLINICAL DISCUSSION: Pseudomyxoma is caused by the production of mucin originating from intra-abdominal organs. Open surgery should be prioritized when the mucinous cystadenoma is detected to do a complete peritoneum evaluation and avoid perioperatively ruptured mucinous neoplasm. Pseudomyxoma often needed repeated surgical treatment and may exhibit different surgical findings and different pathologies. CONCLUSION: Repeated surgery is logical and still no need for adjuvant chemotherapy in both cases. Accurate and precise diagnosis should be prioritized in order to prevent repeated surgery.

Knowledge, attitudes, and practices among Indonesian urban communities regarding HPV infection, cervical cancer, and HPV vaccination.

BACKGROUND: Few studies explored Indonesian understanding of cervical cancer (CC) and the human papillomavirus (HPV) vaccination. We aimed to investigate the association between knowledge, attitudes, and practices (KAP) and socio-demographical influences related to HPV, CC, and vaccination among Indonesian urban citizens. METHODS: We conducted an online survey during March 2020-August 2021 using the Snowball sampling technique. The socio-demographic characteristic and KAP responses were collected via Google Forms from 400 respondents in Jakarta. The knowledge and attitudes were divided into HPV and CC (aspect 1) and HPV vaccination (aspect 2). Correlation between KAP scores was performed using Spearman's test, and multiple logistic regression analyses were conducted to determine KAP predictors. RESULTS: Indonesian urban citizens in Jakarta were found to have poor knowledge in individual aspects of the inquiry but moderate knowledge overall, good attitude in inquiry both in each aspect and overall, and unsatisfying practices. Overall, in the general population, men, and women respectively: 50.8%, 32.4%, and 53.6% had good knowledge; 82.0%, 75.2%, and 84.4% expressed positive attitude; and 30.3%, 15.2%, and 35.6% applied favorable practice regarding questions inquired. Knowledge was weakly correlated towards attitude (ρ = 0.385) but moderately correlated with practice (ρ = 0.485); attitude was moderately correlated with practice (ρ = 0.577), all results: p<0.001. Significant odds ratio (OR) for predictors to good knowledge were female sex (OR = 2.99), higher education (OR = 2.91), and higher mother's education (OR = 2.15). Factors related to positive attitudes were higher mother's education (OR = 4.13), younger age (OR = 1.86), and better results in the knowledge inquiries (OR = 2.96). Factors that suggested better practices were female sex (OR = 2.33), being employed (OR = 1.68), excellent knowledge scores (OR = 4.56), and positive attitudes expressions (OR = 8.05). Having done one vaccination dose and intention to receive vaccines were significantly influenced by good KAP. CONCLUSIONS: KAP had inter-association to successful CC and HPV prevention programs, and socio-demographical characteristics are critical to influencing better KAP.

The Utility of Pre-Treatment Inflammation Markers as Associative Factors to the Adverse Outcomes of Vulvar Cancer: A Study on Staging, Nodal Involvement, and Metastasis Models.

BACKGROUND: Given the role of inflammation in carcinogenesis, this study investigated the utility of pre-treatment inflammatory markers as associative indicators for advanced-stage disease, lymph node metastasis (LNM), and distant metastasis (DM) in vulvar cancer (VC). METHODS: A cross-sectional study was conducted on 86 women with VC in a single centre in Jakarta, Indonesia. The laboratory data was based on C-reactive protein (CRP), procalcitonin, the erythrocyte sedimentation rate (ESR) and fourteen derived, recorded and calculated ratios: leukocyte-to-platelet (LPR), neutrophil-to-lymphocyte (NLR), derived neutrophil-to-lymphocyte (dNLR), neutrophil-to-monocyte (NMR), platelet-to-monocyte (PLR), lymphocyte-to-monocyte (LMR), basophil-to-monocyte (BLR), systemic immune-inflammation index (SII), body mass index, albumin, and NLR (BAN) score, haemoglobin-to-platelet (HPR), prognostic nutritional index (PNI), modified Glasgow Prognostic Score (mGPS), CRP-to-albumin, and CRP-to-procalcitonin. The optimal cut-off for each marker was determined using receiver operating characteristic (ROC) curve analysis, and their diagnostic indicator performances were assessed. The utility of these ratios as associative factors for three endpoints was further evaluated in multivariate regression models. RESULTS: Investigated inflammatory markers exhibited specific performances for individual adverse outcomes, proving a fair to excellent ability in case finding and screening. After adjustment, the BAN score ≤ 334.89 (OR 9.20, p = 0.001) and ESR ≥ 104 (OR 4.18, p = 0.048) become two advanced-stage associative factors with AUC: 0.769. LNM was solely determined by higher NLR ≥ 2.83 (OR 4.15, p = 0.014) with AUC: 0.615. Meanwhile, BLR ≥ 0.035 (OR 5.67, p = 0.001) and ESR ≥ 84 (OR 6.01, p = 0.003) were contributing factors for DM, with AUC: 0.765. CONCLUSIONS: Inflammatory markers are crucial for identifying the deleterious outcomes of VC. Accordingly, yielded models require external validation.

Early stage epithelial ovarian cancer metastasis through peritoneal fluid circulation.

BACKGROUND: Although epithelial ovarian cancer (EOC) spreads through peritoneal circulation, all patients with clinical early-stage ovarian cancer (OC) benefit from routine surgical staging is still unclear. METHODS: This cross-sectional study used data from medical records of patients with clinical early-stage EOC who received complete surgical staging from 2006 to 2016 at our hospital. We excluded patients with non-epithelial OC or with stage IV disease. RESULTS: Among 50 patients with clinical early-stage EOC who underwent surgical staging, biopsies showed EOC cells in peritoneal fluid for 12 patients (24%), in peritoneal tissue for ten patients (20%), and omental tissue for eight patients (16%). Of those 50 patients, 40 patients had undergone peritoneal biopsies, and the other five patients also had omental biopsies. The results showed that only one (2.5%) from 40 patients with peritoneal biopsy and three (6.7%) from 45 patients with omental biopsy had no visible nodules. From cytology examination, 3 out of 26 patients (11.5%) showed positive cytology from peritoneal washing. CONCLUSIONS: Routine peritoneal biopsies do not seem advantageous for patients with clinical early-stage EOC as negative visible nodules with positive biopsy results were only 1 in 40 cases. However, further study with a larger cohort is needed to obtain more information on peritoneal fluid metastasis patterns.

Hysteroscopy Role for Female Genital Tuberculosis.

Female genital tuberculosis affects the quality of women's lives. One of the symptoms is amenorrhea. In our country, it is still underdiagnosed due to limited resources. Hysteroscopy is known as one of the diagnostic tools for this condition. We performed hysteroscopy and endometrial biopsy in four cases. Hysteroscopy findings show various signs. Histopathological examination showed typical features of tuberculosis in some cases. We also learned that hysteroscopy could evaluate the condition of the endometrium when ongoing and after treatment is accomplished. It is useful for further explanation to the client. Hysteroscopy can be utilized as a diagnostic tool for endometrial sampling, evaluate intracavity condition after treatment, and prognostic tool for future reproductive function.

Adult granulosa cell tumor with minor foci of juvenile granulosa cell tumor in postmenopausal woman: A rare case report.

INTRODUCTION: Granulosa cell tumor (GCT) is a rare neoplasm that is divided into adult GCT (AGCT) and juvenile GCT (JGCT). Generally, a patient will only have the AGCT or JGCT subtypes. Here, we presented the first case of AGTC accompanied by focal JGTC in a postmenopausal woman. PRESENTATION OF CASE: A 63-year-old postmenopausal woman came with distended abdomen accompanied by postmenopausal bleeding. CT scan shows a solid mass with cystic degeneration. Laparotomy found a solid mass from the right ovary measuring 18 × 15 × 14 cm. The pathological results showed a diffuse tumor representing AGCT, accompanied by Call-Exner bodies and nuclear groove. In addition, minor foci were also found, which consist of well-defined margins tumor and follicular-like structures that resemble JGCT. The patient underwent bilateral salpingo-oophorectomy with a total hysterectomy and no recurrence in three months follow-up. DISCUSSION: Age and clinical symptoms cannot be used as specific differentiators between AGTC and JGTC. Radiological imaging also shows a similar appearance of solid masses tumors with hemorrhagic or fibrotic changes, multilocular cystic lesions, or completely cystic tumors. The concomitant findings of JGCT and AGCT could be distinguished very carefully by anatomical pathology examination. It is crucial to differentiate AGCT from JGCT, especially to see the prognosis. CONCLUSION: The role of pathologists is needed in differentiating AGCT and JGCT, primarily when found simultaneously.

Rare case of huge vulvar angiomyofibroblastoma in a young female.

Mesenchymal tumours of the vulva are rare and consist of two types, difficult to distinguish but with different prognoses. Angiomyofibroblastoma (AMFB) is a benign tumour, whereas Aggressive Angiomyxoma (AA) is an infiltrating tumour. We describe a 22-year-old nulliparous patient with a vulvar mass sized 19 cm in diameter. After preoperative assessment by ultrasound, chest X-ray, and MRI, wide excision on the tumour was done and diagnosed as AMFB. Differentiation from AA is being discussed.

Fas Ligand (FasL) in Association with Tumor-Infiltrating Lymphocytes (TILs) in Early Stage Cervical Cancer.

OBJECTIVE: To date, little is known about the roles of FasL and TILs in cervical cancer. This study aims to determine the correlation between FasL expression and TILs presence in cervical cancer. METHODS: In this study, we analysed the FasL and TIL presence in 32 squamous cell carcinoma or adenocarcinoma that were obtained from early stage (≤ IIA2) cervical cancer patients using immunohistochemistry. The level of FasL and TIL was assessed qualitatively, and then quantified with the H-Score system. RESULTS: Most of the patients were between 30 to 50 years old (59,4%), and had never taken pap smear examination before (96,9%). Based on the Pearson analysis of FasL and TIL presence, we found that FasL was inversely correlated with CD45 or TIL number when the level of FasL is above 140 and the CD45 is below 160. Based on Chi-Square test of FasL and TIL classification, there was a nine-fold odds ratio (OR) of lower TILs classification in high expression of FasL classification (OR 9, p=0.01). CONCLUSION: An inverse correlation between FasL expression and TILs level, that might indicate FasL-induced TILs apoptosis in tumor tissue, was observed. The strong inverse correlation between FasL and TILs presence showed some insight about the interactions between cancer cells and its surroundings inside of the cervical cancer tissue. This might also be further developed to tailor a prognostic marker that can predict the outcome of therapy in patients, not only in cervical cancer, but generally in all cancer.

Prophylactic salpingectomy and ovarian cancer: An evidence-based analysis.

INTRODUCTION: One of the ovarian carcinogenesis theories was the presence of premalignant cells in the epithelium of the fallopian tube. Therefore, the prophylactic salpingectomy during benign gynecological surgery is now expected as the attempt to reduce the ovarian cancer incidence. We studied the effect of prophylactic bilateral salpingectomy (PBS) in reducing the ovarian cancer incidence. METHODS: This evidence-based report resulted from critical appraisal of 5 articles. It is aimed to answer our clinical question, can bilateral prophylactic salpingectomy reduce the incidence of ovarian cancer among women underwent hysterectomy for benign condition or permanent contraception surgery? The search was conducted on the Cochrane Library®, PubMed®, and Embase® using keywords of "prophylactic salpingectomy," and "ovarian cancer incidence." Reference lists of relevant articles were searched for other possibly relevant articles. RESULTS: Five studies were included in our appraisal. The incidence of ovarian cancer among women underwent prophylactic salpingectomy is lower compared to women who were not underwent any intervention (2.2% to 13% and 4.75% to 24.4%). The salpingectomy may reduce 29.2% to 64% of ovarian cancer incidence. No significant effect of PBS to ovarian function, quality of life, sexuality, surgery duration, and its cost-effective profile were also found throughout our literature study. CONCLUSION: PBS is suggested to be performed for women during benign gynecological surgery as a primary preventive strategy of ovarian cancer. PBS is a cost-effective procedure, risk-reducing for ovarian cancer and has no significant effect to the ovarian function.

Prevalence, Age Distribution, and Risk Factors of Visual Inspection With Acetic Acid-Positive From 2007 to 2011 in Jakarta.

BACKGROUND: Cervical cancer is still the second most frequent cancer among Indonesian women, thus screening program is still critically important to prevent it. Visual inspection with acetic acid (VIA) was introduced as a method which is most suitable with Indonesia's condition compared with the other screening methods. The Female Cancer Program from Jakarta Regional collaborated with Leiden University in 2007 to 2011 has done cervical cancer screening using VIA method, involving 25,406 women spreading across several primary health centers in Jakarta. By using these data, we found out the prevalence, age distribution, and risk factor of VIA positive in Jakarta as a basis to predict the budget and logistics for the next cervical cancer screening and to do an advocating to the Jakarta's government. METHODS: A secondary data analysis was conducted from several areas in Jakarta from 2007 to 2011. VIA test was used as the screening method, and performed by doctors and midwives with technical supervision by gynecologists. RESULTS: From 25,406 women, there were 1,192 cases (4.7%) of VIA test positive. The risk factors that can significantly influence the result of VIA positive were number of marriage, parity, smoking habits, and the use of hormonal contraception with OR 1.51, 1.85, 1.95, and 0.68, respectively. CONCLUSIONS: Prevalence of VIA test-positive is 4.7% in Jakarta population. The findings of precancerous lesions and cervical cancers are not only between thirty and fifty years old, but also below the thirty years old and after fifty years old. We suggest that VIA test should be performed to all reproductive age and elder women who are not screened yet.