Clinical and Management Dilemmas Concerning Early-Stage Cervical Cancer in Pregnancy - A Case Report.

Background: Cervical cancer in pregnancy is rare and its management remains a formidable challenge. Clinical upstaging is a serious concern. Presentation may mimic pregnancy-related conditions, thus delaying diagnosis and leading to an advanced stage at presentation. In addition, concerns regarding chemotherapy safety in pregnancy may hinder its administration. Definitive therapy may also be delayed due to pregnancy. Case Report: A 37-year-old G3P2A0 10-11 weeks pregnant woman was diagnosed with stage IB2 cervical cancer. We originally planned to perform neoadjuvant chemotherapy with paclitaxel 175mg/m2 and carboplatin 6 AUC every 21 days followed by caesarean section and radical hysterectomy. However, preoperatively, the tumor had grown further and progressed to stage IIB. Postpartum radiotherapy was thus indicated. Lower segmental caesarean section along with bilateral salpingectomy and ovarian transposition were performed. Radiotherapy was administered through external beam radiation therapy and brachytherapy. The patient delivered a small for gestational age male baby with no abnormalities. At 2-month follow-up, the infant appeared generally healthy. Conclusion: Cancer diagnosis during pregnancy adversely impacts women's physical and psychological states. Symptoms may mimic pregnancy-related conditions, thus delaying diagnosis. Its management involves a multidisciplinary team to protect both maternal and fetal health.

Comparison of Extravillous Intermediate Trophoblast Invasion Depth and Distribution Pattern Between Placenta Accreta and Non-Accreta.

BACKGROUND Placenta accreta spectrum (PAS) is a complex obstetric complication that poses a major risk for life-threatening hemorrhage. The pathogenesis of PAS is known to be related to placentogenesis, trophoblastic cells invasion, and previous obstetrical procedures that cause uterine wall defects. However, the precise mechanism of this disease has not been fully explained. This study aimed to evaluate the differences in maximum depth of invasion and distribution pattern of implantation site intermediate trophoblasts between PAS and non-accreta cases. MATERIAL AND METHODS This was an observational, analytic, cross-sectional study that utilized paraffin block specimen of peripartum hysterectomy performed in Hasan Sadikin General Hospital Bandung from 2018 to 2020. Sixty-four samples were obtained, then classified as PAS and non-accreta (normal placenta). Implantation site-intermediate trophoblasts were identified using CD-146 staining. Maximum invasion depth of intermediate trophoblasts was measured in micrometers, while the distribution pattern was assessed and classified into 2 groups: confluent and scattered. RESULTS We found that the maximum invasion depth of the intermediate trophoblasts was significantly higher in the PAS group compared to that of the non-accreta group (2453.52±1172.122 µm vs 1613.59±822.588 µm, P=0.009). The confluent distribution pattern was significantly more common in the PAS group compared to that of the non-accreta group (87.2% vs 17.6%, P=0.0001). CONCLUSIONS The findings of our study suggested that implantation site intermediate trophoblasts play a role in the pathophysiology of placenta accreta. Further studies are needed to determine factors that affect trophoblast invasion leading to placenta accreta spectrum.

Predicting Chemotherapy Resistance in Gestational Trophoblastic Neoplasia: Ratio of Neutrophils, Lymphocytes, Monocytes, and Platelets.

BACKGROUND Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) have recently been used as inflammatory biomarkers for cancer patients. This study aims to determine the role of pretreatment NLR, LMR, and PLR in predicting chemoresistance in gestational trophoblastic neoplasia (GTN) patients. MATERIAL AND METHODS A total of 129 low-risk and high-risk GTN patients who had received first-line chemotherapy were enrolled in this historical cohort study. The pretreatment NLR, LMR, and PLR values were analyzed to predict the resistance to first-line chemotherapy in low-risk and high-risk GTN patients. RESULTS Chemoresistant patients had significantly higher NLR than chemosensitive patients in low-risk and high-risk GTN patients (P<0.05). In high-risk GTN, patients with lower LMR and higher PLR tended to have chemoresistance to first-line chemotherapy (P=0.008, P=0.001). Univariate analysis revealed that the NLR, LMR, and PLR cut-off points of 2.654, 3.8, and 192.174, respectively, were associated with chemoresistance in high-risk GTN (P=0.0001, P=0.011, P=0.0001). The combination of NLR, PLR, and FIGO score in high-risk GTN was the best combination among other combinations with cut-off value >17 (P=0.001). CONCLUSIONS Higher NLR, lower LMR, and higher PLR were associated with chemoresistance for high-risk GTN patients. Furthermore, NLR, LMR, and PLR can improve the accuracy of predicting resistance to first-line chemotherapy in high-risk GTN.

Cervical pre-cancerous lesion detection: development of smartphone-based VIA application using artificial intelligence.

OBJECTIVE: Visual inspection of cervix after acetic acid application (VIA) has been considered an alternative to Pap smear in resource-limited settings, like Indonesia. However, VIA results mainly depend on examiner's experience and with the lack of comprehensive training of healthcare workers, VIA accuracy keeps declining. We aimed to develop an artificial intelligence (AI)-based Android application that can automatically determine VIA results in real time and may be further developed as a health care support system in cervical cancer screening. RESULT: A total of 199 women who underwent VIA test was studied. Images of cervix before and after VIA test were taken with smartphone, then evaluated and labelled by experienced oncologist as VIA positive or negative. Our AI model training pipeline consists of 3 steps: image pre-processing, feature extraction, and classifier development. Out of the 199 data, 134 were used as train-validation data and the remaining 65 data were used as test data. The trained AI model generated a sensitivity of 80%, specificity of 96.4%, accuracy of 93.8%, precision of 80%, and ROC/AUC of 0.85 (95% CI 0.66-1.0). The developed AI-based Android application may potentially aid cervical cancer screening, especially in low resource settings.

Myxoid Liposarcoma of the Vulva: A Rare Malignancy Mimicking Benign Vulvar Mass.

BACKGROUND Liposarcoma of the vulva is an exceptionally rare malignant tumor. Clinically, vulvar liposarcoma often mimics benign lesions, thus misdiagnosis is common. Herein, we present a case of myxoid liposarcoma of the vulva. To the best of our knowledge, this is the first case report of vulvar liposarcoma from Indonesia. CASE REPORT We present a case of a 39-year-old woman with left vulvar mass of 6 years duration that progressively increased in size. The patient reported having pressure and discomfort, especially during movement, but reported no pain. Lipoma was initially suspected. Surgical excision was performed and histopathological examination revealed a well-differentiated myxoid liposarcoma. The base and excised margins of the tumor were free of malignant cells. Post-operative course was uneventful and she was discharged in a satisfactory condition. The patient had been under regular follow-up and is currently symptom- and recurrence-free. We also review other cases of vulvar liposarcoma to further comprehend characteristics of this rare malignant tumor. CONCLUSIONS Liposarcoma of the vulva occurs very rarely, but clinicians and pathologists should always consider it as a differential diagnosis when presented with vulvar mass. Biopsy of a vulvar mass is crucial. Surgical excision remains the mainstay of treatment. Adjuvant radiotherapy may be considered in certain cases. Comprehensive follow-up for recurrences or metastasis is recommended throughout life.

Calcitriol potentially alters HeLa cell viability via inhibition of autophagy.

Objective: This study was conducted to evaluate the effect of Calcitriol on cellular death in HeLa cells via autophagy and turn over due to mitochondria homeostasis. Methods: HeLa cell lines were grown in 24-well plates and treated with Calcitriol at varying doses (0.013 µM-0.325 µM) for varying time periods (2, 6, 12, and 18 h). Cell proteins were extracted with scrapers and lysed using RIPA buffer. Western blots were performed for proteins involved with autophagy (Lc3, p62), signaling (mTOR, PI3K, HIF1α), mitochondria (PGC1α, COX4, and Tom 20), and apoptosis (Caspase 3, Caspase 9, and PARP). Protein carbonyl levels were determined by measuring the indirect ROS level. An inhibition study using L-mimosine was performed to analyze the significance of HIF1α. Results: Calcitriol treatment induced cytotoxicity in a dose- and time-dependent manner and caused growth arrest in HeLa cells. The PI3K-AKT-mTOR pathway was activated, leading to inhibition of autophagy and alterations in mitochondria biogenesis homeostasis. Treatment with Calcitriol produced protein carbonyl levels similar to those in the cisplatin-treated and control groups. Increased ROS levels may cause toxicity and induce cell death specifically in cancer cells but not in normal cells. The inhibition of HIF1α partially rescued the HeLa cells from the toxic effects of Calcitriol treatment. Conclusion: We suggest that Calcitriol may shut down mitochondrial homeostasis in HeLa cells by inducing the PI3K-AKT-mTOR pathway and inhibiting autophagy, which leads to cell death.

Prediction of clinical outcomes in women with placenta accreta spectrum using machine learning models: an international multicenter study.

INTRODUCTION: Placenta accreta spectrum is a major obstetric disorder that is associated with significant morbidity and mortality. The objective of this study is to establish a prediction model of clinical outcomes in these women. MATERIALS AND METHODS: PAS-ID is an international multicenter study that comprises 11 centers from 9 countries. Women who were diagnosed with PAS and were managed in the recruiting centers between 1 January 2010 and 31 December 2019 were included. Data were reanalyzed using machine learning (ML) models, and 2 models were created to predict outcomes using antepartum and perioperative features. ML model was conducted using python® programing language. The primary outcome was massive PAS-associated perioperative blood loss (intraoperative blood loss ≥2500 ml, triggering massive transfusion protocol, or complicated by disseminated intravascular coagulopathy). Other outcomes include prolonged hospitalization >7 days and admission to the intensive care unit (ICU). RESULTS: 727 women with PAS were included. The area under curve (AUC) for ML antepartum prediction model was 0.84, 0.81, and 0.82 for massive blood loss, prolonged hospitalization, and admission to ICU, respectively. Significant contributors to this model were parity, placental site, method of diagnosis, and antepartum hemoglobin. Combining baseline and perioperative variables, the ML model performed at 0.86, 0.90, and 0.86 for study outcomes, respectively. Ethnicity, pelvic invasion, and uterine incision were the most predictive factors in this model. DISCUSSION: ML models can be used to calculate the individualized risk of morbidity in women with PAS. Model-based risk assessment facilitates a priori delineation of management.

The Platelet to Lymphocyte and Neutrophil to Lymphocyte Ratios in Predicting Response to Platinum-based Chemotherapy for Epithelial Ovarian Cancer.

OBJECTIVE: The patients with advanced-stage ovarian cancer have higher factors complicating surgery; thus, the best choice for them is surgery with chemotherapy with six cycles of adjuvant chemotherapy. Generally, chemotherapy can be evaluated in various ways, phsychal examination, radiology examination, and laboratory examination. This study aims is to examine if the measurement of the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) can be used to predict a patient's response to chemotherapy. METHODS: Analytic observational study with a case-control design conducted in the Dr. Hasan Sadikin Hospital in Bandung from 2017 to 2018. This study used the medical record of ovarian cancer patients with post-surgery complete blood counts and histopathological reports. The sample size was determined based on the categorical test's statistical calculation to obtain a total number of at minimal 90 samples. All the study subjects who had undergone complete chemotherapy were followed up for 6 months. Their response to chemotherapy was assessed with a clinical examination, ultrasonography, and a CA-125 blood test every 3 months. RESULTS: In 2017-2018, 504 patients were diagnosed with ovarian cancer at the Dr. Hasan Sadikin Hospital in Bandung, Indonesia. After reassessment, 116 patients had stage I to III ovarian cancer and underwent cytoreduction followed by platinum chemotherapy. The age, cancer stage, and types of epithelial cells in the platinum-sensitive and platinum-resistant patients were characterized. There were significant differences between the two groups in age and cancer stage characteristics (p < 0.05). The increase in platelet/lymphocyte (p = 0.003) and neutrophil/lymphocyte ratios (p = 0.026) are associated with the increase in the response to platinum chemotherapy against epithelium-based cancers. CONCLUSION: A patient's NLR and PLR are strongly associated with his response to chemotherapy.

A Rare Case of Early Transformation of Gestational Trophoblastic Neoplasia Following Molar Pregnancy.

BACKGROUND Gestational trophoblastic disease (GTD) encompasses a group of disorders that arise from abnormal growth of trophoblastic tissue. The spectrum of GTD includes 2 major groups: benign and malignant. The benign form is a hydatidiform mole, either complete or partial; the malignant forms, referred to as gestational trophoblastic neoplasia (GTN), consist of invasive moles, choriocarcinomas, placental site trophoblastic tumors, and epithelioid trophoblastic tumors. Most patients who undergo evacuation of a hydatidiform mole by curettage have a disease-free period before a new tumor develops that can be considered malignant. In rare cases, metastasis occurs rapidly and manifests coincidentally before the hydatidiform mole can be evacuated. CASE REPORT A 19-year-old woman in Bandung City, West Java, Indonesia, was diagnosed with a molar pregnancy with early evidence of a mass in her vagina that was suspicious for stage II GTN. The early emergence of a vaginal mass was a rare case of early transformation of a molar pregnancy into GTN. CONCLUSIONS Careful evaluation is warranted of patients with characteristics typical of an intrauterine molar pregnancy who have an early presentation of a vaginal mass because of the possibility that the diagnosis could be GTN.

Analysis of Curcumin as a Radiosensitizer in Cancer Therapy with Serum Survivin Examination: Randomised Control Trial.

OBJECTIVE: One of the important treatments for cervical cancer is radiation therapy. This study sought to determine the role of curcumin as a radio-sensitizing agent for use with radiation therapy for cervical cancer. To accomplish this, we assessed the levels of survivin, which is an anti-apoptotic protein that plays a role in cell division and apoptosis inhibition. METHOD: This study used a quasi-experimental design, including a pretest-posttest control group design approach. The study subjects included cervical carcinoma stage IIB-IIIB patients who were scheduled to undergo surgery at the Hasan Sadikin Hospital Bandung during the research period. The advanced cervical cancer patients were assigned to two groups: i) those who received curcumin + radiation therapy and ii) those who received placebo + radiation therapy. RESULTS: In the group treated with curcumin + radiation, 15 (75%) patients showed decreased survivin levels and 5 (25%) showed increased survivin levels. Whereas, in the placebo + radiation group, there were 8 (40%) patients who showed decreased survivin levels and 12 (60%) who showed increased survivin levels. CONCLUSION: In conclusion, curcumin is an effective, alternative radiosensitizer agent for application in cervical cancer treatment.
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Correlation of Serum Anti-Mullerian Hormone (AMH) Level on Ovarian Volume in Women with Endometrioma.

BACKGROUND: The correlation between endometrioma and serum Anti-mullerian hormone (AMH) level is a benchmark in determining the prognosis and management of endometrioma. Endometrioma causes a decrease in ovarian reserve due to tissue damage that affects the formation of serum AMH. Serum AMH levels in daily practice are useful as a tool to determine ovarian reserve, markers for diagnosis and prognosis in infertility and reproductive abnormalities. The purpose of this study was to determine the relationship of serum AMH level in women with endometrioma and their correlation to ovarian volume. METHODS: This research was an analytical observational study with a cross-sectional design in women of reproductive age who were diagnosed with endometrioma within the period of August 2019-March 2020 at Hasan Sadikin Hospital, Bandung. Forty-four women who met the inclusion and exclusion criteria were then divided into endometrioma (n=22) and control (n=22) groups. In both groups, transvaginal ultrasound examination was performed to measure the volume of the ovary, then a laboratory examination of serum AMH level was carried out. RESULTS: Serum AMH levels in the endometrioma group were significantly lower than those in the control group (P<0.001). Serum AMH level did not differ significantly based on laterality of the observation group (P=1.000). There was a negative correlation between serum AMH level and the volume of ovarian endometrioma, although not statistically significant (r=-0.332; P=0.066). CONCLUSION: There was a correlation between serum AMH level and endometrioma. Serum AMH levels were significantly lower in the endometrioma group but were not influenced by their laterality. We found a negative correlation between serum AMH level and ovarian volume containing endometrioma, but not statistically significant.

Prediction of success of uterus-preserving management in women with placenta accreta spectrum (CON-PAS score): A multicenter international study.

OBJECTIVE: To create a model for prediction of success of uterine-preserving procedures in women with placenta accreta spectrum (PAS). METHODS: PAS-ID is a multicenter study that included 11 centers from 9 countries. Women with PAS, who were managed between January 1, 2010 and December 31, 2019, were retrospectively included. Data were split into model development and validation cohorts, and a prediction model was created using logistic regression. Main outcome was success of uterine preservation. RESULTS: Out of 797 women with PAS, 587 were eligible. Uterus-preserving procedures were successful in 469 patients (79.9%). Number of previous cesarean sections (CS) was inversely associated with management success (adjusted odds ratio [aOR] 0.02, 95% confidence interval [CI] 0.001-3.63 with five previous CS). Other variables were complete placental invasion (aOR 0.14, 95% CI 0.05-0.43), type of CS incision (aOR 0.04, 95% CI 0.01-0.25 for classical incision), compression sutures (aOR 2.48, 95% CI 1.00-6.16), accreta type (aOR 3.76, 95% CI 1.13-12.53), incising away from placenta (aOR 5.09, 95% CI 1.52-16.97), and uterine resection (aOR 102.57, 95% CI 3.97-2652.74). CONCLUSION: The present study provides a prediction model for success of uterine preservation, which may assist preoperative and intraoperative decisions, and promote incorporation of uterine preservation procedures in comprehensive PAS protocols.

Efficacy of Oral Vitamin A in Reducing ß-hCG Levels in Low-Risk Gestational Trophoblastic Neoplasia Patients.

OBJECTIVE: Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy and methotrexate (MTX) as a first-line therapy. Vitamin A helps to increase trophoblast cell regression, as well as to decrease ß-hCG levels. Vitamin A also increases the effectiveness of MTX by inducing more malignant cell death than MTX alone. Therefore, the aim of the current study was to analyze the changes in ß-hCG levels in low-risk GTN patients following vitamin A administration. METHODS: This study was a randomized clinical trial, which examined initial serum vitamin A and ß-hCG levels in GTN patients before and after three cycles of MTX therapy. Patients were given vitamin A supplementation of 6,000 IU (1.8 mg RAEs) per day, and the changes in serum ß-hCG were observed after three cycles. Patients were grouped by ß-hCG levels (decreased or stagnant). RESULTS: A total of 32 low-risks GTN patients were divided into the intervention group (16 patients who received vitamin A supplementation) and the control group (16 patients who did not receive vitamin A supplementation). In the intervention group, the average initial ß-hCG level was 170,949.3 ± 354,452.1 mIU/mL, and the average ß-hCG post-cycle level was 1,611.9 ± 3,652.5 mIU/mL. In the control group, the average initial ß-hCG level was 178,834.1 ± 2913844.6 mIU/mL, and the average ß-hCG post-cycle level was 25,388.5 ± 58,437.7 mIU/mL. CONCLUSION: In patients with low-risk GTN who underwent MTX chemotherapy, the levels of ß-hCG and the incidence of chemo resistance in the intervention group were lower than those in the control group. Older age may also influence the incidence of chemo resistance in GTN patients. Oral administration of 6,000 IU vitamin A could help to reduce ß-hCG levels in low-risk GTN patients who receive MTX chemotherapy.
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Pulsatility Index and Hypoxia Inducible Factor-1α Expression Predict the Clinical Response after External Radiation in Patients with Stage IIB to IVA Cervical Cancer.

Objective: To evaluate the ability of pulsatility index (PI), resistance index (RI), and hypoxia inducible factor-1α (HIF-1α) expression in predicting the clinical response after radiation in patients with cervical cancer. Methods: A prospective cohort was carried on in Department of Obstetric and Gynecology Dr. Hasan Sadikin Hospital/ Faculty of Medicine, Padjadjaran University, during the period of July 2017 to March 2018 which include 51 samples with stage IIB to IVA cervical cancer. Tumor perfusion and oxygenation were evaluated using color Doppler ultrasound indices (pulsatility index and resistance index) and the expression of hypoxia inducible factor-1α (HIF-1α). The clinical response was assessed 2 months after external radiation. Result: Among 51 patients, 31 patients demonstrated good response and 20 patients demonstrated poor response to radiation. The mean value of PI was significantly lower in patients who demonstrated good response as compared to patients with poor response (0.84±0.916 vs. 1.70±1.260, p = 0.004). The mean value of RI did not differ significantly (0.29±0.112 vs. to 0.36±0.189 p =0.173). HIF-1α expression was significantly lower in patients who demonstrated good response as compared to patients with poor response (1.83±1.529 vs. 6.55±2.625, p = 0.0001). In multivariate model, PI and HIF-1α expression both predicted the clinical response after radiation. Conclusion: PI and HIF-1α expression predict the clinical response after radiation in patients with cervical cancer.