A multi-centre randomised controlled trial comparing megestrol acetate to levonorgestrel-intrauterine system in fertility sparing treatment of atypical endometrial hyperplasia.

PURPOSE: The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients. METHODS: The study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40 years old were included. The patients were randomised to receive either MA (160 mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3 months, 6 months and 9 months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes. RESULTS: Thirty-six patients completed the trial. The overall regression rate was 88.9% by 9 months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages. CONCLUSION: Our study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy. TRIAL REGISTRATION NUMBER: The study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct_r/enquiry.do?action=loadSpecificDetail . The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487 .

Combined modality management of advanced cervical cancer including novel sensitizers.

The management of advanced cervical cancer has evolved with time. Combined modality treatments for cervical cancer have been shown to improve clinical outcomes for these patients. The role of surgery is reviewed in this article for specific situations such as the treatment of bulky lymph nodes and even in the metastatic setting. External beam radiotherapy and brachytherapy techniques have improved which has decreased patient toxicity. Systemic therapy such as chemotherapy, immunotherapy, and novel sensitizing agents have been extensively studied and have shown promising results. The combination of these three different modalities of treatment can be tailored to each specific patient to achieve the best outcomes. We review the recent advances and various international guidelines for the management of cervical cancer in this article.

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

INTRODUCTION: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. METHODS: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. RESULTS: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). CONCLUSION: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). METHODS: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. RESULTS: 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. CONCLUSION: Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

Extragonadal teratomas in women and adolescent girls: A systematic review.

INTRODUCTION: Extragonadal teratomas (EGTs) are rare and the commonest intra-abdominal subtype is omental. We present two cases: 1) a parasitic omental teratoma likely secondary to auto-amputation of an ovarian teratoma with subsequent omental reimplantation and 2) an omental immature teratoma likely due to parthenogenetic activation of displaced primordial germ cells. We subsequently conduct a systematic review to characterise EGTs. METHODS: We sourced for English, peer-reviewed case reports of extragonadal teratomas in women and female adolescents aged 11 and above published from inception of each database through 31st June 2020 following PRISMA guidelines. Two authors reviewed each case for appropriateness and each case was graded for methodological quality utilising a modified Newcastle Ottawa Scale. PROSPERO Registration Number: CRD42020190131 RESULTS: Upon literature review between 1920-2020, from an initial screen of 818 articles, 67 articles were selected featuring 70 cases. One case featured an immature teratoma while the remaining were mature. Omental EGTs were the most common (56.5 %) followed by Pouch of Douglas and uterosacral ligament (23.2 %) and upper abdomen (14.5 %). There were statistically significant differences in EGT mean sizes between each location with the largest being in the upper abdomen (10.9 cm) and the smallest being in the adnexa or hernia (6.2 cm). Auto-amputation was deemed the commonest cause amongst omental EGTs (55.3 %) and Pouch of Douglas and uterosacral ligament EGTs (37.5 %) while 70 % of upper abdominal EGTs were likely due to displaced primordial germ cells. We characterise clinical features associated with each pathogenic mechanism and imaging characteristics of EGTs. Characterisation of EGT tumour marker profiles was limited as only 42.9 % of cases reported them but 19.2-25.0 % had raised tumour markers. The main risks are torsion, rupture, immature components and potential malignant change of the cell lines. Treatment is largely surgical. The mean size of EGTs approached laparoscopically and via laparotomy was 5.23 cm and 9.16 cm respectively. CONCLUSIONS: While rare, EGTs should be considered when evaluating pelviabdominal masses with imaging characteristics consistent with teratomas. Confirmation is usually intraoperative and a laparoscopic approach is reasonable if there is good surgeon comfort and the size is about 5 cm.

PD-L1 Expressing Recurrent Clear Cell Carcinoma of the Vulva with Durable Partial Response to Pembrolizumab: A Case Report.

BACKGROUND: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. CASE PRESENTATION: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. CONCLUSION: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

A comparative study between the pioneer cohort of waterbirths and conventional vaginal deliveries in an obstetrician-led unit in Singapore.

OBJECTIVE: Waterbirth has been increasing in popularity in Asia (Lea W. Water babies. The Straits Times 17 February 2011. Available at http://www.nuh.com.sg/news/media-articles_1504.html). National University Hospital, Singapore, is the pioneer hospital offering waterbirths to women since 2006 in a unique setting of a consultant-led service and continuous foetal monitoring. To date, no studies have been done on the conduct of waterbirths in an Asia. This study aims to evaluate if water immersion during delivery is associated with increased rates of adverse maternal and foetal outcomes as compared with conventional vaginal deliveries. MATERIALS AND METHODS: Clinical records of women who birthed underwater at National University Hospital between 2010 and 2013 were retrospectively reviewed. Outcomes of interest were estimated blood loss, third- or fourth degree tears, incidence of postpartum infections or haemorrhage, neonatal Apgars at 1 and 5 min, and neonatal complications requiring intensive care unit admission. Outcomes were compared against a matched control group of women who had conventional vaginal deliveries within ≤1 month. RESULTS: Records of 118 women who birthed underwater were accrued. There was no significant difference in estimated blood loss and postpartum haemorrhage between groups, and there were no cases of maternal infection, third- or fourth-degree perineal tears, or adverse neonatal outcomes in either group. Women in the control group were more likely to have episiotomies (63.6% vs. 0.85%; p < 0.01). Three cases of retained placenta were reported in the waterbirth group (0.03%). CONCLUSION: Waterbirth at our centre does not appear to be associated with an increased incidence of adverse neonatal and maternal outcomes. The results of this study supported waterbirth as a birthing option to groups of low-risk women in an obstetrician-led setting with good midwifery support.

Limited benefit of hepatitis B immunoglobulin prophylaxis in children of hepatitis B e antigen-negative mothers.

INTRODUCTION: In 2006, Singapore adopted the universal hepatitis B immunoglobulin (HBIg) policy. Since then, all infants of hepatitis B surface antigen (HBsAg)-positive mothers receive HBIg, irrespective of maternal hepatitis B e antigen (HBeAg) status. However, the benefits of HBIg for infants of HBeAg-negative mothers are unclear. We compared the vertical transmission rates among children of HBeAg-negative mothers who were given HBIg versus a retrospective cohort who were not given HBIg, to determine its protective effect. METHODS: This observational study involved pregnant HBsAg-positive women seen at National University Hospital, Singapore, between June 2009 and December 2013. If the infants of these mothers completed the recommended vaccination schedule, they were recruited into the study, along with their older siblings. Serological testing for the children was performed three months after completion of the last dose of vaccine, and hepatitis B virus (HBV) surface gene sequencing was carried out if HBV DNA was detected. RESULTS: A total of 111 infants and 47 siblings were recruited. 2 (1.5%) children were found to have vertical transmission despite receiving HBIg, while no incidences of vertical transmission were found among the historical controls who did not receive HBIg (p = 1.00). CONCLUSION: The overall effectiveness of the hepatitis B vaccination programme for children of HBsAg-positive mothers was high, regardless of HBIg administration. The addition of HBIg did not appear to confer additional benefits, in terms of vertical transmission rate, among infants born to HBeAg-negative mothers.

Erratum to: Respiratory consequences of N95-type Mask usage in pregnant healthcare workers-a controlled clinical study.

[This corrects the article DOI: 10.1186/s13756-015-0086-z.].

Respiratory consequences of N95-type Mask usage in pregnant healthcare workers-a controlled clinical study.

BACKGROUND: Outbreaks of emerging infectious diseases have led to guidelines recommending the routine use of N95 respirators for healthcare workers, many of whom are women of childbearing age. The respiratory effects of prolonged respirator use on pregnant women are unclear although there has been no definite evidence of harm from past use. METHODS: We conducted a two-phase controlled clinical study on healthy pregnant women between 27 to 32 weeks gestation. In phase I, energy expenditure corresponding to the workload of routine nursing tasks was determined. In phase II, pulmonary function of 20 subjects was measured whilst at rest and exercising to the predetermined workload while breathing ambient air first, then breathing through N95-mask materials. RESULTS: Exercising at 3 MET while breathing through N95-mask materials reduced mean tidal volume (TV) by 23.0 % (95 % CI -33.5 % to -10.5 %, p < 0.001) and lowered minute ventilation (VE) by 25.8 % (95 % CI -34.2 % to -15.8 %, p < 0.001), with no significant change in breathing frequency compared to breathing ambient air. Volumes of oxygen consumption (VO2) and carbon dioxide expired (VCO2) were also significantly reduced; VO2 by 13.8 % (95 % CI -24.2 % to -3 %, p = 0.013) and VCO2 by 17.7 %, (95 % CI -28.1 % to -8.6 %, p = 0.001). Although no changes in the inspired oxygen and carbon dioxide concentrations were demonstrated, breathing through N95-mask materials during low intensity work (3 MET) reduced expired oxygen concentration by 3.2 % (95 % CI: -4.1 % to -2.2 %, p < 0.001), and increased expired carbon dioxide by 8.9 % (95 % CI: 6.9 % to 13.1 %; p <0.001) suggesting an increase in metabolism. There were however no changes in the maternal and fetal heart rates, finger-tip capillary lactate levels and oxygen saturation and rating of perceived exertion at the work intensity investigated. CONCLUSIONS: Breathing through N95 mask materials have been shown to impede gaseous exchange and impose an additional workload on the metabolic system of pregnant healthcare workers, and this needs to be taken into consideration in guidelines for respirator use. The benefits of using N95 mask to prevent serious emerging infectious diseases should be weighed against potential respiratory consequences associated with extended N95 respirator usage. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov, identifier NCT00265926.

Gynaecologic robot-assisted cancer and endoscopic surgery (GRACES) in a tertiary referral centre.

INTRODUCTION: Robotic-assisted gynaecologic surgery is gaining popularity and it offers the advantages of laparoscopic surgery whilst overcoming the limitations of operative dexterity. We describe our experience with the fi rst 40 cases operated under the GRACES (Gynaecologic Robot- Assisted Cancer and Endoscopic Surgery) programme at the Department of Obstetrics & Gynecology, National University Hospital, Singapore. MATERIALS AND METHODS: A review was performed for the fi rst 40 women who had undergone robotic surgery, analysing patient characteristics, surgical timings and surgery-related complications. All cases were performed utilising the da Vinci® surgical system (Intuitive Surgical, Sunnyvale, CA) with 3 arms and 4 ports. Standardised instrumentation and similar cuff closure techniques were used. RESULTS: Seventeen (56%) were for endometrial cancer and the rest, for benign gynaecological disease. The mean age of the patients was 52.3 years. The average docking time was 11 minutes (SD 0.08). The docking and operative times were analysed in tertiles. Data for patients with endometrial cancer and benign cases were analysed separately. There were 3 cases of complications- cuff dehiscence, bleeding from vaginal cuff and tumour recurrence at vaginal vault. CONCLUSION: Our caseload has enabled us to replicate the learning curve reported by other centres. We advocate the use of a standard instrument set for the fi rst 20 cases. We propose the following sequence for successful introduction of robot-assisted gynaecologic surgery - basic systems training, followed shortly with a clinical case, and progressive development of clinical competence through a proctoring programme.