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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.

Background Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti‐HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm. Methods Serum anti‐HPV‐16/18 antibodies were determined at baseline and every 12 months in baseline DNA‐negative women (N = 2687 for HPV‐16 and 2705 for HPV‐18) by enzyme‐linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6‐months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7‐year period. The association between the risk of type‐specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models. Results Risk of newly detected HPV‐16‐associated 6‐month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC‐US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV‐16‐associated incident infections (HR = 0.81 [0.56; 1.16]) and 12‐month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV‐18‐seropositive vs ‐seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6‐month PIs, HR = 0.31 [0.07; 1.36] for 12‐month PIs, and HR = 0.61 [0.23; 1.61] for ASC‐US+). Conclusions Naturally acquired anti‐HPV‐16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15‐ to 25‐year‐old women.

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.

Optimal treatment for advanced cervical cancer after first line chemotherapy remains undefined. Immune checkpoint inhibition with pembrolizumab, a programmed cell death protein 1(PD-1) inhibitor, is under investigation. We analyzed the micro-environmental and molecular genetic profile of tumors from 4 patients with metastatic cervical cancer treated with off-label second-line pembrolizumab in an effort to identify predictive biomarkers. All patients received 2 mg/kg of pembrolizumab, 3-weekly until disease progression. Immunohistochemistry(IHC) for PD-1, PD-L1, CD3 and CD8, as well as next generation sequencing (NGS) for 50 cancer-related genes were performed on tumor samples. All patients tolerated treatment well with no discontinuation of treatment due to toxicity. One patient experienced dramatic and prolonged partial response, and remains stable on pembrolizumab with a progression free survival (PFS) of 21 months at the time of reporting of this series. Three patients experienced disease progression as best response. In the exceptional responder, there was no tumoral expression of PD-L1, however, combined positive score (CPS) for PD-L1 was 1 and we identified somatic mutations in ERBB4(R612W), PIK3CA(E542K) and RB1(E365K). In 2 patients, despite progressive disease defined by RECIST v1.1, symptom stabilization on pembrolizumab was observed. The tumors of both patients had PD-1 expression in ≥1% of stromal lymphocytes. All patients with response or clinical benefit had CPS for PD-L1 ≥ 1. NGS revealed PIK3CA mutations in 3 tumors. Pembrolizumab is a promising therapeutic option in advanced cervical cancer. Further evaluation of biomarkers may guide optimal patient selection., Highlights • 1 of 4 patients receiving second line pembrolizumab, experienced dramatic and durable response. • All patients with response or clinical benefit had CPS for PD-L1 ≥ 1. • Germline BRCA1 mutation was detected in 1 patient, but she was a non-responder. • All tumors had somatic mutation in PIK3CA or PTEN.

Purpose To report late rectal and bladder toxicity outcomes of a CT-based image-guided brachytherapy (IGBT) technique for treatment of cervical cancer. Methods and Materials Between 2008 and 2014, 95 women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma treated with definitive concurrent cisplatin-based chemotherapy and external beam radiation therapy 50.4 Gy in 28 fractions followed by planned prescription dose of 7 Gy × 4 fractions of high-dose-rate IGBT was retrospectively reviewed. At each implantation, all patients had a urinary catheter in situ and received bowel enema before undergoing planning CT simulation. A high-risk clinical target volume (HRCTV) as per GEC-ESTRO guidelines and the entire cervix, rectum, and bladder was contoured on the simulation CT according to Radiation Therapy Oncology Group Gynaecology Contouring Atlas. Reported doses to HRCTV and organs at risk were recorded. Toxicities were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3. Results The median followup time was 29 months. The mean HRCTV equivalent dose in 2 Gy fractions (EQD2) of external beam radiation therapy combined with brachytherapy was 80 Gy (standard deviation [SD], 11), and the rectal doses to 2 cm3 (D2cc) EQD2 and bladder D2cc EQD2 were 74 Gy (SD, 6) and 79 Gy (SD, 15), respectively. Twenty-two patients (23%) had grade 2 proctitis and 10 patients (11%) had grade 3 proctitis. Four patients (4%) had grade 2 cystitis and two patients (2%) had grade 3 cystitis. No patients had ≥ grade 4 toxicity. Conclusions Despite CT-based brachytherapy planning, reported organ at risk toxicity was still significant compared with reported MRI-based planning series. Coimplementation of interstitial IGBT using the European Study on MRI-guided Brachytherapy in Locally Advanced Cervical Cancer (EMBRACE) protocol or using intensity-modulated radiation therapy during the external beam phase treatment might help to limit these late toxicities.

Background Current recommendation for locally advanced cervical cancer includes pelvic external beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy. Involvement of pelvic lymph nodes is an important prognostic factor in locally advanced cervical cancer and recurrence commonly occurs despite definitive treatment. To date, there is no standard guideline on whether an EBRT boost should be applied to involved pelvic lymph nodes. Our study aims to assess if pelvic EBRT boost would reduce recurrence, benefit survival, and affect associated toxicities. Methods We conducted a retrospective review of locally advanced cervical cancer cases treated with definitive treatment at our institution. Involvement of pelvic lymph nodes were assessed on CT, MRI (> 10 mm or suspicious features) or PET scan (SUVmax > 2.5). EBRT dose ranged from 45 to 50.4 Gy with nodal boost ranging from 3.6–19.8 Gy. Results Between 2008 to 2015, 139 patients with locally advanced cervical cancer underwent treatment. Sixty-seven patients had positive pelvic lymph nodes, of which 53.7% received a nodal boost. Five-year recurrence free survival was 48.6% with vs. 64.5% without nodal boost (P = 0.169) and 5-year overall survival in those with positive pelvic lymph nodes was 74.3% with vs. 80.6% without nodal boost (P = 0.143). There was no significant difference in toxicity with nodal boost. Conclusions EBRT boost to pelvic lymph nodes does not reduce recurrence or improve survival in locally advanced cervical cancer with lymph node involvement at diagnosis.

6086 Background: Precision oncology approaches in EC patients (pts) are evolving with emerging targeted therapy. We reviewed the effect of genomic findings on treatment choice and outcome in an Asian EC cohort. Methods: Recurrent or metastatic ECs were prospectively profiled with next-generation sequencing (NGS) and relevant immunohistochemistry. Clinical data were collected to assess outcomes. Results: Between 12/2014 to 12/2019, 51 Asian EC pts of endometrioid (26/51), serous (7/51), carcinosarcoma (4/51), clear cell (4/51) and mixed (10/51) histology were enrolled. 35/51(69%) of tumors were high grade. The median age at diagnosis was 56 (range 37-77), and the median lines of treatment received was 3 (range 1-8). 45/51(88%) of pts had successful NGS profiling, 31/45(69%) using FoundationOne CDx, and 14/45 (31%) on an in-house platform. Frequent mutations (>20%) occurred in PTEN (60%), PIK3CA (49%), TP53 (46%), ARID1A (27%), CTNNB1 (24%) and KRAS (22%). There were 12/51(24%) MSI-H, 25/51(49%) MSS, and 14/51(27%) MSI-unknown tumors. The 6 mth progression free survival (PFS) rate for MSS versus MSI-H pts treated with front-line carboplatin+paclitaxel (CP) was 83% versus 50% (RR 1.67, fisher’s exact 2-sided p=0.09), with a shorter median PFS after 1st line CP for MSI-H versus MSS pts (median 5.2 mth vs. 8.3 mth, not sig). Upon progression, 29/51(57%) of pts were matched to therapy based on tumor profiles. Of these, 7/29(24%), 13/29(45%) and 9/29(31%) matched to anti-PD1/PD-L1, endocrine therapy and other targeted therapy, respectively. Among 7 MSI-H pts matched to anti-PD1/PD-L1 therapy, median PFS was 14.6 mth (95% CI 0.4-29), and objective response rate was 57%(4/7). In subsequent-line, matching to endocrine therapy (HR 4.3 95% CI 0.95-19.0, p=0.06) or other targeted therapy (HR 5.1, 95% CI 1.1-24.5, p=0.04) was associated with worse PFS compared to anti-PD1/PD-L1 therapy. Despite a short median PFS after front-line CP, median overall survival (OS) was not reached for MSI-H pts, compared to 38 mth (95% CI 30.7-46.0) for MSS and MSI-unknown pts. Conclusions: MSI-H EC pts appear to have shorter PFS to front-line CP chemotherapy compared with MSS pts, but may derive durable responses from immunotherapy in subsequent-line therapy. Early use of immunotherapy in advanced MSI-H EC pts should be considered. Further optimisation of therapy is urgently needed in advanced MSS EC.

42 Background: Cervical cancer is the 4th most common cancer in females. Treatment recommendation for locally advanced cervical cancer includes concurrent chemo-radiotherapy (RT) followed by brachytherapy. However, primary treatment failure is not uncommon and is attributed to RT resistance. In view of RT-associated complications, identification of RT-resistant groups at diagnosis will help to minimize exposure to unnecessary toxicities. Methods: Our initial studies analyzing the genetic profile of RT-sensitive and RT-resistant tumours from xenograft models have identified the GAGE-family protein as a genetic marker that is selectively upregulated in RT-resistant xenograft tumours in vitro & in animal studies and is associated with more aggressive phenotypes of these tumors. To clinically validate these findings, we carried out a pilot study on 8 patients and also analyzed GAGE-family protein levels in retrospective study samples obtained from initial biopsy samples from from patients who have completed chemoRT and brachytherapy for cervical cancer to correlate their initial GAGE-family protein levels with treatment response. Results: Immuno-histological staining of pathology samples from 8 patients in our pilot study have shown that those with a higher expression of GAGE-family protein at mRNA and protein levels are more resistant to standard RT. Our retrospective analysis of 43 cervical cancer biopsy samples showed significantly elevated levels of GAGE-family protein mRNA ( P= 0.0028) and GAGE-family protein intensity score ( P= 0.026) in the 20 patients who were found to be resistant to standard definitive RT on subsequent follow-up compared to 23 patients who responded well. Median follow-up was 42 months. Conclusions: GAGE-family protein mRNA and protein expressions are elevated in patients resistant to standard definitive RT. We aim to develop a classification system to stratify patients into responders versus poor responders based on their GAGE-family protein levels at initial diagnosis in order to personalize treatment regimen whereby good responders can be treated with reduced RT dose and poor responders can receive escalated RT dose and further therapies in order to improve outcome.

Background Hyper-radiation sensitivity is enhanced in cells with mutant p53, which is ubiquitous in high grade serous ovarian cancer (HGSOC). Preclinical data suggests LDWART is a “chemosensitizer” and enhances paclitaxel cytotoxicity. We evaluated the safety and activity of LDWART concurrent with wP (LDWART+wP) in PROC. Methods Patients (pts) with PROC (progressive disease (PD) Results As of 30/4/2019, 10 pts were enrolled (3 part A, 7 part B). All part B pts had HGSOC. Median lines of prior therapy was 5 (range 1-8), including prior wP in 70%, and prior bevacizumab (bev) in 50% of pts. There was no dose-limiting toxicity (DLT) at wP 80mg/m2 (DLT period = 1st 3 weeks of LDWART+wP), which was deemed the MTD. 6/10 pts completed 6 weeks of LDWART+wP. Discontinuations were due to PD (3/10) or pt withdrawal (1/10). Common related all-grade adverse events (AEs) were nausea (60%), neutropenia (60%), fatigue (60%), neuropathy (40%), diarrhea (30%); common related grade ≥3 AEs were neutropenia (50%) and anemia (20%). Median progression free survival was 3.2 mth and overall survival was 13.5 mth. 9 pts were evaluable for response. 44.4% (4/9) of pts achieved biochemical response, defined as CA125 decrease >50% from baseline, 2/4 were confirmed. 1 pt had partial response (PR) despite PD on prior wP, and 5 pts had stable disease (SD), giving an overall response rate of 11.1% (1/9) and disease control rate (PR + SD > 6 weeks) of 66.7% (6/9). 3 pts had durable disease control, and completed 12, 18 and 21 weeks of wP respectively. Conclusions LDWART+wP (80mg/m2) for 6 weeks was safe and tolerable. Encouraging efficacy was seen in this heavily pre-treated population and LDWART+wP may be useful in the context of PROC where bev is contraindicated. Clinical trial identification NCT02545010. Legal entity responsible for the study The authors. Funding RIE2015 National Medical Research Council, National University Cancer Institute Singapore (NCIS) Centre Grant – NCIS Seed Funding. Disclosure D.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. All other authors have declared no conflicts of interest.

Malignant ovarian germ-cell tumours account for about 5% of all ovarian malignancies and typically present in the teenage years. They are almost always unilateral and are exquisitely chemosensitive. As such, the surgical approach in young women with such tumours confined to a single ovary should aim to preserve fertility. In early disease, a unilateral salpingo-oophorectomy with careful surgical staging is of great importance in selecting appropriate adjuvant therapy. In advanced disease, the role of aggressive cytoreducation is not well defined, and removal of both ovaries does not confer improvement in outcome. Bleomycin, etoposide and cisplatin combination chemotherapy is regarded as the gold standard for adjuvant therapy. Studies evaluating ovarian and reproductive capacity after conservative surgery and chemotherapy for malignant ovarian germ-cell tumours have consistently demonstrated excellent prognosis, with the return of normal menstrual function and fertility rates in these women with no increase in the risk of teratogenicity.

Cervical cancer is the most common gynecological cancer encountered in pregnancy. The standard treatment of early cervical cancer is usually surgical removal of the cervix (in selected cases) or, more commonly, the uterus. However, when cervical cancer develops during pregnancy, definitive surgical treatment often needs to be postponed until the fetus reaches maturity. Neoadjuvant chemotherapy (NACT) is an innovative approach in the management of these patients. It helps in controlling the disease and delaying delivery. The paper presents a literature review of the history of NACT, as well as practice points and agenda for further research.

Background:Indications for blood transfusion during trauma resuscitation remain poorly understood. This study aimed to objectively determine the range of factors that lead to initiation of blood transfusion during trauma resuscitation.Design and method:This was a prospective, observational pilot study. A questionnaire was distributed to all clinicians following any transfusion of packed red blood cells during trauma resuscitation. The questionnaire focused on the clinicians’ opinion regarding the indication for red cell transfusion.Results:Complete data on 37 individual episodes of transfusion initiation in the Emergency Department were collected. The most commonly used pre-hospital factors that influenced initiation of transfusion was a pre-hospital systolic blood pressure (SBP) of 1 L (30%) by paramedics. On arrival to hospital, the activation of a massive transfusion protocol was the commonest indication for transfusion, followed by a positive FAST examination (43%), low systolic blood pressure (35%), tachycardia (32%) or pallor (35%). Blood tests to guide initiation of transfusion were less commonly used with 9 (24%) patients transfused for a low haemoglobin level and 6 (16%) patients transfused for coagulopathy.Conclusions:A combination of objective pre- and in-hospital vital signs, together with subjective indicators such as pallor and estimation of blood loss guided initiation of transfusion following injury.

Primary peritoneal serous carcinoma (PPSC), also commonly called primary peritoneal cancer, often presents with clinical features identical to advanced epithelial ovarian carcinoma (EOC). The diagnosis is made only after a laparotomy. The main differentiating feature is advanced peritoneal involvement with tumour without gross involvement of the ovaries. In the absence of any randomised trials, the management of PPSC is very similar to that of EOC, with primary debulking surgery and adjuvant chemotherapy. The prognosis appears to be related to the volume of residual disease, with minimal disease providing a longer disease free interval.

Background: Retroperitoneal hematoma presents with a diagnostic difficulty, especially when it does not present with acute symptoms. Lack of history of any previous intervention, such as femoral catheterization, can add to the diagnostic dilemma. Case: A 71-year-old woman was referred to the Gynaecology Oncology division of the Department of Obstetrics and Gynaecology at the National University Hospital, Singapore for suspected ovarian malignancy. Imaging studies showed a complex adnexal mass infiltrating into the recti muscles. A core biopsy from the mass was inconclusive. Results: Diagnostic laparoscopy confirmed a retroperitoneal hematoma, and the patient was managed conservatively. Conclusions: Retroperitoneal hematoma should be kept as a differential diagnosis of ill-defined pelvic masses with unclear imaging studies, especially in the setting of normal tumor markers and history of anticoagulation therapy. The role of fine needle aspiration cytology (FNAC) and diagnostic laparoscopy should b...

Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women.In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047.The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (1%) and eight (1%) of these events, respectively, were believed to be related to vaccination.In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45.GlaxoSmithKline Biologicals SA.

Cancer in pregnancy, fortunately, is uncommon. This is even more so for gynaecological cancer. Fertility preservation in gynaecological cancer is already a difficult issue, as the common gynaecological cancers affect organs intimately associated with conception and delivery. The presence of a viable pregnancy with gynaecological cancer presents tremendous challenges to the clinician, especially if the woman wants to conserve both her pregnancy and fertility. In this chapter, we address issues involved in such circumstances and suggest management decisions.

The incidence of epithelial ovarian cancer in women aged 40 years and younger is 3–17%. The management of these women is challenging and requires balancing the need to treat epithelial ovarian cancer adequately and preserving reproductive potential. Fertility-sparing surgery, especially for early stage epithelial ovarian cancer, seems to be associated with equivalent clinical and cancer outcomes while preserving reproductive potential. A complete staging and cytoreductive procedure retaining the uterus, and at least one grossly normal ovary, is the minimum recommended procedure. Adjuvant chemotherapy with a platinum-taxane combination is recommended as clinically indicated, and is associated with better cancer and survival outcomes. Adjuvant treatment does not seem to increase the risk of congenital anomalies in subsequent pregnancies. Targeted therapy and ovarian cryopreservation are largely experimental and cannot be recommended as part of the clinical standard of care.

Chronic lung disease characterized by loss of lung tissue, inflammation, and fibrosis represents a major global health burden. Cellular therapies that could restore pneumocytes and reduce inflammation and fibrosis would be a major advance in management.To determine whether human amnion epithelial cells (hAECs), isolated from term placenta and having stem cell-like and antiinflammatory properties, could adopt an alveolar epithelial phenotype and repair a murine model of bleomycin-induced lung injury.Primary hAECs were cultured in small airway growth medium to determine whether the cells could adopt an alveolar epithelial phenotype. Undifferentiated primary hAECs were also injected parenterally into SCID mice after bleomycin-induced lung injury and analyzed for production of surfactant protein (SP)-A, SP-B, SP-C, and SP-D. Mouse lungs were also analyzed for inflammation and collagen deposition.hAECs grown in small airway growth medium developed an alveolar epithelial phenotype with lamellar body formation, production of SPs A-D, and SP-D secretion. Although hAECs injected into mice lacked SPs, hAECs recovered from mouse lungs 2 weeks post-transplantation produced SPs. hAECs remained engrafted over the 4-week test period. hAEC administration reduced inflammation in association with decreased monocyte chemoattractant protein-1, tumor necrosis factor-alpha, IL-1 and -6, and profibrotic transforming growth factor-beta in mouse lungs. In addition, lung collagen content was significantly reduced by hAEC treatment as a possible consequence of increased degradation by matrix metalloproteinase-2 and down-regulation of the tissue inhibitors of matrix metalloproteinase-1 and 2.hAECs offer promise as a cellular therapy for alveolar restitution and to reduce lung inflammation and fibrosis.

Diagnosis of cervical neoplasia hinges upon microscopic inspection of cervical samples. This has inherent operator-dependent variability. Testing for high-risk human papilloma virus (HPV) may help to triage patients with pre-invasive disease in determining clinical intervention and follow-up. However, HPV presence/absence does not reflect the cervical epithelial cell's molecular status. Epigenetic modifications, e.g. DNA methylation, have been observed in the early stages of neoplastic change, preceding gene mutations. Here, we assess the correlation between cytologic/histologic results and combined DNA methylation data of 5 genes in different grades of cervical dysplasia.Cervical specimens collected via the liquid-based cytology system were each microscopically examined. Residual cells were subjected to DNA methylation analysis (Methylight) of gene loci CCNA1, PAX1, HS3ST2, DAPK1 and TFPI2. Methylation data were compared with cytologic/histologic reports. Statistical methods were applied to assess the ability of DNA methylation status to subtype the cervical neoplastic lesions according to their corresponding cytologic/histologic reports.A total of 165 subjects provided cytologically proven 63 HSIL, 49 LSIL and 53 normal samples. All patients with HSIL and LSIL underwent colposcopic examination. Patients with LSIL were all found to be CIN1; patients with HSIL were subsequently subdivided into 10 squamous cell carcinoma (SCC), 31 CIN3, 10 CIN2 and 12 CIN1. For each gene, there was increasing frequency of methylation from normal and LSIL (CIN1), through HSIL (CIN2 and CIN3), to SCC. Methylation of ≥1 of genes investigated was observed in 88% of combined HSIL (CIN2 and CIN3) and SCC cases. All genes showed significant increase in methylation level (PMR value) with increasing disease grade (p0.005). CCNA1 was the only gene that was able to distinguish CIN2 from CIN3 specimens (p=0.016). Based on receiver operating characteristic (ROC) analysis, HS3ST2 was the most significant candidate in segregating HSIL/SCC from normal/LSIL cases (p0.0001); at an optimal cutoff value, sensitivity and specificity between 70% and 80% were obtained.Development of DNA methylation status of a gene panel to improve diagnostic accuracy in cervical neoplasia is warranted.

To assess known cancer biomarkers CA-125, human tissue kallikreins KLK6 and KLK10, hemostatic markers and age with 5-year survival outcome from epithelial ovarian cancer.Forty-one benign cyst cohorts and 83 patients diagnosed with ovarian cancer were recruited. The following assays were performed: fibrinogen, vWF antigen, D: -dimer, ATIII activity, tPA, PAI-1, uPAR, KLK6, KLK10 and CA-125. Follow-up visits of cancer patients of more than 60 months were noted. Data between those who survived past 60 months and mortality from cancer were analyzed.Only 24 patients lived past 60 months, and 31 died (advanced stage n = 27). Those living past 60 months were significantly older and associated with similar pre-operative levels seen in benign cyst cohorts especially for KLK6, fibrinogen, vWF, AT levels despite upregulation of D: -dimer, CA-125 and KLK10. Ovarian cancer cohorts living past 60 months were younger than those who died within 12 months (n = 12). Mortality within 12 months was associated with older age, upregulation of KLK6, fibrinogen, D: -dimer, vWF, tPA antigen and reduced ATIII levels. Similarly, mortality within 36 months of disease showed older age with upregulation of CA-125, KLK6 D: -dimer vWF antigen and tPA antigen levels. Late stage cancer (III/IV) showed upregulated CA-125, KLK6, KLK10, D: -dimer and reduced AT compared to early stage cancer (I/II). The 5-year survival rate for early cancer was 80%, advanced 22.9% and overall 5-year survival rate was 43.6%.Older age together with the novel biomarkers studied and their association with adverse outcome from epithelial ovarian cancer was seen especially within 12 and 36 months of disease. Those who lived past 60 months of disease showed similar pre-operative levels seen in benign cyst cohorts despite elevated D: -dimer, CA125 and KLK 10. An enlarged study is needed to confirm these findings.

Following radical hysterectomy in 42 patients with early invasive carcinoma of the cervix, ureteric strictures developed in 7 patients. They were long, smooth strictures situated in the distal ureter and thought to be of benign origin, related to devascularisation of the ureter. All but one were diagnosed within 8 weeks of surgery and all were treated by a percutaneous approach using a combination of dilating catheters and ureteric stenting: a balloon catheter was used in one patient. In 5 patients treatment was successful. In 1 patient there was an equivocal result as she developed tumour recurrence at 8 months, while in another the procedure failed, probably because the stricture was not detected for 12 months and she had also had radiotherapy. The follow-up period ranged from 6 to 26 months (mean l5 months). Although previous workers have indicated that ureleric strictures following radical hysterectomy would not be expected to respond to transluminal dilatation, in view of the devascularisation of the ureter our experience shows that the majority of these partially devascularised ureters are amenable to percutaneous techniques if detected within 2–3 months of surgery.

Summary Endometrial cancer is one of the gynaecological cancers that carries good overall prognosis because it is often detected at early stages of disease. The International Federation of Gynecology and Obstetrics replaced clinical staging with surgical staging in 1988 and updated the system in 2009. Controversies remain regarding the recommended screening protocol for women with a high risk of endometrial cancer, the role and benefit of retroperitoneal lymph-node dissection, the necessity of ovarian resection, the benefit and type of adjuvant radiation therapy, and the safety of hormone-replacement therapy after treatment. This article reviews the available evidence for optimum management of endometrial cancer and how management strategies can be applied in Asian countries with different levels of health-care resource availability and economic development. An overview of the literature for endometrial-cancer screening, diagnosis, and management is discussed. Consensus statements are formulated on the basis of basic, limited, enhanced, and maximum health-care resource availability, using the framework provided by the Breast Health Global Initiative.

Acute respiratory distress syndrome is characterized by loss of lung tissue as a result of inflammation and fibrosis. Augmenting tissue repair by the use of mesenchymal stem cells may be an important advance in treating this condition. We evaluated the role of term human umbilical cord cells derived from Wharton's jelly with a phenotype consistent with mesenchymal stem cells (uMSCs) in the treatment of a bleomycin-induced mouse model of lung injury. uMSCs were administered systemically, and lungs were harvested at 7, 14, and 28 days post-bleomycin. Injected uMSCs were located in the lung 2 weeks later only in areas of inflammation and fibrosis but not in healthy lung tissue. The administration of uMSCs reduced inflammation and inhibited the expression of transforming growth factor-beta, interferon-gamma, and the proinflammatory cytokines macrophage migratory inhibitory factor and tumor necrosis factor-alpha. Collagen concentration in the lung was significantly reduced by uMSC treatment, which may have been a consequence of the simultaneous reduction in Smad2 phosphorylation (transforming growth factor-beta activity). uMSCs also increased matrix metalloproteinase-2 levels and reduced their endogenous inhibitors, tissue inhibitors of matrix metalloproteinases, favoring a pro-degradative milieu following collagen deposition. Notably, injected human lung fibroblasts did not influence either collagen or matrix metalloproteinase levels in the lung. The results of this study suggest that uMSCs have antifibrotic properties and may augment lung repair if used to treat acute respiratory distress syndrome.

The purpose of this study is to explore the feasibility of combining near-infrared (NIR) autofluorescence and Raman spectroscopy to enhance the in vivo detection of cervical intraepithelial neoplasia.

Fallopian tube carcinoma is a very rare tumor, comprising less than 1% of all gynecologic cancers and found primarily in postmenopausal women. With the disease being so uncommon, little is known about its causes and/or risk factors, and treatment approaches have been taken from experiences with ovarian cancer. We describe a case of a 42-year-old woman with fallopian tube cancer in which the founder mutation BRCA1c.2845insA was detected by mutational analysis. This same mutation was subsequently detected in four unaffected members of her family following genetic counseling. We report an association between this founder mutation and fallopian tube cancer as part of the hereditary breast cancer syndrome in an Asian population. A literature review of the association between this rare malignancy and BRCA mutation carriers and its implications to prophylactic surgery is discussed.

Thirty-five patients diagnosed to have ovarian cancer (early FIGO stage I/II n = 11, advanced FIGO stage III/IV, n = 24) were evaluated for hemostatic parameters relating to survival outcome by 36 months of disease. Systemic plasminogen activators and inhibitors were evaluated and we found no significant association with survival outcome and eventually only fibrinogen, von Willebrand Factor (vWF), antithrombin III (ATIII), and D-dimer levels were determined for their association with disease outcome by 12 months, 24 months, and 36 months. Twenty-four patients succumbed to the disease by 36 months (early n = 2, advanced n = 22). The 11 surviving patients (advanced n = 3, including one deceased at 52 months) is still living past 36 months and 82 months at the time of analysis. Elevated fibrinogen, vWF, and D-dimer together with reduced ATIII levels were found to be associated with poor survival outcome by 12 months of disease. Moreover, elevated vWF and D-dimer with reduced ATIII levels was strongly implicated with poor survival outcome by 36 months from ovarian cancer. The overall survival rate at 36 months from ovarian cancer was 31.4%. It is therefore suggested that fibrinogen, vWF, ATIII, and D-dimer levels be used together as prognostic markers for disease outcome especially in patients with advanced ovarian cancer within 36 months of disease. An expanded study is required to confirm these findings.

Background Genital warts (GW) are a common sexually transmissible infection (STI) among young adults and are associated with poor quality of life (QoL). We investigated the functional and psychosocial effect of GW on Singaporean patients and evaluated for any variations in QoL between genders. Methods: Patients with GW completed a standard questionnaire containing the Short Form-36 (SF-36) health survey and the Cuestionario Específico para Condiloma Acuminado in a cross-sectional survey. QoL deficits were determined by comparing the SF-36 scores with local population norms. Variations in SF-36 (norm-based) scores among patients with different characteristics were examined using multiple linear regressions. All data analyses were performed for male and female patients separately. Results: The mean age of male (n = 100) and female patients (n = 80) was 31 years. The typical patient profile was male, ethnic Chinese, single, tertiary education level and presenting with recurrent warts and a history of prior STIs. Compared with the general population, male patients had similar or better functioning and wellbeing, whereas female patients had lower levels of productivity, mental health and general health. Among male patients, individuals afflicted with their first episode of GW and currently with a partner had better QoL. In contrast, for females, tertiary education, older age and being a nonsmoker were positively associated with better QoL. Conclusions: Patients with GW have a significant psychosocial burden, with differences in certain aspects of QoL between genders. We hope that with active intervention, we will be able to mitigate the associated negative impact to QoL.

The levels of prostaglandin F2 alpha metabolites (PGFM) in the peripheral blood were measured during third stage in a group of patients not given any oxytocic and this was compared with the levels produced in other groups given different oxytocics. There was a significant rise in PGFM within 5 min of delivery in all groups but there was no statistical difference in the serum concentrations of PGFM between the different groups. This suggests that oxytocics given during third stage do not act through release of prostaglandins.

The efficacy and side effects of a new synthetic compound, 16-phenoxy-W-17, 18, 19, 20-tetranor prostaglandin E2 methylsulfonylamide, for menstrual induction. The study was conducted in an outpatient clinic in 240 patients with a delay in menstruation of 6-14 days. In 206 patients (86%) the immunologic pregnancy test was positive before prostaglandin administration. Most of the remaining 34 (14%) patients with a negative pregnancy test had symptoms suggestive of pregnancy. Whenever there was doubt that amenorrhea was due to reasons other than pregnancy, the patients were not treated with prostaglandins. The patients' age range was 16-32 years; the parity range was 0-6. The treatment was successful in 228 patients (95%), i.e., there was uterine bleeding after prostaglandin administration followed by a negative pregnancy test within 14 days. In 6 patients with failed treatment, there was uterine bleeding after prostaglandin administration lasting for 2-13 days but the pregnancy remained positive. Prostaglandin failed to induce bleeding in 4 patients. In 3 of the patients the pregnancy test was positive before and 14 days after prostaglandin administration. The uterus was evacuated by vacuum aspiration in 9 patients. In 1 patient who had no uterine bleeding, pregnancy test was negative both before and 2 weeks after prostaglandin administration. 2 patients were admitted to the hospital the day after prostaglandin treatment for excessive bleeding. Curettage was carried out in both these patients and the bleeding stopped. 1 patient was readmitted to the hospital 8 hours after prostaglandin administration with severe pain in the lower abdominal region. On further examination a tubal pregnancy was diagnosed and confirmed by laparotomy. 2 patients were successfully treated for pelvic infection with antibiotics 7-10 days after prostaglandin administration. All patients experienced mild uterine pain a few minutes after prostaglandin administration. 16 patients required analgesics. The majority of the patients described the bleeding as heavier and longer in duration than their normal menstrual period. The average length of bleeding was 7.3 days with a range of 2-13 days. Side effects included 1 or 2 episodes of vomiting in 13 patients and headache in 9 patients.

A prospective randomized study is presented of 161 patients with cervical intraepithelial neoplasia (CIN) comparing treatment either by "cold" coagulation or cryotherapy. Following colposcopy with directed biopsy confirmation of CIN, patients were randomized on the basis of their medical record numbers and received outpatient therapy. Seven patients were excluded from analysis of final cure rates. The follow-up period ranged from 3 months to 4 years, with 81% of subjects being followed for longer than 1 year. Of 154 patients assessable for cure following single or repeat treatment using the same modality, 89 had received cold coagulation and 65 cryotherapy. Final cure rates using cold coagulation were for CIN I 95.3%, CIN II 100%, and CIN III 92.6%; the overall cure rate for the three grades combined was 95.5%. In the 65 patients treated with cryotherapy, the final cure rates for CIN I, II, and III were 96.7%, 100%, and 84.2%, respectively, and overall, for the three grades combined, it was 93.8%...

Metastatic gestational trophoblastic disease poses problems in diagnosis and management and has a poorer prognosis than the non-metastatic variant. The lung is the most common site of metastases. This paper reviews 97 patients with pulmonary metastasis developing after gestational trophoblastic disease who were seen at one centre over 26 years. Most patients had an antecedent molar pregnancy but an associated choriocarcinomatous lesion in the uterus was absent in the majority. In many patients the pulmonary lesion was asymptomatic. Whilst chemotherapy was the treatment of choice, selective thoracotomy in cases with solitary lung nodules reduced the treatment time and need for aggressive multi-drug combination regimens. The overall survival rate at 2 years after diagnosis was 65%. A higher mortality was found when the antecedent pregnancy ended at term, when the time interval between the preceding pregnancy and diagnosis of pulmonary metastases was greater than 1 year, when multiple pulmonary secondaries were present or when cerebral metastases occurred. The main causes of death were cerebral haemorrhage, respiratory failure and pulmonary embolism.

Molar pregnancy should always be considered as a possible diagnosis in any pregnancy that does not conform to the normal. The practice of subjecting all pregnant women to ultrasound B-scan at their first visit in some centres is commendable, but unfortunately not possible in the areas of high incidence, owing to lack of facilities. Close, regular and meticulous follow-up with facilities for radio-immunoassay of HCG is a necessity after a mole has been treated. Early detection of lesions and individualized treatment of patients, with close monitoring of progress, are essential. Where necessary, enlightened use of drugs with adjuvant surgery and occasionally radiotherapy will give the optimum chance of recovery. To achieve complete eradication of the tumour, treatment may be required even after the HCG test appears to be negative.

Multiple primary cancers account for only 0.38% of all cases in the Singapore Cancer Registry. The close temporal association of nasopharyngeal carcinoma (NPC) in three Chinese women with uterine cervical adenocarcinoma was observed in our department within a 3-month period; one other case was extracted from the local literature. Although NPC is a common neoplasm in local Chinese women, uterine cervical adenocarcinomas comprise only 8% of cervical cancers locally. The close occurrence of these cancers does not seem to be related to the therapy used for cervical cancer and suggests that an association of the Epstein-Barr virus (EBV) with uterine cervical adenocarcinoma should be further investigated.

Pelvic lymphocysts occur infrequently after radical surgery for cervical cancer. The problem is one of recognition. In a retrospective analysis of patients seen over 10 years in this department, the incidence was 25.3%. All were diagnosed by bimanual, clinical examination only. The only factor that appears to relate to the formation of lymphocysts is the presence of poorly differentiated tumors; 70.8% of patients developing lymphocysts had poorly differentiated tumors. All the lymphocysts in this series resolved spontaneously and did not produce any major complications.

Metastatic choriocarcinoma can present in bizarre fashions. Two cases with primary neurological presentations are reviewed. Cerebral metastases in choriocarcinoma generally denote a poor prognosis. However, in solitary metastases in the brain, craniotomy and excision followed by chemotherapy may be curative as illustrated by the following two cases. The first patient was diagnosed to have brain metastases 112 years after an evacuation of her molar pregnancy while the other patient developed cerebral choriocarcinoma 5 months following a spontaneous first trimester abortion. Both presented with neurological symptoms. Both patients are alive and well now, 9 and 5 years respectively after craniotomy and chemotherapy. A brief review of current considerations in the management of cerebral metastases in gestational trophoblastic disease is presented.

Ogilvie's syndrome of colonic pseudo-obstruction has been reported in a wide variety of systemic disorders including blunt and surgical trauma but apparently not as a complication of radical hysterectomy with pelvic and paraaortic lymphadenectomy. Its occurrence following extensive paraaortic dissection in this case but no report so far of its occurrence after routine radical hysterectomy supports the most commonly proposed etiology of disturbed splanchnic nerve supply to the colon as a cause. Colonic pseudo-obstruction following radical hysterectomy with pelvic and paraaortic lymphadenectomy is reported and the etiology, diagnosis, and management are discussed to highlight the condition so that possible associated morbidity/mortality may be avoided.

EDITORIAL COMMENT: This well documented case of cerebral infarction during the puerperium causing permanent partial blindness was accepted for publication because of its unique interest. There is no message regarding prevention; the patient did not have cardiovascular risk factors and the single episode of hypertension and proteinuria at 38 weeks' gestation seems quite unrelated to the complication which occurred 2 weeks after delivery.