Search

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.

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.

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.

Raman spectroscopy is a vibrational spectroscopic technique capable of optically probing the biomolecular changes associated with neoplastic transformation. The purpose of this study was to apply near-infrared (NIR) Raman spectroscopy in the high wavenumber (HW) region (2800-3700 cm(-1)) for in vivo detection of cervical dysplasia. A rapid-acquisition NIR Raman spectroscopy system associated with a ball-lens fiber-optic Raman probe was developed for in vivo spectroscopic measurements at 785 nm excitation. A total of 92 in vivo HW Raman spectra (46 normal, 46 dysplasia) were acquired from 46 patients with Pap smear abnormalities of the cervix. Significant difference in Raman intensities of prominent Raman bands at 2850 and 2885 cm(-1) (CH(2) stretching of lipids), 2940 cm(-1) (CH(3) stretching of proteins), and the broad Raman band of water (peaking at 3400 cm(-1) in the 3100-3700 cm(-1) range) were observed in normal and dysplasia cervical tissue. The diagnostic algorithms based on principal components analysis and linear discriminant analysis together with the leave-one-patient-out cross-validation method on in vivo HW Raman spectra yielded a diagnostic sensitivity of 93.5% and specificity of 97.8% for dysplasia tissue identification. This study demonstrates for the first time that HW Raman spectroscopy has the potential for the noninvasive, in vivo diagnosis and detection of precancer of the cervix.

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.

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.

This study aims to evaluate the feasibility of applying high wavenumber (HW) confocal Raman spectroscopy for non-invasive assessment of menopause-related hormonal changes in the cervix as well as for determining the effect of Vagifem(®) treatment on postmenopausal women with atrophic cervix. A rapid HW confocal Raman spectroscopy system coupled with a ball lens fiber-optic Raman probe was utilized for in vivo cervical tissue Raman measurements at 785 nm excitation. A total of 164 in vivo HW Raman spectra (premenopausal (n = 104), postmenopausal-prevagifem (n = 34), postmenopausal-postvagifem (n = 26)) were measured from the normal cervix of 26 patients undergoing colposcopy. We established the biochemical basis of premenopausal, postmenopausal-prevagifem and postmenopausal-postvagifem cervix using semiquantitative biomolecular modeling derived from Raman-active biochemicals (i.e., lipids, proteins and water) that play a critical role in HW Raman spectral changes associated with the menopausal process. The diagnostic algorithms developed based on partial least squares-discriminant analysis (PLS-DA) together with leave-one patient-out, cross-validation yielded the diagnostic sensitivities of 88.5%, 91.2% and 88.5%, and specificities of 91.7%, 90.8% and 99.3%, respectively, for non-invasive in vivo discrimination among premenopausal, postmenopausal-prevagifem and postmenopausal-postvagifem cervix. This work demonstrates for the first time that HW confocal Raman spectroscopy in conjunction with biomolecular modeling can be a powerful diagnostic tool for identifying hormone/menopause-related variations in the native squamous epithelium of normal cervix, as well as for assessing the effect of Vagifem treatment on postmenopausal atrophic cervix in vivo during clinical colposcopic inspections.

Raman spectroscopy is a vibrational spectroscopic technique capable of nondestructively probing endogenous biomolecules and their changes associated with dysplastic transformation in the tissue. The main objectives of this study are (i) to develop a simultaneous fingerprint (FP) and high-wavenumber (HW) confocal Raman spectroscopy and (ii) to investigate its diagnostic utility for improving in vivo diagnosis of cervical precancer (dysplasia). We have successfully developed an integrated FP/HW confocal Raman diagnostic system with a ball-lens Raman probe for simultaneous acquistion of FP/HW Raman signals of the cervix in vivo within 1 s. A total of 476 in vivo FP/HW Raman spectra (356 normal and 120 precancer) are acquired from 44 patients at clinical colposcopy. The distinctive Raman spectral differences between normal and dysplastic cervical tissue are observed at ~854, 937, 1001, 1095, 1253, 1313, 1445, 1654, 2946, and 3400 cm(-1) mainly related to proteins, lipids, glycogen, nucleic acids and water content in tissue. Multivariate diagnostic algorithms developed based on partial least-squares-discriminant analysis (PLS-DA) together with the leave-one-patient-out, cross-validation yield the diagnostic sensitivities of 84.2%, 76.7%, and 85.0%, respectively; specificities of 78.9%, 73.3%, and 81.7%, respectively; and overall diagnostic accuracies of 80.3%, 74.2%, and 82.6%, respectively, using FP, HW, and integrated FP/HW Raman spectroscopic techniques for in vivo diagnosis of cervical precancer. Receiver operating characteristic (ROC) analysis further confirms the best performance of the integrated FP/HW confocal Raman technique, compared to FP or HW Raman spectroscopy alone. This work demonstrates, for the first time, that the simultaneous FP/HW confocal Raman spectroscopy has the potential to be a clinically powerful tool for improving early diagnosis and detection of cervical precancer in vivo during clinical colposcopic examination.

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.

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.

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.

Gestational trophoblastic diseases are a heterogenous group of conditions ranging from the benign hydatidiform mole to the malignant choriocarcinoma. Optimal therapy in this group of diseases rest in the correct diagnosis, assessing their risk for malignant behavior using prognostic scoring systems and administering appropriate treatment. Their rarity makes it imperative that these patients are treated in special centres by experts. Benign moles are treated surgically with evacuation of the uterus or hysterectomy. In malignant gestational trophoblastic disease, chemotherapy is the treatment of choice; single agent for non-metastatic and low-risk metastatic disease and combination chemotherapy for high-risk metastatic disease. Judicious use of surgery and radiotherapy in these cases will improve the survival rate. With appropriate treatment, the cure rates approach 100% in the low-risk group and 80% to 85% in the high risk group.

Raman spectroscopy is a unique optical technique that can probe the changes of vibrational modes of biomolecules associated with tissue premalignant transformation. This study evaluates the clinical utility of confocal Raman spectroscopy over near-infrared (NIR) autofluorescence (AF) spectroscopy and composite NIR AF/Raman spectroscopy for improving early diagnosis of cervical precancer in vivo at colposcopy. A rapid NIR Raman system coupled with a ball-lens fiber-optic confocal Raman probe was utilized for in vivo NIR AF/Raman spectral measurements of the cervix. A total of 1240 in vivo Raman spectra [normal (n=993), dysplasia (n=247)] were acquired from 84 cervical patients. Principal components analysis (PCA) and linear discriminant analysis (LDA) together with a leave-one-patient-out, cross-validation method were used to extract the diagnostic information associated with distinctive spectroscopic modalities. The diagnostic ability of confocal Raman spectroscopy was evaluated using the PCA-LDA model developed from the significant principal components (PCs) [i.e., PC4, 0.0023%; PC5, 0.00095%; PC8, 0.00022%, (p

This study aimed to evaluate the clinical utility of applying near-infrared (NIR) Raman spectroscopy and genetic algorithm-partial least squares-discriminant analysis (GA-PLS-DA) to identify biomolecular changes of cervical tissues associated with dysplastic transformation during colposcopic examination. A total of 105 in vivo Raman spectra were measured from 57 cervical sites (35 normal and 22 precancer sites) of 29 patients recruited, in which 65 spectra were from normal sites, while 40 spectra were from cervical precancerous lesions (i.e., 7 low-grade CIN and 33 high-grade CIN). The GA feature selection technique incorporated with PLS was utilized to study the significant biochemical Raman bands for differentiation between normal and precancer cervical tissues. The GA-PLS-DA algorithm with double cross-validation (dCV) identified seven diagnostically significant Raman bands in the ranges of 925-935, 979-999, 1080-1090, 1240-1260, 1320-1340, 1400-1420, and 1625-1645 cm(-1) related to proteins, nucleic acids and lipids in tissue, and yielded a diagnostic accuracy of 82.9% (sensitivity of 72.5% (29/40) and specificity of 89.2% (58/65)) for precancer detection. The results of this exploratory study suggest that Raman spectroscopy in conjunction with GA-PLS-DA and dCV methods has the potential to provide clinically significant discrimination between normal and precancer cervical tissues at the molecular level.

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.

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.

The term gestational trophoblastic disease encompasses a wide spectrum of disorders ranging from the benign hydatidiform mole to the malignant choriocarcinoma and placental site trophoblastic tumor. Recent advances in cytogenetics and pathological criteria have brought to light the occurrence of the partial mole, which is probably more common than the complete mole. The World Health Organisation has proposed a classification to rectify the current confusion that exists with clinical and pathological terms. Evacuation of the uterus followed by meticulous followup with sensitive beta subunit Human Chorionic Gonadotropin assay remain the cornerstone of management of molar pregnancy. Prompt chemotherapy is the most important aspect in managing malignant sequelae. Newer chemotherapy regimes have helped to salvage failures from the usual drugs. Judicial use of surgery in metastatic trophoblastic disease can reduce the duration and toxicity of chemotherapy. All patients with gestational trophoblastic disease should be managed in a tertiary care centre with the expertise and facilities easily available to manage these cases.

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.

Prostaglandin E2 administered orally and combined with amniotomy was used for induction of labour at or near term in 1533 patients. The study was carried out as a collaborative project between the University Departments of Obstetrics and Gynaecology in Singapore, Medan (Indonesia) and Kuala Lumpur (Malaysia). The overall success rates for Medan, Kuala Lumpur and Singapore were 95.6%, 88.1% and 84.7% respectively.

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.

What was once an almost uniformly fatal disease has now become highly curable, with survival rates of 100% being reported for the early stages of the disease. This is the direct result of improved techniques of diagnosis, recognition of high risk groups, effective and intensive chemotherapy, adjunctive surgery in selected cases and most important of all, a close follow-up of all patients with monitoring of the tumour marker, human chorionic gonadotrophin (hCG). This review will highlight the advances made in these areas and how these have helped in reducing morbidity and mortality from gestational trophoblastic disease (GTD).

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.

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.

Cervical cancer is the commonest female genital tract cancer in Singaporean women with an annual age-standardized rate of 17.4 per 100,000. High risk factors are early sexual intercourse, multiple sexual partners and cigarette smoking. Population screening with annual cervical (Pap) smears after beginning sexual activity until age 35 and at 5 year intervals after that can reduce both incidence and mortality rate from invasive cervical cancer. Benign, premalignant and malignant conditions may be identified in smears. The term cervical intra-epithelial neoplasia (CIN) reflects better the continuum of change in precursor lesions and is preferred over the older dual terminology of dysplasia/carcinoma-in-situ for precursors of cervical cancer. Colposcopy is essential for evaluation of all patients with abnormal cervical smears. Colposcopy is used to identify the site, severity and extent of abnormality as well as to aid directed biopsy, plan treatment and allow use of conservative methods to treat the precursor lesions. Colposcopy however, has no role as a primary screening procedure for cervical cancer but instead cervical smears are used for screening.

The amnion is the inner of two membranes surrounding the fetus. That it arises from embryonic epiblast cells prior to gastrulation suggests that it may retain a reservoir of stem cells throughout pregnancy. We found that human amniotic epithelial cells (hAECs) harvested from term-delivered fetal membranes express mRNA and proteins present in human embryonic stem cells (hESCs), including POU domain, class 5, transcription factor 1; Nanog homeobox; SRY-box 2; and stage-specific embryonic antigen-4. In keeping with possible stem cell-like activity, hAECs were also clonogenic, and primary hAEC cultures could be induced to differentiate into cardiomyocytic, myocytic, osteocytic, adipocytic (mesodermal), pancreatic, hepatic (endodermal), neural, and astrocytic (neuroectodermal) cells in vitro, as defined by phenotypic, mRNA expression, immunocytochemical, and/or ultrastructural characteristics. However, unlike hESCs, hAECs did not form teratomas upon transplantation into severe combined immunodeficiency mice testes. Last, using flow cytometry we have shown that only a very small proportion of primary hAECs contain class IA and class II human leukocyte antigens (HLAs), consistent with a low risk of tissue rejection. However, following differentiation into hepatic and pancreatic lineages, significant proportions of cells contained class IA, but not class II, HLAs. These observations suggest that the term amnion, an abundant and easily accessible tissue, may be a useful source of multipotent stem cells that possess a degree of immune privilege.