Jeffrey Low

Epithelial ovarian cancer.

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.

Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors

Effective combination chemotherapy has improved the previously dismal prognosis for malignant ovarian germ cell tumors (MOGCT) dramatically. In young patients, conservative surgery with adjuvant chemotherapy has made the preservation of fertility possible, even in patients with advanced disease. The increase in cure rates has shifted the focus of recent studies to the long term menstrual, reproductive, and gynecologic outcomes in these patients.

High wavenumber Raman spectroscopy for in vivo detection of cervical dysplasia.

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.

Simultaneous fingerprint and high-wavenumber confocal Raman spectroscopy enhances early detection of cervical precancer in vivo.

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.

Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004

Borderline ovarian tumors account for 15% of epithelial ovarian cancers and are different from invasive malignant carcinoma. Majority are early stage, occurring in women in the reproductive age group, where fertility is important. We reviewed retrospectively 247 such cases treated at the Gynaecological-Oncology Unit, KK Womens and Childrens Hospital, between January 1991 and December 2004. The mean age was 38 years (16–89 years). Majority of the cases (92%) were FIGO stage I (Ia, 75%; Ib, 1%; and Ic, 16%). Seven (3.5%) patients were diagnosed as having stage II disease, six (2.5%) as stage IIIa, two (1%) as stage IIIb, and four (2%) as stage IIIc. Histological origin was as follows: mucinous (68%), serous (26%), endometrioid (2.6%), and clear cell (1.2%). Primary surgical procedures undertaken were as follows: hysterectomy with bilateral salpingo-oophorectomy (52%), unilateral salpingo-oophorectomy (33%), or ovarian cystectomy (15%). Adjuvant chemotherapy was administered in 13 patients (5.2% of cases), of which 4 patients were given chemotherapy only because of synchronous malignancies. There were six recurrences (2.4% of cases). Overall mean time to recurrence was 59 months. Recurrence rate for patients who underwent a primary pelvic clearance was 1.6% compared to fertility-sparing conservative surgery (3.3%; although P= 0.683). No significant difference was noted in recurrence and mortality between staged versus unstaged procedures. The overall survival rate was 98.0%. There were a total of five deaths (2.8%): three (1.5%) from invasive ovarian/peritoneal carcinoma and two from synchronous uterine malignancies. It appears that surgical resection is the mainstay of treatment, with conservative surgery where fertility is desired or pelvic clearance if the family is complete. Surgical staging is important to identify invasive extraovarian implants that portend an adverse prognosis. The role of adjuvant chemotherapy is not established.

Fertility and Ovarian Function After Conservative Surgery for Germ Cell Tumours of the Ovary

Malignant ovarian germ cell tumours (MOGCT) principally occur in girls and young women and are generally unilateral. Effective combination chemotherapy with conservative surgery has seen a dramatic improvement in survival rates. This increase has shifted the focus to long‐term fertility and reproductive outcome. The present study describes 45 patients with MOGCT treated with conservative surgery to preserve fertility, with or without the addition of chemotherapy. The age range was 10 to 32 years with a mean of 20 years. The majority of the subjects had Stage 1 tumours; 44 underwent unilateral salpingo‐oophorectomy and 1 patient ovarian cystectomy. Adjuvant chemotherapy was administered in 29 patients. Overall mean follow‐up was 58.7 months. There were 4 recurrences and 2 deaths. Survival of those with Stage 1 disease was 97% and for advanced stages 87%. During chemotherapy 50% became amenorrhoeic but 96% resumed normal menstrual function on completion. Seven healthy babies were recorded in the chemotherapy group and no documented birth defects occurred in any of these. There was no case of persistent infertility; 3 patients experienced temporary problems. It is concluded that conservative fertility‐sparing surgery is the treatment of choice in these young women and advanced disease is not necessarily a contraindication. The majority can anticipate normal menstrual function and fertility.

Malignant ovarian germ-cell tumours

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.

Trends in Gynecologic Cancer Mortality in East Asian Regions

Objective To evaluate uterine and ovarian cancer mortality trends in East Asian countries. Methods For three Asian countries and one region (Japan, Korea, Singapore, and Hong Kong), we extracted number of deaths for each year from the World Health Organization (WHO) mortality database, focusing on women ≥20 years old. The WHO population data were used to estimate person-years at risk for women. The annual age-standardized, truncated rates were evaluated for four age groups. We also compared age-specific mortality rates during three calendar periods (1979 to 1988, 1989 to 1998, and 1999 to 2010). Joinpoint regression was used to determine secular trends in mortality. To obtain cervical and uterine corpus cancer mortality rates in Korea, we re-allocated the cases with uterine cancer of unspecified subsite according to the proportion in the National Cancer Incidence Databases. Results Overall, uterine cancer mortality has decreased in each of the Asian regions. In Korea, corrected cervical cancer mortality has declined since 1993, at an annual percentage change (APC) of -4.8% (95% confidence interval [CI], -5.3 to -4.4). On the other hand, corrected uterine corpus cancer mortality has abruptly increased since 1995 (APC, 6.7; 95% CI, 5.4 to 8.0). Ovarian cancer mortality was stable, except in Korea, where mortality rates steadily increased at an APC of 6.2% (95% CI, 3.4 to 9.0) during 1995 to 2000, and subsequently stabilized. Conclusion Although uterine cancer mortality rates are declining in East Asia, additional effort is warranted to reduce the burden of gynecologic cancer in the future, through the implementation of early detection programs and the use of optimal therapeutic strategies.

Respiratory competent mitochondria in human ovarian and peritoneal cancer.

Impaired respiration was proposed by Warburg to be responsible for aerobic glycolysis in cancer cells. However, intact mitochondria isolated from human ovarian and peritoneal cancer tissues exhibit substantive oxidative phosphorylating activities in terms of membrane potential, ATP biosynthesis and oxygen consumption. The specific activities of succinate, malate and glutamate dehydrogenases are comparable to reported values for human skeletal muscle, heart and liver but the rate of ATP production is one order of magnitude lower compared to human skeletal muscle. It was concluded that the TCA cycle is functional in these ovarian cancer tissues which contain OXPHOS competent mitochondria.

Cervical dysplasia: Assessing methylation status (Methylight) of CCNA1, DAPK1, HS3ST2, PAX1 and TFPI2 to improve diagnostic accuracy

PURPOSE 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 cells 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. EXPERIMENTAL DESIGN 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. RESULTS 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 (p<0.005). 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 (p<0.0001); at an optimal cutoff value, sensitivity and specificity between 70% and 80% were obtained. CONCLUSIONS Development of DNA methylation status of a gene panel to improve diagnostic accuracy in cervical neoplasia is warranted.