The landscape of somatic mutations in Indonesian cervical cancer is predominated by the PI3K pathway.

OBJECTIVE: To investigate the prevalence of somatic mutations in Indonesian cervical carcinoma patients in the context of histology and human papillomavirus (HPV) type. METHODS: In total 174 somatic hot-spot mutations in 13 genes were analyzed by mass spectrometry in 137 Indonesian cervical carcinomas. RESULTS: In 66/137 tumors (48%) 95 mutations were identified. PIK3CA was most frequently mutated (24%), followed by FBXW7 (7%), CTNNB1 (6%), and PTEN (6%). In squamous cell carcinomas more often multiple mutations per sample (p=0.040), and more PIK3CA (p=0.039) and CTNNB1 (p=0.038) mutations were detected compared to adenocarcinomas. PIK3CA mutations were associated with HPV 16 positivity, CDKN2A mutations with HPV 52 positivity, and, interestingly, PTEN mutations with HPV negativity. Balinese tumor samples more often carried multiple mutations (p=0.019), and more CTNNB1, CDKN2A, and NRAS mutations compared to Javanese tumor samples. CONCLUSIONS: Potentially targetable somatic mutations occurred in 48% of Indonesian cervical carcinomas. The landscape of mutations is predominated by mutations concerning the PI3K pathway, and we prompt for more research on developing therapies targeting this pathway, explicitly for the more advanced stage cervical carcinoma patients.

Ovarian survival after pelvic radiation: transposition until the age of 35 years.

PURPOSE: To evaluate the effectiveness of ovarian transposition (OT) prior to radiation therapy (RT) and to evaluate the effect of age on ovarian survival (OS) after OT. METHODS: We performed a retrospective control study, with women (aged < 45 years) who underwent OT prior to pelvic radiation, versus women diagnosed with cervical cancer and treated with hysterectomy/trachelectomy and radiation therapy. All women were treated between 1989 and 2010. The 5 years OS rate was calculated, with a sub-analysis for age (25-30; 31-35 and 36-40 years). Ovarian failure was defined as climacteric complaints (with or without starting hormone replacement therapy) and/or laboratory measurements (FSH > 40 IU/L and/or estradiol < 100 pmol/L), or bilateral salpingo oophorectomy. Women were censored at recurrence. RESULTS: Twenty-seven women after OT and 29 controls were included. The radiation dose was 44.8 Gy (25.0-63.0 Gy) and 46.3 Gy (45.0-50.0 Gy), respectively. The 5-year ovarian survival rate was 60.3% versus controls 0% (p < 0.001 95% CI 3.48-11.50). Despite the decrease in ovarian survival after OT with increasing age, in all age groups (25-30, 30-35 and 35-40) ovarian survival after OT was significantly better compared to women without OT (p = 0.001; p = 0.004 and p = 0.000, respectively). Neither intra-vaginal radiation therapy of concomitant chemotherapy in addition to pelvic radiation significantly altered ovarian survival. CONCLUSIONS: Our data shows that ovarian transposition prior to pelvic radiation is effective in women until the age of 35 years and needs to be discussed in patients aged 36-40 years.

Sentinel Lymph Node Biopsy in Vulvar Cancer Using Combined Radioactive and Fluorescence Guidance.

OBJECTIVE: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has recently been introduced to improve the sentinel lymph node (SLN) procedure. Several optical tracers have been successfully tested. However, the optimal tracer formulation is still unknown. This study evaluates the performance of ICG-technetium-99m (99mTc)-nanocolloid in relation to 2 most commonly used ICG-based formulas during SLN biopsy in vulvar cancer. METHODS AND MATERIALS: Twelve women who planned to undergo SLN biopsy for stage I vulvar cancer were prospectively included. Sentinel lymph node mapping was performed using the dual-modality radioactive and NIR fluorescence tracer ICG-99mTc-nanocolloid. All patients underwent combined SLN localization using NIR fluorescence and the (current) gold standard using blue dye and radioactive guidance. RESULTS: In all 12 patients, at least 1 SLN was detected during surgery. A total of 21 lymph nodes (median 2; range, 1-3) were resected. Median time between skin incision and first SLN detection was 8 (range, 1-22) minutes. All resected SLNs were both radioactive and fluorescent, although only 13 (62%) of 21 SLNs stained blue. Median brightness of exposed SLNs, expressed as signal-to-background ratio, was 5.4 (range, 1.8-11.8). Lymph node metastases were found in 3 patients. CONCLUSIONS: Near-infrared fluorescence-guided SLN mapping is feasible and outperforms blue dye staining. Premixing ICG with 99mTc-nanocolloid provides real-time intraoperative imaging of the SN and seems to be the optimal tracer combination in terms of intraoperative detection rate of the SN (100%). Moreover, ICG-99mTc-nanocolloid allows the administration of a 5-times lower injected dose of ICG (compared with ICG and ICG absorbed to human serum albumin) and can be injected up to 20 hours before surgery.

CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.

BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.

Nerve-sparing radical abdominal trachelectomy versus nerve-sparing radical hysterectomy in early-stage (FIGO IA2-IB) cervical cancer: a comparative study on feasibility and outcome.

OBJECTIVES: Standard treatment in early-stage cervical cancer is a radical hysterectomy (RH) with pelvic lymphadenectomy. In women who wish to preserve fertility radical vaginal trachelectomy has been proposed; however, this is not feasible in larger tumors, and nerve-sparing surgery is not possible. Nerve-sparing radical abdominal trachelectomy (NSRAT) overcomes these disadvantages. METHODS: Case-control study of women with early-stage cervical cancer (International Federation of Gynecology and Obstetrics IA2-IB) submitted to NSRAT from 2000 until 2011. Women submitted to nerve-sparing RH with early-stage cervical cancer were included as control subjects. RESULTS: Twenty-eight patients and 77 control subjects were included. Neoadjuvant chemotherapy was administered in 3 women before NSRAT because the linear extension was or exceeded 40 mm. Local recurrence rate was 3.6% (95% confidence interval [CI], 0.00-10.6) in the NSRAT group compared with 7.8% (95% CI, 1.7-13.9) in the control group (P = 0.44). No significant difference was found between both groups regarding disease-free survival and survival. The overall pregnancy rate was 52.9% (95% CI, 28.7%-77.2%). The mean follow-up was 47.3 months (range, 6-122 months) for NSRAT and 51.8 months (11-129.6 months) for nerve-sparing RH. CONCLUSIONS: Nerve-sparing radical abdominal trachelectomy seems safe and effective in women with early-stage cervical cancer who wish to preserve fertility. Respective women should be informed about this treatment option, especially if the tumor is too large for radical vaginal trachelectomy.

HLA-E expression in cervical adenocarcinomas: association with improved long-term survival.

BACKGROUND: Cervical cancer is the third most common cancer in women worldwide. The most common histopathological subtype is cervical squamous cell carcinoma (SCC, 75-80%), followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC; together 15-20%). Rising incidence rates of AC have been observed relative and absolute to SCC and evidence is accumulating that cervical AC is a distinct clinical entity. Cervical SCC, ASC, and AC are caused by a persistent infection with high-risk human papillomavirus (HPV) and failed control of the immune system plays a pivotal role in the carcinogenesis of all three histopathological subtypes. Human leukocyte antigen E (HLA-E), a non-classical HLA class Ib molecule, plays an important role in immune surveillance and immune escape of virally infected cells. In this study we investigated HLA-E expression in three well-defined cohorts of cervical AC, ASC, and SCC patients, and determined whether HLA-E expression was associated with histopathological parameters and patient survival. METHODS AND RESULTS: HLA-E expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections of 79 SCC, 38 ASC, and 75 AC patients. All patients included were International Federation of Gynaecology and Obstetrics stage I-II and underwent radical hysterectomy with lymphadenectomy as primary treatment. Significant differences between the histopathological subgroups were detected for age distribution, HPV positivity, HPV type distribution, tumour size, tumour infiltration depth, lymph-vascular space invasion, and adjuvant radiotherapy. High expression of HLA-E was found in 107/192 (56%) cervical carcinomas, with significantly more overexpression in cervical AC compared to SCC and ASC (37/79 SCC, 18/38 ASC, and 52/75 AC; P = 0.010). High HLA-E expression in cervical AC was associated with favourable long term disease-specific and recurrence-free survival (P = 0.005 and P = 0.001, respectively). CONCLUSION: High expression of HLA-E occurred in the majority of all histopathological subtypes of cervical cancer; especially in cervical AC. High HLA-E expression in cervical AC was associated with improved patient survival. This study also highlights the importance of careful evaluation of cervical carcinomas to distinguish histopathological subtypes. In the future, insight into the biological behaviour and distinct molecular carcinogenetic processes of the AC, ASC, and SCC subtypes may contribute to the development of more tumour-specific treatment strategies.

Randomized comparison of near-infrared fluorescence lymphatic tracers for sentinel lymph node mapping of cervical cancer.

OBJECTIVE: Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone. METHODS: Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 µM ICG:HSA or 500 µM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation. RESULTS: SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P=.72) or average number of detected SLNs (2.9 vs 2.7, P=.84) was found between the ICG:HSA group and the ICG alone group, respectively. CONCLUSIONS: In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.

Optimization of near-infrared fluorescent sentinel lymph node mapping for vulvar cancer.

OBJECTIVES: Near-infrared fluorescence imaging has the potential to improve sentinel lymph node mapping in vulvar cancer, which was assessed in the current study. Furthermore, dose optimization of indocyanine green adsorbed to human serum albumin was performed. STUDY DESIGN: Nine vulvar cancer patients underwent the standard sentinel lymph node procedure using (99m)technetium-nancolloid and patent blue. In addition, intraoperative imaging was performed after peritumoral injection of 1.6 mL of 500, 750, or 1000 µM of indocyanine green adsorbed to human serum albumin. RESULTS: Near-infrared fluorescence sentinel lymph node mapping was successful in all patients. A total of 14 sentinel lymph nodes (average, 1.6; range, 1-4) were detected: 14 radioactive (100%), 11 blue (79%), and 14 near-infrared fluorescent (100%). CONCLUSION: This study demonstrates feasibility and accuracy of sentinel lymph node mapping using indocyanine green adsorbed to human serum albumin. Considering safety, cost, and pharmacy preferences, an indocyanine green adsorbed to human serum albumin concentration of 500 µM appears optimal for sentinel lymph node mapping in vulvar cancer.

Optimization of near-infrared fluorescent sentinel lymph node mapping in cervical cancer patients.

OBJECTIVE: In early cervical cancer, a total pelvic lymphadenectomy is the standard of care, even though most patients have negative nodes and thus undergo lymphadenectomy unnecessarily. Although the value of sentinel lymph node (SLN) mapping in early-stage cervical cancer has not yet been established, near-infrared (NIR) fluorescence imaging is a promising technique to perform this procedure. Near-infrared fluorescence imaging is based on invisible NIR light and can provide high sensitivity, high-resolution, and real-time image guidance during surgery. METHODS: Clinical trial subjects were 9 consecutive cervical cancer patients undergoing total pelvic lymphadenectomy. Before surgery, 1.6 mL of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected transvaginally and submucosally in 4 quadrants around the tumor. Patients were allocated to 500-, 750-, or 1000-µM ICG:HSA concentration groups. The Mini-FLARE imaging system was used for NIR fluorescence detection and quantitation. RESULTS: Sentinel lymph nodes were identified in all 9 patients. An average of 3.4 ± 1.2 SLNs was identified per patient. No differences in signal to background of the SLNs between the 500-, 750-, and 1000-µM dose groups were found (P = 0.73). In 2 patients, tumor-positive lymph nodes were found. In both patients, tumor-positive lymph nodes confirmed by pathology were also NIR fluorescent. CONCLUSIONS: This study demonstrated preliminary feasibility to successfully detect SLNs in cervical cancer patients using ICG:HSA and the Mini-FLARE imaging system. When considering safety, cost-effectiveness, and pharmacy preferences, an ICG:HSA concentration of 500 µM was optimal for SLN mapping in cervical cancer patients.

Tobacco use and its association with HPV infection in normal uterine cervix: A study from a Sustainable Development Goals perspective.

INTRODUCTION: To achieve the Sustainable Development Goals (SDGs) target 2030, the United Nations (UN) endorsed tobacco use reduction, which is essential in decreasing unnecessary deaths caused by tobacco-induced disease. This study investigates the association between tobacco use and Human Papillomavirus (HPV) infection in clinically normal uterine cervix populations from the SDGs perspective. METHODS: This study is a 7-year cross-sectional study of a clinically normal uterine cervix population, based on negative Visual Inspection of Acetic Acid (VIA). Subjects were recruited consecutively from the medical records of several public and private health providers in Jakarta. The Statistical Product and Service Solutions (SPSS) for Windows version 20.0 were used to analyze the data. RESULTS: A total of 1397 negative VIA subjects were collected, consisting of 4.9% (69/1397) tobacco users, and 95.1% (1328/1397) non-users. HPV-DNA positive were 4.3% (3/69) in the tobacco user group and 3.7% (49/1328) in the non-user group. Statistical analysis showed unadjusted OR was 1.19 (95% CI: 0.36-3.91, p=0.778) and adjusted OR was 1.18 (95% CI: 0.36-3.89, p=0.786). High-risk HPV (hrHPV) infections of tobacco and non-tobacco users' groups were found in 2/3 and 27/49 (55.1%), respectively. CONCLUSIONS: This study showed an insignificant statistical association between tobacco use and HPV infection in normal uterine cervix. However, the proportion of hrHPV infection was higher in tobacco users than non-users. From the SDGs perspective, cervical cancer is closely related to tobacco use and poverty. Further study is needed to support this result and evaluate other co-factor role-related cervical cancer history to achieve SDGs in 2030.

Nerve-sparing radical hysterectomy: local recurrence rate, feasibility, and safety in cervical cancer patients stage IA to IIA.

UNLABELLED: To clarify the debate about the possible threat of sparing the pelvic autonomic nerves in radical hysterectomy for cervical cancer to radicality, comparative studies of nerve-sparing and conventional surgery are necessary. The aim of his study was to analyze and compare local recurrence rate, feasibility, and safety of nerve-sparing and non-nerve-sparing radical hysterectomy. METHODS: In a cohort study with 2 years of follow-up, 246 patients with cervical cancer of stages IA to IIA were analyzed: 124 in the non-nerve-sparing group (1994-1999) and 122 in the group where nerve-sparing was the intention-to-treat (2001-2005). Local recurrence rate, local recurrence-free survival, feasibility, and safety were analyzed and compared. RESULTS: The clinical characteristics of the treatment groups were comparable. Sparing the nerves unilaterally or bilaterally was possible in 80% of cases of the nerve-sparing group. Local recurrence rates in the non-nerve-sparing (4.9%) and nerve-sparing (8.3%) group were not significantly different. Mean local recurrence-free survival within 2 years were 22.7 and 22.0 months, respectively. Univariate and multivariate regression analyses showed that nerve-sparing treatment was not a significant prognostic factor for local recurrence. With respect to perioperative and postoperative parameters, operating time and blood loss were less in the nerve-sparing group and mortality was equal (1 patient); the postoperative course of the nerve-sparing group was similar to the state-of-the-art of conventional radical hysterectomy. CONCLUSIONS: On the basis of the results of our study, we consider the nerve-sparing technique for cervical cancer stages IA to IIA feasible and safe.

Physical status of multiple human papillomavirus genotypes in flow-sorted cervical cancer cells.

Multiple human papilloma virus (HPV) infections have been detected in cervical cancer. To investigate the significance of multiple HPV infections, we studied their prevalence in cancer samples from a low-risk (Dutch) and a high-risk (Surinamese) population and the correlation of HPV infection with tumor cell aneuploidy. SPF(10) LiPA was used for HPV detection in formalin-fixed cervical carcinoma samples from 96 Dutch and 95 Surinamese patients. Samples with HPV type 16 or 18 infections were sorted by flow cytometry, and fluorescence in situ hybridization was performed on the diploid and aneuploid subpopulations to detect HPV 16 and 18 genotypes simultaneously. Multiple HPV infections were present in 11 of 80 (13.8%) Dutch and 17 of 77 (22.1%) Surinamese carcinomas. Three cases had an HPV 16 and HPV 18 coinfection: in two cases, integrated HPV copies of HPV 16 or 18 were detected in the aneuploid fraction, and in one case both HPV 16 and 18 were present solely as episomes. Based on our findings, multiple HPV infections are present in cervical cancer samples from both high- and low-risk populations. Furthermore, multiple HPV types can be present in an episomal state in both diploid and aneuploid tumor cells, but integrated HPV genomes are detectable only in the aneuploid tumor cell subpopulations.

Reasons for early interventions by gynaecologists in a clinical follow-up study on cervical intraepithelial neoplasia.

OBJECTIVE: In a previous clinical follow-up study on psychosocial factors and cervical intraepithelial neoplasia (CIN), we had noticed a high percentage of early interventions to the cervix by gynaecologists, in discordance with the research protocol. The aim of the current study was to investigate the reasons for these interventions. STUDY DESIGN: We retrospectively analysed the study records of the clinical study, concerning the follow-up of 98 patients with a CIN 1 or 2 lesion for 2.25 years by colposcopy and cervical smears. We recorded the number of early interventions that had occurred in the clinical study as well as the reasons for these interventions. A distinction was made between acceptable and unacceptable reasons for early intervention. RESULTS: During follow-up, 39 out of 98 women (40%) had undergone intervention in discordance with the protocol. No acceptable reason for these interventions was found for 67% of these patients (26/39). In the majority of these cases either no reason for the intervention had been given, or the gynaecologist had feared for progression of the CIN lesion. CONCLUSION: Gynaecologists tend to intervene during follow-up of CIN, partly out of fear for progression. This tendency may complicate follow-up studies on CIN.

Prevalence, Age Distribution, and Risk Factors of Visual Inspection With Acetic Acid-Positive From 2007 to 2011 in Jakarta.

BACKGROUND: Cervical cancer is still the second most frequent cancer among Indonesian women, thus screening program is still critically important to prevent it. Visual inspection with acetic acid (VIA) was introduced as a method which is most suitable with Indonesia's condition compared with the other screening methods. The Female Cancer Program from Jakarta Regional collaborated with Leiden University in 2007 to 2011 has done cervical cancer screening using VIA method, involving 25,406 women spreading across several primary health centers in Jakarta. By using these data, we found out the prevalence, age distribution, and risk factor of VIA positive in Jakarta as a basis to predict the budget and logistics for the next cervical cancer screening and to do an advocating to the Jakarta's government. METHODS: A secondary data analysis was conducted from several areas in Jakarta from 2007 to 2011. VIA test was used as the screening method, and performed by doctors and midwives with technical supervision by gynecologists. RESULTS: From 25,406 women, there were 1,192 cases (4.7%) of VIA test positive. The risk factors that can significantly influence the result of VIA positive were number of marriage, parity, smoking habits, and the use of hormonal contraception with OR 1.51, 1.85, 1.95, and 0.68, respectively. CONCLUSIONS: Prevalence of VIA test-positive is 4.7% in Jakarta population. The findings of precancerous lesions and cervical cancers are not only between thirty and fifty years old, but also below the thirty years old and after fifty years old. We suggest that VIA test should be performed to all reproductive age and elder women who are not screened yet.

A novel keratin 13 variant in a four-generation family with white sponge nevus.

We report a novel KRT13 germ line variant that causes white sponge nevus (WSN) with mucosal dysplasia. Genital, vaginal, and cervical WSN were observed in four female patients, of whom two had premalignant cervical lesions at young age. Two of the 12 patients with oral WSN developed oral squamous cell carcinoma.

Prognostic value and clinicopathologic characteristics of L1 cell adhesion molecule (L1CAM) in a large series of vulvar squamous cell carcinomas.

BACKGROUND: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. RESULTS: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P=.014, disease specific survival 63.8% vs 80.0%, P=.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10-7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. METHODS: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (ß-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. CONCLUSION: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC's. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity.

Frequent HLA class I loss is an early event in cervical carcinogenesis.

Loss at chromosome 6p21.3, the human leukocyte antigen (HLA) region, is the main cause of HLA downregulation, occurring in the majority of invasive cervical carcinomas. To identify the stage of tumor development at which HLA class I aberrations occur, we selected 12 patients with cervical carcinoma and adjacent cervical intraepithelial neoplasia (CIN). We investigated HLA class I and beta2-microglobulin expression by immunohistochemistry in tumor and adjacent CIN. Loss of heterozygosity (LOH) was studied using microsatellite markers covering the HLA region. Fluorescent in situ hybridization with HLA class I probes was performed to investigate the mechanism of HLA loss. Immunohistochemistry showed absent or weak HLA class I expression in 11/12 cases. In 10 of these 11 cases, downregulation occurred in both tumor and CIN. Only in one case did the concomitant CIN lesion show normal expression. In 9/12 cases, LOH was present for at least one marker in both tumor and CIN, 1 case showed only LOH in the CIN lesion, and 1 case showed retention of heterozygosity for all markers in both tumor and CIN. We conclude that HLA class I aberrations occur early and frequently in cervical carcinogenesis. This might allow premalignant CIN lesions to escape immune surveillance and progress to invasive cancer.

An evaluation of the current state of sexual and reproductive health and rights of women in Ghana.

OBJECTIVE: To provide a current account of women's sexual and reproductive health and rights (SRHR) in Ghana (West Africa), a priority area in achieving the World Health Organization's Millennium Development Goals. METHOD: The study was observational. Three-hundred ninety Ghanaian women attending cervical cancer screening were surveyed about their SRHR. The data were analyzed with chi-squared test (p ≤ 0.05, two-sided). RESULTS: 22.1% had a life-time history of non-consensual sexual experience and 55.4% a previous history of abortion, mostly using services of a registered clinic (68.5%). Experience of sexual violence increased life-time risk of abortion (p = 0.018). The overall use of contraceptives was high (>60%); however, condom use during sexual intercourse with a new partner was low (23%), even among the highly educated women (32.7%) and women who stated to have received information on the risks and benefits of condom use (26.0%). Although condom use among the highly educated women was low, it was still 2 times higher than among the lower educated women, 15.7% (p < 0.001). There was also less condom use among the women with multiple sexual partners compared to single-partnered women (p = 0.001). CONCLUSION: More than a decade after the inception of the Millennium Development Goals, there is still work to be done in Ghana, especially on education and sexual violence.

Precise Classification of Cervical Carcinomas Combined with Somatic Mutation Profiling Contributes to Predicting Disease Outcome.

INTRODUCTION: Squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC) are the most common histological subtypes of cervical cancer. Differences in the somatic mutation profiles of these subtypes have been suggested. We investigated the prevalence of somatic hot-spot mutations in three well-defined cohorts of SCC, AC, and ASC and determined the additional value of mutation profiling in predicting disease outcome relative to well-established prognostic parameters. MATERIALS AND METHODS: Clinicopathological data were collected for 301 cervical tumors classified as SCC (n=166), AC (n=55), or ASC (n=80). Mass spectrometry was used to analyze 171 somatic hot-spot mutations in 13 relevant genes. RESULTS: In 103 (34%) tumors, 123 mutations were detected (36% in SCC, 38% in AC, and 28% in ASC), mostly in PIK3CA (20%) and KRAS (7%). PIK3CA mutations occurred more frequently in SCC than AC (25% vs. 11%, P=0.025), whereas KRAS mutations occurred more frequently in AC than SCC (24% vs. 3%, P<0.001) and ASC (24% vs. 3%, P<0.001). A positive mutation status correlated with worse disease-free survival (HR 1.57, P=0.043). In multivariate analysis, tumor diameter, parametrial infiltration, and lymph node metastasis, but not the presence of a somatic mutation, were independent predictors of survival. CONCLUSION: Potentially targetable somatic mutations occurred in 34% of cervical tumors with different distributions among histological subtypes. Precise classification of cervical carcinomas in combination with mutation profiling is valuable for predicting disease outcome and may guide the development and selection of tumor-specific treatment approaches.

The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer.

OBJECTIVE: In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting. METHODS: Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions. RESULTS: 6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99). CONCLUSIONS: This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16945066.