The potential of RAS/RAF/MEK/ERK (MAPK) signaling pathway inhibitors in ovarian cancer: A systematic review and meta-analysis.

BACKGROUND: The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events. METHODS: We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model. RESULTS: We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I2 = 0%) and 27% (95%-CI 10-48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients. CONCLUSIONS: MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.

Estimating risk of malignancy in adnexal masses: external validation of the ADNEX model and comparison with other frequently used ultrasound methods.

OBJECTIVES: To validate externally the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and compare this model with other frequently used models in the differentiation between benign and malignant adnexal masses. METHODS: In this retrospective diagnostic accuracy study, we assessed data collected prospectively from patients with adnexal pathology who underwent real-time transvaginal or transrectal ultrasound by a single expert ultrasonographer in a tertiary care hospital between July 2011 and July 2015. The presence of a malignancy was determined by subjective assessment and use of four prediction models: the ADNEX model, simple ultrasound-based rules (simple rules), Logistic Regression model 2 (LR2) and the Risk of Malignancy Index (RMI), of which three different variants were assessed. Pathology was the clinical reference standard. RESULTS: In total, 851 consecutive patients underwent ultrasound examination for an adnexal mass. For 326 patients (128 premenopausal and 198 postmenopausal), pathology results were available (211 (64.7%) benign; 115 (35.3%) malignant) and these were included in the analysis. The area under the receiver-operating characteristics curve (AUC) of the ADNEX model for the discrimination between benign and malignant tumors was 0.93 (95% CI, 0.89-0.95). AUCs for the subtypes of malignancy (i.e. borderline, Stage I-IV and metastatic adnexal tumors) ranged between 0.60 and 0.90. Only subjective assessment (AUC, 0.96 (95% CI, 0.93-0.98)) was superior to the ADNEX model (P = 0.01) in differentiating malignant from benign tumors. AUCs for the other models were 0.92 (95% CI, 0.89-0.95) for LR2, 0.85 (95% CI, 0.81-0.89) for RMI-I, 0.82 (95% CI, 0.77-0.86) for RMI-II and 0.84 (95% CI, 0.80-0.88) for RMI-III. At the proposed cut-off of ≥ 10%, the ADNEX model had the highest sensitivity (0.98 (95% CI, 0.93-1.00)) but the lowest specificity (0.62 (95% CI, 0.55-0.68)) compared with the other models. Both subjective assessment (sensitivity, 0.90 (95% CI, 0.83-0.95); specificity 0.91 (95% CI, 0.86-0.94)) and the simple rules model with inconclusive cases classified by subjective assessment (sensitivity, 0.89 (95% CI, 0.81-0.94); specificity, 0.90 (95% CI, 0.85-0.94)) had lower sensitivity, but their sensitivity and specificity were better balanced. CONCLUSIONS: Although the test performance of subjective assessment by an expert remains superior, the ADNEX model can help in the differentiation between benign and malignant ovarian tumors. The advantage of the ADNEX model as a polytomous model remains to be shown. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Fingermark age determinations: Legal considerations, review of the literature and practical propositions.

The question of the age of fingermarks is often raised in investigations and trials when suspects admit that they have left their fingermarks at a crime scene but allege that the contact occurred at a different time than the crime and for legal reasons. In the first part of this review article, examples from American appellate court cases will be used to demonstrate that there is a lack of consensus among American courts regarding the admissibility and weight of testimony from expert witnesses who provide opinions about the age of fingermarks. Of course, these issues are not only encountered in America but have also been reported elsewhere, for example in Europe. The disparity in the way fingermark dating cases were managed in these examples is probably due to the fact that no methodology has been validated and accepted by the forensic science community so far. The second part of this review article summarizes the studies reported on fingermark dating in the literature and highlights the fact that most proposed methodologies still suffer from limitations preventing their use in practice. Nevertheless, several approaches based on the evolution of aging parameters detected in fingermark residue over time appear to show promise for the fingermark dating field. Based on these approaches, the definition of a formal methodological framework for fingermark dating cases is proposed in order to produce relevant temporal information. This framework identifies which type of information could and should be obtained about fingermark aging and what developments are still required to scientifically address dating issues.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients--a study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD).

BACKGROUND: Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients. METHODS: The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR). RESULTS: 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽ 58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations. CONCLUSIONS: Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.

Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy.

OBJECTIVE: Based on its expression profile, folate receptor alpha (FRA) is an attractive candidate for targeted diagnostics and therapeutics. However, applicability of these agents in residual or recurrent disease could be influenced by chemotherapy. We evaluated whether chemotherapy modified FRA expression in non-mucinous epithelial ovarian (EOC) and endometrial carcinoma (EC). METHODS: FRA staining was evaluated by immunohistochemistry, using MAb 26B3, in 81 patients (41 EOCs and 40 ECs) and 17 control tissues (5 benign ovarian cysts, 5 normal ovarian, and 7 normal endometrial tissues). Chemotherapy effect was evaluated in 42 patients (30 paired samples at primary and interval debulking surgery and 12 from primary and recurrent disease). FRA expression was assessed using a semi-quantitative staining algorithm, the M-score (range 0-50). RESULTS: Median difference in M-score between tumor and control samples was 27.5 for EOC (95% CI 10.0 to 45.0) and 6.7 for EC (95% CI -6.7 to 21.7). Paired samples from both primary and interval debulking surgery did not differ in FRA expression in EOC (median difference of M-score between paired samples of 0.0 [95% CI -2.6 to 2.6]). Recurrent EOC tumors reflected FRA status at diagnosis (median difference of M-score between paired samples of 3.3 [95% CI -7.0 to 13.6]). CONCLUSIONS: This study shows no significant difference in FRA expression after chemotherapy, strengthening the rationale for FRA targeted diagnostics and therapeutics in FRA expressing tumors, whether newly diagnosed or at recurrence.

On the autofluorescence of fingermarks.

The autofluorescence of fingermarks is used for their detection. The components responsible for this autofluorescence are largely unknown. Thin layer chromatography and fluorescence spectroscopy were used to identify autofluorescent components and evaluate their forensic value. Based on our results, tryptophan is hypothesized to be a major contributor to the autofluorescence when part of peptides or proteins, id est, not in its free form. Part of the autofluorescence could be assigned to a kynurenine derivative. Pheophorbide A, a metabolite of chlorophyll, is inferred as a red fluorescent fingermark component. Chlorophyll is a plant pigment which implies that dietary information can potentially be retrieved from fingermarks.

Breast cancer prevention: lifestyle changes and chemoprevention.

Susceptibility to breast cancer is caused by a combination of genetic and environmental factors. Research is exploring which factors influence breast cancer risk, and by which mechanisms they exert their influence. Women should be informed about lifestyle factors influencing their life time breast cancer risk and encouraged by their physician to adapt changes in diet, physical activity, reproductive issues and use of hormone substitution after menopause, to minimize the risk. Patients identified as high risk to develop breast cancer can consider prophylactic surgery, chemo-preventive therapies and take part in personalized screening programs.

Polypoid endometriosis of the bladder during pregnancy mimicking urachal carcinoma.

We report a case of polypoid bladder endometriosis in pregnancy. Diagnostic workup showed a vesicouterine well-vascularized polypoid mass, suspicious for malignancy. During pregnancy, the mass was surgically resected with safe oncological margins. Pathological examination of the resected specimen revealed pseudotumoral polypoid endometriosis of the bladder. We illustrate diagnostic pitfalls in the differentiation between bladder endometriosis during pregnancy and malignancy. As a result of pregnancy-related decidualization of vesical endometriosis, differentiation between this rare occurrence and malignant transformation is challenging.

The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment.

OBJECTIVES: Ovarian cancer remains a major health problem for women. Although there is considerable clinico-pathological heterogeneity, the molecular genetic basis of ovarian cancer remains poorly understood. Recently, high-resolution genomic maps generated by genome-wide SNP analyses and novel sequencing technologies, have started to dissect the genetic basis of ovarian cancer. METHODS: Here, we will describe our first insights on how somatic mutations may contribute to the diagnostic re-classification of ovarian cancer. We will discuss how copy number alterations and epigenetic changes represent promising biomarkers to predict resistance to treatment in ovarian cancer, and will also highlight how some of the recently-discovered microRNAs might represent interesting therapeutic targets for ovarian cancer. RESULTS AND CONCLUSIONS: Future studies, such as the Cancer Genome Atlas Project, involving a large number of ovarian tumors and combining various high-throughput genetic technologies with sophisticated integrative bioinformatic analyses, will be required and are expected to fine-map the full genetic spectrum of ovarian cancer. It is hoped, however, that once the molecular genetic basis of ovarian cancer is understood, this will lead to better and personalized treatments for ovarian cancer.

Role of lymphadenectomy and pelvic radiotherapy in patients with clinical FIGO stage I endometrial adenocarcinoma: An analysis of 208 patients.

Two hundred and eight patients with a clinical stage I endometrial carcinoma were studied (164 fulfilled the inclusion criteria). High risk was defined as nonendometrioid, or endometrioid tumors grade 3 (G3), or G2 with any or G1 with deep (>1/2) myometrial infiltration. The low-risk group consisted of the remaining patients. Surgical staging in the high-risk group included pelvic lymphadenectomy with para-aortic lymphadenectomy in selected cases. Twelve percent of the high-risk patients had nodal metastasis. Patients with low-risk (group A, n = 85) and high-risk disease confined to the uterus (group B, n = 57) did not receive adjuvant radiotherapy. Patients with nodal metastases (group C, n = 10) received postoperative irradiation. The total recurrence rate of the entire population was 12.5%, and the actuarial overall survival, disease-specific survival, and disease-free survival were 90%, 94%, and 88%, respectively. All patients with only vaginal relapse (n = 9) were cured locally with salvage radiotherapy until the date of analysis. The pelvic relapse rate was low as only one patient of group B recurred in the pelvis. In conclusion, lymphadenectomy remains indicated to better select patients at high risk of pelvic recurrence that may benefit from postoperative radiotherapy.

Mechanistic study of the photodynamic inactivation of Candida albicans by a cationic porphyrin.

The growing resistance against antifungal agents has renewed the search for alternative treatment modalities, and antimicrobial photodynamic inactivation (PDI) is a potential candidate. The cationic porphyrin 5-phenyl-10,15,20-Tris(N-methyl-4-pyridyl)porphyrin chloride (TriP[4]) is a photosensitizer that in combination with light can inactivate bacteria, fungi, and viruses. For future improvement of the efficacy of PDI of clinically relevant fungi such as Candida albicans, we sought to understand the working mechanism by following the response of C. albicans exposed to PDI using fluorescence confocal microscopy and freeze-fracture electron microscopy. The following events were observed under dark conditions: TriP[4] binds to the cell envelope of C. albicans, and none or very little TriP[4] enters the cell. Upon illumination the cell membrane is damaged and eventually becomes permeable for TriP[4]. After lethal membrane damage, a massive influx of TriP[4] into the cell occurs. Only the vacuole membrane is resistant to PDI-induced damage once TriP[4] passes the plasma membrane. Increasing the incubation time of C. albicans with TriP[4] prior to illumination did not increase the influx of TriP[4] into the cell or the efficacy of PDI. After the replacement of 100% phosphate-buffered saline (PBS) by 10% PBS as the medium, C. albicans became permeable for TriP[4] during dark incubation and the efficacy of PDI increased dramatically. In conclusion, C. albicans can be successfully inactivated by the cationic porphyrin TriP[4], and the cytoplasmic membrane is the target organelle. TriP[4] influx occurred only after cell death.