Recurrent postmenopausal bleeding: Pathological findings and predictive factors. A multicenter, prospective, observational study.

INTRODUCTION: Recurrent postmenopausal bleeding (PMB) occurs in 6%-25% of postmenopausal women who have experienced a previous episode of PMB. The question of whether recurrent PMB leads to a higher risk of endometrial cancer (EC) in comparison to a single episode of PMB is, however, controversial. Furthermore, little is known about predictive factors for recurrent PMB. MATERIAL AND METHODS: A multicenter prospective cohort study was conducted over a 5-year period in four hospitals in the Netherlands. Women with PMB undergoing endometrial sampling and aged 40 years and older were included. Occurrence of recurrent PMB was retrospectively determined. Primary outcomes included (1) the incidence of recurrent PMB and (2) differences in pathological findings between patients with a single episode versus recurrent PMB. Secondary outcomes included (1) the association between diagnosis of benign polyps at first PMB and pathological findings at recurrent PMB and (2) factors predictive for recurrent PMB. RESULTS: A total of 437 women with PMB were included, of whom 360 were at risk of recurrent PMB. With a median follow-up of 61 months (IQR (Interquartile range) 44-73), 26.4% experienced recurrent PMB. Patients with recurrent PMB were more often diagnosed with benign polyps (34.7% vs. 25.1%, p-value 0.015) and less frequently with a malignancy (5.3% vs. 17.8%, p-value 0.015), compared to patients with a single episode of PMB. Benign polyps at initial PMB were not associated with a (pre)malignancy at recurrence (OR 4.16, 95% CI 0.75-23.03). Predictive factors for recurrent PMB included use of hormone replacement therapy (HRT) (OR 3.32, 95% CI 1.64-6.72), and benign polyps at initial PMB (OR 1.80, 95% CI 1.07-3.04). CONCLUSIONS: Recurrent PMB is common in women with a previous episode of PMB. Compared to patients with a single episode of PMB, patients with recurrent PMB and benign histological outcomes at accurate workup during their first episode were less often diagnosed with malignancies and more frequently with benign polyps. Benign polyps at first PMB are predictive for recurrent PMB, but not for a higher risk of (pre)malignancy.

Does "One Size Fits All"? Rethinking FIGO Depth of Invasion Measurements in Vulvar Cancer.

Depth of invasion (DOI) is an important diagnostic parameter in patients with vulvar carcinoma, where a cutoff value of 1 mm largely determines the tumor stage and the need for groin surgery. DOI measurement should be reproducible and straightforward. In light of the new recommendation on how to measure DOI in the International Federation of Gynecology and Obstetrics (FIGO) staging system 2021, an exploratory study was conducted on the current practice of DOI measurement in vulvar cancer. In this study of 26 selected cases, 10 pathologists with high exposure to vulvar cancer cases in daily practice assessed both the conventional (FIGO 2009) and alternative (FIGO 2021) DOI methods for applicability and preference. In this set of cases, the DOI measurement according to FIGO 2009 was generally considered easier to apply than the measurement according to FIGO 2021, with applicability being rated as "easy to reasonable" in 76.9% versus 38.5% of cases, respectively ( P =0.005). The preferred method was FIGO 2009 or tumor thickness in 14 cases and FIGO 2021 in 6 cases. No invasion was preferred in 1 case. For the remaining 5 cases, half of the pathologists opted for the FIGO 2009 method and half for the FIGO 2021 method. Although the FIGO 2009 method proved to be more readily applicable in most of the cases studied, the method may differ for each case. There may not be a "one size fits all" solution for all cases of vulvar cancer.

Tropomyosin1 isoforms underlie epithelial to mesenchymal plasticity, metastatic dissemination, and resistance to chemotherapy in high-grade serous ovarian cancer.

Phenotypic plasticity, defined as the ability of individual cells with stable genotypes to exert different phenotypes upon exposure to specific environmental cues, represent the quintessential hallmark of the cancer cell en route from the primary lesion to distant organ sites where metastatic colonization will occur. Phenotypic plasticity is driven by a broad spectrum of epigenetic mechanisms that allow for the reversibility of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions (EMT/MET). By taking advantage of the co-existence of epithelial and quasi-mesenchymal cells within immortalized cancer cell lines, we have analyzed the role of EMT-related gene isoforms in the regulation of epithelial mesenchymal plasticity (EMP) in high grade serous ovarian cancer. When compared with colon cancer, a distinct spectrum of downstream targets characterizes quasi-mesenchymal ovarian cancer cells, likely to reflect the different modalities of metastasis formation between these two types of malignancy, i.e. hematogenous in colon and transcoelomic in ovarian cancer. Moreover, upstream RNA-binding proteins differentially expressed between epithelial and quasi-mesenchymal subpopulations of ovarian cancer cells were identified that underlie differential regulation of EMT-related isoforms. In particular, the up- and down-regulation of RBM24 and ESRP1, respectively, represent a main regulator of EMT in ovarian cancer cells. To validate the functional and clinical relevance of our approach, we selected and functionally analyzed the Tropomyosin 1 gene (TPM1), encoding for a protein that specifies the functional characteristics of individual actin filaments in contractile cells, among the ovarian-specific downstream AS targets. The low-molecular weight Tpm1.8/9 isoforms are specifically expressed in patient-derived ascites and promote invasion through activation of EMT and Wnt signaling, together with a broad spectrum of inflammation-related pathways. Moreover, Tpm1.8/9 expression confers resistance to taxane- and platinum-based chemotherapy. Small molecule inhibitors that target the Tpm1 isoforms support targeting Tpm1.8/9 as therapeutic targets for the development of future tailor-made clinical interventions.

The ftz upstream element drives late ftz stripes but is not required for regulation of Ftz target genes.

The regulation of gene expression in precise, rapidly changing spatial patterns is essential for embryonic development. Multiple enhancers have been identified for the evolving expression patterns of the cascade of Drosophila segmentation genes that establish the basic body plan of the fly. Classic reporter transgene experiments identified multiple cis-regulatory elements (CREs) that are sufficient to direct various aspects of the evolving expression pattern of the pair-rule gene fushi tarazu (ftz). These include enhancers that coordinately activate expression in all seven stripes and stripe-specific elements that activate expression in one or more ftz stripes. Of the two 7-stripe enhancers, analysis of reporter transgenes demonstrated that the upstream element (UPS) is autoregulatory, requiring direct binding of Ftz protein to direct striped expression. Here, we asked about the endogenous role of the UPS by precisely deleting this 7-stripe enhancer. In ftzΔUPS7S homozygotes, ftz stripes appear in the same order as wildtype, and all but stripe 4 are expressed at wildtype levels by the end of the cellular blastoderm stage. This suggests that the zebra element and UPS harbor information to direct stripe 4 expression, although previous deletion analyses failed to identify a stripe-specific CRE within these two 7-stripe enhancers. However, the UPS is necessary for late ftz stripe expression, with all 7 stripes decaying earlier than wildtype in ftzΔUPS7S homozygotes. Despite this premature loss of ftz expression, downstream target gene regulation proceeds as in wildtype, and segmentation is unperturbed in the overwhelming majority of animals. We propose that this late-acting enhancer provides a buffer against perturbations in gene expression but is not required for establishment of Ftz cell fates. Overall, our results demonstrate that multiple enhancers, each directing distinct aspects of an overall gene expression pattern, contribute to fine-tuning the complex patterns necessary for embryonic development.

Long-term consequences of juvenile vulvar lichen sclerosus: A cohort study of adults with a histologically confirmed diagnosis in childhood or adolescence.

INTRODUCTION: Vulvar lichen sclerosus (VLS) occurs in at least one in 900 girls. There is limited knowledge as to what extent the disease persists in adulthood and what the repercussions in adulthood may be. The aim of this study is to evaluate the long-term consequences of VLS diagnosed in childhood or adolescence. MATERIAL AND METHODS: The population of females histologically diagnosed with VLS in childhood or adolescence in the Netherlands between 1991 and 2015 was identified through the national pathology database. Histological specimens were retrieved and re-evaluated. Potential participants for whom the diagnosis was reconfirmed and who are now adults, were then traced and surveyed. Descriptive statistics were calculated and compared with the literature. Main outcome measures are the demographics of the cohort, their scores on standardized quality of life (QoL) and sexuality questionnaires and answers to additional questions regarding patients' experience with the disease. The questionnaires used were the Dermatology Life Quality Index (DLQI), the Skindex-29, the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R). Secondary outcome measures include obstetric history and histological features found in the original tissue specimens. RESULTS: A total of 81 women participated, median age 29.0 years, median follow-up from childhood diagnosis 19.5 years. Both QoL and sexuality were somewhat affected in 51.9% of cases. Less than half (45%) reported having regular check-ups. Forty-five (56%) reported symptoms within the past year; of those with symptoms, 14 (31%) were not under surveillance. Cesarean section rate (14.5%) was comparable to the general population, and there were more high-grade obstetric anal sphincter injuries with vaginal deliveries than expected. Sixteen respondents (20%) were not aware of the childhood diagnosis prior to this study. CONCLUSIONS: Symptoms due to VLS are reported by most adults diagnosed as juveniles. QoL and sexuality are affected and correlate to recent symptoms. VLS as a juvenile does not preclude a vaginal delivery. Women diagnosed with VLS in childhood or adolescence are often lost to follow-up.

Late effects of prematurity: Psychiatric outcomes of 17-year-olds born very preterm.

AIM: Very preterm (VPT) birth is a known early vulnerability factor, impacting both physical and mental health over the life-span. The additional burden of psychiatric illness in VPT adolescents is likely to adversely affect critical developmental tasks and personal, social and academic/vocational trajectories. Our aim was to examine the magnitude and extent of the risk of psychological burden by determining the prevalence of psychiatric disorders in our prospectively followed-up VPT and full-term (FT) control cohorts, in this period of developmental transition at age 17 years. METHODS: Rates of psychiatric disorder in the VPT and FT control cohorts were ascertained at clinical interview of the adolescents and their care giver(s) by an adolescent psychiatrist. RESULTS: VPT birth was associated with a greater risk of generalised anxiety disorder (VPT vs. FT risk ratio (RR) 2.33; 95% confidence interval (CI): 1.16, 4.67, P = 0.02), as well as attentional problems (VPT vs. FT RR 3.46; 95% CI: 1.01, 11.88, P = 0.03). Although care givers of VPT adolescents reported many social and communication difficulties, and observation at clinical interview supported this, our data did not reach clinical threshold for group differences in autistic spectrum disorder. For all other psychiatric disorders, there was no difference between VPT and FT control adolescents. CONCLUSION: Our longitudinal cohort follow-up study examining the late effects of VPT birth has demonstrated increased rates of clinically significant psychiatric disorder in this period of important developmental transition. Families and health professionals need to be aware of the increased risk so they can monitor for symptoms and seek effective mental health treatments and support.

Pelvic lymph node dissection for cervical or bladder cancer: embedding residual fat tissue offers no added value.

Diagnosis of lymph node metastases in pelvic lymph node dissection (PLND) is important for staging and treatment. Standard practice is to submit visible or palpable lymph nodes for histology. We assessed the added value of embedding all residual fatty tissue.Patients (n = 85) who underwent PLND for cervical (n = 50) or bladder cancer (n = 35) between 2017 and 2019 were included. Study approval was obtained (MEC-2022-0156, 18.03.2022, retrospectively registered).The median lymph node yield with conventional pathological dissection was 21 nodes (Interquartile range (IQR) 18-28). This led to discovery of positive lymph nodes in 17 (20%) patients. Extended pathological assessment found 7 (IQR 3-12) additional nodes, but did not result in identification of more node metastases.Histopathological analysis of residual fatty tissue harvested at PLND resulted in an increased lymph node yield, but not in the detection of additional lymph node metastases.

Serous endometrial intra-epithelial carcinoma: an observational study.

BACKGROUND: Serous endometrial intra-epithelial carcinoma is described as a malignant, superficial spreading lesion with risk of extra-uterine spread at time of diagnosis, and poor outcome. OBJECTIVE: To evaluate the surgical management of patients with serous endometrial intra-epithelial carcinoma and its impact on oncologic outcomes and complications. METHODS: This Dutch observational retrospective cohort study evaluated all patients diagnosed with pure serous endometrial intra-epithelial carcinoma in the Netherlands, between January 2012 and July 2020. The pathological examination was reviewed by two pathologists with expertise in gynecological oncology. Clinical data were obtained when the diagnosis was confirmed. Primary outcome is progression-free survival, secondary outcomes are duration of follow-up, adverse events related to surgery, and overall survival. RESULTS: A total of 23 patients from 13 medical centers were included, of whom 15 (65.2%) presented with post-menopausal blood loss. In 17 patients (73.9%) the intra-epithelial lesion was present in an endometrial polyp. All patients underwent hysterectomy, of whom 12 patients (52.2%) were surgically staged. None of the staged patients showed extra-uterine disease. Two patients received adjuvant brachytherapy. There were no recurrences of disease (median follow-up duration of 35.6 months (range 1.0-108.6) and no disease-related deaths in this cohort. CONCLUSION: In patients with serous endometrial intra-epithelial carcinoma, median progression-free survival reached nearly 3 years and no recurrences have been reported. Our results do not endorse World Health Organization 2014 advice to treat serous endometrial intra-epithelial carcinoma as high-grade, high-risk endometrial carcinoma. Full surgical staging might possibly lead to overtreatment.

The effects of neutral argon plasma versus electrocoagulation on tissue in advanced-stage ovarian cancer: a case series.

BACKGROUND: The aim of surgery for advanced-stage ovarian cancer is a complete cytoreduction, because this is the most important independent prognostic factor for prolonged survival. Yet this can be difficult to achieve when there are micrometastases on the intestinal mesentery or intestines. The PlasmaJet device is an instrument to remove these micrometastases, but little is known about the depth of damage in human tissue compared to electrocoagulation devices. METHODS: A prospective study was performed for the ex-vivo comparison of the histological depth of thermal damage of neutral argon plasma (PlasmaJet®) and electrocoagulation devices, in a series of 106 histological slides of 17 advanced-stage ovarian cancer patients. Depending on the tissue types resected during complete cytoreductive surgery, samples were collected from reproductive organs (uterus, ovaries), intestines (ileum, colon, rectum) and omentum, intestinal mesentery and peritoneum. RESULTS: Average thermal damage depth was 0.15 mm (range 0.03-0.60 mm) after use of neutral argon plasma and 0.33 mm (range 0.08-1.80 mm) after use of electrocoagulation (p < 0.001). Greater disruption of the tissue surface was often observed after electrocoagulation. CONCLUSION: Our case series suggests that the use of neutral argon plasma during cytoreductive surgery produces significantly less thermal damage than electrocoagulation treatment. It is therefore considered a thermally safe alternative, aiding in the achievement of cytoreductive surgery.

Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel.

The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.

Hyperspectral Imaging for Tissue Classification after Advanced Stage Ovarian Cancer Surgery-A Pilot Study.

The most important prognostic factor for the survival of advanced-stage epithelial ovarian cancer (EOC) is the completeness of cytoreductive surgery (CRS). Therefore, an intraoperative technique to detect microscopic tumors would be of great value. The aim of this pilot study is to assess the feasibility of near-infrared hyperspectral imaging (HSI) for EOC detection in ex vivo tissue samples. Images were collected during CRS in 11 patients in the wavelength range of 665−975 nm, and processed by calibration, normalization, and noise filtering. A linear support vector machine (SVM) was employed to classify healthy and tumorous tissue (defined as >50% tumor cells). Classifier performance was evaluated using leave-one-out cross-validation. Images of 26 tissue samples from 10 patients were included, containing 26,446 data points that were matched to histopathology. Tumorous tissue could be classified with an area under the curve of 0.83, a sensitivity of 0.81, a specificity of 0.70, and Matthew's correlation coefficient of 0.41. This study paves the way to in vivo and intraoperative use of HSI during CRS. Hyperspectral imaging can scan a whole tissue surface in a fast and non-contact way. Our pilot study demonstrates that HSI and SVM learning can be used to discriminate EOC from surrounding tissue.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers In a Phase 1 trial, patients with refractory lymphoid cancers, an antibody-drug complex directed against ROR1 had no unexpected toxicities. About half of the patients with mantle cell lymphoma and diffuse large B-cell lymphoma had clinically meaningful responses.

Cardiac structure and function in very preterm-born adolescents compared to term-born controls: A longitudinal cohort study.

BACKGROUND: There is emerging evidence of differences in cardiac structure and function in preterm-born adults and increased risk of heart failure. However, there is a paucity of data in populations who have been exposed to modern intensive care and the impact of perinatal factors is unclear. AIMS: To compare echocardiographic measures of cardiac structure and function in a regional cohort of 17-year-olds born very preterm compared to term-born peers and the influence of perinatal factors. STUDY DESIGN: Observational longitudinal cohort study. SUBJECTS: A regional cohort of ninety-one 17-year-olds born at <32 weeks gestation compared to sixty-two term-born controls. OUTCOME MEASURES: Echocardiographic measures of cardiac structure and function. RESULTS: Left ventricular and right atrial volume and left ventricular mass, indexed to body surface area, were significantly smaller in preterm-born adolescents compared to term-born controls even when adjusted for sex. There were no between group differences in cardiac function. Within those born preterm we found a significant association between gestational age and birthweight z-score and measures of cardiac function at 17 years. Within the preterm group, those with a diagnosis of bronchopulmonary dysplasia had higher left ventricular posterior wall thickness, higher mitral deceleration time and lower left atrial area and tricuspid annular plane of systolic excursion. CONCLUSIONS: Adolescents born very prematurely, who have received modern intensive care, have measurable differences in heart structure compared to their term-born peers but heart function is preserved. For those born preterm, gestational age, birthweight and bronchopulmonary dysplasia are associated with differences in cardiac function.

Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial.

PURPOSE: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). RESULTS: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. CONCLUSIONS: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.

The fushi tarazu zebra element is not required for Drosophila viability or fertility.

Expression of genes in precisely controlled spatiotemporal patterns is essential for embryonic development. Much of our understanding of mechanisms regulating gene expression comes from the study of cis-regulatory elements (CREs) that direct expression of reporter genes in transgenic organisms. This reporter-transgene approach identifies genomic regions sufficient to drive expression but fails to provide information about quantitative and qualitative contributions to endogenous expression, although such conclusions are often inferred. Here we evaluated the endogenous function of a classic Drosophila CRE, the fushi tarazu (ftz) zebra element. ftz is a pair-rule segmentation gene expressed in seven stripes during embryogenesis, necessary for formation of alternate body segments. Reporter transgenes identified the promoter-proximal zebra element as a major driver of the seven ftz stripes. We generated a precise genomic deletion of the zebra element (ftzΔZ) to assess its role in the context of native chromatin and neighboring CREs, expecting large decreases in ftz seven-stripe expression. However, significant reduction in expression was found for only one stripe, ftz stripe 4, expressed at ∼25% of wild type levels in ftzΔZ homozygotes. Defects in corresponding regions of ftzΔZ mutants suggest this level of expression borders the threshold required to promote morphological segmentation. Further, we established true-breeding lines of homozygous ftzΔZ flies, demonstrating that the body segments missing in the mutants are not required for viability or fertility. These results highlight the different types of conclusions drawn from different experimental designs and emphasize the importance of examining transcriptional regulatory mechanisms in the context of the native genomic environment.

Serous endometrial intraepithelial carcinoma (SEIC): Current clinical practice in The Netherlands.

INTRODUCTION: Serous endometrial intraepithelial carcinoma (SEIC) is a rare diagnosis, defined as an intraepithelial lesion with cells identical to serous type endometrial carcinoma. SEIC is considered to be potentially metastatic, however clear and robust data on prognosis are lacking, potentially leading to variability in clinical management. OBJECTIVE: The aim is to establish the opinion of gynecologists on the optimal management of patients with SEIC. METHODS: An online questionnaire with 15 multiple choice questions was sent to all gynecologists with expertise in gynecological oncology in 19 expert centers in The Netherlands. RESULTS: A total of 24 gynecologists participated. The majority of respondents (n = 18/24, 75%) do not consult a guideline regarding the treatment of SEIC. In current practice, 14 of the 24 respondents perform surgical staging in women with SEIC (58.3%) while seven choose hysterectomy with bilateral salpingo-oophorectomy (29.2%), and three (12.5%) have no firm preference. Eleven of the 14 respondents who perform a surgical staging procedure believe that this is certainly the optimal treatment. The majority of respondents have no firm opinion on whether lymph node sampling or lymph node dissection is preferable during surgical staging (n = 15/23, 65.2%). Most respondents do not give adjuvant therapy (n = 15/24, 62.5%), 25.0% recommend brachytherapy (n = 6/24). Follow-up is for 5 years in almost all cases (n = 23/24). CONCLUSION: There is no consensus on the optimal surgical treatment and the use of adjuvant therapy for patients with SEIC. Our research team is therefore conducting a nationwide cohort study in which treatment modality, morbidity and survival will be evaluated.

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma.

DNA methylation is the most widely studied mechanism of epigenetic modification, which can influence gene expression without alterations in DNA sequences. Aberrations in DNA methylation are known to play a role in carcinogenesis, and methylation profiling has enabled the identification of biomarkers of potential clinical interest for several cancers. For vulvar squamous cell carcinoma (VSCC), however, methylation profiling remains an under-studied area. We sought to identify differentially methylated genes (DMGs) in VSCC, by performing Infinium MethylationEPIC BeadChip (Illumina) array sequencing, on a set of primary VSCC (n = 18), and normal vulvar tissue from women with no history of vulvar (pre)malignancies (n = 6). Using a false-discovery rate of 0.05, beta-difference (Δß) of ±0.5, and CpG-island probes as cut-offs, 199 DMGs (195 hyper-methylated, 4 hypo-methylated) were identified for VSCC. Most of the hyper-methylated genes were found to be involved in transcription regulator activity, indicating that disruption of this process plays a vital role in VSCC development. The majority of VSCCs harbored amplifications of chromosomes 3, 8, and 9. We identified a set of DMGs in this exploratory, hypothesis-generating study, which we hope will facilitate epigenetic profiling of VSCCs. Prognostic relevance of these DMGs deserves further exploration in larger cohorts of VSCC and its precursor lesions.

Raman spectroscopy for guidance of vulvar cancer surgery: a pilot study.

For vulvar squamous cell carcinoma (VSCC), the mainstay of treatment is surgical removal with tumour-free margins. Surgeons still operate without objective tools that provide margin-status. This study assesses Raman spectroscopy potentiality for distinguishing ex-vivo VSCC from healthy tissue in 11 patients. Grid-based Raman maps were obtained from processed spectra. Water content and C-H band ratio (2,910-2,966 cm-1 / 2810-2890 cm-1) were calculated per spectrum and used as linear discriminant parameters. Healthy tissue was differentiated from VSCC with 0.90 discriminative power, 0.79 sensitivity and 0.86 specificity.This is an important step towards the development of objective tools for VSCC surgical guidance.

Relationship of human papillomavirus with seborrheic keratosis of the female genital tract - a case-series and literature review.

Seborrheic keratoses (SKs) are benign lesions of uncertain etiology, which can develop in both genital and extra-genital locations. For genital SKs, there has been conjecture about the pathogenic role of human papillomavirus (HPV), in view of the frequent association of this virus with genital lesions. In light of the potential consequences on patient management, we investigated the relationship between HPV and SKs of the female genital tract (FGT). For this, we evaluated the current evidence on this relationship by performing an in-depth review of the literature. Furthermore, to add to the evidence on this association, we investigated the presence of HPV in a series of vulvar SKs (n=15), using a novel multimodal approach. This involved whole tissue section-polymerase chain reaction (WTS-PCR) using SPF10-DEIA-LipA25 for HPV detection and genotyping. In addition, immunohistochemistry (IHC) was performed with cellular biomarkers p16 and MIB-1, and viral biomarker E4, to augment HPV-testing. Finally, laser-capture microdissection-PCR (LCM-PCR) was performed to locate HPV to specific lesional cells, and to rule out incidental detection of resident HPV with WTS-PCR. Our findings from the literature review, as well as, the case-series are presented.

Effectiveness of interpersonal psychotherapy for community living depressed women involved with the justice system.

BACKGROUND: Despite the prevalence of depression among women in the justice system, and its potentially significant consequences, there is a dearth of studies investigating psychological treatments for depression in this context, especially outside prison. AIMS: Our aim was to gather preliminary data on whether individual interpersonal psychotherapy (IPT) is an acceptable and effective treatment for depression in women at an early stage in the justice system. METHOD: In this pilot study, IPT was offered to 24 depressed women following their first or second contact with the justice system. The women were assessed using a range of scales to quantify depression, anxiety, post-traumatic stress disorder (PTSD) and social support. Multilevel models were used to explore interactions between change in depression and other features given the multiplicity and complexity of problems. Details on engagement and attrition were also collected. RESULTS: Therapy attrition was low, despite challenging life-circumstances and depression scores followed a linear trajectory with scores significantly decreasing over the time (ß = -0.59, SE = 0.07, p < 0.001). Participants with more adverse life events, attachment related anxiety and lower social support had poorer outcomes. CONCLUSIONS AND IMPLICATIONS: Results are encouraging. More than half of the hard-to-reach women who were eligible did engage, and retention rates suggest the therapy was acceptable to them. Depression scores improved, and potential factors affecting treatment outcome were identified. A randomised controlled trial is now warranted, ensuring adequate supplementary support for women with dependants living on their own and without employment.