Investigating a clinically actionable BRAF mutation for monitoring low-grade serous ovarian cancer: A case report.

Low-grade serous ovarian cancer (LGSOC) poses a specific clinical challenge due to advanced presentation at diagnosis and the lack of effective systemic treatments. The aim of this study was to use a precision medicine approach to identify clinically actionable mutations in a patient with recurrent LGSOC. Primary, metastatic and recurrence tissue, and blood samples were collected from a stage IV LGSOC patient. Single-gene testing for clinically actionable mutations (BRAF V600, KRAS and NRAS) and subsequent whole-exome sequencing (WES) were performed. Droplet digital PCR was used to evaluate the presence of an identified BRAF D594G mutation in the matched plasma cell-free DNA (cfDNA). No clinically actionable mutations were identified using single-gene testing. WES identified a BRAF D594G mutation in six of seven tumor samples. The patient was commenced on a MEK inhibitor, trametinib, but with minimal clinical response. A newly designed ddPCR assay detected the BRAF alteration in the matched tissues and liquid biopsy cfDNA. The identification and sensitive plasma detection of a common "druggable" target emphasises the impact of precision medicine on the management of rare tumors and its potential contribution to novel monitoring regimens in this field.

Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment.

STUDY QUESTION: Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER: Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY: Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1ß, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S): Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NA.

Patient perceptions and understanding of obesity related endometrial cancer.

Obesity is the greatest risk factor for endometrial cancer. There is often a lack of recognition amongst patients about this risk. Evidence for weight-loss in the management of endometrial cancer is emerging. This was questionnaire-based study, that examined opinions and attitudes of patients with endometrial cancer and obesity towards obesity as a risk factor for cancer as well as examining their willingness to engage in weight loss interventions as an alternative treatment to endometrial cancer. This survey was conducted in a gynaeoncology out-patient department in Ireland. A total of 45/50 (90%) of questionnaires were completed. The majority of the patients questioned (86.7%; 39/45) agreed that obesity is a disease. Just over half of the cohort (53.3%; 24/45) believed that obesity can cause cancer. Over one-third, 39.9% (18/45) either disagreed or strongly disagreed that obesity is a risk factor for endometrial cancer while 35.5% (16/45) agreed or strongly agreed. Two-thirds (66.6%; 30/45) knew that the greatest amount of weight could be lost through metabolic surgery. Over three-quarters (82.1%; 37/45) of patients surveyed would be willing to engage in a combination of treatments in order to achieve weight-loss should it be proven to have a role in the management of endometrial cancer. This study demonstrates a need for patient education regarding the strong relationship between obesity and endometrial cancer risk. Patients are willing to consider weight loss interventions if they were proven to be as safe and effective as pelvic surgery in the management of endometrial cancer.

Canadian results from the European Men-who-have-sex-with-men Internet survey (EMIS-2017).

BACKGROUND: In 2017, the international European Men-who-have-sex-with-men Internet Survey (EMIS-2017) collected data from 50 countries, including Canada for the first time. OBJECTIVE: To provide an overview of the Canadian EMIS-2017 data to describe the sexually transmitted and other bloodborne infection (STBBI) related needs of gay, bisexual and other men who have sex with men (gbMSM). METHODS: The EMIS-2017 questionnaire was an updated version of EMIS-2010. It included self-reported sociodemographic data, experience of discrimination, mental health and substance use, knowledge of preexposure prophylaxis (PrEP) for HIV, sexual practices and history of STBBI testing and diagnosis. Analysis was largely descriptive. RESULTS: Of the 6,059 respondents from Canada, 5,165 participants met the inclusion criteria for this analysis. The majority of participants were born in Canada (79.3%); and over half of the respondents (56.7%) were under the age of 39. In terms of discrimination related to their attraction to other men, participants reported high levels of intimidation (31.9%), verbal abuse (22.1%) and physical violence (1.5%) in the previous year. Regarding mental health, 23.9% had a moderate to severe depression/anxiety score. Almost two-thirds (64.1%) indicated substance use and one-fifth (21.5%) reported chemsex (or the use of stimulant drugs to make sex more intense or last longer). Only 8.4% of participants reported use of PrEP for HIV; however, 51.7% reported being likely to use PrEP if it was available and affordable. Sexual practices, such as condom use, varied by PrEP use with 91.3% of men using PrEP reporting condomless anal intercourse (CAI) compared with 71.5% of men not on PrEP. In terms of STBBI testing, 1.5% reported being diagnosed with hepatitis C and 9.0% reported an HIV diagnosis. Of those with an HIV diagnosis, most were on treatment (99.1%) and had an undetectable viral load (96.7%). CONCLUSION: gbMSM in Canada experienced stigma, discrimination and mental health problems; substance use was high as were high-risk sexual practices, such as CAI, among some groups of men. There was a gap between the proportion of men who were interested in PrEP and those who actually used it; and comprehensive STBBI testing was low.These findings can inform public health action and provide a baseline to examine the impact of current and new interventions.

Downregulation of the cancer susceptibility protein WRAP53ß in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.

Alterations in the scaffold protein WRAP53ß have previously been linked to carcinogenesis and, in particular, associated with an increased risk for epithelial ovarian cancer. Here, we investigated the pathogenic impact and prognostic significance of WRAP53ß in connection with epithelial ovarian cancer and examined the underlying mechanisms. We find that reduced expression of WRAP53ß in ovarian tumors correlated with attenuated DNA damage response and poor patient survival. Furthermore, in ovarian cancer cell lines, WRAP53ß was rapidly recruited to DNA double-strand breaks, where it orchestrated the recruitment of repair factors involved in homologous recombination and non-homologous end joining, including RNF168, 53BP1, BRCA1 and RAD51. Mechanistically, WRAP53ß accomplishes this by facilitating the necessary ubiquitinylation at DNA breaks. Finally, we demonstrate that loss of WRAP53ß significantly impairs the repair of DNA double-strand breaks, resulting in their accumulation. Our findings establish WRAP53ß as a regulator of homologous recombination and non-homologous end joining repair in ovarian cancer cells, suggesting that loss of this protein contributes to the development and/or progression of ovarian tumors. Moreover, our current observations identify the nuclear levels of WRAP53ß as a promising biomarker for the survival of patients with ovarian cancer.

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

Routine mobilization of the splenic flexure is not necessary during anterior resection for rectal cancer.

PURPOSE: Splenic flexure mobilization is widely considered to be an essential component of anterior resection for rectal cancer. It was our hypothesis that selective splenic flexure mobilization would reduce operative times without increasing morbidity or affecting cure. METHODS: A total of 100 consecutive patients with rectal cancer (mean 8 (range, 4-15) cm from anal verge) who underwent anterior resection for cure between 1996 and 2002 had splenic flexure mobilization only as required to achieve a tension-free anastomosis. Operative time, postoperative morbidity, pathologic findings, and recurrence rates were recorded. RESULTS: There were no clinicopathologic differences between those who had splenic flexure mobilization (n = 26) and those who did not (n = 74). Mean operative time in the splenic flexure mobilization group was longer, 167 (range, 130-200) minutes vs. 120 (range, 95-180) minutes in the nonmobilized group (P = 0.023). Mean length of specimen resected was longer in the splenic flexure mobilization group: 36 vs. 18 cm (P = 0.008). Anastomotic complications (4 percent), local recurrence (7 percent, median follow-up, 38 months), perioperative morbidity (32 percent) and mortality (2 percent), and survival did not differ between the two groups. CONCLUSIONS: Routine splenic flexure mobilization is not required for safe anterior resection in patients with rectal cancer. Avoiding splenic flexure mobilization results in shorter operative times and does not increase postoperative morbidity, anastomotic leakage, or local recurrence.

Chronic lymphocytic leukaemia complicated by recurrent Bell's palsy.

A patient who presented with a transient right-sided Bell's palsy (lower motor neurone lesion of the facial nerve) and chronic lymphocytic leukaemia (CLL) is described. During the following 5 years whilst receiving intermittent treatment for her CLL, the patient experienced two further episodes of Bell's palsy, one on the right side and the other left-sided. Each episode completely resolved. This is the first reported case of recurrent Bell's palsy complicating CLL.