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Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.

ABSTRACTBackground: Liquid biopsies offer significant potential for informing on cancer progression and therapeutic resistance via minimally invasive serial monitoring of genetic alterations. Although the cancer epigenome is a central driving force in most neoplasia, the accuracy of monitoring the tumor methylome using liquid biopsies remains relatively unknown. Objectives: to investigate how well two types of liquid biopsy (urine and blood) capture the prostate cancer methylome, and may thus serve as a non-invasive surrogate for studying the tumor epigenome. Methods: A cohort of four metastatic treatment naïve prostate cancer (PCa) patients was selected. Matched biopsy cores (tumor and histologically matched-normal), post-DRE, pre-biopsy urine, and peripheral blood plasma were available for each subject. DNA methylation was profiled utilizing the Infinium® MethylationEPIC BeadChip (Illumina) and analysed using the RnBeads software. Significantly (FDR adjusted P< 0.05) differentially methylated probes (DMPs) between tumor and MN were identified and examined in the liquids (done at a grouped and individual subject level). Results: DNA methylation analysis of urine and blood in men with metastatic PCa showed highly correlated patterns between the different liquid types (ρ = 0.93, P< 0.0001), with large contributions from non-tumor sources. DNA methylation profiles of liquids were more similar between subjects, than intra-individual liquid-tumor correlations. Overall, both urine and plasma are viable surrogates for tumor tissue biopsies, capturing up to 39.40% and 64.14% of tumor-specific methylation alterations, respectively. Conclusion: We conclude that both urine and blood plasma are easily accessible and sensitive biofluids for the study of PCa epigenomic alterations.

The incidence of Cesarean scar pregnancies (CSPs) is rising globally. Ultrasound criteria for the diagnosis of CSPs have been described by the International Society of Ultrasound in obstetrics and gynecology and appear to be well used in various centers around the world. There is no guidance on best practices for expectant management of CSP, and there is considerable variation in how this is offered globally. Many studies have reported significant maternal morbidity in cases of CSP with fetal cardiac activity managed expectantly, largely relating to hemorrhage and cesarean hysterectomy from placenta accreta spectrum. However, high live birth rates are also reported. Literature describing the diagnosis and expectant management of CSP in low-resource settings is lacking. Expectant management in selected cases where no fetal cardiac activity is present is a reasonable option and can be associated with good maternal outcomes. Standardization in reporting different types of CSPs and correlating these with pregnancy outcomes will be an important next step in developing guidance for expectant management of this high-risk pregnancy with a high burden of complications.

Despite prostate cancer being the most frequent cancer in men in the Western world, tissue biomarkers for predicting disease recurrence after surgery have not been incorporated into clinical practice. Our group has previously identified β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) as independent predictors of biochemical recurrence after radical prostatectomy. The purpose of the present study was to use automated image analysis, enabling quantitative determination of MSMB and CRISP3 expressions in a large cohort and to validate the previous findings. MSMB and CRISP3 protein expressions were assessed on tissue microarrays constructed from 3268 radical prostatectomy specimens. Whole-slide digital images were captured, and a novel cytoplasmic algorithm was used to develop a quantitative scoring model for cytoplasmic staining. Classification regression tree analysis was used to group patients, with different risk for biochemical recurrence, depending on level of protein expression. Patients with tumors expressing high levels of MSMB had a significantly reduced risk for biochemical recurrence after radical prostatectomy (HR=0.468; 95% CI 0.394–0.556; P<0.001). Multivariate analysis adjusted for clinicopathological parameters revealed that MSMB expression was an independent predictor of decreased risk of recurrence (HR=0.710; 95% CI 0.578–0.872; P<0.001). We found no correlation between CRISP3 expression and biochemical recurrence. In this current study, we applied a novel image analysis on a large independent cohort and successfully verified that MSMB is a strong independent factor, predicting favorable outcome after radical prostatectomy for localized prostate cancer.

Despite prostate cancer being the most frequent cancer in men in the Western world, tissue biomarkers for predicting disease recurrence after surgery have not been incorporated into clinical practice. Our group has previously identified β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) as independent predictors of biochemical recurrence after radical prostatectomy. The purpose of the present study was to use automated image analysis, enabling quantitative determination of MSMB and CRISP3 expressions in a large cohort and to validate the previous findings. MSMB and CRISP3 protein expressions were assessed on tissue microarrays constructed from 3268 radical prostatectomy specimens. Whole-slide digital images were captured, and a novel cytoplasmic algorithm was used to develop a quantitative scoring model for cytoplasmic staining. Classification regression tree analysis was used to group patients, with different risk for biochemical recurrence, depending on level of protein expression. Patients with tumors expressing high levels of MSMB had a significantly reduced risk for biochemical recurrence after radical prostatectomy (HR=0.468; 95% CI 0.394–0.556; P<0.001). Multivariate analysis adjusted for clinicopathological parameters revealed that MSMB expression was an independent predictor of decreased risk of recurrence (HR=0.710; 95% CI 0.578–0.872; P<0.001). We found no correlation between CRISP3 expression and biochemical recurrence. In this current study, we applied a novel image analysis on a large independent cohort and successfully verified that MSMB is a strong independent factor, predicting favorable outcome after radical prostatectomy for localized prostate cancer.

Aberrant expression of the MAD2 protein has been linked to chromosomal instability, malignant transformation and chemoresistance. Although reduced MAD2 expression is well recognised in human cancer cell lines, the mechanism(s) underlying its down-regulation remain elusive.

Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n=1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (P<0.001), small tumors (P<0.001), estrogen receptor (ER) positivity (P<0.001) and Ki-67 negativity (P<0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30–0.79, P=0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors.

Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n=1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (P<0.001), small tumors (P<0.001), estrogen receptor (ER) positivity (P<0.001) and Ki-67 negativity (P<0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30–0.79, P=0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors.

This study systematically analyzes platelet-derived growth factor (PDGF) receptor expression in six types of common tumors as well as examines associations between PDGF β-receptor status and clinicopathological characteristics in breast cancer. PDGF receptor expression was determined by immunohistochemistry on tumor tissue microarrays. Breast tumor data were combined with prognostic factors and related to outcome endpoints. PDGF α- and β-receptors were independently expressed, at variable frequencies, in the tumor stroma of all tested tumor types. There was a significant association between PDGF β-receptor expression on fibroblasts and perivascular cells in individual colon and prostate tumors. In breast cancer, high stromal PDGF β-receptor expression was significantly associated with high histopathological grade, estrogen receptor negativity, and high HER2 expression. High stromal PDGF β-receptor expression was correlated with significantly shorter recurrence-free and breast cancer-specific survival. The prognostic significance of stromal PDGF β-receptor expression was particularly prominent in tumors from premenopausal women. Stromal PDGF α- and β-receptor expression is a common, but variable and independent, property of solid tumors. In breast cancer, stromal PDGF β-receptor expression significantly correlates with less favorable clinicopathological parameters and shorter survival. These findings highlight the prognostic significance of stromal markers and should be considered in ongoing clinical development of PDGF receptor inhibitors.

This study will aim to assess if a composite intervention which involves a specific evidence-based intervention for management of insomnia and non-hormonal pharmacotherapy to manage vasomotor symptoms (VMS) of menopause can improve quality of life for patients experiencing troublesome VMS after cancer who are not eligible for standard systemic menopausal hormone therapy (MHT). Participants will be asked to nominate a partner or companion to support them during this process as an additional form of support.

Breast cancer is the one of leading causes of cancer-related deaths in women within economically developed regions of the world. A major focus of present research into this malignancy is the identification of new biomarkers and drug targets to improve detection and treatment. Proteomics represents one of the latest technological developments in this context. It aims to analyse the complex circuitry of the breast cancer proteome. Here, the authors review how breast cancer proteomics has progressed so far, with emphasis on its potential application to clinically relevant scenarios.

There are > 1.15 million cases of breast cancer diagnosed worldwide annually, and it is the second leading cause of cancer death in the European Union. The optimum management of patients with breast cancer requires accurate prognostic and predictive factors. At present, only a small number of such factors are used clinically. DNA microarrays have the potential to measure the expression of tens of thousands of genes simultaneously. Recent preliminary findings suggest that DNA microarray-based gene expression profiling can provide powerful and independent prognostic information in patients with newly diagnosed breast cancer. As well as providing prognostic information, emerging results suggest that DNA microarrays can also be used for predicting response or resistance to treatment, especially to neoadjuvant chemotherapy. Prior to clinical application, these preliminary findings must be validated using large-scale prospective studies. This article reviews these advances and also examines the role of DNA microarrays in reducing the number of patients who receive inappropriate chemotherapy. The most recent data supporting the integration of various publicly available data sets is also reviewed in detail.

IMPORTANCE: Cervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results. OBJECTIVES: To estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results. DESIGN, SETTING, AND PARTICIPANTS: This decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged =25 years), considering different levels of HPV vaccination. MAIN OUTCOMES AND MEASURES: The number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence. RESULTS: In a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies). CONCLUSIONS AND RELEVANCE: In this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.