The incidence of cervical cancer in women with postcoital bleeding and abnormal appearance of the cervix referred through the 2-week wait pathway in the United Kingdom: A retrospective cohort study.

AIM: To determine the incidence of cervical cancer in women referred through the 2-week-wait pathway for postcoital bleeding and abnormal appearance of the cervix. METHODS: A retrospective cohort study was conducted of women with postcoital bleeding, or abnormal appearance of the cervix referred to colposcopy clinics through the 2-week-wait pathway for suspected cervical cancer at Cambridge University Hospitals in the United Kingdom over 5 years. Women were identified from a departmental database. Clinical and demographic data were collected. Categorical data was analyzed with chi-squared or Fisher's exact tests and predictive values were calculated. RESULTS: Of the 604 women referred, 1.16% were diagnosed with cervical cancer. None of the women who were up-to-date with cervical screening were diagnosed with cervical cancer, while 6.25% of women out-of-date with cervical screening or outside the screening age group were diagnosed with cervical cancer (p < 0.001). The positive predictive value for diagnosing cervical cancer was 1.70% for postcoital bleeding (95% confidence interval [CI] 0.64-3.7) and 0.31% for abnormal appearance of the cervix (95% CI 0.0008-1.7). CONCLUSIONS: The incidence of cervical cancer in women referred through the 2-week-wait pathway for postcoital bleeding and abnormal appearance of the cervix is low. These referrals have considerable implications for both patients and clinicians, and have a low predictive value for diagnosing cervical cancer. In light of emerging evidence and changing practices, referral guidelines should be reviewed based on up-to-date data and current practices.

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Organ-sparing central pelvic compartment resection for the treatment of vulvo-vaginal melanomas.

Vulvo-vaginal melanomas are one of the rarest gynecological oncology diseases with a poor survival compared with other malignancies. The 5-year survival varies from 13% to 32.3%. Vulvo-vaginal melanomas involving the upper 2/3rds of the vagina are usually treated with total pelvic exenteration (TPE). TPE surgery carries a 50% risk of major complications and also morbidity associated with double stomas. Central pelvic compartment resection is a novel organ-sparing surgical approach entailing radical total laparoscopic hysterectomy, bilateral salpingo-oophrectomy, laparoscopic vaginectomy and vulvectomy to reduce morbidity compared with TPE. Permanent suprapubic catheters are used if there is urethral involvement but require quality of life studies to assess their long-term outcomes.

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

Influence of normal mammary epithelium on breast cancer progression: the protective role of early pregnancy.

AIMS AND BACKGROUND: The microenvironment has a well recognized role in breast cancer progression. Despite different theories, the mechanism of early pregnancy protection in mammary carcinogenesis is unknown. Since pregnancy is responsible for mammary gland differentiation, we tested the hypothesis that differentiated mammary epithelial cells may inhibit breast cancer progression. In other words, the protective role of early pregnancy could be due to the inhibitory influences of the more differentiated mammary tissue. METHODS: In order to test our hypothesis, we used 30 female Balb/c nude mice and MCF-7 cells of breast adenocarcinoma. The female mice were divided into two test groups, group I (GI) and group II (GII), and a control group. In GII, the animals were submitted to epithelial removal in the left fourth inguinal mammary gland at 3 weeks of age. Both groups were given continuous hormonal treatment to simulate the pregnancy development of the mammary gland. Two million MCF-7 cells were then injected into the fourth inguinal mammary gland (GI) or in the respective cleared mammary fat pad (GII). Five weeks later the mice were sacrificed and their tumors removed. Tumor development rates and tumor volumes were determined and proliferation and apoptosis were evaluated by immunohistochemistry. RESULTS: Tumors of GII mice had a larger mean volume than those of GI mice (P = 0.001, Mann-Whitney U-test) and an apparent increase in proliferation, demonstrated by a higher staining intensity for proliferating cell nuclear antigen (PCNA). As tumors presented caspase 8 staining, there may be apoptotic activation involved in cell death, mainly through an extrinsic pathway. CONCLUSIONS: These results suggest that a differentiated intact mammary gland may have an inhibitory influence on mammary tumor growth in mice.

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

Microdialysis: improving local chemotherapy in cancer using a mathematical model.

Although intratumoral chemotherapy administration has been evaluated in the past, its results have not been frequently comparable to those from systemic administration. We recently described microdialysis as a method for local chemotherapy administration with increasing effectiveness while reducing systemic toxicity. We present a mathematical model which supports the successful application of this procedure in optimizing the administered drug in different cases, using informatics tools and considering several parameters. We also review and discuss important aspects of cancer biology that should be taken into consideration in cancer chemotherapy, such as tumor heterogeneity, drug resistance and metastasis, and how this technique may be used to overcome any set-backs presented by these.