Serum HE4 as a prognostic marker in endometrial cancer : a population based study

Objective HE4 has emerged as a promising biomarker in gynaecological oncology. The purpose of this study was to evaluate serum HE4 as a biomarker for high-risk phenotypes in a population-based endometrial cancer cohort. Methods Peri-operative serum HE4 and CA125 were measured in 373 patients identified from the prospective Australian National Endometrial Cancer Study (ANECS). HE4 and CA125 were quantified on the ARCHITECT instrument in a clinically accredited laboratory. Receiver operator curves (ROC), Spearman rank correlation coefficient, and chi-squared and Mann–Whitney tests were used for statistical analysis. Survival analysis was performed using Kaplan–Meier and Cox multivariate regression analyses. Results Median CA125 and HE4 levels were higher in stage III and IV tumours (p < 0.001) and in tumours with outer-half myometrial invasion (p < 0.001). ROC analysis demonstrated that HE4 (area under the curve (AUC) = 0.76) was a better predictor of outer-half myometrial invasion than CA125 (AUC = 0.65), particularly in patients with low-grade endometrioid tumours (AUC 0.77 vs 0.64 for CA125). Cox multivariate analysis demonstrated that elevated HE4 was an independent predictor of recurrence-free survival (HR = 2.40, 95% CI 1.19–4.83, p = 0.014) after adjusting for stage and grade of disease, particularly in the endometrioid subtype (HR = 2.86, 95% CI 1.25–6.51, p = 0.012). Conclusion These findings demonstrate the utility of serum HE4 as a prognostic biomarker in endometrial cancer in a large, population-based study. In particular they highlight the utility of HE4 for pre-operative risk stratification to identify high-risk patients within low-grade endometrioid endometrial cancer patients who might benefit from lymphadenectomy.

Quality of life of women with lower limb swelling or lymphedema 3-5 years following endometrial cancer

Objective To quantitatively assess and compare the quality of life (QoL) of women with a self-reported diagnosis of lower limb lymphedema (LLL), to women with lower limb swelling (LLS), and to women without LLL or LLS following treatment for endometrial cancer. Methods 1399 participants in the Australian National Endometrial Cancer Study were sent a follow-up questionnaire 3–5 years after diagnosis. Women were asked if they had experienced swelling in the lower limbs and, if so, whether they had received a diagnosis of lymphedema by a health professional. The 639 women who responded were categorised as: Women with LLL (n = 68), women with LLS (n = 177) and women without LLL or LLS (n = 394). Multivariable-adjusted generalized linear models were used to compare women’s physical and mental QoL by LLL status. Results On average, women were 65 years of age and 4 years after diagnosis. Women with LLL had clinically lower physical QoL (M= 41.8, SE= 1.4) than women without LLL or LLS (M= 45.1, SE= 0.8, p = .07), however, their mental QoL was within the normative range (M= 49.6; SE= 1.1 p = 1.0). Women with LLS had significantly lower physical (M= 41.0, SE= 1.0, p = .003) and mental QoL (M= 46.8; SE= 0.8, p < .0001) than women without LLL or LLS (Mental QoL: M= 50.6, SE= 0.8). Conclusion Although LLL was associated with reductions in physical QoL, LLS was related to reductions in both physical and mental QoL 3-5 years after cancer treatment. Early referral to evidence-based lymphedema programs may prevent long-term impairments to women’s QoL.

Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo

Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors. GHSR gene silencing was achieved in the Ishikawa and KLE endometrial cancer cell lines, using a lentiviral short-hairpin RNA targeting GHSR. The effects of GHSR1a knockdown were further analyzed in vivo using the Ishikawa cell line in a NOD/SCID xenograft model. Cell proliferation was reduced in cultured GHSR1a knockdown Ishikawa and KLE cells compared with scrambled controls in the absence of exogenously applied ghrelin and in response to exogenous ghrelin (1,000 nM). The tumor volumes were reduced significantly in GHSR1a knockdown Ishikawa mouse xenograft tumors compared with scrambled control tumours. Using immunohistochemistry, we demonstrated that ghrelin and GHSR1a are expressed in benign and cancerous glands in human endometrial tissue specimens, although there was no correlation between the intensity of staining and cancer grade. These data indicate that downregulation of GHSR expression significantly inhibits endometrial cancer cell line and mouse xenograft tumour growth. This is the first preclinical evidence that downregulation of GHSR may be therapeutic in endometrial cancer.

Polymorphisms in inflammation pathway genes and endometrial cancer risk

BACKGROUND Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

Expression and in vitro functions of the ghrelin axis in endometrial cancer

Ghrelin is a peptide hormone produced in the stomach and a range of other tissues, where it has endocrine, paracrine and autocrine roles in both normal and disease states. Ghrelin has been shown to be an important growth factor for a number of tumours, including prostate and breast cancers. In this study, we examined the expression of the ghrelin axis (ghrelin and its receptor, the growth hormone secretagogue receptor, GHSR) in endometrial cancer. Ghrelin is expressed in a range of endometrial cancer tissues, while its cognate receptor, GHSR1a, is expressed in a small subset of normal and cancer tissues. Low to moderately invasive endometrial cancer cell lines were examined by RT-PCR and immunoblotting, demonstrating that ghrelin axis mRNA and protein expression correlate with differentiation status of Ishikawa, HEC1B and KLE endometrial cancer cell lines. Moreover, treatment with ghrelin potently stimulated cell proliferation and inhibited cell death. Taken together, these data indicate that ghrelin promotes the progression of endometrial cancer cells in vitro, and may contribute to endometrial cancer pathogenesis and represent a novel treatment target.

Predicting positive and negative impacts of cancer among long-term endometrial cancer survivors

OBJECTIVE Although the survival outcomes among women diagnosed with endometrial cancer are very favorable, little is known about the long-term impact of their cancer experience. This study identifies the extent of positive and negative impacts of cancer and factors associated with this, amongst long-term survivors of endometrial cancer. METHODS Australian women diagnosed with endometrial cancer (N=632) were sent questionnaires at the time of diagnosis and 3-5 years later. Hierarchical multiple regression models were used to examine whether a range of variables at diagnosis/treatment predicted subsequent scores on the Impact of Cancer Scale, which examines positive (e.g. health awareness) and negative (e.g. appearance concerns) impacts amongst cancer survivors. RESULTS Overall, women had a higher mean score for the positive than negative impact scales (M=3.5 versus M=2.5, respectively). An intermediate grade of endometrial cancer, a prior diagnosis of cancer and lower levels of education were significant, but weak, predictors of higher scores on the positive impact scale. Higher scores on the negative impact scale were predicted by a higher grade of cancer, poor physical and mental health, a younger age, being single or having lower levels of education. CONCLUSIONS The study demonstrates that factors that predict positive impact in cancer survivors differ to those that predict negative impact, suggesting that interventions to optimize cancer survivors' quality of life will need to be multi-dimensional, and this supports the need for tailored intervention.

The cost-effectiveness of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer

Objective To summarise how costs and health benefits will change with the adoption of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer. Design Cost-effectiveness modelling using the information from a randomised controlled trial. Participants Two hypothetical modelled cohorts of 1000 individuals undergoing total laparoscopic hysterectomy and total abdominal hysterectomy. Outcome measures Surgery costs; hospital bed days used; total healthcare costs; quality-adjusted life years; and net monetary benefits. Results For 1000 individuals receiving total laparoscopic hysterectomy surgery, the costs were $509 575 higher, 3548 hospital fewer bed days were used and total health services costs were reduced by $3 746 221. There were 39.13 more quality-adjusted life years for a 5 year period following surgery. Conclusions The adoption of total laparoscopic hysterectomy is almost certainly a good decision for health services policy makers. There is 100% probability that it will be cost saving to health services, a 86.8% probability that it will increase health benefits and a 99.5% chance that it returns net monetary benefits greater than zero.

Rapid on-site evaluation of fine needle aspiration specimens by cytology scientists : a review of 3032 specimens

Objectives To determine: (1) the accuracy of cytology scientists at assessing specimen adequacy by rapid on-site evaluation (ROSE) at fine needle aspiration (FNA) cytology collections; and (2) whether thyroid FNA with ROSE has lower inadequacy rates than non-attended FNAs. Methods The ROSE of adequacy for 3032 specimens from 17 anatomical sites collected over a 20-month period was compared with the final report assessment of adequacy. ROSE was performed by 19 cytology scientists. The report profile for 1545 thyroid nodules with ROSE was compared with that for 1536 consecutive non-ROSE thyroid FNAs reported by the same cytopathologists during the study period. Results ROSE was adequate in 75% (2276/3032), inadequate in 12% (366/3032) and in 13% (390/3032) no opinion was rendered. Of the 2276 cases assessed as adequate by ROSE, 2268 (99.6%) were finally reported as adequate for assessment; eight specimens had adequacy downgraded on the final report. Fifty eight per cent of cases with a ROSE assessment of inadequate were reported as adequate (212/366), whereas 93% (363/390) with no opinion rendered were reported as adequate. The overall final report adequacy rate for the 3032 specimens was 94% (2843/3032). Confirmation of a ROSE of adequacy at reporting was uniformly high amongst the 19 scientists, ranging from 98% to 100%. The inadequacy rate for thyroid FNAs with ROSE (6%) was significantly (P < 0.0001) lower than for non-ROSE thyroid FNAs (17%). A significantly (P = 0.02) higher proportion of adequate ROSE thyroid specimens was reported with abnormalities, compared with non-ROSE thyroid collections. Conclusions Cytology scientists are highly accurate at determining specimen adequacy at ROSE for a wide range of body sites. ROSE of thyroid FNAs can significantly reduce inadequate reports.

Performance measures for Australian laboratories reporting cervical cytology : a decade of data 1998–2008

Aim Performance measures for Australian laboratories reporting cervical cytology are a set of quantifiable measures relating to the profile and accuracy of reporting. This study reviews aggregate data collected over the ten years in which participation in the performance measures has been mandatory. Methods Laboratories submit annual data on performance measures relating to the profile of reporting, including reporting rates for technically unsatisfactory specimens, high grade or possible high grade abnormalities and abnormal reports. Cytology-histology correlation data and review findings of negative smears reported from women with histological high grade disease are also collected. Suggested acceptable standards are set for each measure. This study reviews the aggregate data submitted by all laboratories for the years 1998-2008 and examines trends in reporting and the performance of laboratories against the suggested standards. Results The performance of Australian laboratories has shown continued improvement over the study period. There has been a fall in the proportion of laboratories with data outside the acceptable standard range in all performance measures. Laboratories are reporting a greater proportion of specimens as definite or possible high grade abnormality. This is partly attributable to an increase in the proportion of abnormal results classified as high grade or possible high grade abnormality. Despite this, the positive predictive value for high grade and possible high grade abnormalities has continued to rise. Conclusion Performance measures for cervical cytology have provided a valuable addition to external quality assurance procedures in Australia. They have documented continued improvements in the aggregate performance, as well as providing benchmarking data and goals for acceptable performance for individual laboratories.

Fine-needle aspiration cytology of Merkel cell carcinoma-A review of 69 cases

Background This study reviewed the clinical presentation, cytologic findings and the immunophenotype of 69 Merkel Cell Carcinoma (MCC) cases sampled by FNA. Methods Demographic and clinical data, the cytology findings and results of ancillary testing were reviewed. Results Median patient age was 78 years (37 – 104) with a 1:1.8 female to male ratio. The most common FNA sites sampled included lymph nodes in the neck, the axillary region, the inguinal region and the parotid gland. Most patients had a history of MCC (68%) &/or non-MCC malignancy (70%). The common cytologic pattern was a cellular smear with malignant cells arranged in a dispersed pattern with variable numbers of disorganised groups of cells. Cytoplasm was scant or absent and nuclei showed mild to moderate anisokaryosis, stippled chromatin, inconspicuous nucleoli and nuclear molding. Numerous apoptotic bodies were often present. Cell block samples (28 cases) were usually positive for cytokeratins in a perinuclear dot pattern, including 88% of cases with CK20 positivity. CD56 was the most sensitive (95%) neuroendocrine marker on cell blocks and was also positive with flow cytometry in 9 cases tested. Conclusions MCC is most commonly seen in FNA specimens from the head and neck of elderly patients, often with a history of previous skin lesions. Occasional cases present in younger patients and some may be mistaken for other round blue cell tumors, such as lymphoma. CD 56 may be a useful marker in cell block preparations and in flow cytometric analysis of MCC.

Prevalence, predictors, and correlates of supportive care needs among women 3–5 years after a diagnosis of endometrial cancer

Purpose The purpose of this study is to examine the prevalence, sociodemographic and clinical predictors, and physical and psychosocial correlates of unmet needs among women 3–5 years following treatment for endometrial cancer. Methods Women with endometrial cancer completed a survey around the time of diagnosis and again 3–5 years later. The follow-up survey asked women about their physical and psychosocial functioning and supportive care needs (CaSUN). Multivariable-adjusted logistic regression identified the predictors and correlates of women’s unmet needs 3–5 years after diagnosis. Results Of the 629 women who completed the cancer survivors’ unmet needs measure (CaSUN), 24 % (n = 153) women reported one or more unmet supportive care needs in the last month. Unmet needs at 3–5 years post-diagnosis were predicted by younger age (OR = 4.47; 95 % CI: 2.09–9.56) and advanced disease stage at diagnosis (OR = 2.47; 95 % CI: 1.38–4.45) and correlated with greater cancer symptoms (OR = 1.78; 95 % CI: 1.05–3.02), lower limb swelling (OR = 2.50; 95 % CI: 1.51–4.15), symptoms of anxiety (OR = 2.21; 95 % CI: 1.31–3.72), and less availability of social support (OR = 3.42; 95 % CI: 1.92–6.11). Women with a history of comorbidities (OR = 0.47; 95 % CI: 0.27–0.82) and those living in a rural area at the time of diagnosis (OR = 0.56; 95 % CI: 0.34–0.92) were less likely to report unmet needs. Conclusions Sociodemographic, health, and psychosocial factors seem important for identifying women who will or will not have unmet needs several years following endometrial cancer. Longitudinal assessments of people’s needs over the course of their cancer trajectory may be an effective way to identify areas that should receive further attention by health providers.

Improving treatment for obese women with early stage cancer of the uterus : rationale and design of the levonorgestrel intrauterine device ±Metformin ±weight loss in endometrial cancer (feMME) trial

Purpose Endometrial adenocarcinoma (EC) is the most common gynaecologic cancer. Up to 90% of EC patients are obese which poses a health threat to patients post-treatment. Standard treatment for EC includes hysterectomy, although this has significant side effects for obese women at high risk of surgical complications and for women of childbearing age. This trial investigates the effectiveness of non-surgical or conservative treatment options for obese women with early stage EC. The primary aim is to determine the efficacy of: levonorgestrel intrauterine device (LNG-IUD); with or without metformin (an antidiabetic drug); and with or without a weight loss intervention to achieve a pathological complete response (pCR) in EC at six months from study treatment initiation. The secondary aim is to enhance understanding of the molecular processes and to predict a treatment response by investigating EC biomarkers. Methods An open label, three-armed, randomised, phase-II, multi-centre trial of LNG-IUD ± metformin ± weight loss intervention. 165 participants from 28 centres are randomly assigned in a 3:3:5 ratio to the treatment arms. Clinical, quality of life and health behavioural data will be collected at baseline, six weeks, three and six months. EC biomarkers will be assessed at baseline, three and six months. Conclusions There is limited prospective evidence for conservative treatment for EC. Trial results could benefit patients and reduce health system costs through a reduction in hospitalisations and through lower incidence of adverse events currently observed with standard treatment.

Women’s perceptions of their lifestyle and quality of life several years after a diagnosis of endometrial cancer

Background Few studies have examined the long-term changes experienced by women treated for endometrial cancer. Objective The objectives of this study were to describe what women perceived important to their lifestyle and quality of life in the years following their diagnosis and to provide new insights that might inform healthcare practice. Methods This was a thematic analysis of 237 open-ended comments from Australian women diagnosed with endometrial cancer 3 to 5 years previously. Results We identified 3 main themes: (1) personal change, in which women spoke about cancer as permanently altering their lives in mostly negative but sometimes positive ways; (2) continuity of former life, which described both the minimal impact of cancer on women's lives and identities and the difficulties negotiating this within the dominant "cancer survivorship" culture; (3) social support, where women wrote about how the quality of their relationships shaped their cancer trajectory. Conclusions While typical "survivorship" issues exist for many women with endometrial cancer (eg, physical, emotional, sexual health changes), a proportion of women will not be focused on their cancer and can be encouraged to form lives and identities that are not situated within the "cancer survivorship" culture. Implications for Practice A network of support, sensitive to women's responses to having cancer, may benefit women's long-term adjustment. Regular standardized assessment of women's needs may facilitate appropriate support for those with concerns, whereas those without concerns could be reassured by health professionals that their experience is normal and shared by other people with cancer. This may encourage women to form lives that are personally meaningful.

The varied presentation of metastatic melanoma in fine needle aspiration cytology of the breast

Objective To identify cytomorphological patterns of metastatic melanoma (MM) in breast fine needle aspiration (FNA) specimens and highlight the differential diagnoses and features most useful in identifying MM. Methods The clinical, radiological and FNA findings of 16 cases were reviewed. Cytological features evaluated related to cell arrangement, size and shape of cells, nuclear and cytoplasmic features, and the presence or absence of necrosis. Results The series consisted of 14 females and two males, ranging in age from 24 to 83 years (mean = 50 years). A previous history of melanoma was available in 12/16 (75%) cases at the time of FNA reporting; however the clinical/radiological impression in 4/16 cases was of a breast cyst. The cases were classified into six morphological variants: classical (8/16), pseudopapillary (3/16), spindle-cell (1/16), melanin-rich (1/16), pleomorphic (2/16) and lymphoma-like (1/16). The varying patterns raised a wide range of differential diagnoses; however, discohesion, binucleation and granular cytoplasm were the major features seen in 94% of all cases. In 14/16 cases (88%), plasmacytoid cells, prominent nucleoli and cytoplasmic vacuolation were identified. Melanin and multinucleation were detected in 44% of cases and intranuclear cytoplasmic invaginations in 63%. Necrosis was present in more than half of the cases (56%). Conclusion MM should be considered in the differential diagnosis of breast FNA specimens when atypical cells are seen that present as plasmacytoid cells in a dispersed or pseudopapillary pattern, or as spindle, pleomorphic or pigmented cells. These features, combined with clinical history and immunocytochemistry, may assist in correctly identifying MM and directing optimal treatment.

‘Healthy mobile check-ins’ study: using GIS in smartphones to track use of urban environment by survivors of endometrial cancer

Aims/Objectives Our study aims to test the capacity of a newly developed smartphone innovation to obtain data on social, structural, and spatial determinants of the daily health-related behaviours of women living in urban Brisbane neighbourhoods who have survived endometrial cancer. Methods The women used a mobile web app designed specifically for the project to record GIS/location data on every destination they visited within their local urban neighbourhoods over a two-week period. Additionally, we gathered textual data on the social context/reasons for travel, as well as mode of transport to reach these destinations. The data was transported to SPSS and Google Earth for statistical and spatial analysis. We then met with the women to discuss lifestyle interventions to maximise their use of their local neighbourhoods in ways that could increase their physical activity levels and improve their overall health and well-being. These interventions will be evaluated and translated into a large-scale national study if effective. Results Initial findings about patterns in the group’s use of the local urban environment will be displayed, including daily distances travelled, types of locations visited, walking levels, use of public transport, use of green spaces and use of health-related resources. Any socio-demograpahic differences found between the women will be reported. Qualitative, quantitative, and spatial/mapping data will be displayed Conclusion The benefits and limitations of the mobile website designed to collect a range of data types about human-neighbourhood interactions with implications for intervention design will be discussed.