Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. ...Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often concerned about why they developed an MPN and epidemiological studies enable the identification of potential causative factors. Previous work in small heterogeneous studies has identified a variety of risk factors associated with MPNs including family history of MPN, autoimmune conditions, some occupational exposures, and blood donation. At a population level, germline predisposition factors in various populations have been associated with MPNs. The pilot MOSAICC (Myeloproliferative Neoplasm: An In-depth Case-Control) study is one of the largest epidemiological studies in MPN ever carried out to date. It demonstrated the most effective methods for carrying out a significant epidemiological study in this patient group including the best way of recruiting controls, as well as how to evaluate occupational and lifestyle exposures, evaluate symptoms, and collect biological samples. Significant results linked to MPNs in the pilot study of 106 patients included smoking, obesity, and childhood socioeconomic status. The methodology is now in place for a much larger ongoing MOSAICC study which should provide further insight into the potential causes of MPNs.
A National Network of Safe Havens: Scottish Perspective Gao, Chuang; McGilchrist, Mark; Mumtaz, Shahzad ...
JMIR. Journal of medical internet research/Journal of medical internet research,
03/2022, Volume:
24, Issue:
3
Journal Article
Peer reviewed
Open access
For over a decade, Scotland has implemented and operationalized a system of Safe Havens, which provides secure analytics platforms for researchers to access linked, deidentified electronic health ...records (EHRs) while managing the risk of unauthorized reidentification. In this paper, a perspective is provided on the state-of-the-art Scottish Safe Haven network, including its evolution, to define the key activities required to scale the Scottish Safe Haven network's capability to facilitate research and health care improvement initiatives. A set of processes related to EHR data and their delivery in Scotland have been discussed. An interview with each Safe Haven was conducted to understand their services in detail, as well as their commonalities. The results show how Safe Havens in Scotland have protected privacy while facilitating the reuse of the EHR data. This study provides a common definition of a Safe Haven and promotes a consistent understanding among the Scottish Safe Haven network and the clinical and academic research community. We conclude by identifying areas where efficiencies across the network can be made to meet the needs of population-level studies at scale.
Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide ...polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1 × 10(-7)). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk.
Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over ...anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses.
Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance.
The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29).
The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.
Over the last three decades, the incidence of thyroid cancer has increased worldwide. The reasons for this increase remain controversial. In Algeria, however, to date, information on thyroid cancer ...has been limited to a hospital-based case series. We analyzed data from a population-based cohort study in Oran District, Algeria, to describe demographic and clinicopathological characteristics of patients diagnosed with thyroid cancer between 1993 and 2013. Medical records and pathology reports of thyroid cancer patients who had surgery were reviewed. Changes in demographic and clinicopathological features over the 21-year period are described. During the study period, thyroid cancer was diagnosed in 1248 women (86.5%, mean age 43.7±15.2 years) and 195 men (23.4%, mean age 48.1±15.9 years). Most cases (83.1% for women and 69.8% for men) sought a diagnosis following a self-neck check. The most common histologic types were papillary (58.3%), follicular (29.7%), anaplastic (4.1%), and medullary (0.8%) carcinomas. The incidence of papillary carcinomas significantly increased (p<0.001) while the incidence of other histologic types significantly decreased over time. Tumor size overall significantly decreased (p<0.001) while the frequency of small (≤20 mm) and larger (>20 mm) carcinomas significantly increased (p<0.05). The frequency of thyroid cancers with capsular effractions and angioinvasions also decreased over time. Thyroid cancer incidence in Algeria has increased substantially in line with international trends with changes in clinical practice being a possible contributing factor. However, the increasing papillary-to-follicular cancer ratio may be due to changes in iodine nutrition status in Algeria. Further research, including exploration of biological and molecular features of thyroid cancer, will enable a better understanding of risk factors and etiopathogenetic mechanisms.
•Trastuzumab significantly reduces recurrence rates in small cell HER2 breast cancer.•Younger patients with larger tumours were more likely to receive treatment.•Treatment should be offered ...regardless of tumor size.
HER2-positive breast cancers, representing up to 20% of all breast cancers, are more aggressive and have poorer outcomes. Systemic therapy has been proven to prevent disease recurrence and improve survival. Existing literature provides only limited evidence to support this in smaller HER2-positive tumors. The study aimed to evaluate HER-2 positive breast cancer management and treatment of all T1N0 tumors in the North of Scotland, diagnosed 2012–2019. Clinical-pathological details, comorbidities, treatments and clinical events were retrieved from the Scottish North Cancer Alliance audit database and analyzed using univariate and multivariate analysis including cox-regression and log-rank testing (SPSSv23).Overall, 299 patients (41% screen detected/ 56.9% symptomatic /2.1% other), median age 63 years and median tumor size 13 mm, were included. Most cancers were grade 2/3 (43.1%/ 55.5%). Most patients (59.5%) received treatment with trastuzumab (tT); 40.8% concurrent with chemotherapy and endocrine therapy. 7.7% of patients received neo adjuvant chemotherapy. Median follow-up time was 2.6 years, with recurrence on average occurring 2.9 years after diagnosis. Patients receiving trastuzumab were younger, had a higher grade and larger size tumor. 78.5% of patients in the untreated group (non-tT) were ER positive compared to 65.2% in the treated group (tT). Trastuzumab significantly lowered breast cancer recurrence (Tt=3.4% versus non-Tt=8.3%, p = 0.022 HR= 0.096, 95% CI 0.025–0.361). In conclusion, receiving anti-HER2 treatment significantly improved clinical outcome in this T1N0 patient group. Consideration, at the very least informed discussions with patients, should be undertaken to treat these early stage HER2-positive breast cancers.
Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to ...relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach.
Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n=84), gene expression profiling (n=47), matched pre- and post-AI aCGH (n=19 pairs) and Ki67-based AI-response analysis (n=39).
Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1).
These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response.
In Scotland 17 % of the population reside rurally and previous research has demonstrated worse cancer outcomes in this group. The underlying reason for this is unclear. This study aims to determine ...whether patient presenting factors, GP consultation factors or the diagnostic pathways differ between urban and rural patients within Scotland.
This study combined two Scottish National Cancer Diagnosis Audits. Participating GPs collected data on the diagnostic pathway from primary to secondary care for cancer patients diagnosed during the audit period. Using the Scottish Government Urban Rural Classification, patients were designated as rural or urban dwellers and compared in descriptive analyses. Key cancer intervals (primary, diagnostic, secondary and treatment interval) were compared between urban and rural dwellers with an additional adjusted analysis for the main cancer sites.
A total of 4309 cancer diagnoses were included in the study; 22 % were in patients from rural locations. Rural patients had significantly more consultations and investigations prior to referral than their urban counterparts. There was no difference in prolonged cancer pathways between the two groups except in lung cancer patients where rural patients had a significantly increased odds of a diagnostic interval of >90 days.
Our findings suggest differences in the interaction between patients and GPs prior to referral in urban and rural settings. However, this does not appear to lead to prolonged patient pathways, except in lung cancer. Further research is needed to determine whether this delay is clinically significant and contributing to poorer outcomes in Scottish rural dwellers with lung cancer.
•Geographical cancer inequality has still not been explained in Scotland.•This study compares urban and rural cancer diagnosis in Scottish primary care.•Rural patients and GPs may interact differently prior to cancer diagnosis.•Delays were not significantly prolonged except for lung cancer.•Further research should confirm possible inequality for rural lung cancer patients.
Abstract Background Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for ...patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time. Methods We analysed about 250,000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999–2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub-site. Results Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999–2001 to 2005–2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five-year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five-year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx). Conclusions This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.
Abstract
Background
Myeloproliferative neoplasms (MPNs) are a relatively new group of blood cancers arising from genetic mutations in haematopoietic stem cells. Diagnostic delay is associated with ...thromboses, strokes and heart attacks. We investigated geographic variation in diagnosis and survival for classic MPNs.
Methods
Data for classic MPNs were obtained from the Australian Cancer Database. Leroux spatial models for incidence and survival were fitted using CARBayes, WinBUGS via R and tests for spatial clustering were conducted.
Results
The age-standardised incidence rate was 4.9 (95% CI: 4.8-5.0) per 100,000 person-years during 2007-2016 with relative survival of 78% (77%, 79%) at 5 years after diagnosis.
Strong evidence of spatial variation in incidence was observed (p < 0.001), with incidence rates low in Tasmania (4.2 per 100,000 person-years, 95% CI: 3.5-5.0) and Western Australia (6.1, 5.6-6.6) and high in Victoria (9.5, 9.2-9.9) and Queensland (10.6, 10.2-11.1).
Differences between states and territories could not be explained by population rates of genetic testing or the proportion of registered cases with histological evidence.
Conclusions
Stark spatial differences in incidence rates of classic MPNs suggest that varying diagnosis and registration patterns between states results in under-recognition, and potentially undertreatment. It is imperative that reporting is consistent so that sound evidence is available for efforts to reduce disparities in diagnosis and management.
Key messages
Early identification of MPNs is crucial, however, strong spatial geographical variation in incidence rates suggest diagnostic and notification practices may not be consistent across the country.
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