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The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers. We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011-31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the \"risk threshold\" at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. A total of 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1,321 (2.6%) with non-ovarian cancer. Of women with a CA125 level ≥35 U/ml, 3.4% aged <50 years and 15.2% aged ≥50 years had ovarian cancer. Of women with a CA125 level ≥35 U/ml who were aged ≥50 years and who did not have ovarian cancer, 20.4% were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings. CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.

Background The diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities. Methods Age-standardised incidence rate (ASR), 1-year overall survival, hazard ratios and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013–2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology. Results A total of 15,222 NENs were identified, with an ASR (2013–2015 combined) of 8.6 per 100,000 (95% CI 8.5–8.7); 4.6 per 100 000 (95% CI, 4.5–4.7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73.9–75.4) varying significantly by sex. Site and morphology were prognostic. NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs. Conclusion Advanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement.

ObjectiveMulti-cancer early detection (MCED) tests are novel technologies that detect cancer signals from a broad set of cancer types using a single blood sample. The objective of this study was to estimate the effect of screening with an MCED test at different intervals on cancer stage at diagnosis and mortality endpoints.DesignThe current model is based on a previously published state-transition model that estimated the outcomes of a screening programme using an MCED test when added to usual care for persons aged 50–79. Herein, we expand this analysis to model the time of cancer diagnosis and patient mortality with MCED screening undertaken using different screening schedules. Screening intervals between 6 months and 3 years, with emphasis on annual and biennial screening, were investigated for two sets of tumour growth rate scenarios: ‘fast (dwell time=2–4 years in stage I) and ‘fast aggressive’ (dwell time=1–2 years in stage I), with decreasing dwell times for successive stages.SettingInputs for the model include (1) published MCED performance measures from a large case-control study by cancer type and stage at diagnosis and (2) Surveillance, Epidemiology and End Results (SEER) data describing stage-specific incidence and cancer-specific survival for persons aged 50–79 in the US for all cancer incidence.Outcome measuresWe used the following outcome measures: diagnostic yield, stage shift, and mortality.ResultsAnnual screening under the fast tumour growth scenario was associated with more favourable diagnostic yield. There were 370 more cancer signals detected/year/100,000 people screened, 49% fewer late-stage diagnoses, and 21% fewer deaths within 5 years than usual care. Biennial screening had a similar, but less substantial, impact (292 more cancer signals detected/year/100,000 people screened; 39% fewer late-stage diagnoses, and 17% fewer deaths within 5 years than usual care). Annual screening prevented more deaths within 5 years than biennial screening for the fast tumour growth scenario. However, biennial screening had a higher positive predictive value (54% vs 43%); it was also more efficient per 100,000 tests in preventing deaths within 5 years (132 vs 84), but prevented fewer deaths per year.ConclusionAdding MCED test screening to usual care at any interval could improve patient outcomes. Annual MCED test screening provided more overall benefit than biennial screening. Modelling the sensitivity of outcomes to different MCED screening intervals can inform timescales for investigation in trials.

The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

Background Routinely collected data are increasingly being used for cancer research and health service evaluation. For both purposes, accurately identifying metastatic disease at diagnosis is essential. We developed an approach to identify metastatic disease at time of primary diagnosis according to national hospital administrative data (HAD) in patients identified with colorectal cancer (CRC) in the English national cancer registry (CR). Methods A national cohort of CRC patients diagnosed between 2013 and 2018 in England identified in CR data were linked to HAD. Metastatic disease was assumed to be present at diagnosis according to HAD if at least one of a set of pre-specified diagnostic ICD-10 codes appeared in a record of a hospital admission between one month before and six months after CRC diagnosis date. Results Of 186,236 patients, 40,421 (21.7%) had metastatic cancer according to HAD, 42,843 (23.0%) according to CR data, 49,827 (26.8%) according to either data source, and 33,437 (18.0%) according to both. Metastatic information was missing in CR data in 14,065 patients and 1,930 of these (13.7%) had metastatic cancer according to HAD. 1-year mortality was 59.3% (95%-CI: 58.8 − 59.8%) in patients with metastatic disease and 7.4% (7.2 − 7.5%) in patients without if HAD and CR data agreed. Mortality fell between these results if HAD and CR data disagreed. High mortality was seen in patients with missing metastatic data in the CR: 74.4% (72.4 − 76.3%) in patients with metastatic disease and 45.2% (44.3-46.1%) in patients without metastatic disease according to HAD. Conclusions HAD should be linked to CR data to provide more accurate information on metastatic CRC at diagnosis including sites of metastasis. Linkage to HAD increased the number of patients identified with metastatic CRC by 14%, compared to CR data alone. Patients with metastatic disease at diagnosis in either data source had mortality outcomes expected for patients with metastatic cancer. CRC patients with missing metastasis data in CR data are likely to have metastatic disease and linkage to HAD provides important prognostic information.

Pathology reports contain critical information necessary for the management of cancer patient care. Efforts to structure pathology cancer reports by the College of American Pathologists and the International Collaboration on Cancer Reporting (ICCR) have been successful in standardizing pathology reports. Likewise, standards development organizations have advanced methods to improve data computability and exchange, by enabling interoperability of pathology cancer reports. This study aimed to provide a tractable method to render pathology cancer reports computable and interoperable using published cancer reporting protocols, SNOMED Clinical Terms (SNOMED CT) and Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR). The ICCR colorectal cancer (CRC) reporting dataset (version 1.0) was evaluated by terminologists and pathologists. SNOMED CT concepts were bound to the data elements. The dataset was then converted into a FHIR structured data capture (SDC) questionnaire using the United States National Library of Medicine tooling and rendered into a FHIR-conformant message for data exchange. The ICCR CRC dataset contained 216 data elements; 207 data elements were bound to SNOMED CT and incorporated into a FHIR SDC construct. The 9 uncoded data elements were ambiguous and could not be reliably encoded. The resultant FHIR SDC form fully represented the ICCR CRC dataset and rendered these data in an R4 JSON format for data exchange. This study demonstrates a tractable and extensible approach to making cancer pathology reports fully computable and interoperable that can be broadly adopted. ICCR datasets are supported internationally and supported by multiple national pathology societies. These datasets can be fully represented using SNOMED CT to render data elements computable and semantically faithful to their intended meaning. The use of the FHIR SDC construct enables widespread and standardized data exchange of clinical information. While challenges remain, including FHIR adoption and the need to maintain current clinical content and standard terminology, this approach provides a clear pathway toward implementation.

Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). To develop standardized templates for brain tumor diagnostic pathology reporting. As a response to the 2016 updated 4th edition of the (World Health Organization) (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world.

Disease burden is the most important determinant of survival in patients with cancer. This domain, reflected by the cancer stage and codified using the tumour-node-metastasis (TNM) classification, is a fundamental determinant of prognosis. Accurate and consistent tumour classification is required for the development and use of treatment guidelines and to enable clinical research (including clinical trials), cancer surveillance and control. Furthermore, knowledge of the extent and stage of disease is frequently important in the context of translational studies. Attempts to include additional prognostic factors in staging classifications, in order to facilitate a more accurate determination of prognosis, are often made with a lack of knowledge and understanding and are one of the main causes of the inconsistent use of terms and definitions. This effect has resulted in uncertainty and confusion, thus limiting the utility of the TNM classification. In this Position paper, we provide a consensus on the optimal use and terminology for cancer staging that emerged from a consultation process involving representatives of several major international organizations involved in cancer classification. The consultation involved several steps: a focused literature review; a stakeholder survey; and a consultation meeting. This aim of this Position paper is to provide a consensus that should guide the use of staging terminology and secure the classification of anatomical disease extent as a distinct aspect of cancer classification.

Differences in the recording of cancer case status and diagnosis date have been observed between cancer registry (CR) – the reference standard – and electronic health records (EHRs); such differences may affect estimates of cancer risk or misclassify diagnostic pathways. This study aims to quantify differences in recording of case status and date of cancer diagnosis between cancer registry and EHRs. Linked primary care (Clinical Practice Research Datalink (CPRD)), secondary care (Hospital Episode Statistics (HES)) and national Cancer Registry (CR) data, were used to identify 14,301 patients with a recorded diagnosis of brain, colon, lung, ovarian, or pancreatic cancer between 1999 and 2018. Agreement in case status between datasets, differences in recorded diagnosis dates, and change in agreement over time were investigated for each cancer site. Between 84 % (ovary) to 92 % (colon) of diagnoses in cancer registry were also recorded in combined CPRD-HES data. Agreement with cancer registry was slightly lower in HES (78 % (ovary) to 86 % (colon)) and CPRD (61 % (ovary, pancreas) to 72 % (brain)). The proportion of CPRD-HES diagnoses confirmed in CR varied by cancer site (50 % (brain) to 86 % (lung)). Agreement between CR and HES was relatively stable within cancer sites over time. Concordance between CR and CPRD was more heterogeneous between cancer sites and over time. Best agreement in diagnosis date was observed between CR and HES (median difference 0 or 1 days, all cancer sites). Agreement between CR and EHR data is heterogeneous across cancer sites. Concordance does not appear to have improved over time. Combined data from primary and secondary care may be sufficient to approximate case status in CR in some circumstances, but the date we consider to represent the diagnosis may impact study outcomes. •Research using routinely-collected data relies on accurate diagnosis recording.•Differences exist in cancer recording in registry vs primary/secondary care data.•Using primary care data alone likely results in false positives and false negatives.•Combined primary and secondary care data can approximate the cancer registry.

The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers. We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011-31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and [greater than or equal to]50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off ([greater than or equal to]35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the \"risk threshold\" at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. CA125 is a useful test for ovarian cancer detection in primary care, particularly in women [greater than or equal to]50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.