Carcinoma in Situ

For evaluation of timeliness, all incident cases reported to the NBCR in 2013 were included (N = 8654), and the difference in time between the earliest date of diagnosis and the reporting date in the registry was calculated.
Completeness was assessed by comparing the cases in the NBCR with registrations in the Swedish Cancer Registry (SCR) [9 ], to which reporting is mandatory according to the National Board of Health and Welfare’s regulations (SOSFS2006:15). Data from the time period 2010–2014 was used. The completeness of the SCR is secured as any diagnosed cancer case is reported by the clinician and from the pathology laboratory after verification of morphological examinations i e biopsies and autopsy. Two publications describe in detail the process [10 (link), 11 (link)].
Comparability refers to the recording and coding practices and should be clear, nationally uniform and follow international guidelines to enable comparisons between regions and countries. Inclusion criteria are: location (primary breast cancer); sex (women and men); age (all ages); morphology (invasive breast cancer and carcinoma in situ); basis for diagnosis (all cases except diagnosis at autopsy).
Two control functions secure comparability. Firstly, the manual and the report form are unique documents. Secondly, monitoring is performed at the regional cancer centers whereby adherence to inclusion criteria and or any erroneously reported data and or ambiguity will be corrected.
Comparability concerning the workflow was assessed by a questionnaire addressing how different breast units handled reporting routines, involved staff, time allotted, and management support [12 ].
To assess validity, re-abstracted data from medical records was compared to the reported data via an independent review process. Eight hundred recorded cases between September 2013 and January 2014, were randomly selected using a two-stage cluster sampling plan.
Two hospitals offering breast cancer services (ranked according to size) from each health care region were selected. Within each region (cluster), a subsample of all breast cancer patient records in the 12 selected hospitals were drawn with a probability proportional to the size of region and hospital. The sampling plan was chosen to ensure national representation as well as participation from both large and small breast cancer units.
Re-abstraction of medical records took place in the second part of 2014 and was performed by three specialist nurses with previous experience in register validation and monitoring, henceforth referred to as validators. The re-abstracted information was entered into a specially designed module and subsequently merged with the originally recorded data to calculate exact data agreement. Exact agreement corresponds to the proportion of women for whom the data recorded in the NBCR is the same as in the validation data set. Missing observations were also included in the calculations of exact agreement to account for the plausible situations when 1) data had been reported to the NBCR but could not be found in the medical records, 2) the information was available in the medical records but had not been reported to the NBCR. Strength of agreement was measured by Cohen’s Kappa (κ) scores for categorical variables, including 95% confidence intervals (CI), and Pearson correlation coefficients (r) for numerical variables.

It is important to clearly define any endpoints examined (see Item 7). Events typically considered in tumor marker prognostic studies include death due to any cause, death from cancer, distant recurrence, local recurrence, tumor progression, new primary tumor, or tumor response to treatment. The clinical endpoint is reached when the event occurs. For death, recurrence, progression, and new primary tumor, there is usually interest not only in whether the event occurs (endpoint reached), but also the time elapsed (for example, from the date of surgery or date of randomization in a clinical trial) until it occurs. Time until last evaluation is used for patients without an event (time censored). The clinical outcome is the combination of the attainment or non-attainment of the endpoint and the time elapsed. Such clinical outcomes are referred to as time-to-event outcomes. Commonly examined outcomes in tumor marker prognostic studies are disease-free survival (DFS), distant DFS, and overall survival (OS). Different event types are sometimes combined to define a composite endpoint, for example DFS usually includes any recurrence (local, regional, or distant) and death due to any cause. For composite endpoints, the time-to-event is the time elapsed until the first of any of the events comprising the composite endpoint occurs. As recently shown, a majority of articles failed to provide a complete specification of events included in endpoints [197] (link).
Many clinical endpoints do not have standard definitions, although there have been some recent efforts to standardize definitions for some disease sites. The STandardized definitions for Efficacy End Points (STEEP) system [67] (link) proposed standardized endpoint definitions for adjuvant breast cancer trials to address inconsistencies such as the fact that new primary tumors, non-cancer death, and in situ cancers may or may not be included as events in DFS for breast cancer. Different names may be used interchangeably for one survival time outcome, for example, recurrence-free survival and DFS. Furthermore, there is not always agreement on which endpoint is the most relevant endpoint to consider in a particular disease setting. For example, reliable information about cause of death is sometimes not available, so considering death due to any cause is often preferred. In some situations, for example, in an older patient population with small risk of dying from the cancer, it can be argued that death due to cancer is more relevant because it is expected that many deaths will be unrelated to the cancer and including them in the endpoint could make the estimated prognostic effect of the marker difficult to interpret.
The endpoints to be examined should be decided on the basis of clinical relevance. The results for all endpoints that were examined should be reported regardless of the statistical significance of the findings (see Items 15 to 17 and Box 5). A demonstrated association of a marker with one of these endpoints does not guarantee its association with all of the endpoints. For example, local recurrence may be an indication of insensitivity to local or regional therapy (such as radiation therapy) whereas distant recurrence requires that tumor cells have the ability to metastasize. Different markers may be indicative of these distinct characteristics.

This was a longitudinal prospective observational analytic cohort study that includes patients from nineteen public hospitals representing nine provinces in Spain, all of which operate under the Spanish National Health Service (SNHS), which is responsible for most of the country’s population, with a planned patient follow-up period of 5 years. Patients with colon or rectal cancer scheduled to undergo surgery between June 2010 and December 2012 were informed of the aims of the study and invited to participate. Only patients who provided written informed consent were allowed to enroll in the study. The study was approved by the Basque Ethics Committee (Approval Number: 11/23/2010 and PI2014084) and all study data were kept confidential. Patients were deemed eligible for this study if they were on the surgical waiting list of one of the participating hospitals and had a diagnosis of surgically resectable colon or rectal cancer. Exclusion criteria were in situ cancer, an unresectable tumor, terminal disease, inability to respond to questionnaires for any reason, and any severe mental or physical conditions that might prevent the patient from responding to questionnaires, as well as failure to consent to participate. Detailed information of the protocol has been published elsewhere [20 ].

Study participants were women with breast cancer recruited between 2001 and 2015 for the WCHS, a multisite case–control study conducted in New York City and 10 counties in eastern New Jersey. Details on study recruitment have been described elsewhere (22, 23 (link)). The design of the case–control study recruited Black women and White women in 1:1 ratio; in a later stage, the tissue collection effort was more focused on the enrolled Black women than White women. All participants provided written informed consent. The protocol was approved by all relevant Institutional Review Boards and conducted in accordance with the Declaration of Helsinki. In brief, the cases included patients who self-identified as Black women or as White women between 20 and 75 years of age, able to speak English, with no previous history of cancer other than nonmelanoma skin cancer and who were within 9 months of having received a diagnosis of primary, histologically confirmed, invasive breast cancer or carcinoma in situ. Of patients eligible for inclusion, >95% allowed for the use of their tumor tissue as part of the informed consent form. Clinical and tumor characteristics were obtained from pathology reports. Formalin-fixed paraffin-embedded tissue specimens were used for tissue microarray (TMA) construction that included at least two tumor tissue cores and an adjacent-normal tissue core when available per patient. In total, samples from 865 cases included in TMAs were available for laboratory assays. After immunostaining, tumor tissue cores <25 cells for scoring were excluded. Subsequently, 739 cases (668 invasive breast cancer and 71 carcinoma in situ) who had at least one tumor tissue core scored with any of the mTOR pathway proteins assayed and data on PA variables were retained for statistical analyses. A subset of cases (N = 125) who had adjacent-normal tissue paired with the tumor tissue were also analyzed.