Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk.

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.

Evaluating the effects of a risk-adapted screening program for familial colorectal cancer in individuals between 25 and 50 years of age: study protocol for the prospective population-based intervention study FARKOR.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignant disease and the second most common cause of cancer death in Germany. Official CRC screening starts at age 50. As there is evidence that individuals with a family history of CRC have an increased risk of developing CRC before age 50, there are recommendations to start screening for this group earlier. This study aims to evaluate the clinical and economic effects of a risk-adapted screening program for CRC in individuals between 25 and 50 years of age with potentially increased familial CRC risk. METHODS: FARKOR (Familiäres Risiko für das Kolorektale Karzinom) is a population-based prospective intervention study. All members of cooperating statutory health insurance companies between 25 and 50 years of age living in a model region in Germany (federal state of Bavaria, 3.5 million inhabitants in this age group) can participate in the program between October 2018 and March 2020. Recruitment takes place through physicians and through a public campaign. Additionally, insurances contact recently diagnosed CRC patients in order to encourage their relatives to participate in the program. Physicians assess a participant's familial history of CRC using a short questionnaire. All participants with a family history of CRC are invited to a shared decision making process to decide on further screening options consisting of either undergoing an immunological test for fecal occult blood or colonoscopy. Comprehensive data collection based on self-reported lifestyle information, medical documentation and health administrative databases accompanies the screening program. Longterm benefits, harms and the cost-effectiveness of the risk-adapted CRC screening program will be assessed by decision analytic modeling. DISCUSSION: The data collected in this study will add important pieces of information that are still missing in the evaluation of the effects and the cost-effectiveness of a risk-adapted CRC screening strategy for individuals under 50 years of age. TRIAL REGISTRATION: German Clinical Trials Register, DRKS-IDDRKS00015097.

Enhancing requirements engineering for patient registry software systems with evidence-based components.

INTRODUCTION: Patient registries are instrumental for medical research. Often their structures are complex and their implementations use composite software systems to meet the wide spectrum of challenges. Commercial and open-source systems are available for registry implementation, but many research groups develop their own systems. Methodological approaches in the selection of software as well as the construction of proprietary systems are needed. We propose an evidence-based checklist, summarizing essential items for patient registry software systems (CIPROS), to accelerate the requirements engineering process. METHODS: Requirements engineering activities for software systems follow traditional software requirements elicitation methods, general software requirements specification (SRS) templates, and standards. We performed a multistep procedure to develop a specific evidence-based CIPROS checklist: (1) A systematic literature review to build a comprehensive collection of technical concepts, (2) a qualitative content analysis to define a catalogue of relevant criteria, and (3) a checklist to construct a minimal appraisal standard. RESULTS: CIPROS is based on 64 publications and covers twelve sections with a total of 72 items. CIPROS also defines software requirements. Comparing CIPROS with traditional software requirements elicitation methods, SRS templates and standards show a broad consensus but differences in issues regarding registry-specific aspects. DISCUSSION: Using an evidence-based approach to requirements engineering for registry software adds aspects to the traditional methods and accelerates the software engineering process for registry software. The method we used to construct CIPROS serves as a potential template for creating evidence-based checklists in other fields. CONCLUSION: The CIPROS list supports developers in assessing requirements for existing systems and formulating requirements for their own systems, while strengthening the reporting of patient registry software system descriptions. It may be a first step to create standards for patient registry software system assessments.

Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score.

The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.

Colorectal Cancer Screening for Persons With a Positive Family History­Evaluation of the FARKOR Program for the Secondary Prevention of Colorectal Cancer in Persons Aged 25 to 50.

BACKGROUND: Persons with a positive family history of colorectal cancer (CRC) are more likely than others to develop CRC and are also younger at the onset of the disease. Nonetheless, the German Federal Joint Committee (G-BA, Gemeinsamer Bundes - ausschuss) recommends screening all persons aged 50 and above regardless of their family history. FARKOR was a project supported by the Innovation Fund of the G-BA to study the feasibility, efficacy, and safety of a risk-adapted early detection program for CRC among persons aged 25 to 50 without any specific past medical history. METHODS: Physicians in private practice in Bavaria documented their activities relating to FARKOR online. The FARKOR process comprised a declaration of consent, a simplified family history for CRC, an optional, more comprehensive family history, a counseling session for participatory decision-making on further measures, and various modalities of screening (an immunological fecal occult blood test [iFOBT], colonoscopy, or no screening). Related physician activities outside the FARKOR process were assessed by record linkage between study data and data of the patients' health insurance carriers. RESULTS: The simplified family history was documented in 25 847 persons and positive for CRC in 5769 (22.3%). 3232 persons had a more comprehensive family history, among whom 2054 (63.6%) participated in screening measures. 1595 underwent colonoscopy; 278 persons who had already undergone colonoscopy in the preceding five years were excluded from the analysis. Colonoscopy revealed adenoma in 232 persons (17,6 %), advanced adenoma in 78 (5.9%) and carcinoma in 4 (0.3%). There were no serious complications. CONCLUSION: The detection rates in this study corresponded to those of persons aged 55 to 59 in the current early detection program. Despite numerous problems in the performance of the study (inconsistencies in documentation, external performance of screening measures on program participants), the results support the feasibility of a risk-adapted early detection program in the young target population with a family history of CRC.

Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models.

BACKGROUND: The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. METHODS: We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. RESULTS: In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. CONCLUSIONS: Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.

Incorporation of Multiple Sources into IT - and Data Protection Concepts: Lessons Learned from the FARKOR Project.

The IT- and data protection concept of the FAmiliäres Risiko für das KOloRektale Karzinom (FARKOR) project will be presented. FARKOR is a risk adapted screening-project in Bavaria, Germany focusing on young adults with familial colorectal cancer (CRC). For each participant, data from different sources have to be integrated: Treatment records centrally administered by the resident doctors association (KVB), data from health insurance companies (HIC), and patient reported lifestyle data. Patient privacy rights must be observed. Record Linkage is performed by a central independent trust center. Data are decrypted, integrated and analyzed in a secure part of the scientific evaluation center with no connection to the internet (SECSP). The presented concept guarantees participants privacy through different identifiers, separation of responsibilities, data pseudonymization, public-private key encryption of medical data and encrypted data transfer.

IT Infrastructure of an Oncological Trial Where Xenografts Inform Individual Second Line Treatment Decision.

Translational clinical research is often characterized by a unidirectional information flow from clinical to molecular data by using phenotypes to elucidate molecular disease processes. Here we present the RESIST study which uses xenograft information for individual treatment decisions after resistance to a specific anticancer treatment establishing a bidirectional information flow between patient and molecular biology. The paper discusses the specific challenges related to the IT infrastructure for such bidirectional translational projects and proposes solutions. A specific focus is the safeguarding genomic privacy.

Data for the elaboration of the CIPROS checklist with items for a patient registry software system: Examples and explanations.

The data presented relates to the publication "Enhancing Requirements Engineering for Patient Registry Software Systems with Evidence-based Components" (Lindoerfer and Mansmann, 2017) [1], which describes the strategy behind the development of the CIPROS checklist. This manuscript also compares CIPROS with general requirements specification templates, and standards. The data is shortly described in Section 2.4 and presented in . The examples represent the material extracted from the literature used in qualitative analysis. The explanations summarize the example contents from which the CIPROS checklist was created. Patient registries are a crucial part of medical research. High quality registries use efficient information systems software selected from a wide variety of existing software solutions. An efficient selection process requires focused selection criteria. The evidence-based CIPROS checklist [2] accelerates this requirements engineering process. CIPROS was developed in a multistep procedure: (1) A systematic literature review provided an exhaustive collection of relevant publications (64 articles), (2) a catalogue of relevant criteria was derived by a qualitative content analysis, and (3) the checklist containing 72 items was composed which provides a minimal appraisal standard. The data presented per checklist item provide the relevant textual information (examples) and a first qualitative summary (explanation). The examples and explanations provide the background information on CIPROS. They elucidate how to implement the checklist items in other projects. The literature list and the selected texts serve as a reference for scientists and system developers.

Evaluation of the IT Infrastructure of the RESIST Study with the Evidence-Based CIPROS Checklist.

Efficient and powerful information systems are substantial to perform medical research projects successfully. Especially, translational medicine poses specific challenges to the corresponding IT infrastructure. The RESIST study is a translational research project in oncology where xenografts inform about patients second-line treatment. DBFORM, an in-house developed system, was used as EDC system. It was enhanced with project specific features. We demonstrate how the CIPROS checklist has the potential to optimize the related requirements engineering process. The CIPROS checklist consists of 72 items, organized within 12 Aspects/Topics and was developed to assess such patient registry software systems. In this paper we use the CIPROS checklist (1) to elucidate the projects requirements and (2) to assess systems features. The application of the CIPROS checklist to fix the RESIST project requirements and system features was successful. The interplay between (1) and (2) helped to accelerate the requirements engineering process and to set up a system suitable to perform the translational research project successful.

Proposing an Evidence-Based Strategy for Software Requirements Engineering.

This paper discusses an evidence-based approach to software requirements engineering. The approach is called evidence-based, since it uses publications on the specific problem as a surrogate for stakeholder interests, to formulate risks and testing experiences. This complements the idea that agile software development models are more relevant, in which requirements and solutions evolve through collaboration between self-organizing cross-functional teams. The strategy is exemplified and applied to the development of a Software Requirements list used to develop software systems for patient registries.

CIPROS--a checklist with items for a patient registry software system.

Patient registries are an important instrument in medical research. Their implementation uses complex software systems to meet the wide spectrum of challenges. There is a wide range of systems available and a critical appraisal of their architecture is needed. Therefore, we developed, based on a systematic review of the literature, a checklist for patient registry software systems (CIPROS) which is organised in 67 items and 10 sections. CIPROS supports developers to assess requirements of an existing system. It also supports the reporting of patient registry software system descriptions in papers and it can be a first step to create standards for patient registry software systems.