Research progress of laboratory biomarker for colorectal cancer / 中华预防医学杂志

Colorectal cancer (CRC) has become a major medical and public health threat to human life and health. At present, the clinical diagnosis and treatment of CRC mainly depends on the laboratory tests. With the increasing demand for treatment and prognosis, screening methods for CRC are emerging. In order to provide a reference for reasonable selection of laboratory diagnostic biomarkers, and further improve the accuracy and reliability of colorectal cancer screening, auxiliary diagnosis, efficacy monitoring, as well as prognostic evaluation, this article reviews the laboratory screening and diagnostic methods for CRC, and makes outlook for the future detection markers of CRC.

Pruebas no invasivas para el tamizaje del cáncer colon: fundamentos básico-clínicos y recientes avances biotecnológicos / Non-invasive tests for colorectal cancer screening: basic-clinical fundamentals and recent biotechnological advances

Colorectal Cancer (CRC) is the third most frequent neoplasia worldwide. Despite the significant advances in surgical techniques and the development of new targeted antineoplastic therapies for this type of tumor, primary prevention and early diagnosis of malignant precursor lesions will continue to be the best strategies to reduce their incidence, morbidity, and mortality. Technologies for CRC screening can be classified into two groups, those of an invasive nature, such as colonoscopy and all its different modalities of use, and those of a non-invasive nature, such as laboratory tests and imaging. This review, will focus exclusively on non-invasive screening tests, excluding imaging. Specifically, it will address those that use depositions as a sample. This review will approach the latest international recommendations, regarding the age at which they should be used, their technical-biological bases, the two main types currently used (biochemical and immunological), and we will put into perspective their advantages and their possible disadvantages. Towards the end of this article, the most recent biotechnological developments in relation to molecular tests based on the study of blood samples, will be discussed. Although these tests are not yet in routine clinical use given their high costs, they are promising for the early detection of CRC.

El cáncer colorrectal (CCR) es la tercera neoplasia más común en todo el mundo. A pesar de los avances significativos en las técnicas quirúrgicas y en el desarrollo de nuevas terapias antineoplásicas para este tipo de tumor, la prevención primaria y el diagnóstico precoz de lesiones precursoras malignas siguen siendo las mejores estrategias para reducir la incidencia, morbilidad y mortalidad asociadas al CCR. Existen dos tipos de tecnologías para el tamizaje del CCR: las invasivas, como la colonoscopia, y las no invasivas, como los ensayos de laboratorio y la imagenología. Esta revisión, se centrará exclusivamente en las pruebas de tamizaje no invasivas que utilizan muestras de deposiciones, excluyendo las imágenes. Se abordarán las últimas recomendaciones internacionales sobre el momento etario en que se deben utilizar, sus bases técnico-biológicas, los dos principales tipos utilizados en la actualidad (bioquímico e inmunológico) y pondremos en perspectiva sus ventajas y posibles desventajas. Al final de esta revisión, se discutirá brevemente los últimos avances biotecnológicos relacionados con pruebas moleculares basadas en el estudio de muestras sanguíneas. Aunque estas pruebas aún no son de uso clínico habitual debido a sus altos costos, representan una prometedora innovación para la detección temprana del CCR.

Cáncer colorrectal ­ diagnóstico y tratamiento: revisión bibliográfica / Colorectal cancer ­ diagnosis and treatment: literature review

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Although improvements in detection and treatment have been implemented; CRC incidence, prevalence, and mortality remain high, even in developed countries. The risk of developing this cancer is related to poor eating habits, smoking, inflammatory bowel disease, polyps, genetic factors, and aging. There are several methods for detecting colorectal cancer, including the guaiac test, stool immunochemical test, stool DNA test, sigmoidoscopy, colonoscopy, and barium enema. The stage at which the cancer is detected determines the patient's prognosis, survival, and treatment. Treatments include endoscopic and surgical local excision, preoperative radiation therapy and systemic downstage therapy, extensive surgery for locoregional and metastatic disease, local ablative therapies for metastases, and palliative, targeted chemotherapy and immunotherapy.

El cáncer colorrectal (CCR) es el tercer cáncer más prevalente a nivel mundial. A pesar de que se han implementado mejoras en la detección y el tratamiento; la incidencia, la prevalencia y la mortalidad del CCR siguen siendo altas, incluso en países desarrollados. El riesgo de desarrollar este cáncer está relacionado con malos hábitos alimentarios, tabaquismo, enfermedad inflamatoria intestinal, pólipos, factores genéticos y envejecimiento. Existen varios métodos para detectar el cáncer colorrectal, como la prueba de guayaco, la prueba inmunoquímica de heces, la prueba de ADN en heces, la sigmoidoscopia, la colonoscopia y el enema de bario. El estadio en el que se detecta el cáncer determina el pronóstico, la supervivencia y el tratamiento del paciente. Los tratamientos incluyen escisión local endoscópica y quirúrgica, radioterapia preoperatoria y terapia sistémica de reducción del estadio, cirugía extensa para enfermedad locorregional y metastásica, terapias ablativas locales para metástasis y quimioterapia paliativa, terapia dirigida e inmunoterapia.

A robust microsatellite instability detection model for unpaired colorectal cancer tissue samples / 中华医学杂志(英文版)

BACKGROUND@#Microsatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples.@*METHODS@#From January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR.@*RESULTS@#We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes ( MLH1 , MSH2 , MSH6 , and PMS2 ).@*CONCLUSION@#MSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.

Low-cost colonoscopic simulator and colonoscope to train basic skills in colonoscopy during undergraduate studies

Objective: To develop a low-cost simulator model and a colonoscope with materials that are easily accessible to offer training on colonoscopy skills during undergraduate studies. Since this is the procedure of choice for colorectal cancer screening, the general practitioner must be able to recognize its main indications, preparation, and complications. Methods: Using materials such as a mannequin, a vehicle inspection camera, a conduit, polyvinyl chloride (PVC) pipe, acrylic, wood, and red paint, we built a simulator and a 150-cm long and 20-to-25-mm thick colonoscope. The colonoscope's handle and handhold were made of acrylic, the colonoscope's mobile end was made with articulated PVC rings, and the up and down movements were performed according to the traction of the steel cables. The camera attached to its distal end enables connection to a smartphone to view the image. In the simulator, the conduit was inserted into the mannequin to simulate the curvatures of the colon. Red spray paint was used to simulate the staining of the colonic mucosa in the inner region of the mannequin and the adventitial layer in the outer region. Results: We were able to build a simulator and a colonoscope with a total amount of R $ 182.82 (roughly US$ 36.50). Both were tested and proved to be useful in the acquisition of psychomotor and cognitive skills in colonoscopy. Conclusion The simulator and colonoscope developed by us are cost-effective, useful in the acquisition of psychomotor and cognitive skills in colonoscopy, and can facilitate the structuring of a training program for undergraduate students. (AU)

Watch and wait, worth It?

Background: The surgery with total mesorectal excision recommended by R. J. Heald in 1982 is the gold standard. Rectal cancer (RC) surgery has a morbidity rate ranging from 6 to 35%, and it can cause functional issues such as sexual, urinary, and bowel dysfunction in the long term. Neoadjuvant chemoradiotherapy (CRT) has been gaining ground in patients with lesions in the middle and lower rectum. The aim of the present study is to present the experience of a reference service in the treatment of RC. Patients and Methods: A retrospective study involving 53 patients diagnosed with RC between January 2017 and December 2019 with follow-up until December 2020. We examined tumor location, disease stage, digital rectal exam findings, carcinoembryonic antigen (CEA), therapeutic modality offered, and follow-up time. Results: A total of 32% of the patients were men and 68% were women, with a mean age of 60 years old. Location: upper rectum in 6 cases, middle rectum in 21 cases, and lower rectum in 26 cases with evolution from 9.8 to 13.5 months. The most frequent complaints were hematochezia and constipation. A total of 36 patients underwent neoadjuvant therapy: 11 complete clinical response (CCR) (30.5%), 20 (55.5%) partial clinical response (PCR), and no response in 5 patients (14%). The follow-up ranged from 12 to 48 months, with a mean of 30.5 months. A total of 25% of the patients had RC that went beyond the mesorectal fascia, and 22.64% had metastases in other parts of the body when they were diagnosed. Conclusion: Neoadjuvant radio and chemotherapy present themselves as an alternative in the treatment of rectal cancer. In 36 patients, 30.5% had a complete clinical response, 55.5% had a partial clinical response, and 14% had no response. It was worth doing the "Watch and Wait" (W&W) to sample. A definitive colostomy was avoided. However, it is necessary to expand the study to a larger follow-up and more patients. Additionally, it is necessary to implement a multicenter study. (AU)

Serum long-noncoding RNA H19 and beta-catenin as biomarkers for early diagnosis of colorectal cancer in egyptian patients: a case control study

Colorectal cancer (CRC) is the third most prevalent cancer and the second most common cause of cancer death; however, its early detection can improve the survival. Colonic polyps are considered one of the CRC's major risk factors. Throughout many biological processes and malignancies, the non-coding RNAs have essential functions. Certain long noncoding RNAs (lncRNAs), including H19, were supposed to be CRC possible biomarkers. Also, H19 has been reported to play a role in regulating the activity of beta-catenin, a protein that regulates cell-to-cell adhesion, as well as gene transcription. The current work aimed to investigate the potential significance of LncRNA H19 relative serum expression level by quantitative polymerase chain reaction (q-PCR) and beta-catenin by enzyme-linked immunosorbent assay (ELISA) as noninvasive biomarkers to discriminate between colorectal cancer and colonic polyps. The statistical analysis of the studied factors revealed that the serum expression of H19 and beta-catenin in cancer cases were substantially greater than colonic polyp cases and normal control. Conclusion: The relative expressions of H19 and beta-catenin in the serum can significantly discriminate patients with CRC from those with polyp and normal controls, which could help when screening for CRC. (AU)

Risk factors associated with colorectal cancer in octogenarians can help stratify the need for colonoscopy

Objective: Colonoscopy is increasingly performed in octogenarians for the detection of colorectal cancer (CRC), but its benefits may be outweighed by its risks. The aim of the present study was to identify the risk factors for CRC in octogenarians presenting for colonoscopy to help stratify the need for this procedure. Methods: A retrospective analysis of 434 patients aged ≥ 80 years referred for a colonoscopy between January 2018 and December 2019. Comparisons were made between those with and without CRC and advanced adenoma (AA). The primary endpoint was to identify the clinical variables predictive of CRC and AA, and the secondary endpoints were complications and death 30 days after the procedure. Results: Colonoscopy was performed in 434 octogenarians, predominantly for symptoms, with CRC in 65 (15.0%) patients. Iron deficiency was associated with a higher risk of having CRC identified on colonoscopy (odds ratio [OR]: 2.33; 95% confidence interval [95%CI] = 1.36-4.00), but not symptoms such as bleeding, weight loss, or diarrhea. A colonoscopy in the last 10 years was protective, with a lower risk of CRC (OR: 0.45; 95% CI = 0.22-0.93). Patients with both normal iron stores and a colonoscopy within 10 years had a 92.5% chance of not having CRC. No variables were predictive of AA. Patients with complications, including death, were older and more likely to have underlying cardiorespiratory disease. Conclusion: Iron status and colonoscopy within 10 years can be used to predict the risk of CRC in octogenarians. Those with low predicted risk, especially if older and with cardiorespiratory disease, should be considered for non-invasive tests, such as computed tomography (CT) colonography, over colonoscopy. (AU)

Expression Levels of the CA9, WT1, and PRAME genes and genotyping-associated antigens for the diagnosis and prognosis of colorectal cancer

Background: Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, and is one of the major health problems in Asia, Africa, Europe, and America. The tumor antigens recently are of interesting indicators as diagnostic and prognostic tools, The aim of the present study is to detect the expression levels of carbonic anhydrase IX (CA9), the Wilms tumor gene (WT1), and the preferentially expressed antigen in melanoma (PRAME) in the peripheral blood of CRC patients in comparison with healthy controls. Methods: A prospective case-control study of CRC patients was conducted. We included 25 newly-diagnosed CRC eligible patients and obtained peripheral blood samples of them as well as 10 blood samples from the control group. All samples were then submitted to deoxyribonucleic acid (DNA) extraction and a molecular study through real-time polymerase chain reaction (PCR). Results: The CRC group consisted of 15 (60%) female and 10 (40%) male patients with a mean age of 50.52 ± 9.8 years, while the control group included 4 (40%) female and 6 (60%) male patients with a mean age of 47.7 ± 7.9 years. The CRC group, 24 (96%) of patient samples were CA9-positive with strong statistically significant differences (p < 0.00001; sensitivity: 96%; specificity: 90%). Regarding the WT1 gene, there were 11 (44%) positive samples in the CRC group, with no statistically significant differences (p = 0.055; sensitivity: 44%; specificity: 90%). The PRAME gene was positive in 9 (36%) samples in the CRC group, with no statistically significant differences (p = 0.357; sensitivity: 36%; specificity: 80%. Among CA9 (24 patients; 96%) of patients with CRC expressed positive results, in WT1 11(91.6%) CRC patients expressed gene, and in PRAME gene, 9 patients with CRC (81.8%) expressed positive results. Conclusion: Overexpression of the CA9 gene in CRC of high sensitivity and specificity to be used as a tool to discriminate CRC from benign associate with high accuracy compare to WT1 and PRAME genes. (AU)

Surgical approach of megacecum secondary to descending colon tumor / Abordagem cirúrgica de megaceco secundário a tumor de cólon descendente

Intestinal obstruction is the most frequent clinical manifestation of colon tumors, most of which are located in the descending and recto-sigmoid colon. Emergency bowel obstruction surgery is associated with high mortality and morbidity risks and the ideal approach remains controversial. Multi-stage procedures and the use of stents as bridges for surgery are promising options. A case of a 61-year-old patient with an acute obstructive abdomen secondary to colorectal neoplasm is presented, with emphasis on its diagnosis and treatmen (AU)

Obstrução intestinal é a manifestação clínica mais frequente de tumores de cólon sendo esses, em sua maioria, localizados no cólon descendente e reto-sigmoide. A cirurgia de emergência para obstrução intestinal é associada a altos riscos de mortalidade e de morbidade e a abordagem ideal permanece controversa. Procedimentos em vários estágios e o uso de stents como ponte para cirurgia são opções promissoras. É apresentado um caso de paciente de 61 anos, com abdome agudo obstrutivo secundário à neoplasia colorretal, com ênfase em seu diagnóstico e tratamento (AU)

Analysis of patients undergoing colonoscopies and the importance of exam quality for colorectal cancer screening

Objective: To determine the impact of the quality of colonoscopy examination for colorectal cancer screening. Methods: Retrospective observational study ofmedical records from patients treated at the endoscopy and colonoscopy service of Hospital Universitário Evangélico Mackenzie (Curitiba, PR, Brazil) from January 2019 to January 2020. Results: The analysis was based on 337 medical records from patients with adenomas identified during colonoscopy, and 1,385 medical records from patients without adenomas. The estimated occurrence rate of diagnosis of adenoma during colonoscopy in the target population of the study was of 19.6%, with a 95% confidence interval ranging from 17.7 to 21.5%. Of the 337 patients with adenoma, 136 (40.4%) presented the advanced form. Statistical analysis indicated a significant association between the quality of colonoscopy preparation and test completion. Conclusion: The quality of colonoscopy images is a critical factor for colorectal cancer screening, as it leads to higher rates of adenoma detection and test completion. (AU)

Artificial intelligence-assisted colonoscopy: a narrative review of current data and clinical applications

Colonoscopy is the reference standard procedure for the prevention and diagnosis of colorectal cancer, which is a leading cause of cancer-related deaths in Singapore. Artificial intelligence systems are automated, objective and reproducible. Artificial intelligence-assisted colonoscopy has recently been introduced into clinical practice as a clinical decision support tool. This review article provides a summary of the current published data and discusses ongoing research and current clinical applications of artificial intelligence-assisted colonoscopy.

Current status, controversy and challenge in the neoadjuvant immunotherapy of colorectal cancer / 中华胃肠外科杂志

Neoadjuvant therapy for colorectal cancer is widely used in rectal cancer, locally advanced colon cancer, and resectable metastatic and recurrent colorectal cancer. Mismatch repair deficient(dMMR) and microsatellite instablity-high (MSI-H) colorectal cancer patients who benefit from the efficacy of immune checkpoint inhibitors are expected to further improve the efficacy of traditional neoadjuvant therapy based on radiotherapy and chemotherapy. In this paper, the current status of immunotherapy (with emphasis on immune checkpoint inhibitors) is elucidated, and the opportunities of its application in neoadjuvant therapy are analyzed, including poor sensitivity of dMMR tumors to traditional therapy, good immune response of early tumors, predictable, manageable and controllable toxicity of immune checkpoint inhibitors. Colorectal cancer patients have growing and diverse needs to be met. Current controversies and challenges are analyzed, and the future directions are pointed out, including active screening of benefit groups, exploration of efficacy prediction markers, optimization of neoadjuvant immunotherapy models, attention to efficacy evaluation and new therapeutic endpoints. Neoadjuvant therapy should be effective, moderate and accurate based on the treatment target. It is the prerequisite and basis to guarantee medical safety and improve therapeutic effect to attach importance to the standardization and safety of clinical research and to pay attention to patients' interests and legal and ethical demands.

Neoplasia primaria sincrónica de estómago, colon y recto: reporte de un caso / Synchronous stomach, colon and rectum primary neoplasias: a case report

Presentamos el caso de un paciente masculino de 40 años de edad, con estreñimiento de un año de evolución y antecedentes de enfermedad por reflujo gastroesofágico, se realiza endoscopia digestiva alta y baja y se realiza diagnóstico sincrónico de adenocarcinoma de estómago, recto y colon descendente, realizamos tomografía por emisión de positrones con tomografía computarizada pre quirúrgico y cirugía como tratamiento primario. Mostramos una descripción del caso y una revisión de la bibliografía.

We present the case of a 40-year-old man with a one year evolution constipation and a history of GERD. An upper and lower digestive endoscopy was performed and a synchronous diagnosis of adenocarcinoma of the stomach, rectum and descending colon was established. A PET-CT pre-surgical was performed and the surgery was carried out as primary treatment. We show a description of the case and a bibliographic review.

Postcolonoscopy colorectal cancer: an overview and future directions

Over the past decade, there has been a great interest in postcolonoscopy colorectal cancer (PCCRC). Its etiology is complex and multifactorial. Monitoring for PCCRC is even more complex. The strategies to decrease the incidence of PCCRC start by defining the problem, identifying the factors contributing to its development, followed by an attempt to define methods to decrease its incidence.We believe that the quality of the colonoscopy and the endoscopist's expertise are the key factors in decreasing the incidence of PCCRC. (AU)

Hemofilia adquirida como manifestación inicial de recidiva de adenocarcinoma colorrectal / Acquired hemophilia as the initial manifestation of colorectal cancer's recurrence

Resumen Presentamos el caso de un varón de 86 años con un hematoma espontáneo en el músculo ilíaco izquierdo y diagnóstico previo de cáncer de colon en 1998 (estadio pT3N0M0), tratado quirúrgicamente mediante colectomía transversal, considerado en remisión completa. Tras realización de estudios complementarios se demostró la presencia de autoanticuerpos inhibidores del Factor VIII que confirmaron el diagnóstico de hemofilia adquirida. Durante el ingreso el paciente presentó un sangrado digestivo bajo que conllevó al descubrimiento de recidiva del adenocarcinoma colorrectal tratado previamente. Respondió de forma favorable a la terapia inicial con corticoides sistémicos y el complejo coagulante anti inhibidor que incluye el Factor VII activado [FEIBA].

Abstract We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA].

Carcinoma colorrectal en niños y adolescentes / Colorectal carcinoma in children and adolescent

Si bien el carcinoma colorrectal (CCR) es la tercera enfermedad oncológica más frecuente en adultos, solo el 1-4 % ocurre en menores de 25-30 años. Su presentación suele confundirse con otras patologías, lo cual lleva a significativas demoras diagnósticas. Dada su baja incidencia, pocos pediatras se enfrentarán con algún caso a lo largo de su carrera. Sin embargo, existen en la niñez múltiples síndromes hereditarios que predisponen al CCR. El objetivo de esta revisión es brindar una actualización sobre los síndromes predisponentes al CCR. Se revisarán las indicaciones de tamizaje, dado que el diagnóstico precoz en estadios localizados es el principal factor pronóstico. Además, se fortalecerán las herramientas de consejería genética para el paciente y su familia. A su vez, se discutirán las manifestaciones clínicas e histológicas y los factores pronósticos propios del CCR en la población pediátrica. Si bien las guías de tratamiento se extrapolan de la experiencia en adultos, se resumirán los lineamientos terapéuticos.

Although colorectal carcinoma (CRC) is the third most common type of cancer in adults, only 1-4 % of cases are reported in individuals younger than 25-30 years. Its presentation is usually confused with other diseases, leading to significant delays in diagnosis. Given its low incidence, few pediatricians will see a case throughout their practice. However, multiple hereditary syndromes during childhood predispose to CRC.The objective of this review is to provide an update on syndromes predisposing to CRC. Screening indications will be reviewed because an early diagnosis during localized stages is the main prognostic factor. In addition, patient and family genetic counseling tools will be enhanced. In turn, the clinical and histological manifestations and prognostic factors typical of CRC in the pediatric population will be discussed. Although treatment guidelines are extrapolated from the adult experience, therapy guidelines will be summarized here.

Test de sangre oculta en deposiciones para programas de cribado de cáncer colorrectal: actualización / Fecal occult blood test for colorectal cancer screening

Screening programs for colorectal cancer (CRC) are standard in most developed countries because they reduce mortality and are cost-effective. Within them, colonoscopy allows to directly visualize the colon and remove neoplastic lesions. However, it is an expensive exam with low adherence in asymptomatic individuals. The fecal occult blood test (FOBT) is a low-cost and risk-free method for the user, which results in a high rate of adherence, explaining its use in most screening programs. This article analyzes the effectiveness of different fecal occult blood tests in screening programs. The main conclusions are that the sensitivity of the guaiac-based chemical test for the detection of colorectal cancer is lower than that observed with qualitative and quantitative immunological tests. Automated quantitative methods allow objective readings independent of the operator and the reaction reading time, necessary for the analysis of large numbers of samples. The participation rate with immunological FOBTs is higher than with chemical ones, which is why they are preferred by the different countries that have screening programs. The use of quantitative tests allows stratification of symptomatic and asymptomatic patients at higher risk, in the screening programs.