Participation rates for organized colorectal cancer screening programmes: an international comparison.

OBJECTIVE: Participation, an indicator of screening programme acceptance and effectiveness, varies widely in clinical trials and population-based colorectal cancer (CRC) screening programmes. We aimed to assess whether CRC screening participation rates can be compared across organized guaiac fecal occult blood test (G-FOBT)/fecal immunochemical test (FIT)-based programmes, and what factors influence these rates. METHODS: Programme representatives from countries participating in the International Cancer Screening Network were surveyed to describe their G-FOBT/FIT-based CRC screening programmes, how screening participation is defined and measured, and to provide participation data for their most recent completed screening round. RESULTS: Information was obtained from 15 programmes in 12 countries. Programmes varied in size, reach, maturity, target age groups, exclusions, type of test kit, method of providing test kits and use, and frequency of reminders. Coverage by invitation ranged from 30-100%, coverage by the screening programme from 7-67.7%, overall uptake/participation rate from 7-67.7%, and first invitation participation from 7-64.3%. Participation rates generally increased with age and were higher among women than men and for subsequent compared with first invitation participation. CONCLUSION: Comparisons among CRC screening programmes should be made cautiously, given differences in organization, target populations, and interpretation of indicators. More meaningful comparisons are possible if rates are calculated across a uniform age range, by gender, and separately for people invited for the first time vs. previously.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

The consensus molecular subtypes of colorectal cancer.

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

Programme cantonal vaudois de dépistage du cancer colorectal: information et décision partagée [Shared decision making in the colorectal cancer screening program in the canton of Vaud].

Le programme cantonal vaudois de dépistage du cancer colorectal vise à faciliter ce dépistage pour la population de 50 à 69 ans. Les deux modalités retenues sont la recherche immunologique de sang dans les selles (FIT) et la coloscopie. La décision de réaliser un test de dépistage et la modalité de dépistage s'appuient sur une consultation individuelle avec un médecin de famille. L'assurance de base prend en charge le remboursement. Le programme vaudois permet l'exemption de la franchise pour la consultation médicale d'information et les deux modalités de dépistage, ainsi que pour la coloscopie de confirmation en cas de test FIT positif. La quote-part de 10 % reste à charge des participants. Des outils de communication ont été développés pour faciliter un entretien de décision partagée dans le cadre d'une consultation médicale. The colorectal cancer screening program of the canton of Vaud aims to facilitate screening for this cancer for the population aged 50 to 69 years old. The two screening modalities offered are fecal immunochemical testing (FIT) and colonoscopy. The decision to undergo screening and the screening modality is based on an individual medical encounter with a primary care physician. Both screening modalities are reimbursed through basic health coverage in Switzerland. The participation to the screening program allows the exemption of the deductible for the medical encounter and the chosen screening modality. A copay of 10% is maintained for all costs. Communication tools were developed on the basis of recommendations in the literature to facilitate shared decision-making in a medical encounter.

Poorly differentiated clusters (PDC) in colorectal cancer: what is and ought to be known.

BACKGROUND: The counting of poorly differentiated clusters of 5 or more cancer cells lacking a gland-like structure in a tumor mass has recently been identified among the histological features predictive of poor prognosis in colorectal cancer. MAIN BODY: Poorly differentiated clusters can easily be recognized in the histological sections of colorectal cancer routinely stained with haematoxylin and eosin. Despite some limitations related to specimen fragmentation, counting can also be assessed in endoscopic biopsies. Based on the number of poorly differentiated clusters that appear under a microscopic field of a ×20 objective lens (i.e., a microscopic field with a major axis of 1 mm), colorectal cancer can be graded into malignancies as follows: tumors with <5 clusters as grade 1, tumors with 5 to 9 clusters as grade 2, and tumors with ≥10 clusters as grade 3. High poorly differentiated cluster counts are significantly associated with peri-neural and lympho-vascular invasion, the presence of nodal metastases or micrometastases, as well as shorter overall and progression free survival to colorectal cancer. CONCLUSION: The morphological aspects and clinical relevance of poorly differentiated clusters counting in colorectal cancer are discussed in this review.

Risk factors for colorectal cancer in subjects with family history of the disease.

The relationship between lifestyle factors, past medical conditions, daily meal frequency, diet and the risk of 'familial' colorectal cancer has been analysed using data from a case-control study conducted in northern Italy. A total of 1584 colorectal cancer patients and 2879 control subjects were admitted to a network of hospitals in the Greater Milan area and the Pordenone province. The subjects included for analysis were the 112 cases and the 108 control subjects who reported a family history of colorectal cancer in first-degree relatives. Colorectal cancer cases and control subjects with family history were similarly distributed according to sex, age, marital status, years of schooling and social class. Familial colorectal cancer was associated with meal frequency, medical history of diabetes (relative risk, RR = 4.6) and cholelithiasis (RR = 5.2). Significant positive trends of increasing risk with more frequent consumption were observed for pasta (RR = 2.5, for the highest vs the lowest intake tertile), pastries (RR = 2.4), red meat (RR = 2.9), canned meat (RR = 1.9), cheese (RR = 3.5) and butter (RR = 1.9). Significant inverse associations and trends in risk were observed for consumption of poultry (RR = 0.4), tomatoes (RR = 0.2), peppers (RR = 0.3) and lettuce (RR = 0.3). Significant inverse trends in risk with increasing consumption for beta-carotene and ascorbic acid were observed (RR = 0.5 and 0.4 respectively, highest vs lowest intake tertile). These results suggest that risk factors for subjects with a family history of colorectal cancer in first-degree relatives are not appreciably different from recognized risk factors of the disease in the general population.

Copy number variations of colorectal cancer by whole exome sequencing data

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death worldwide. About 85% of the cases of CRC are known to have chromosomal instability, an allelic imbalance at several chromosomal loci, and chromosome amplification and translocation. The aim of this study is to determine the recurrent copy number variant (CNV) regions present in stage II of CRC through whole exome sequencing, a rapidly developing targeted next-generation sequencing (NGS) technology that provides an accurate alternative approach for accessing genomic variations. 42 normal-tumor paired samples were sequenced by Illumina Genome Analyzer. Data was analyzed with Varscan2 and segmentation was performed with R package R-GADA. Summary of the segments across all samples was performed and the result was overlapped with DEG data of the same samples from a previous study in the group1. Major and more recurrent segments of CNV were: gain of chromosome 7pq(13%), 13q(31%) and 20q(75%) and loss of 8p(25%), 17p(23%), and 18pq(27%). This results are coincident with the known literature of CNV in CRC or other cancers, but our methodology should be validated by array comparative genomic hybridisation (aCGH) profiling, which is currently the gold standard for genetic diagnosis of CNV.

Intestinal microbiota in the adenoma progression to colorectal cancer: a cross-sectional study

Background: Colorectal cancer is a major health problem worldwide and many efforts have been done to delineate risk factors and develop screening strategies to reduce its incidence and mortality. Colorectal adenomas have been clearly considered preneoplastic lesions due to their potential malignant transformation via the adenoma-carcinoma sequence. Over the last years, intestinal microbiota has been studied in several diseases and it has been hypothesized that colonic microbiota could influence colorectal cancer pathogenesisObjective: The goal of this study is to analyse whether there is an association between the fecal microbiota profiling and the presence and progression of colorectal adenomas, detected in population undergoing colonoscopy, to better understand the role of intestinal microbiota in colorectal carcinogenesisDesign: A cross-sectional study in the Gastroenterology Department at Hospital Universitari Doctor Josep Trueta in Girona, in a period of time of two yearsParticipants: General population undergoing screening or diagnostic colonoscopy in the Digestive Endoscopy UnitOutcomes: Identification and characterization of intestinal microbiota in stool samples from healthy patients and patients with low and high risk colorectal adenomas

Surgical Treatment of Colorectal Cancer. Controversial Issues

Aims: This study was carried out to evaluate surgical treatment of colorectal cancer (CRC) with special interest in present status and controversial issues: stenting as a palliative procedure for metastasized CRC (I), duration of thromboprophylaxis after the surgical treatment of CRC (II), treatment of the increasing population of elderly people (III) and the quality of life (QoL) after surgery for rectal cancer with special reference to pelvic floor dysfunction (IV). Materials and methods: The material consisted of patients with CRC operated on at Turku University Hospital between 2003 and 2008. In study II the data was collected retrospectively from electronic archives. In other studies the follow-up data was collected at postoperative control visits. In study IV the RAND-36 standardized questionnaire and additional questions assessing urinary, sexual and anorectal dysfunction were used. Results: The results of the current study showed that self-expanding metallic stents provided an alternative to palliative surgery in the treatment of obstructive CRC. Low molecular heparin given s.c. for a median of 11 days until hospital discharge seemed to provide sufficient thromboprophylaxis after surgery. With preoperative selection elderly patients with rectal cancer were suitable for major surgery for rectal cancer with morbidity and mortality rates comparable to those in younger patients. There was no difference between preoperative and one year postoperative general QoL for operated rectal cancer patients. Postoperative pelvic dysfunction was associated with an impaired QoL in some dimensions. Conclusions: Many individual factors regarding the patient and the disease must be taken into account when making treatment decisions in CRC to ensure successful treatment of CRC, patient satisfaction and QoL.

Factors Affecting Cancer Behavior with Special Reference to Lymphatic Vessels, Macrophages, EGFR, and Pim-1 in Colorectal Cancer

Syövän käyttäytymiseen ja ennusteeseen vaikuttavat monet tekijät, muun muassa muutokset syöpäsoluissa sekä kasvainta ympäröivässä mikroympäristössä. Tutkimuksen tavoitteena oli tutkia uusia prediktiivisiä ja prognostisia ennustetekijöitä syöpäsoluissa (EGFR geenikopiomäärä, EGFR, onkogeeni pim-1) sekä syöpäkasvaimen mikroympäristöön kuuluvissa imuteissä (CLEVER-1, podoplaniini), makrofageissa (CD68, CLEVER-1) ja T lymfosyyteissä (CD3) kolorektaalisyövässä. Lisäksi tutkittiin imuteiden molekulaarisia ominaisuuksia tarkemmin (CD73, LYVE-1, podoplaniini) kuten myös lymfosyyttien ja dendriittisolujen liikennöintiä imuteissä. Tutkimustulokset osoittavat että korkea Pim-1 ekspressiotaso, suuri peritumoraalinen CD68+ makrofagimäärä sekä varhaisen vaiheen taudissa suuri CLEVER-1+ peritumoraalinen makrofagimäärä ovat hyvän ennusteen tekijöitä kolorektaalisyövässä. Metastaattisessa taudissa sen sijaan suuri määrä CLEVER-1+ makrofageja, sekä intra- että peritumoraalisesti, liittyy huonoon tautiennusteeseen. EGFR geenikopiomäärä, EGFR proteiinipitoisuuden ohjaaman hopea in situ hybridisaatiomenetelmän avulla määritettynä, ennusti vastetta anti-EGFR hoidolle metastaattisessa kolorektaalisyövässä tarkemmin kuin nykyisin rutiinisti käytössä oleva KRAS määritys. Lisäksi havaittiin että imutiet ovat monimuotoisia imutiemarkkeri ekspressionsa suhteen sekä normaali- että syöpäkudoksissa. CD73 molekyylin funktio imuteissä poikkesi selvästi molekyylin funktiosta verisuonissa. Yhteenvetona voidaan todeta että kolorektaalisyövän ennusteeseen vaikuttavien tekijöiden merkitys vaihtelee taudin levinneisyysasteen sekä imuteiden että makrofagien sijainnin perusteella. Korkea Pim-1 ilmentyminen on yhteydessä hyvään kolorektaalisyöpäennusteeseen. Lisäksi EGFR geenikopiomäärä osoittautui lupaavaksi uudeksi prediktiiviseksi ennustetekijäksi KRAS villintyypin metastaattista kolorektaalisyöpää sairastavilla potilailla.

The prognostic and predictive value of selected biomarkers in colorectal cancer

Tissue-based biomarkers are studied to receive information about the pathologic processes and cancer outcome, and to enable development of patient-tailored treatments. The aim of this study was to investigate the potential prognostic and/or predictive value of selected biomarkers in colorectal cancer (CRC). Group IIA secretory phospholipase A2 (IIA PLA2) expression was assessed in 114 samples presenting different phases of human colorectal carcinogenesis. Securin, Ki-67, CD44 variant 6 (CD44v6), aldehyde dehydrogenase 1 (ALDH1) and β-catenin were studied in a material including 227 rectal carcinoma patients treated with short-course preoperative radiotherapy (RT), long-course preoperative (chemo)RT (CRT) or surgery only. Epidermal growth factor receptor (EGFR) gene copy number (GCN), its heterogeneity in CRC tissue, and association with response to EGFR-targeted antibodies cetuximab and panitumumab were analyzed in a cohort of 76 metastatic CRC. IIA PLA2 expression was decreased in invasive carcinomas compared to adenomas, but did not relate to patient survival. High securin expression after long-course (C)RT and high ALDH1 expression in node-negative rectal cancer were independent adverse prognostic factors, ALDH1 specifically in patients treated with adjuvant chemotherapy. The lack of membranous CD44v6 in the rectal cancer invasive front associated with infiltrative growth pattern and the risk of disease recurrence. Heterogeneous EGFR GCN increase predicted benefit from EGFR-targeted antibodies, also in the chemorefractory patient population. In summary, high securin and ALDH1 protein expression independently relate to poor outcome in subgroups of rectal cancer patients, potentially because of resistance to conventional chemotherapeutics. Heterogeneous increase in EGFR GCN was validated to be a promising predictive factor in the treatment of metastatic CRC.