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BACKGROUND: The TNM (tumor-node-metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor-stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes. PATIENTS AND METHODS: The 'Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit assessment of adjuvant chemotherapy (ACT) and overall survival (OS). RESULTS: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was significantly shorter in stroma-high (n = 428) than in stroma-low patients (n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS (P < 0.001, hazard ratio 1.49, 95% confidence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma-high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT (n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma-high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma-high was noticeable (74% versus 83% stroma-low; P = 0.102). CONCLUSION: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, confirming worse outcomes in stroma-high patients. The TSR improved current selection criteria for patients at risk of events, and stroma-high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment.

Asunto(s)

Neoplasias del Colon , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pronóstico , Neoplasias del Colon/patología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/terapia , Células del Estroma/patología , Estadificación de Neoplasias , Estudios Prospectivos , Adulto , Supervivencia sin Enfermedad , Anciano de 80 o más Años , Quimioterapia Adyuvante/métodos

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PURPOSE: This study aims to evaluate quality of life trajectory during the first year after surgical treatment in patients with resectable primary colon cancer. METHODS: Patients with resectable primary colon cancer diagnosed between 2013 and 2019 who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort study (PLCRC). Health-related quality of life (HR-QoL) was assessed using EORTC-QLQ-C30 questionnaire before surgery, and three and twelve months after surgery. HR-QoL scores varied between 0 and 100 and outcomes were compared according to age (< 70 years, ≥ 70 years), comorbidity (yes, no) and treatment type (adjuvant chemotherapy, surgical treatment only). The extent of resilience, defined as a recovery of HR-QoL to baseline level after a clinically relevant decline in HR-QoL at months, was calculated twelve months post-surgery. RESULTS: For all 458 patients, the mean age was 66.4 years (SD 9.5), 40% were aged 70 years and older and 68% were men. Baseline level of HR-QoL summary score was relatively high with a mean of 87.9 (SD 11.5), and did not significantly differ between older and younger patients. The strongest decline of HR-QoL compared to baseline was observed at three months with a gradual recovery over time. Fourteen percent of all patients were non-resilient or showed a late decline at twelve months post-surgery. Compared to younger patients, older patients who received adjuvant chemotherapy were less resilient (respectively, 53 and 32%, p = 0.07) and at risk of a late decline in HR-QoL 1 year post-surgery (respectively, 3% versus 16%, p = 0.02). Comorbidity status had no significant impact on the HR-QoL trajectory. CONCLUSION: Colon cancer treatment was associated with a decline in HR-QoL three months post-surgery, but most patients return to baseline level within twelve months. Still, particularly older patients who received adjuvant chemotherapy were less resilient and at risk of a late decline in HR-QoL. These data could help in patients counselling regarding colon cancer treatment.

Asunto(s)

Neoplasias del Colon , Calidad de Vida , Masculino , Humanos , Anciano , Anciano de 80 o más Años , Femenino , Estudios Prospectivos , Estudios de Cohortes , Quimioterapia Adyuvante/efectos adversos , Neoplasias del Colon/etiología

RESUMEN

Machine learning can be used to explore the complex multifactorial patterns underlying postsurgical graft detachment after endothelial corneal transplantation surgery and to evaluate the marginal effect of various practice pattern modulations. We included all posterior lamellar keratoplasty procedures recorded in the Dutch Cornea Transplant Registry from 2015 through 2018 and collected the center-specific practice patterns using a questionnaire. All available data regarding the donor, recipient, surgery, and practice pattern, were coded into 91 factors that might be associated with the occurrence of a graft detachment. In this research, we used three machine learning methods; a regularized logistic regression (lasso), classification tree analysis (CTA), and random forest classification (RFC), to select the most predictive subset of variables for graft detachment. A total of 3647 transplants were included in our analysis and the overall prevalence of graft detachment was 9.9%. In an independent test set the area under the curve for the lasso, CTA, and RFC was 0.70, 0.65, and 0.72, respectively. Identified risk factors included: a Descemet membrane endothelial keratoplasty procedure, prior graft failure, and the use of sulfur hexafluoride gas. Factors with a reduced risk included: performing combined procedures, using pre-cut donor tissue, and a pre-operative laser iridotomy. These results can help surgeons to review their practice patterns and generate hypotheses for empirical research regarding the origins of graft detachments.

Asunto(s)

Queratoplastia Endotelial de la Lámina Limitante Posterior , Distrofia Endotelial de Fuchs , Humanos , Distrofia Endotelial de Fuchs/cirugía , Queratoplastia Endotelial de la Lámina Limitante Posterior/efectos adversos , Hexafluoruro de Azufre , Agudeza Visual , Sistema de Registros , Aprendizaje Automático , Endotelio Corneal/trasplante

RESUMEN

Because of the difficulty of measuring nanoplastics (NP), the use of NPs doped with trace metals has been proposed as a promising approach to detect NP in environmental media and biota. In the present study, the freshwater amphipod Gammarus pulex were exposed to palladium (Pd)-doped NP via natural sediment at six spiking concentrations (0, 0.3, 1, 3, 10 and 30 g plastic per kg of sediment dry weight) with the aim of assessing their uptake and chronic effects using 28 days standardized single species toxicity tests. NP concentrations were quantified based on Pd concentrations measured by ICP-MS on digests of the exposed organisms and faecal pellets excreted during a post-exposure 24 hour depuration period. Additionally, NP concentrations were measured in sediments and water to demonstrate accuracy of NP dosing and to quantify the resuspension of NP from the sediment caused by the organisms. A significant positive linear relationship between the uptake of NP by G. pulex and the concentration of NP in the sediments was observed, yet no statistically significant effects were found on the survival or growth of G. pulex. A biodynamic model fitted well to the data and suggested bioaccumulation would occur in two kinetic compartments, the major one being reversible with rapid depuration to clean medium. Model fitting yielded a mass based trophic transfer factor (TTF), conceptually similar to the traditional biota sediment accumulation factor, for NP in the gut of 0.031. This value is close to a TTF value of 0.025 that was obtained for much larger microplastic particles in a similar experiment performed previously. Mechanistically, this suggests that ingestion of plastic is limited by the total volume of ingested particles. We demonstrated that using metal-doped plastics provides opportunities for precise quantification of NP accumulation and exposure in fate and effect studies, which can be a clear benefit for NP risk assessment.

RESUMEN

BACKGROUND: Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. METHODS/DESIGN: MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. DISCUSSION: The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. TRIAL REGISTRATION: Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Neoplasias del Colon/terapia , Recurrencia Local de Neoplasia/epidemiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Quimioterapia Adyuvante/economía , Quimioterapia Adyuvante/psicología , Quimioterapia Adyuvante/normas , Quimioterapia Adyuvante/estadística & datos numéricos , Colectomía , Neoplasias del Colon/sangre , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/mortalidad , Análisis Costo-Beneficio , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Biopsia Líquida , Masculino , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Neoplasia Residual , Países Bajos/epidemiología , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Aceptación de la Atención de Salud/psicología , Aceptación de la Atención de Salud/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias del Colon/terapia , Terapia Neoadyuvante/normas , Recurrencia Local de Neoplasia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Capecitabina/uso terapéutico , Quimioterapia Adyuvante/normas , Toma de Decisiones Clínicas/métodos , Colectomía , Colon/patología , Colon/cirugía , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Países Bajos/epidemiología , Oxaliplatino/uso terapéutico , Selección de Paciente , Guías de Práctica Clínica como Asunto , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Sistema de Registros/estadística & datos numéricos , Medición de Riesgo/métodos

RESUMEN

Multiple platforms are commercially available for the detection of circulating cell-free tumour DNA (ctDNA) from liquid biopsies. Since platforms have different input and output variables, deciding what platform to use for a given clinical or research question can be daunting. This study aimed to provide insight in platform selection criteria by comparing four commercial platforms that detect KRAS ctDNA hotspot mutations: Bio-Rad droplet digital PCR (ddPCR), BioCartis Idylla, Roche COBAS z480 and Sysmex BEAMing. Platform sensitivities were determined using plasma samples from metastatic colorectal cancer (mCRC) patients and synthetic reference samples, thereby eliminating variability in amount of plasma analysed and ctDNA isolation methods. The prevalence of KRAS nucleotide alterations was set against platform-specific breadth of target. Platform comparisons revealed that ddPCR and BEAMing detect more KRAS mutations amongst mCRC patients than Idylla and COBAS z480. Maximum sample throughput was highest for ddPCR and COBAS z480. Total annual costs were highest for BEAMing and lowest for Idylla and ddPCR. In conclusion, when selecting a platform for detection of ctDNA hotspot mutations the desired test sensitivity, breadth of target, maximum sample throughput, and total annual costs are critical factors that should be taken into consideration. Based on the results of this study, laboratories will be able to select the optimal platform for their needs.

Asunto(s)

Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Neoplasias Colorrectales/diagnóstico , Análisis Mutacional de ADN/clasificación , Análisis Mutacional de ADN/métodos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Neoplasias Colorrectales/genética , Humanos , Biopsia Líquida , Reacción en Cadena de la Polimerasa/métodos , Estudios Prospectivos

RESUMEN

OBJECTIVE: To describe the effect of population screening for colorectal carcinoma (CRC) with the faecal immunochemical test, introduced in 2014, on the incidence of CRC in the Netherlands and to analyse differences between patient and tumour characteristics, stage distribution and treatment of carcinomas that were screening-detected and were not detected by screening (non-screening-detected). DESIGN: Retrospective observational study. METHOD: We analysed data from the Netherlands Cancer Registry. We selected all CRCs diagnosed in the 2010-2016 period and calculated incidence rates standardised for the European population. For comparison between screening-detected and non-screening-detected carcinomas, we selected all CRCs diagnosed in 2015. RESULTS: The number of newly diagnosed CRCs rose from 13,028 in 2013 to 15,185 in 2014 and to 15,807 in 2015. This increase could only be seen for the birth years of people who had been invited for population screening during that particular year. The percentage of men was higher for screening-detected carcinomas than for non-screening-detected carcinomas (62% vs 55%). Screening-detected carcinomas were also more often in the left side of the colon (76% vs 64%). The percentage of patients with stage I CRC was higher in the group with screening-detected carcinomas (48% vs 16%). Patients with screening-detected carcinomas more often underwent local treatment or only resection without adjuvant or neoadjuvant treatment than the patients with non-screening-detected carcinomas. CONCLUSION: During the first years after the introduction of population screening, the incidence of CRC has increased as the result of earlier detection. Screening-detected carcinomas have a more favourable stage distribution and these patients are undergoing less-invasive treatment more often.

Asunto(s)

Neoplasias Colorrectales , Detección Precoz del Cáncer , Heces , Inmunoquímica/métodos , Tamizaje Masivo/métodos , Anciano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Sangre Oculta , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos

RESUMEN

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

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Neoplasias Gastrointestinales , Estudios Observacionales como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Bancos de Muestras Biológicas , Estudios de Cohortes , Humanos , Sistema de Registros

RESUMEN

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Asunto(s)

Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Países Bajos , Neutropenia/inducido químicamente , Pronóstico , Pirrolidinas , Timina , Resultado del Tratamiento , Trifluridina/efectos adversos , Uracilo/efectos adversos , Uracilo/uso terapéutico

RESUMEN

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Asunto(s)

Bancos de Muestras Biológicas , Neoplasias Colorrectales/patología , Estudios de Cohortes , Neoplasias Colorrectales/sangre , Humanos , Países Bajos , Selección de Paciente , Estudios Prospectivos , Distribución Aleatoria , Encuestas y Cuestionarios

RESUMEN

AIM: This randomized, controlled trial examined the medium-term effectiveness of online behavioral training in migraine self-management (oBT; N = 195) versus waitlist control (WLC; N = 173) on attack frequency, indicators of self-management (primary outcomes), headache top intensity, use of rescue medications, quality of life and disability (secondary outcomes). METHODS: An online headache diary following the ICHD-II and questionnaires were completed at baseline (T0), post-training (T1) and six months later (T2). Missing data (T1: 24%; T2: 37%) were handled by multiple imputation. We established effect sizes (ES) and tested between-group differences over time with linear mixed modelling techniques based on the intention-to-treat principle. RESULTS: At T2, attack frequency had improved significantly in oBT (-23%, ES = 0.66) but also in WLC (-19%; ES = 0.52). Self-efficacy, internal and external control in migraine management--and triptan use--improved only in oBT, however. This indicates different processes in both groups and could signify (the start of) active self-management in oBT. Also, only oBT improved migraine-specific quality of life to a sizable extent. CONCLUSIONS: oBT produced self-management gains but could not account for improved attack frequency, because WLC improved as well. The perspective that BT effects develop gradually, and that online delivery will boost BT outreach, justifies further research.

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Terapia Conductista/tendencias , Manejo de la Enfermedad , Internet/tendencias , Trastornos Migrañosos/terapia , Autocuidado/tendencias , Adulto , Terapia Conductista/métodos , Femenino , Humanos , Masculino , Registros Médicos , Persona de Mediana Edad , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/psicología , Estudios Prospectivos , Autocuidado/métodos , Autocuidado/psicología , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.

Asunto(s)

Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Adulto , Anciano , Antígeno Ca-125/sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Procedimientos Quirúrgicos Ginecológicos , Humanos , Tamizaje Masivo , Persona de Mediana Edad , Estadificación de Neoplasias , Síndromes Neoplásicos Hereditarios/sangre , Síndromes Neoplásicos Hereditarios/cirugía , Neoplasias Ováricas/sangre , Neoplasias Ováricas/cirugía , Resultado del Tratamiento

RESUMEN

The aim of this experiment was to study the effect of Renin-Angiotensin System (RAS) blockade by means of valsartan on the colonic and systemic circulation in pigs during low flow sigmoideal ischemia in combination with hypovolemic shock. This condition resembles the situation that occurs in patients suffering from a ruptured aneurysm and a compromised colonic circulation. An experimental study in pigs was performed : 6 pigs with low flow sigmoideal ischemia and hypovolemic shock were treated with valsartan and a control group of 5 pigs with low flow sigmoideal ischemia and hypovolemic shock without medical treatment.Valsartan, 3 mg/kg, was administered intravenously. The operation was performed via left sided lumbotomy. The distal aorta was partially occluded to a flow reduction of 30% of the initial value. Hypovolemic shock was induced by withdrawing 20 ml/kg blood in 45 min. Resuscitation with 30 ml/kg haemaccel was iniated after 2 h of shock. The following parameters were measured: blood pressure, cardiac output; hemoglobin, lactate, angiotensin II in mixed venous blood (obtained from pulmonary artery) and in splanchnic blood (obtained from caudal mesenteric vein); and endoluminal pulse oximetry of the sigmoideal mucosa. Statistical analysis was performed by ANOVA and Wilcoxon signed rank test. There was a significant increase of lactate levels both in systemic and splanchnic circulation (P<0.05) in both groups. In the control group, the mean angiotensin II concentrations in the systemic circulation increased, after induction of ischaemia and shock. In the experimental group, the increase in angiotensin concentrations after resuscitation was significantly more prominent. In the colonic circulation, in both groups, there was a significant increase in angiotensin II levels in the splanchnic circulation following ischaemia and reperfusion (P<0.05), but there was no significant difference between the groups. There were no detectable mucosal signals measured by pulse oximetry after induction of shock throughout the experiment, whereas in the experimental group, median mucosal oxygen saturations of 81, 74.5 and 85% were achieved after resuscitation and declamping (P<0.01).In conclusion, angiotensin II inhibition during hypovolemic shock improves the colonic circulation, measured by pulse oximetry. However, other parameters of tissue ischaemia did not improve.

Asunto(s)

Colon Sigmoide/irrigación sanguínea , Isquemia/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Choque/tratamiento farmacológico , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico , Antagonistas de Receptores de Angiotensina , Animales , Rotura de la Aorta/tratamiento farmacológico , Rotura de la Aorta/fisiopatología , Hemodinámica/efectos de los fármacos , Hemoglobinas/metabolismo , Isquemia/fisiopatología , Oximetría , Choque/fisiopatología , Porcinos , Valsartán

Asunto(s)

Metilación de ADN , Síndrome del Cromosoma X Frágil/genética , Linfocitos/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Proteínas de Unión al ARN , Adolescente , Adulto , Southern Blotting , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/inmunología , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/psicología , Expresión Génica , Humanos , Inteligencia/genética

RESUMEN

An appropriate animal model is required for the study of treatments that enhance bone healing. A new segmental long bone defect model was developed for this purpose, and dual energy x-ray absorptiometry was used to quantify healing of this bone defect. In 15 sheep, a 3-cm segmental defect was created in the left tibia and fixed with an interlocking intramedullary nail. In seven animals, the defect was left empty for the assessment of the spontaneous healing response. In eight animals serving as a positive control, autologous bone grafting was performed. After 12 weeks, healing was evaluated with radiographs, a torsional test to failure, and dual energy x-ray absorptiometry. The mechanical test results were used for the assessment of unions and nonunions. Radiographic determination of nonunion was not reliably accomplished in this model. By means of dual energy x-ray absorptiometry, bone mineral density and content were measured in the middle of the defect. Bone mineral density was 91+/-7% (mean +/- SEM) and 72+/-6% that of the contralateral intact tibia in, respectively, the autologous bone-grafting and empty defect groups (p = 0.04). For bone mineral content, the values were, respectively, 117+/-18 and 82+/-9% (p = 0.07). Torsional strength and stiffness were also higher, although not significantly, in the group with autologous bone grafting than in that with the empty defect. Bone mineral density and content were closely related to the torsional properties (r2 ranged from 0.76 to 0.85, p < or = 0.0001). Because interlocking intramedullary nailing is a very common fixation method in patients, the newly developed segmental defect model has clinical relevance. The interlocking intramedullary nail provided adequate stability without implant failure. This model may be useful for the study of treatments that affect bone healing, and dual energy x-ray absorptiometry may be somewhat helpful in the analysis of healing of this bone defect.

Asunto(s)

Densidad Ósea , Modelos Animales de Enfermedad , Ovinos , Fracturas de la Tibia/fisiopatología , Cicatrización de Heridas/fisiología , Absorciometría de Fotón , Animales , Fenómenos Biomecánicos , Femenino , Análisis de Regresión , Instrumentos Quirúrgicos , Fracturas de la Tibia/diagnóstico por imagen , Anomalía Torsional

RESUMEN

Colonic ischaemia is a serious complication after aortic surgery, and is most frequent after repair of ruptured aortic aneurysms. It was felt that the increased risk of colonic ischaemia during shock might be the result of a local effect of the renin-angiotensin system in the splanchnic circulation, which is exacerbated by poor perfusion. In order to evaluate the activity of the renin-angiotensin system in the colonic circulation, a subtotal occlusion of the distal aorta was induced in nine pigs. A colonic flow reduction of 70% was created for 4 hours. In the experimental group (n = 6), induce hypovolaemic shock, 20 cm3/kg blood was sampled at 45 min before resuscitation was performed with 20 cm3/kg haemaccel. The sham group (n = 3) did not have hypovolaemic shock induced. Blood samples were taken for determinations of angiotensin II, haemoglobin and lactate. Blood gas was obtained from the pulmonary artery and the caudal mesenteric vein for blood gas analysis and lactate determinations. ANOVA and the Wilcoxon sum rank test were used for statistical analysis. There was a significant increase in angiotensin II after induction of ischaemia in both groups. The increase in angiotensin II in the splanchnic circulation was more prominent than the increase in the systemic circulation (P < 0.01). In the experimental group, there was a sustained increase in angiotensin II levels in the splanchnic circulation following shock and reperfusion (P < 0/01). The increase in lactate concentrations, which was significantly higher in the experimental group (P < 0.05), was evidence of intestinal ischaemia. There was a significant decline in cardiac output and blood pressure during the period of shock (P < 0.05). The combination of colonic ischaemia and hypovolaemic shock followed by reperfusion leads to an increase in angiotensin II activity. The increase of the local activity of the renin-angiotensin system in the splanchnic circulation is more prominent after ischaemia and reperfusion. This is probably caused by a selective response of the splanchnic vasculature to shock, ischaemia and reperfusion.

Asunto(s)

Colon Sigmoide/irrigación sanguínea , Isquemia/fisiopatología , Sistema Renina-Angiotensina , Choque/fisiopatología , Animales , Modelos Animales de Enfermedad , Hemodinámica , Circulación Esplácnica/fisiología , Porcinos

Asunto(s)

Cooperación Internacional/historia , Guerra Nuclear/historia , Rol Profesional/historia , Monitoreo de Radiación/historia , Historia del Siglo XX , Humanos , Política , Política Pública , U.R.S.S. , Estados Unidos

RESUMEN

Sigmoideal ischemia after aortic grafting is a severe complication with high morbidity and mortality. To investigate the basics of this circulatory problem an animal model was created with sigmoideal ischemia that could be quantified. For this purpose a new pig model was developed with stable general circulatory and ventilatory parameters for several hours, while at the same time controlled sigmoideal ischemia was induced. In five pigs a left retroperitoneal approach to the aorta was performed to isolate the caudal mesenteric artery (CMA). Sigmoideal ischemia was achieved by ligating the collateral circulation and constricting the distal aorta. A flow probe was applied to the CMA. An intravascular saturation probe was introduced in the caudal mesenteric vein (CMV) and a pulse oximeter was applied to the serosal surface of the sigmoid. Every hour, blood gas analyses from the carotic artery, CMA, and CMV were completed. Registrations of all circulatory and ventilatory parameters were performed with the help of a computer. The mean flow in the CMA was 29 mL/min (13-45) and decreased to 5 mL/min (3-7) after aortic constriction. Parameters reflecting the stability of the model, such as the cardiac index (mean 89 mL/min kg-1), the mixed venous oxygen saturation (mean 67%), and the total body oxygen consumption (mean 3.3 mL/min kg-1), did not change with statistical significance during 4 h of partial aortic constriction. The conclusion is that a new model has been developed of quantitative sigmoideal ischemia in the pig that was stable for several hours.

Asunto(s)

Aorta/cirugía , Presión Sanguínea/fisiología , Colon/irrigación sanguínea , Isquemia/fisiopatología , Animales , Prótesis Vascular , Modelos Animales de Enfermedad , Oxígeno/sangre , Porcinos