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BACKGROUND & AIMS: In more than half of the colorectal cancer screening participants with a positive fecal immunochemical test (FIT) result, no advanced neoplasia (AN) is detected at colonoscopy. The positive FIT result could also be generated by cancers located proximal to the colon: upper gastrointestinal, oral cavity, nose, and throat cancers. We evaluated screenees' risk of being diagnosed with a cancer proximal to the colon within the 3 years and compared risks between those with a positive vs those with a negative FIT. METHODS: Data of Dutch colorectal cancer screening participants who underwent biennial FIT-based screening 2014-2018 were collected from the national screening database and linked to the National Cancer Registry. Screenees were classified into 3 groups: FIT-positives with AN (FIT+/AN+), FIT-positives without AN (FIT+/AN-), and FIT-negatives (FIT-). We compared the cumulative incidence of cancers proximal to the colon in each group 3 years after FIT. A Cox regression analysis with left truncation and right censoring, using FIT positivity as time-dependent variable and stratified for sex, was performed to compare the hazard of cancers proximal to the colon in participants who were FIT-positive vs FIT-negative. RESULTS: Three-year cumulative incidence of cancers proximal to the colon in FIT+/AN+ (n = 65,767), FIT+/AN- (n = 50,661), and FIT- (n = 1,831,647) screenees was 0.7%, 0.6%, and 0.4%, respectively (P < .001). FIT-positives were older and more frequently male than FIT-negatives (P < .001). Significantly more cancers proximal to the colon were detected among FIT-positives (P < .001; hazard ratio, 1.55; 95% CI, 1.44-1.67). CONCLUSION: FIT-positive screenees were at significantly increased risk of being diagnosed with a cancer proximal to the colon within 3 years after FIT, although the 3-year cumulative incidence was still less than 1%.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Sangre Oculta , Humanos , Masculino , Femenino , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Detección Precoz del Cáncer/métodos , Persona de Mediana Edad , Anciano , Incidencia , Países Bajos/epidemiología , Colonoscopía , Medición de Riesgo , Factores de Riesgo , Sistema de Registros , Tamizaje Masivo/métodosRESUMEN
BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Masculino , Femenino , Humanos , Medios de Contraste , Estudios Prospectivos , Tomografía Computarizada por Rayos X/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética/métodos , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patologíaRESUMEN
BACKGROUND: The 2023 Duke-International Society of Cardiovascular Infectious Diseases (ISCVID) criteria for infective endocarditis (IE) were introduced to improve classification of IE for research and clinical purposes. External validation studies are required. METHODS: We studied consecutive patients with suspected IE referred to the IE team of Amsterdam University Medical Center (from October 2016 to March 2021). An international expert panel independently reviewed case summaries and assigned a final diagnosis of "IE" or "not IE," which served as the reference standard, to which the "definite" Duke-ISCVID classifications were compared. We also evaluated accuracy when excluding cardiac surgical and pathologic data ("clinical" criteria). Finally, we compared the 2023 Duke-ISCVID with the 2000 modified Duke criteria and the 2015 and 2023 European Society of Cardiology (ESC) criteria. RESULTS: A total of 595 consecutive patients with suspected IE were included: 399 (67%) were adjudicated as having IE; 111 (19%) had prosthetic valve IE, and 48 (8%) had a cardiac implantable electronic device IE. The 2023 Duke-ISCVID criteria were more sensitive than either the modified Duke or 2015 ESC criteria (84.2% vs 74.9% and 80%, respectively; P < .001) without significant loss of specificity. The 2023 Duke-ISCVID criteria were similarly sensitive but more specific than the 2023 ESC criteria (94% vs 82%; P < .001). The same pattern was seen for the clinical criteria (excluding surgical/pathologic results). New modifications in the 2023 Duke-ISCVID criteria related to "major microbiological" and "imaging" criteria had the most impact. CONCLUSIONS: The 2023 Duke-ISCVID criteria represent a significant advance in the diagnostic classification of patients with suspected IE.
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Enfermedades Transmisibles , Endocarditis Bacteriana , Endocarditis , Humanos , Endocarditis Bacteriana/diagnóstico , Endocarditis/diagnóstico , Enfermedades Transmisibles/diagnóstico , Diagnóstico DiferencialRESUMEN
BACKGROUND & AIMS: Desmoid tumors (DT) are an important cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). DT development might be related to the type and approach of colectomy. We aimed to compare DT development after colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: We performed an international historical cohort study in patients with FAP who underwent IRA or IPAA between 1961 and 2020. The primary outcome was the incidence of abdominal DT (either mesenteric, retroperitoneal, or abdominal wall). Patients with a DT diagnosis before or at colectomy were excluded. Time to DT was considered censored at an eventual secondary proctectomy after IRA. We used multivariable Cox regression modelling to adjust for potential confounders. RESULTS: We analyzed data from 852 patients: 514 after IRA and 338 after IPAA (median follow-up, 21 and 16 years, respectively). DTs were diagnosed in 64 IRA patients (12%) and 66 IPAA patients (20%). The cumulative DT incidence at 5 and 10 years was 7.5% and 9.3% after open IRA and 4.7% and 10.9% after laparoscopic IRA. These estimates were 13.6% and 15.4% after open IPAA and 8.4% and 10.0% after laparoscopic IPAA. The postoperative risk was significantly higher after IPAA (P < .01) in multivariable analysis, whereas approach did not significantly influence the risk. CONCLUSIONS: The risk of developing an abdominal DT was found to be significantly higher after IPAA than after IRA. Postoperative DT risk should be taken into account when choosing between IRA and IPAA in FAP.
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BACKGROUND AND AIMS: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. APPROACH AND RESULTS: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). CONCLUSIONS: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.
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Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/patología , Fibrosis , Algoritmos , Biomarcadores , Aprendizaje Automático , Biopsia , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patologíaRESUMEN
STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) prior to hysterosalpingography (HSG) or HSG prior to HyFoSy affect visible tubal patency when compared HSG or HyFoSy alone? SUMMARY ANSWER: Undergoing either HyFoSy or HSG prior to tubal patency testing by the alternative method does not demonstrate a significant difference in visible tubal patency when compared to HyFoSy or HSG alone. WHAT IS KNOWN ALREADY: HyFoSy and HSG are two commonly used visual tubal patency tests with a high and comparable diagnostic accuracy for evaluating tubal patency. These tests may also improve fertility, although the underlying mechanism is still not fully understood. One of the hypotheses points to a dislodgment of mucus plugs that may have disrupted the patency of the Fallopian tubes. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of the randomized controlled FOAM study, in which women underwent tubal patency testing by HyFoSy and HSG, randomized for order of the procedure. Participants either had HyFoSy first and then HSG, or vice versa. Here, we evaluate the relative effectiveness of tubal patency testing by HyFoSy or HSG prior to the alternative tubal patency testing method on visible tubal patency, compared to each method alone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women aged between 18 and 41 years scheduled for tubal patency testing were eligible for participating in the FOAM study. Women with anovulatory cycles, endometriosis, or with a partner with male infertility were excluded. To evaluate the effect HyFoSy on tubal patency, we relied on HSG results by comparing the proportion of women with bilateral tubal patency visible on HSG in those who underwent and who did not undergo HyFoSy prior to their HSG (HyFoSy prior to HSG versus HSG alone). To evaluate the effect of HSG on tubal patency, we relied on HyFoSy results by comparing the proportion of women with bilateral tubal patency visible on HyFoSy in those who underwent and who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone). MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, we randomized 1160 women (576 underwent HyFoSy first followed by HSG, and 584 underwent HSG first followed by HyFoSy). Among the women randomized to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467/537 (87%) women, compared with 472/544 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: -3.8% to 4.2%). Among the women randomized to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394/471 (84%) women, compared with 428/486 (88%) women who underwent HyFoSy alone (risk difference -4.4%; 95% CI: -8.8% to 0.0%). LIMITATIONS, REASONS FOR CAUTION: The results of this secondary analysis should be interpreted as exploratory and cannot be regarded as definitive evidence. Furthermore, it has to be noted that pregnancy outcomes were not considered in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Tubal patency testing by either HyFoSy or HSG, prior to the alternative tubal patency testing method does not significantly affect visible tubal patency, when compared to alternative method alone. This suggests that both methods may have comparable abilities to dislodge mucus plugs in the Fallopian tubes. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, or interpretation of the data. H.R.V. reports consultancy fees from Ferring. M.v.W. received a travel grant from Oxford University Press in the role of Deputy Editor for Human Reproduction and participates in a Data Safety and Monitoring Board as an independent methodologist in obstetrics studies in which she has no other role. M.v.W. is coordinating editor of Cochrane Fertility and Gynaecology. B.W.J.M. received an investigator grant from NHMRC (GNT1176437) and research funding from Merck KGaA. B.W.J.M. reports consultancy for Organon and Merck KGaA, and travel support from Merck KGaA. B.W.J.M. reports holding stocks of ObsEva. V.M. received research grants from Guerbet, Merck and Ferring and travel and speaker fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.
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STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost 136 and HSG 280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were 3307 for the HyFoSy strategy and 3427 for the HSG strategy (mean difference -119; 95% CI: -125 to -114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was 10 042, meaning that by using HyFoSy instead of HSG we would save 10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.
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Pruebas de Obstrucción de las Trompas Uterinas , Histerosalpingografía , Infertilidad Femenina , Ultrasonografía , Humanos , Femenino , Histerosalpingografía/métodos , Histerosalpingografía/economía , Infertilidad Femenina/terapia , Infertilidad Femenina/economía , Adulto , Embarazo , Pruebas de Obstrucción de las Trompas Uterinas/métodos , Pruebas de Obstrucción de las Trompas Uterinas/economía , Ultrasonografía/economía , Ultrasonografía/métodos , Análisis Costo-Beneficio , Índice de Embarazo , Nacimiento Vivo , Tasa de NatalidadRESUMEN
BACKGROUND: Accurate polyp size measurement is important for polyp risk stratification and decision-making regarding polypectomy and surveillance. Recently, a virtual scale (VS) function has been developed that allows polyp size measurement through projection of an adaptive VS onto colorectal polyps during real-time endoscopy. We aimed to evaluate the VS in terms of variability and systematic differences. METHODS: We conducted a video-based study with 120 colorectal polyps, measured by eight dedicated colorectal gastroenterologists (experts) and nine gastroenterology residents following endoscopy training (trainees). Three endoscopic measurement methods were compared: (1) visual, (2) snare and (3) VS measurement. We evaluated the method-specific variance (as measure of variability) in polyp size measurements and systematic differences between these methods. RESULTS: Variance in polyp size measurements was significantly lower for VS measurements compared to visual and snare measurements for both experts (0.52 vs. 1.59 and 1.96, p<0.001) and trainees (0.59 vs. 2.21 and 2.53, p<0.001). VS measurement resulted in a higher percentage of polyps assigned to the same size category by all endoscopists compared to visual and snare measurements (experts: 69% vs. 55% and 59%; trainees: 67% vs. 51% and 47%) and reduced the maximum difference between individual endoscopists regarding the percentage of polyps assigned to the >10 mm size category (experts: 1.7% vs. 10.0% and 5.0%; trainees: 2.5% vs. 6.7% and 11.7%). Systematic differences between methods were <0.5 mm. Conclusions Use of the VS leads to lower polyp size measurement variability and more uniform polyp sizing by individual endoscopists compared to visual and snare measurements.
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BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.
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Diagnóstico por Imagen de Elasticidad , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diagnóstico por Imagen de Elasticidad/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Curva ROC , Hígado/patología , Hígado/diagnóstico por imagen , Cirrosis Hepática/diagnóstico , Biopsia , Tamizaje Masivo/métodosRESUMEN
OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.
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Neoplasias Colorrectales , Tamizaje Masivo , Humanos , Estudios Prospectivos , Detección Precoz del Cáncer , Neoplasias Colorrectales/epidemiología , Colonoscopía , Sangre Oculta , HecesRESUMEN
BACKGROUND: Combining the faecal immunochemical test (FIT) result with risk factors for advanced neoplasia (AN) may increase the yield of colorectal cancer (CRC) screening without increasing the number of colonoscopies. We conducted a randomised controlled trial in the Dutch CRC screening programme to evaluate a previously developed risk model including FIT, age, sex, smoking status, and CRC family history. METHODS: A total of 22,748 individuals aged 56-75 years were pre-randomised to the risk-model group or the FIT-only group. Both groups received the FIT; those allocated to the risk-model group also received a single-page questionnaire. Study participants with a positive result (FIT ≥ 15 µg Hb/g faeces and/or risk ≥0.10) were referred for colonoscopy. The primary outcome measure was the proportion of invitees in whom AN was detected. RESULTS: In the risk-model group, 3113/11,364 invitees (27%) returned the FIT and questionnaire versus 3061/11,384 invitees (27%) in the FIT-only group (p = 0.40). The yield of AN was 3.70/1000 invitees in the risk-model group versus 3.43/1000 in the FIT-only group (absolute difference: 0.27/1000, 95%CI: -1.30 to 1.82, p = 0.82). CONCLUSIONS: Combining FIT with risk factors for CRC did not increase the yield of AN compared to FIT-only in an existing CRC screening programme. There was no difference in participation between groups. CLINICAL TRIAL REGISTRATION: NCT04490551 (ClinicalTrials.gov).
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Factores de Riesgo , Sangre Oculta , Heces/química , Hemoglobinas/análisis , Tamizaje MasivoRESUMEN
Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Biomarcadores/metabolismo , Desarrollo de MedicamentosRESUMEN
BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.
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Enfermedades Pulmonares , Humanos , Rayos X , Radiografía , Enfermedades Pulmonares/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Servicio de Urgencia en HospitalRESUMEN
Systematic reviews of diagnostic accuracy studies can provide the best available evidence to inform decisions regarding the use of a diagnostic test. In this guide, the authors provide a practical approach for clinicians to appraise diagnostic accuracy systematic reviews and apply their results to patient care. The first step is to identify an appropriate systematic review with a research question matching the clinical scenario. The user should evaluate the rigor of the review methods to evaluate its credibility (Did the review use clearly defined eligibility criteria, a comprehensive search strategy, structured data collection, risk of bias and applicability appraisal, and appropriate meta-analysis methods?). If the review is credible, the next step is to decide whether the diagnostic performance is adequate for clinical use (Do sensitivity and specificity estimates exceed the threshold that makes them useful in clinical practice? Are these estimates sufficiently precise? Is variability in the estimates of diagnostic accuracy across studies explained?). Diagnostic accuracy systematic reviews that are judged to be credible and provide diagnostic accuracy estimates with sufficient certainty and relevance are the most useful to inform patient care. This review discusses comparative, noncomparative, and emerging approaches to systematic reviews of diagnostic accuracy using a clinical scenario and examples based on recent publications.
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Diagnóstico , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Humanos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Biparametric (bp)-MRI and multiparametric (mp)-MRI may improve the diagnostic accuracy of renal mass histology. PURPOSE: To evaluate the available evidence on the diagnostic accuracy of bp-MRI and mp-MRI for solid renal masses in differentiating malignant from benign, aggressive from indolent, and clear cell renal cell carcinoma (ccRCC) from other histology. STUDY TYPE: Systematic review. POPULATION: MEDLINE, EMBASE, and CENTRAL up to January 11, 2022 were searched. FIELD STRENGTH/SEQUENCE: 1.5 or 3 Tesla. ASSESSMENT: Eligible studies evaluated the accuracy of MRI (with at least two sequences: T2, T1, dynamic contrast and diffusion-weighted imaging) for diagnosis of solid renal masses in adult patients, using histology as reference standard. Risk of bias and applicability were assessed using QUADAS-2. STATISTICAL TESTS: Meta-analysis using a bivariate logitnormal random effects model. RESULTS: We included 10 studies (1239 masses from approximately 1200 patients). The risk of bias was high in three studies, unclear in five studies and low in two studies. The diagnostic accuracy of malignant (vs. benign) masses was assessed in five studies (64% [179/281] malignant). The summary estimate of sensitivity was 95% (95% confidence interval [CI]: 77%-99%), and specificity was 63% (95% CI: 46%-77%). No study assessed aggressive (vs. indolent) masses. The diagnostic accuracy of ccRCC (vs. other subtypes) was evaluated in six studies (47% [455/971] ccRCC): the summary estimate of sensitivity was 85% (95% CI: 77%-90%) and specificity was 77% (95% CI: 73%-81%). DATA CONCLUSION: Our study reveals deficits in the available evidence on MRI for diagnosis of renal mass histology. The number of studies was limited, at unclear/high risk of bias, with heterogeneous definitions of solid masses, imaging techniques, diagnostic criteria, and outcome measures. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
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Carcinoma de Células Renales , Neoplasias Renales , Adulto , Humanos , Sensibilidad y Especificidad , Imagen por Resonancia Magnética , Imagen de Difusión por Resonancia MagnéticaRESUMEN
BACKGROUND AND AIMS: Patients with familial adenomatous polyposis (FAP) undergo (procto)colectomy to prevent colorectal cancer from developing. Interestingly, after proctocolectomy with ileal pouch-anal anastomosis (IPAA), most patients develop adenomas in the pouch. This is not well described for patients with end ileostomy. We aimed to compare ileal adenoma development in patients with IPAA with those with end ileostomy. METHODS: This historical cohort study included FAP patients with IPAA or end ileostomy who underwent surveillance endoscopies between 2001 and 2021. Primary outcomes were the proportion of patients with ileal adenomas, location of adenomas, and proportion of patients undergoing surgical excision of pouch/end ileostomy. RESULTS: Overall, 144 patients with IPAA (n = 111) and end ileostomy (n = 33) were included. Five years after surgery, 15% of patients with IPAA had ileal adenomas versus 4% after ileostomy. At 10 years, these estimates were 48% versus 9% and at 20 years were 85% versus 43% (log-rank P < .001). Adenomas developed more often in the pouch body (95%) in the IPAA group and more often at the everted site of the ileostomy (77%) in the ileostomy group. Numbers for surgical excision of the pouch (n = 9) or ileostomy (n = 3) for polyposis or cancer were comparable. Taking into account potential confounders in a multivariable Cox regression analysis, having an IPAA was significantly associated with ileal adenoma development. CONCLUSIONS: After proctocolectomy, FAP patients with IPAA more often developed ileal adenomas than patients with end ileostomy. This could potentially affect long-term management, and patients with end ileostomy might benefit from less-frequent endoscopic surveillance.
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Adenoma , Poliposis Adenomatosa del Colon , Reservorios Cólicos , Proctocolectomía Restauradora , Humanos , Proctocolectomía Restauradora/efectos adversos , Reservorios Cólicos/efectos adversos , Ileostomía , Estudios de Cohortes , Poliposis Adenomatosa del Colon/cirugía , Adenoma/epidemiología , Anastomosis Quirúrgica/efectos adversosRESUMEN
OBJECTIVE: The yield of pulmonary imaging in patients with suspected infection but no respiratory symptoms or signs is probably limited, ultra-low-dose CT (ULDCT) is known to have a higher sensitivity than Chest X-ray (CXR). Our objective was to describe the yield of ULDCT and CXR in patients clinically suspected of infection, but without respiratory symptoms or signs, and to compare the diagnostic accuracy of ULDCT and CXR. METHODS: In the OPTIMACT trial, patients suspected of non-traumatic pulmonary disease at the emergency department (ED) were randomly allocated to undergo CXR (1210 patients) or ULDCT (1208 patients). We identified 227 patients in the study group with fever, hypothermia, and/or elevated C-reactive protein (CRP) but no respiratory symptoms or signs, and estimated ULDCT and CXR sensitivity and specificity in detecting pneumonia. The final day-28 diagnosis served as the clinical reference standard. RESULTS: In the ULDCT group, 14/116 (12%) received a final diagnosis of pneumonia, versus 8/111 (7%) in the CXR group. ULDCT sensitivity was significantly higher than that of CXR: 13/14 (93%) versus 4/8 (50%), a difference of 43% (95% CI: 6 to 80%). ULDCT specificity was 91/102 (89%) versus 97/103 (94%) for CXR, a difference of - 5% (95% CI: - 12 to 3%). PPV was 54% (13/24) for ULDCT versus 40% (4/10) for CXR, NPV 99% (91/92) versus 96% (97/101). CONCLUSION: Pneumonia can be present in ED patients without respiratory symptoms or signs who have a fever, hypothermia, and/or elevated CRP. ULDCT's sensitivity is a significant advantage over CXR when pneumonia has to be excluded. CLINICAL RELEVANCE STATEMENT: Pulmonary imaging in patients with suspected infection but no respiratory symptoms or signs can result in the detection of clinically significant pneumonia. The increased sensitivity of ultra-low-dose chest CT compared to CXR is of added value in vulnerable and immunocompromised patients. KEY POINTS: ⢠Clinical significant pneumonia does occur in patients who have a fever, low core body temperature, or elevated CRP without respiratory symptoms or signs. ⢠Pulmonary imaging should be considered in patients with unexplained symptoms or signs of infections. ⢠To exclude pneumonia in this patient group, ULDCT's improved sensitivity is a significant advantage over CXR.
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Hipotermia , Neumonía , Humanos , Rayos X , Radiografía Torácica/métodos , Neumonía/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Servicio de Urgencia en HospitalRESUMEN
The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.
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Servicios de Laboratorio Clínico , Juego de Reactivos para Diagnóstico , Humanos , Juego de Reactivos para Diagnóstico/normas , Unión Europea , Servicios de Laboratorio Clínico/legislación & jurisprudenciaRESUMEN
BACKGROUND: Timely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, the early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data. METHODS: Our study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnoea and/or peripheral oedema within the Amsterdam metropolitan area from 2011 to 2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized, cause-specific multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor. RESULTS: Data from 31,905 patients were included (40% male, median age 60 years) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (nâ =â 25,524) and validation (nâ =â 6,381) set. TARGET-HF attained a C-statistic of 0.853 (95% CI, 0.834 to 0.872) on the validation set, which proved to provide a better discrimination than Câ =â 0.822 for age alone (95% CI, 0.801 to 0.842, Pâ <â 0.001) and Câ =â 0.824 for the hospital-based model (95% CI, 0.802 to 0.843, Pâ <â 0.001). CONCLUSION: The TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at the time of GP consultation.
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Insuficiencia Cardíaca , Calidad de Vida , Humanos , Masculino , Persona de Mediana Edad , Femenino , Factores de Riesgo , Pronóstico , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Medicina Familiar y Comunitaria , Atención a la SaludRESUMEN
Whereas diagnostic tests help detect the cause of signs and symptoms, prognostic tests assist in evaluating the probable course of the disease and future outcome. Studies to evaluate prognostic tests are longitudinal, which introduces sources of bias different from those for diagnostic accuracy studies. At present, systematic reviews of prognostic tests often use the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to assess risk of bias and applicability of included studies because no equivalent instrument exists for prognostic accuracy studies.QUAPAS (Quality Assessment of Prognostic Accuracy Studies) is an adaptation of QUADAS-2 for prognostic accuracy studies. Questions likely to identify bias were evaluated in parallel and collated from QUIPS (Quality in Prognosis Studies) and PROBAST (Prediction Model Risk of Bias Assessment Tool) and paired to the corresponding question (or domain) in QUADAS-2. A steering group conducted and reviewed 3 rounds of modifications before arriving at the final set of domains and signaling questions.QUAPAS follows the same steps as QUADAS-2: Specify the review question, tailor the tool, draw a flow diagram, judge risk of bias, and identify applicability concerns. Risk of bias is judged across the following 5 domains: participants, index test, outcome, flow and timing, and analysis. Signaling questions assist the final judgment for each domain. Applicability concerns are assessed for the first 4 domains.The authors used QUAPAS in parallel with QUADAS-2 and QUIPS in a systematic review of prognostic accuracy studies. QUAPAS improved the assessment of the flow and timing domain and flagged a study at risk of bias in the new analysis domain. Judgment of risk of bias in the analysis domain was challenging because of sparse reporting of statistical methods.