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Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.
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Leucocitos Mononucleares/citología , Linfocitos T/inmunología , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Técnicas de Cultivo de Célula , Técnicas de Cocultivo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Humanos , Técnicas In Vitro , Interferón gamma/farmacología , Leucocitos Mononucleares/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).
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Antineoplásicos Inmunológicos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Colon , Reparación de la Incompatibilidad de ADN , Ipilimumab , Terapia Neoadyuvante , Nivolumab , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Supervivencia sin Enfermedad , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Tiempo de Tratamiento , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Países Bajos , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and healthcare. Stool tests may help to reduce surveillance colonoscopies, by limiting colonoscopies to individuals at increased risk of AN. METHODS: This cross-sectional observational study included individuals aged 50-75 with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA (mt-sDNA) test and two fecal immunochemical tests (FITs). Test accuracies were calculated for all surveillance indications. Only for the post-polypectomy indication, most common and associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the ASCCA model. Stool-based strategies were simulated to tune each tests' positivity threshold to obtain strategies at least as effective as colonoscopy surveillance. RESULTS: 3453 individuals had results for all stool tests and colonoscopy. 2226 had previous polypectomy, 1003 previous CRC and 224 familial risk. Areas under the receiver operating characteristic curve for AN were 0.72 (95% CI; 0.69-0.75) for the mt-sDNA test, 0.61 (95% CI; 0.58-0.64) for the FIT OC-Sensor and 0.59 (95% CI; 0.56-0.61) for the FIT FOB-Gold. Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance, reduced the number of colonoscopies by 15-41% and required 5.6-9.5 stool tests over the lifetime of a person. Mt-sDNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs. CONCLUSIONS: This study shows that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%.
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Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Escherichia coli , Heces , Sintasas Poliquetidas , Humanos , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/diagnóstico , Heces/microbiología , Heces/enzimología , Escherichia coli/aislamiento & purificación , Escherichia coli/enzimología , Escherichia coli/genética , Masculino , Detección Precoz del Cáncer/métodos , Femenino , Persona de Mediana Edad , Anciano , Sintasas Poliquetidas/genética , Colonoscopía , Factores de Riesgo , Adenoma/microbiología , Adenoma/diagnóstico , Medición de Riesgo , Biomarcadores de Tumor , Estudios de Casos y ControlesRESUMEN
OBJECTIVE: Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals. DESIGN: In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months. RESULTS: A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high. CONCLUSION: A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm. TRIAL REGISTRATION NUMBER: NTR7477.
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Pólipos del Colon , Neoplasias Colorrectales , Resección Endoscópica de la Mucosa , Humanos , Pólipos del Colon/cirugía , Colonoscopía , Neoplasias Colorrectales/cirugíaRESUMEN
BACKGROUND: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening. METHODS: Individuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 µg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete. FINDINGS: Between March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening. INTERPRETATION: The higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening. FUNDING: Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.
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Adenoma , Neoplasias Colorrectales , Humanos , Detección Precoz del Cáncer , Defecación , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Adenoma/diagnóstico , Adenoma/epidemiología , HemoglobinasRESUMEN
Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.
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Adenoma , Supervivientes de Cáncer , Pólipos del Colon , Neoplasias Colorrectales , Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Masculino , Humanos , Persona de Mediana Edad , Pólipos del Colon/epidemiología , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/epidemiología , Prevalencia , Colonoscopía , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/diagnóstico , Adenoma/patología , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors before diagnosis of PDAC. METHODS: We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal computed tomography scans and 10 different blood-based biomarkers up to 36 months before diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for 3-dimensional quantification of body composition on computed tomography scans. Longitudinal trends of body composition and blood-based biomarkers before PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. RESULTS: We included 1690 patients in body composition analysis, of whom 516 (30.5%) had ≥2 prediagnostic computed tomography scans. For analysis of longitudinal trends of blood-based biomarkers, 3332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (ß = -1.94 [95% confidence interval (CI), -2.39 to -1.48] and ß = -2.59 [95% CI, -3.17 to -2.02]) in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (eg, low-density lipoprotein [ß = -2.83; 95% CI, -3.31 to -2.34], total cholesterol [ß = -2.69; 95% CI, -3.18 to -2.20], and triglycerides [ß = -1.86; 95% CI, -2.61 to -1.11]), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months before diagnosis. CONCLUSIONS: This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.
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Composición Corporal , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Tomografía Computarizada por Rayos X , Humanos , Masculino , Estudios Retrospectivos , Carcinoma Ductal Pancreático/diagnóstico , Femenino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Anciano , Biomarcadores de Tumor , Detección Precoz del Cáncer/métodos , AdultoRESUMEN
BACKGROUND & AIMS: Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance. METHODS: In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under surveillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time. RESULTS: Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, year of diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non-surveillance patients vs 71.0% of surveillance patients underwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by a 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than in non-surveillance patients. CONCLUSION: Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Puntaje de Propensión , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Pronóstico , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
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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OBJECTIVES: Colonoscopy surveillance for Lynch syndrome is burdensome and post-colonoscopy colorectal cancers (CRCs) still occur. The non-invasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. METHODS: Prospective, multi-center observational study in which individuals with Lynch syndrome performed a quantitative FIT prior to high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 µg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AA] and advanced serrated lesions [ASL]) and non-advanced adenomas (NAA). RESULTS: Of the 217 included individuals (59% female, median age 51y), 4 had CRC, 5 AA, 4 ASL and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 µg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value (NPV) of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and NPV, specificity for advanced neoplasia optimized to 94% at threshold 4.1 µg/g. Per 100 FITs at threshold 4.1 µg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia. CONCLUSIONS: FIT at thresholds ≤ 4.1 µg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 out of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.
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BACKGROUND: Colibactin, a genotoxin produced by polyketide synthase harboring (pks+) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks+Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88. METHODS: In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. RESULTS: NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. CONCLUSIONS: These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.
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Adenoma , Carcinoma , Neoplasias Colorrectales , Policétidos , Humanos , Mutación , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Péptidos/genética , Escherichia coli/genética , Adenoma/genéticaRESUMEN
BACKGROUND: Screen-detected colorectal cancers (CRCs) are often treated less invasively than stage-matched non-screen-detected CRCs, but the reasons for this are not fully understood. This study evaluated the treatment of stage I CRCs detected within and outside of the screening program in the Netherlands. METHODS : Data from the Netherlands Cancer Registry for all stage I CRCs diagnosed between January 1, 2008 and December 31, 2020 were analyzed, comparing patient, tumor, and treatment characteristics of screen-detected and non-screen-detected stage I CRCs. Multivariable logistic regression was used to assess the association between treatment (local excision only vs. surgical oncologic resection) and patient and tumor characteristics, stratified for T stage and tumor location. RESULTS: Screen-detected stage I CRCs were relatively more often T1 than T2 compared with non-screen-detected stage I CRCs (66.9â% vs. 53.3â%; Pâ<â0.001). When only T1 tumors were considered, both screen-detected colon and rectal cancers were more often treated with local excision only than non-screen-detected T1 cancers (odds ratio [OR] 2.19, 95â%CI 1.93-2.49; and OR 1.29, 95â%CI 1.05-1.59, respectively), adjusted for sex, tumor location, lymphovascular invasion (LVI) status, and tumor differentiation. CONCLUSIONS : Less invasive treatment of screen-detected stage I CRC is partly explained by the higher rate of T1 cancers compared with non-screen-detected stage I CRCs. T1 stage I screen-detected CRCs were also more likely to undergo less invasive treatment than non-screen-detected CRCs, adjusted for risk factors such as LVI and tumor differentiation. Future research should investigate whether the choice of local excision was related to unidentified cancer-related factors or the expertise of the endoscopists.
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Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Detección Precoz del Cáncer/métodos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Factores de Riesgo , ColonoscopíaRESUMEN
BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Metástasis Linfática , Estadificación de Neoplasias , Humanos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/diagnóstico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Detección Precoz del Cáncer/métodos , Países Bajos/epidemiología , Factores de Riesgo , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Modelos de Riesgos Proporcionales , Colonoscopía/estadística & datos numéricos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To assess the impact of delayed invitation on screen-detected and interval colorectal cancers (CRC) within a faecal immunochemical testing (FIT)-based CRC screening programme. DESIGN: All individuals that participated in 2017 and 2018 with a negative FIT and were eligible for CRC screening in 2019 and 2020 were included using individual-level data. Multivariable logistic regression analyses were used to assess the association between either the different time periods (ie, 'before', 'during' and 'after' the first COVID-19 wave) or the invitation interval on screen-detected and interval CRCs. RESULTS: Positive predictive value for advanced neoplasia (AN) was slightly lower during (OR=0.91) and after (OR=0.95) the first COVID-19 wave, but no significant difference was observed for the different invitation intervals. Out of all individuals that previously tested negative, 84 (0.004%) had an interval CRC beyond the 24 months since their last invitation. The time period of invitation as well as the extended invitation interval was not associated with detection rates for AN and interval CRC rate. CONCLUSION: The impact of the first COVID-19 wave on screening yield was modest. A very small proportion of the FIT negatives had an interval CRC possibly due to an extended interval, which potentially could have been prevented if they had received the invitation earlier. Nonetheless, no increase in interval CRC rate was observed, indicating that an extended invitation interval up to 30 months had no negative impact on the performance of the CRC screening programme and a modest extension of the invitation interval seems an appropriate intervention.
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COVID-19 , Neoplasias Colorrectales , Humanos , Detección Precoz del Cáncer , COVID-19/diagnóstico , COVID-19/epidemiología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/prevención & control , Valor Predictivo de las Pruebas , Sangre Oculta , Tamizaje Masivo , ColonoscopíaRESUMEN
OBJECTIVES: To examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC). DESIGN: Prognostic model. SETTING: Dutch biennial FIT-based screening programme during 2014-2018. PARTICIPANTS: 265 881 participants completing three rounds of FIT, with negative test results (F-Hb <47 µg Hb/g faeces) in rounds 1 and 2. INTERVENTIONS: Colonoscopy follow-up in participants with a positive FIT (F-Hb ≥47 µg Hb/g faeces). MAIN OUTCOMES: We evaluated prognostic models for detecting advanced neoplasia (AN) and CRC in round 3, with as predictors, participant age, sex, F-Hb in rounds 1 and 2, and categories/combinations/non-linear transformations of F-Hb. Primary evaluation criteria included: risk prediction accuracy (calibration), discrimination of participants with versus without AN or CRC (optimism-adjusted C-statistics, range 0.5-1.0), the degree of risk stratification and C-statistics in external validation. RESULTS: Among study participants, 8806 (3.3%) had a positive FIT result, 3254 (1.2%) had AN detected and 557 (0.2%) had cancer. F-Hb concentrations in rounds 1 and 2 were the strongest outcome predictors, with adjusted ORs of up to 9.4 (95% CI 7.5 to 11.7) for the highest F-Hb category. Risk predictions matched the observed risk for most participants (calibration intercept -0.008 to -0.099; slope 0.982-0.998), and discriminated participants with versus without AN or CRC with C-statistics of 0.78 (95% CI 0.77 to 0.79) and 0.73 (95% CI 0.71 to 0.75), respectively. The predicted risk ranged from 0.4% to 36.7% for AN and from 0.0% to 5.5% for CRC across participants. In external validation, the model retained similar discrimination accuracy for AN (C-statistic 0.77, 95% CI 0.66 to 0.87) and CRC (C-statistic 0.78, 95% CI 0.66 to 0.91). CONCLUSION: Participants at lower versus higher risk of future AN or CRC can be accurately identified based on their age, sex and particularly, prior F-Hb concentrations. Risk stratification should be considered based on this information.
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Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/diagnóstico , Pronóstico , Sangre Oculta , Colonoscopía/métodos , Heces/química , Detección Precoz del Cáncer/métodos , Hemoglobinas/análisisRESUMEN
The interval colorectal cancer (CRC) rate after negative fecal immunochemical testing (FIT) is an important quality indicator of CRC screening programs. We analyzed the outcomes of two rounds of the FIT-based CRC screening program in the Netherlands, using data from individuals who participated in FIT-screening from 2014 to 2017. Data of individuals with one prior negative FIT (first round) or two prior negative FITs (first and second round) were included. Outcomes included the incidence of interval CRC in FIT-negative participants (<47 µg Hb/g feces [µg/g]), FIT-sensitivity, and the probability of detecting an interval CRC by fecal hemoglobin concentration (f-Hb). FIT-sensitivity was estimated using the detection method and the proportional incidence method (based on expected CRC incidence). Logistic regression analysis was performed to estimate whether f-Hb affects probability of detecting interval CRC, adjusted for sex- and age-differences. Incidence of interval CRC was 10.4 per 10 000 participants after the first and 9.6 after the second screening round. FIT-sensitivity based on the detection method was 84.4% (95%CI 83.8-85.0) in the first and 73.5% (95% CI 71.8-75.2) in the second screening round. The proportional incidence method resulted in a FIT-sensitivity of 76.4% (95%CI 73.3-79.6) in the first and 79.1% (95%CI 73.7-85.3) in the second screening round. After one negative FIT, participants with f-Hb just below the cut-off (>40-46.9 µg/g) had a higher probability of detecting an interval CRC (OR 16.9; 95%CI: 14.0-20.4) than had participants with unmeasurable f-Hb (0-2.6 µg/g). After two screening rounds, the odds ratio for interval CRC was 12.0 (95%CI: 7.8-17.6) for participants with f-Hb just below the cut-off compared with participants with unmeasurable f-Hb. After both screening rounds, the Dutch CRC screening program had a low incidence of interval CRC and an associated high FIT-sensitivity. Our findings suggest there is a potential for further optimizing CRC screening programs with the use of risk-stratified CRC screening based on prior f-Hb.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Detección Precoz del Cáncer/métodos , Hemoglobinas/análisis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Sangre Oculta , Heces/química , Tamizaje Masivo/métodos , ColonoscopíaRESUMEN
BACKGROUND & AIMS: For colorectal cancer (CRC) screening to be effective, it is important that screen-detected cancers are found at an early stage. Studies on stage distribution of screen-detected CRC at repeat screening of large population-based fecal immunochemical test (FIT)-based screening programs and the impact of FIT cut-off values on staging currently are lacking. METHODS: We obtained data for FIT-positive participants (FIT cut-off, 47 µg hemoglobin/g feces) at their first or second (ie, repeat) screening from the Dutch National Screening Database from 2014 to 2018. Tumor characteristics were acquired through linkage with The Netherlands Cancer Registry. We compared stage at diagnosis (I-II vs III-IV) of CRCs detected at a first or second screening. In addition, we analyzed the hypothetical yield and stage distribution of CRC for different FIT cut-off values up to 250 µg hemoglobin/g feces. RESULTS: At the first and second screenings, respectively, 15,755 and 3304 CRCs were detected. CRCs detected at the first or second screening were equally likely to be stages I to II (66.5% vs 67.7%; relative risk, 1.02; 95% CI, 1.00-1.05). A hypothetical increase of the FIT cut-off value from 47 µg to 250 µg resulted in a reduction of detected CRCs by 88.3% and 79.0% at the first or second screening, respectively. Even then, the majority of detected CRCs (63%-64%) still would be diagnosed at stages I to II. CONCLUSIONS: FIT-based screening is effective in downstaging CRC, and also at repeat screening. Increasingly, the FIT cut-off level has a limited impact on the stage distribution of detected CRCs, although it greatly affects CRC detection and thus is important to keep low.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Detección Precoz del Cáncer/métodos , Sangre Oculta , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Estadificación de Neoplasias , Hemoglobinas/análisis , Heces/química , Tamizaje Masivo/métodos , ColonoscopíaRESUMEN
BACKGROUND AND AIMS: Screening for colorectal cancer (CRC) aims to decrease CRC incidence and mortality. Biennial fecal immunochemical test screening started in the Netherlands in 2014 for individuals 55-75 years of age. This study investigated the effect of screening on stage-specific incidence, with focus on stage III and IV CRC. METHODS: Inhabitants diagnosed with CRC in 2009-2018 were included. CRC incidence per stage, year, and detection method (ie, screen-detected vs clinically detected) was evaluated. Patient, tumor, and treatment characteristics, and survival of patients with stage III and IV CRC, were compared according to the detection method. RESULTS: Included were 140,649 CRCs in 136,882 patients. An initial peak of stage I-III CRC diagnoses after initiation of screening was followed by a continuous decrease within screening-eligible ages. Total CRC incidence remained higher than before screening, although stage II and IV CRC incidence decreased below prescreening levels. Screen-detected CRCs were significantly more frequently located in the left-sided colon (stage III; 43.7% vs 30.9%; stage IV: 45.1% vs 36.1%), and the primary tumor resection rate was higher (stage III colon: 99.8% vs 99.0%, rectum: 97.3% vs 89.7%; stage IV colon: 65.4% vs 56.6%, rectum: 47.3% vs 33.5%). Patients with screen-detected stage IV CRC had significantly more often single-organ metastases (74.5% vs 57.0%; P < .001) and more frequently received treatment with curative intent (colon: 41.3% vs 27.4%; rectum: 33.8% vs 24.6%). Overall survival significantly improved for patients with screen-detected CRCs (stage III: P < .001; stage IV: P < .001). CONCLUSIONS: Five years after the start of a nationwide CRC screening program, a decrease in stage II and IV CRC incidence was observed. Patients with screen-detected stage III and stage IV CRC had less extensive disease and improved survival compared with those with clinically detected CRC.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Incidencia , Detección Precoz del Cáncer/métodos , Neoplasias Colorrectales/diagnóstico , Tamizaje Masivo/métodos , Países Bajos/epidemiologíaRESUMEN
BACKGROUND : Advanced serrated polyps (ASPs) have a comparable risk to advanced adenomas for progression to colorectal cancer (CRC). The yield of most CRC screening programs, however, is based on advanced adenomas and CRC only. We assessed the ASP detection rate, and positive predictive value (PPV) including ASPs in a fecal immunochemical test (FIT)-based screening program. METHODS : We analyzed the findings of follow-up colonoscopies of FIT-positive screenees in the Dutch CRC screening program from 2014 until 2020. Data were retrieved from the national screening and pathology database. An ASP was defined as any serrated polyp of ≥â10âmm, sessile serrated lesion with dysplasia, or traditional serrated adenoma. The ASP detection rate was defined as the proportion of colonoscopies with ≥â1 ASP. PPV was originally defined as the proportion of individuals with a CRC or advanced adenoma. The updated PPV definition included CRCs, advanced adenomas, and/or ASPs. RESULTS : 322â882 colonoscopies were included in the analyses. The overall detection rate of ASPs was 5.9â%. ASPs were detected more often in women than men (6.3â% vs. 5.6â%; Pâ<â0.001). ASP detection rates in individuals aged 55-59, 60-64, 65-69, and 70â+âwere 5.2â%, 6.1â%, 6.1â%, and 5.9â%, respectively (Pâ<â0.001). The PPV for CRCs and advanced adenomas was 41.1â% and increased to 43.8â% when including ASPs. The PPV increase was larger in women than in men (3.2 vs. 2.4 percentage points). CONCLUSIONS : 5.9â% of FIT-positive screenees had ASPs, but half of these were detected in combination with a CRC or advanced adenoma. Therefore, including ASPs results in a small increase in the yield of FIT-based screening.