Risk Prediction of Metachronous Colorectal Cancer from Molecular Features of Adenomas: A Nested Case-Control Study.

Current morphologic features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy-number profiles were determined, by low-coverage whole-genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (OR) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex.CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline [OR, 1.14; 95% confidence interval CI), 1.03-1.26; P = 0.012], advanced adenomas (OR, 2.46; 95% CI, 1.50-4.01; P < 0.001) and with the presence of ≥3 DNA copy-number losses (OR, 1.90; 95% CI. 1.02-3.54; P = 0.043).Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. SIGNIFICANCE: Identifying new biomarkers may improve prediction of me-CRC for individuals with adenomas and optimize surveillance intervals to reduce risk of colorectal cancer and reduce oversurveillance of patients with low risk of colorectal cancer. Use of DNA CNAs alone does not improve prediction of me-CRC. Further research to improve risk classification is required.

A Comparison of Risk Classification Systems of Colorectal Adenomas: A Case-Cohort Study.

BACKGROUND & AIMS: Because post-polypectomy surveillance uses a growing proportion of colonoscopy capacity, more targeted surveillance is warranted. We therefore compared surveillance burden and cancer detection using 3 different adenoma classification systems. METHODS: In a case-cohort study among individuals who had adenomas removed between 1993 and 2007, we included 675 individuals with colorectal cancer (cases) diagnosed a median of 5.6 years after adenoma removal and 906 randomly selected individuals (subcohort). We compared colorectal cancer incidence among high- and low-risk individuals defined according to the traditional (high-risk: diameter ≥10 mm, high-grade dysplasia, villous growth pattern, or 3 or more adenomas), European Society of Gastrointestinal Endoscopy (ESGE) 2020 (high-risk: diameter ≥10 mm, high-grade dysplasia, or 5 or more adenomas), and novel (high-risk: diameter ≥20 mm or high-grade dysplasia) classification systems. For the different classification systems, we calculated the number of individuals recommended frequent surveillance colonoscopy and estimated number of delayed cancer diagnoses. RESULTS: Four hundred and thirty individuals with adenomas (52.7%) were high risk based on the traditional classification, 369 (45.2%) were high risk based on the ESGE 2020 classification, and 220 (27.0%) were high risk based on the novel classification. Using the traditional, ESGE 2020, and novel classifications, the colorectal cancer incidences per 100,000 person-years were 479, 552, and 690 among high-risk individuals, and 123, 124, and 179 among low-risk individuals, respectively. Compared with the traditional classification, the number of individuals who needed frequent surveillance was reduced by 13.9% and 44.2%, respectively, and 1 (3.4%) and 7 (24.1%) cancer diagnoses were delayed using the ESGE 2020 and novel classifications. CONCLUSIONS: Using the ESGE 2020 and novel risk classifications will substantially reduce resources needed for colonoscopy surveillance after adenoma removal.

Long-term colorectal cancer incidence and mortality after adenoma removal in women and men.

BACKGROUND: Women and men with colorectal adenomas are at increased risk of colorectal cancer and colonoscopic surveillance is recommended. However, the long-term cancer risk remains unknown. AIMS: To investigate colorectal cancer incidence and mortality after adenoma removal in women and men METHODS: We identified all individuals who had adenomas removed in Norway from 1993 to 2007, with follow-up through 2018. We calculated standardized incidence ratios (SIR) and incidence-based mortality ratios (SMR) with 95% confidence intervals (CI) for colorectal cancer in women and men using the female and male population for comparison. We defined high-risk adenomas as ≥2 adenomas, villous component, or high-grade dysplasia. RESULTS: The cohort comprised 40 293 individuals. During median follow-up of 13.0 years, 1079 women (5.5%) and 866 men (4.2%) developed colorectal cancer; 328 women (1.7%) and 275 men (1.3%) died of colorectal cancer. Colorectal cancer incidence was more increased in women (SIR 1.64, 95% CI 1.54-1.74) than in men (SIR 1.12, 95% CI 1.05-1.19). Colorectal cancer mortality was increased in women (SMR 1.13, 95% CI 1.02-1.26) and reduced in men (SMR 0.79, 95% CI 0.71-0.89). Women with high-risk adenomas had an increased risk of colorectal cancer death (SMR 1.37, 95% CI 1.19-1.57); women with low-risk adenomas (SMR 0.90, 95% CI 0.76-1.07) and men with high-risk adenomas had a similar risk (SMR 0.89, 95% CI 0.76-1.04), while men with low-risk adenomas had reduced risk (SMR 0.70, 95% CI 0.59-0.84). CONCLUSIONS: After adenoma removal, women had an increased risk of colorectal cancer death, while men had reduced risk, compared to the general female and male populations. Sex-specific surveillance recommendations after adenoma removal should be considered.

Treatment outcomes and prognostic factors after chemoradiotherapy for anal cancer.

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with rising incidence, associated with human papilloma virus (HPV). Chemoradiotherapy (CRT) is the preferred treatment. The purpose was to investigate treatment failure, survival and prognostic factors after CRT. MATERIAL AND METHODS: In this prospective observational study from a large regional centre, 141 patients were included from 2013 to 2017, and 132 were eligible for analysis. The main inclusion criteria were SCCA, planned radiotherapy, and performance status (ECOG) ≤2. Patient characteristics, disease stage, treatment, and treatment response were prospectively registered. Disease-free survival (DFS), overall survival (OS), and locoregional treatment failure after CRT were analysed. Hazard ratios (HRs) were estimated with Cox`s proportional hazards model. RESULTS: Median follow-up was 54 (range 6-71) months. Eighteen patients (14%) had treatment failures after CRT; of these 10 (8%) had residual tumour, and 8 (6%) relapse as first failure. The first treatment failure was locoregional (11 patients), distant (5 patients), and both (2 patients). Salvage abdomino-perineal resection was performed in 10 patients, 2 had resections of metastases, and 3 both. DFS was 85% at 3 years and 78% at 5 years. OS was 93% at 3 years and 86% at 5 years. In analyses adjusted for age and gender, HPV negative tumours (HR 2.5, p = 0.024), N3 disease (HR 2.6, p = 0.024), and tumour size ≥4 cm (HR 2.4, p = 0.038) were negative prognostic factors for DFS. CONCLUSION: State-of-the-art chemoradiotherapy for SCCA resulted in excellent outcomes, and improved survival compared with previous national data, with <15% treatment failures and a 3-year DFS of >80%.

Implications of different guidelines for surveillance after serrated polyp resection in United States of America and Europe.

INTRODUCTION: Because individuals with serrated polyps and adenomas are at increased risk of developing new polyps and colorectal cancer (CRC), surveillance after resection is justified. After adenoma resection, most international guidelines are consistent, but recommendations for surveillance after serrated polyp resection vary. The United States Multi-Society Taskforce on CRC (US-MSTF) base surveillance intervals on serrated polyp subtype (traditional serrated adenoma, sessile serrated polyp, hyperplastic polyps), while the European Society of Gastrointestinal Endoscopy (ESGE) guidelines do not take serrated polyp subtype into account. We evaluated the implications of this difference in a primary colonoscopy screening cohort. METHODS: We included participants from a large colonoscopy screening trial. In a post-hoc simulation, assuming full protocol adherence, we determined the surveillance interval for each subject based on their polyp burden, using the most recent US-MSTF and ESGE guidelines. RESULTS: We included 5323 participants, of whom 1228 had one or more serrated polyps. In 5201 of all participants (98 %; Cohen's kappa 0.90) and in 1106 of those with serrated polyps (90 %; Cohen's kappa 0.80), both guidelines recommended identical surveillance intervals. Recommendations for a 3-year surveillance interval were identical between the two guidelines. All 122 subjects with discordant recommendations would receive a follow-up colonoscopy after 10 years using ESGE guidance and after 5 years using US-MSTF guidance. CONCLUSION: Despite the different criteria used to determine surveillance after serrated polyp resection, most individuals are recommended identical colonoscopy surveillance intervals whether following the ESGE or US-MSTF guidelines. This suggests that surveillance recommendations do not need to consider the serrated polyp subtype.

Anal cancer chemoradiotherapy outcome prediction using 18F-fluorodeoxyglucose positron emission tomography and clinicopathological factors.

OBJECTIVE: To assess the role of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET), obtained before and during chemoradiotherapy, in predicting locoregional failure relative to clinicopathological factors for patients with anal cancer. METHODS: 93 patients with anal squamous cell carcinoma treated with chemoradiotherapy were included in a prospective observational study (NCT01937780). FDG-PET/CT was performed for all patients before treatment, and for a subgroup (n = 39) also 2 weeks into treatment. FDG-PET was evaluated with standardized uptake values (SUVmax/peak/mean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and a proposed Z-normalized combination of MTV and SUVpeak (ZMP). The objective was to predict locoregional failure using FDG-PET, tumor and lymph node stage, gross tumor volume (GTV) and human papilloma virus (HPV) status in univariate and bivariate Cox regression analysis. RESULTS: N3 lymph node stage, HPV negative tumor, GTV, MTV, TLG and ZMP were in univariate analysis significant predictors of locoregional failure (p < 0.01), while SUVmax/peak/mean were not (p > 0.2). In bivariate analysis HPV status was the most independent predictor in combinations with N3 stage, ZMP, TLG, and MTV (p < 0.02). The FDG-PET parameters at 2 weeks into radiotherapy decreased by 30-40 % of the initial values, but neither absolute nor relative decrease improved the prediction models. CONCLUSION: Pre-treatment PET parameters are predictive of chemoradiotherapy outcome in anal cancer, although HPV negativity and N3 stage are the strongest single predictors. Predictions can be improved by combining HPV with PET parameters such as MTV, TLG or ZMP. PET 2 weeks into treatment does not provide added predictive value. ADVANCES IN KNOWLEDGE: Pre-treatment PET parameters of anal cancer showed a predictive role independent of clinicopathological factors. Although the PET parameters show substantial reduction from pre- to mid-treatment, the changes were not predictive of chemoradiotherapy outcome.

Does preoperative magnetic resonance imaging reduce the rate of positive surgical margins at radical prostatectomy in a randomised clinical trial?

BACKGROUND: Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). OBJECTIVE: To evaluate the benefit of performing MRI prior to RP. DESIGN, SETTING, AND PARTICIPANTS: This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robot-assisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). INTERVENTION: Patients were preoperatively randomly assigned to non-MRI or MRI groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. RESULTS AND LIMITATIONS: A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group (p=0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group (p=0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. CONCLUSIONS: MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. PATIENT SUMMARY: This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer.

Preoperative magnetic resonance imaging for detecting uni- and bilateral extraprostatic disease in patients with prostate cancer.

OBJECTIVE: The objective of the study was to evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) for detecting uni- and bilateral extraprostatic disease (T3) in patients with prostate cancer (PCa). MATERIALS AND METHODS: This prospective study included 199 patients with biopsy-proven PCa who underwent MRI prior to radical prostatectomy from December 2009 to July 2012. Extraprostatic extension and seminal vesicle invasion represented T3 disease, and was classified as uni- (right or left) or bilateral. MRI detection of T3 disease was assessed by descriptive statistics and odds ratio (OR). Whole-mount histopathology was used as the reference standard. RESULTS: The overall prevalence of pT3 was 105/199 (53 %), unilateral in 81/105 (77 %) and bilateral in 24/105 (23 %). The sensitivity of MRI for predicting pT3 was 76/105 (72 %), specificity 61/94 (65 %), accuracy 137/199 (69 %), and OR 4.8 (95 % CI 2.7-8.8). A complete match with respect to the laterality of pT3 was found in 52/105 (50 %), and the side-specific accuracy was 113/199 (57 %). When unilateral pT3 was found, MRI falsely suggested contralateral T3 in 4/81 (5 %) and bilateral in 8/81 (10 %). When bilateral pT3 was found, MRI falsely suggested unilateral T3 in 12/24 (50 %). CONCLUSION: Magnetic resonance imaging (MRI) detected 72 % of all patients with T3 disease, and the accuracy dropped from 69 to 57 % when considering the laterality of T3. Thus far, the MRI technique is not yet adequate to meet the increasing demands of accurate diagnosis of locally advanced disease, and the contemporary MRI staging should be careful.

Detection of radiorecurrent prostate cancer using diffusion-weighted imaging and targeted biopsies.

OBJECTIVE: The primary purpose of this study was to evaluate the detection rate of local radiorecurrent prostate cancer by using diffusion-weighted MR imaging (DWI) and targeted biopsies. The secondary purpose was to assess the value of performing random biopsies. MATERIALS AND METHODS: This study included 42 consecutive patients with biochemical recurrence after external beam radiation therapy (EBRT). At the time of biopsy, the mean age±SD was 67±6 years, median serum prostate-specific antigen level was 4.0±3.0 ng/mL, and mean elapsed time between EBRT and biopsy was 5.6±2.8 years. MRI examination included high-resolution axial T2-weighted and DWI sequences and was classified as either negative or positive. Transrectal ultrasound-guided targeted biopsies were obtained from all patients with positive findings on MRI using a soft image fusion system. Random sextant biopsies were obtained from both lobes in patients with negative findings on MRI and from the lobe contralateral to the MRI target in patients with positive findings on MRI. The biopsy results were classified as negative or positive and defined as the criterion standard. RESULTS: MRI findings were positive in 40 of 42 (95%) patients, and the overall positive biopsy rate was 79% (33 of 42 patients). Targeted biopsies were positive in 33 of 40 (83%) patients. Random biopsies were positive in 6 of 30 (20%) patients, all of whom had positive targeted biopsies. CONCLUSION: DWI is highly sensitive for detecting radiorecurrent prostate cancer, and a few targeted biopsies may confirm a positive diagnosis. However, random biopsies may assess the tumor burden more exactly.

Detection of the index tumour and tumour volume in prostate cancer using T2-weighted and diffusion-weighted magnetic resonance imaging (MRI) alone.

OBJECTIVE: To examine the performance of T2-weighted (T2W) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for detecting the index tumour in patients with prostate cancer and to examine the agreement between MRI and histology when assessing tumour volume (TV) and overall tumour burden. PATIENTS AND METHODS: The study included 199 consecutive patients with biopsy confirmed prostate cancer randomised to MRI before radical prostatectomy from December 2009 to July 2012. MRI-detected tumours (MRTs) were ranked from 1 to 3 according to decreasing volume and were compared with histologically detected tumours (HTs) ranked from 1 to 3, with HT 1 = index tumour. Whole-mount section histology was used as a reference standard. The TVs of true-positive MRTs (MRTVs 1-3) were compared with the TVs found by histology (HTVs 1-3). All tumours were registered on a 30-sector map and by classifying each sector as positive/negative, the rate of true-positive and -negative sectors was calculated. RESULTS: The detection rate for the HT 1 (index tumour) was 92%; HT 2, 45%; and HT 3, 37%. The MRTV 1-3 vs the HTV 1-3 were 2.8 mL vs 4.0 mL (index tumour, P < 0.001), 1.0 mL vs 0.9 mL (tumour 2, P = 0.413), and 0.6 mL vs 0.5 mL (tumour 3, P = 0.492). The rate of true-positive and -negative sectors was 50% and 88%, κ = 0.39. CONCLUSION: A combination of T2W and DW MRI detects the index tumour in 92% of cases, although MRI underestimates both TV and tumour burden compared with histology.