Supporting self-regulated-learning in colonoscopy training-A comparison cohort trial.

Aim: This study aimed to demonstrate that using a self-regulated learning (SRL) approach can improve colonoscopy performance skills. Background: Colonoscopy is the gold standard for detecting colorectal cancer and removing its precursors: polyps. Acquiring proficiency in colonoscopy is challenging, requiring completion of several hundred procedures. SRL seems to be beneficial to help trainees acquire competencies in regulating their future learning processes and enhance the outcomes of current learning situations. SRL is a learner-centred approach that refers to a trainee's ability to understand and control their learning environment, including cognitions, motivations and emotions. The key abilities include self- and situational awareness, task analysis, and strategic planning. This study is the first to use an SRL approach for workplace-based colonoscopy training. Methods: In this comparison cohort trial, participants used two SRL supports: a self-review of videotaped performance, and an online learning platform with procedural and conceptual knowledge about colonoscopy. In the control cohort, participants performed patient-based colonoscopy as usual in their departments. Improvement was monitored via three video-based ratings (study start, end of the study period, and follow-up) using the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT). Outcomes were analysed using two-way analysis of variance with repeated measurements. Results: This study recruited 21 participants (12, intervention cohort; nine, control cohort); 58 videos were recorded. The intraclass correlation coefficient was 0.88 (95% CI 0.61-0.98; p < 0.001). The global rating scale (GRS) and checklist (CL) in GiECAT were analysed separately. No statistically significant main effects of cohort (GRS: F(1,16) = 2.84, p = 0.11; CL: F(1,16) = 1.06, p = 0.32), test (GRS: F(2,32) = 2.56, p = 0.09; CL: F(2,32) = 0.76, p = 0.48), or interactions between cohort and test were observed (GRS: F(2,32) = 1.16, p = 0.33; CL: F(2,32) = 1.01, p = 0.37). Conclusions: SRL in patient-based colonoscopy is feasible; however, no clear effect on performance scores was observed.

Laser speckle contrast imaging for intraoperative assessment of intestinal microcirculation in normo- and hypovolemic circulation in a porcine model.

INTRODUCTION: Healing is essential for successful colorectal surgery. Optimal microcirculation is needed to ensure this; however, this is only subjectively assessed by the surgeon. Laser Speckle Contrast Imaging (LSCI) is an objective non-contact, image-based method to quantify microcirculation in bowel ends. This study aimed to evaluate the application of LSCI in an open surgery porcine model, determine differences between normal and impaired microcirculation, and test the LSCI applicability to repeated measurements. METHOD: A midline laparotomy was made in ten healthy female pigs to expose the colon and small intestine. Subsequently, baseline measurements were conducted. A local arteria supplying the colonic or small intestine mesentery was clamped for 5 min. and LSCI measures were made again. After an hour's rest, LSCI measurements were done in two unaffected areas on the colon and the small intestine, and baseline values were recorded. Hypotension was induced with rapid bleeding and LSCI measurements were done. After the mean arterial blood pressure (MAP) dropped to 50-60 mmHg, norepinephrine infusion was started. At a stable MAP of 85-100 mmHg, LSCI measurements were repeated at 0 min. and 30 min. during continuous norepinephrine infusion. RESULTS: Cross-clamping caused LSCI levels to drop equally in both the colon and small intestine by 60% in the entire the clamped zone. Compared to baseline, the microcirculation measured by LSCI in the unclamped adjacent transition zone was diminished by 33% and 40%, colon and small intestines, respectively. During hypotension due to bleeding, LSCI decreased as expected. When MAP was stabilized by norepinephrine infusion, LSCI values dropped further: compared to baseline, measurements decreased with 24% and 20% in colon and small intestines, respectively. CONCLUSION: LSCI can be used as a quantitative, real-time, non-contact method to detect changes in the microcirculation during open intestinal surgery with large changes in microcirculation due to e.g., hypovolemic and norepinephrine infusion. It is simple to use and in contrast to the existing intraoperative microcirculation assessment techniques, LSCI stands out primarily for its elimination of the requirement for a dye. As our study has shown, this feature allows us to perform time-independent measurements and repeat them indefinitely in nearby regions without compromising the effectiveness of the method.

Technical assessment in minimally invasive complete mesocolic excision: Is the complete mesocolic excision competency assessment tool valid and reliable?

AIM: The complete mesocolic excision competency assessment tool (CMECAT) is a novel tool designed to assess technical skills in minimally invasive complete mesocolic excision (CME) surgery. The aim of this study was to assess construct validity and reliability of CMECAT in a clinical context. METHOD: Colorectal surgeons were asked to submit video recorded laparoscopic CME resections for independent assessment of their technical abilities. The videos were grouped by surgeons' training level, and four established CME experts were recruited as CMECAT assessors. Extended reliability analysis (G-theory) was applied to describe assessor agreement. RESULTS: A total of 19 videos and 72 assessments were included in the analysis. Overall, technical skills assessed by CMECAT improved with increased training level: the experts scored significantly better than the untrained surgeons (3.3 vs. 2.5 points; p < 0.01). On right-sided resections, significantly higher scores were reported with increased training level for all categories and sections, while for left-sided resections, the variance across groups was smaller and significantly higher scores were only reported for oncological safety describing items. Overall, assessor agreement was high (G-coefficient: 0.81). CONCLUSION: This study confirms that CMECAT can be applied to video recorded CME cases for technical skill assessment. Further, it can reliably assess technical performance in right sided CME surgery, where construct validity has now been established. More videos are required to evaluate its validity on left colonic CME. In the future, we hope CMECAT can improve feedback during CME training, serve as a tool in certification processes and contribute to distinguishing CME from conventional surgery in future research.

Quality of life and symptom burden after rectal cancer surgery: a randomised controlled trial comparing patient-led versus standard follow-up.

PURPOSE: After curatively intended rectal cancer (RC) surgery, new follow-up strategies are warranted, seeking more individualised care and targeting health-related quality of life (HRQoL) and functional outcomes. The FURCA trial aimed to investigate the effect of patient-led follow-up on HRQoL and symptom burden 3 years after surgery. METHODS: RC patients from four Danish centres were randomised 1:1 to intervention (patient-led follow-up with patient education and self-referral to a specialist nurse) or control (standard follow-up with five routine doctor visits). Patients in both groups had a computed tomography (CT) at 1 and 3 years. The primary outcome (HRQoL) was assessed by the Functional Assessment of Cancer Therapy - colorectal (FACT-C) score (Ward et al. in Qual Life Res. 8(3):181-95, 18). Secondary outcomes were functional measures, patient involvement and satisfaction and cancer recurrence at 3 years. RESULTS: From Feb 2016 to Aug 2018, 336 patients were included of whom 248 completed 3 years of follow-up. Between-group differences were found neither for the primary endpoint, nor for functional outcomes. The recurrence rate did not differ between the groups. Patient involvement and satisfaction were higher in the intervention group with statistical significance in almost half of the items. CONCLUSIONS: We found no effect on HRQoL and symptom burden from patient-led follow-up, although it may improve patient-perceived involvement and satisfaction. IMPLICATIONS FOR CANCER SURVIVORS: The findings in this study suggest that patient-led follow-up is a more tailored approach to meet cancer survivors' needs and might improve their ability to cope with survivorship. GOV IDENTIFIER: R97-A6511-14-S23.

Impact of Whole Genome Doubling on Detection of Circulating Tumor DNA in Colorectal Cancer.

OBJECTIVE: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. METHODS: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. RESULTS: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12-2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22-5.03) and Stage II (OR = 1.76, 95%CI: 1.11-2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44-1.53) patients. CONCLUSION: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.

Development of a procedure-specific tool for skill assessment in left- and right-sided laparoscopic complete mesocolic excision.

AIM: To (1) develop an assessment tool for laparoscopic complete mesocolic excision (LCME) and (2) report evidence of its content validity. METHOD: Assessment statements were revealed through (1) semi-structured expert interviews and (2) consensus by the Delphi method, both involving an expert panel of five LCME surgeons. All experts were interviewed and then asked to rate LCME describing statements from 1 (strongly disagree) to 5 (strongly agree). Responses were returned anonymously to the panel until consensus was reached. Statements were directly included as content in the assessment tool if ≥60% of the experts responded "agree" or "strongly agree" (ratings 4 and 5), with the remaining responses being "neither agree nor disagree" (rating 3). Interclass correlation coefficient (ICC) was calculated for expert agreement evaluation. All included statements were subsequently reformulated as tool items and approved by the experts. RESULTS: Four Delphi rounds were performed to reach consensus. Disagreement was reported for statements describing instrument handling around pancreas; visualisation of landmarks before inferior mesenteric artery ligation; lymphadenectomy around the inferior mesenteric artery, and division of the terminal ileum and transverse colon. ICC in the last Delphi-round was 0.84. The final tool content included 73 statements, converted to 48 right- and 40 left-sided items for LCME assessment. CONCLUSION: A procedure-specific, video-based tool, named complete mesocolic excision competency assessment tool (CMECAT), has been developed for LCME skill assessment. In the future, we hope it can facilitate assessment of LCME surgeons, resulting in improved patient outcome after colon cancer surgery.

Implementation of a standardized surgical technique in robot-assisted restorative rectal cancer resection: a single center cohort study.

BACKGROUND: Despite increasing focus on the technical performance of total mesorectal excision over recent decades, anastomotic leakage (AL) continues to be a serious complication for many patients, even in the hands of experienced surgical teams. This study describes implementation of standardized surgical technique in an effort to reduce variability, decrease the risk of anastomotic leakage, and improve associated short-term outcomes for rectal cancer patients undergoing robot-assisted restorative rectal resection (RRR). METHODS: We evaluated all rectal cancer patients undergoing robot-assisted RRR at Aarhus University Hospital between 2017 and 2020. Six standardized surgical steps directed to improve anastomotic healing were mandatory for all RRR. Additional changes were made during the period with prohibition of systemic dexamethasone and limiting the use of endoscopic stapling devices. RESULTS: The use of the full standardization, including all six surgical steps, increased from 40.3% (95% CI, 0.28-0.54) to 86.2% (95% CI, 0.68-0.95). The incidence of AL decreased from 21.0% (95% CI, 0.12-0.33) to 6.9% (95% CI, 0.01-0.23). Length of hospital stay (LOS) decreased from 6 days (range 2-50) to 5 days (range 2-26). The rate of patients readmitted within 90 days decreased from 21.0% (95% CI, 0.12-0.33), to 6.9% (95% CI, 0.01-0.23). CONCLUSION: The full standardization was effectively implemented for rectal cancer patients undergoing robot-assisted RRR. The risk of AL, LOS and readmission decreased during the study period. A team focus on high-reliability and peri-operative complications can improve patient outcomes.

Comparing single-target and multitarget approaches for postoperative circulating tumour DNA detection in stage II-III colorectal cancer patients.

Circulating tumour DNA (ctDNA) detection for postoperative risk stratification in cancer patients has great clinical potential. However, low ctDNA abundances complicates detection. Multitarget (MT) detection strategies have been developed to increase sensitivity. Yet, empirical evidence supporting performance gains of MT vs. single-target (ST) strategies in a postoperative setting is limited. We compared ctDNA detection in 379 paired plasma samples from 112 stage II-III colorectal cancer patients by ST digital PCR and MT sequencing of 16 patient-specific variants. The strategies exhibited good concordance (90%, Cohen's Kappa 0.79), with highly correlated ctDNA quantifications (Pearson r = 0.985). A difference was observed in ctDNA detection preoperatively (ST 72/92, MT 88/92). However, no difference was observed immediately after surgery in recurrence (ST 11/22, MT 10/22) or nonrecurrence (both 2/34) patients. In serial samples, detection was similar within recurrence (ST 13/16, MT 14/16) and nonrecurrence (ST 3/49, MT 1/49) patients. Both approaches yielded similar lead times to standard-of-care radiology (ST 4.0 months, MT 4.1 months). Our findings do not support significant performance gains of the MT strategy over the ST strategy for postoperative ctDNA detection.

The impact of multiple firings on the risk of anastomotic leakage after minimally invasive restorative rectal cancer resection and the impact of anastomotic leakage on long-term survival: a population-based study.

PURPOSE: The aim of this study was to evaluate the anastomotic leakage (AL) rate and predictors for AL following minimally invasive restorative rectal resection (RRR) among rectal cancer patients managed according to up-to-date standardized treatment. Furthermore, we explored the impact of symptomatic AL on long-term survival. METHODS: The study cohort was rectal cancer patients undergoing minimally invasive RRR in Central Denmark Region between 2013 and 2017. Data was retrieved from a prospective clinical quality database and supplemented with data from medical records. The AL rate was calculated as the proportion of patients who developed symptomatic AL within 30 days. Predictors for AL were identified through logistic regression. The impact of AL on long-term survival was analyzed using Kaplan-Meier methods and Cox regression. RESULTS: AL occurred in 15.1% of 604 patients. The AL rate for males was 20.1% (95% CI 16.3-24.3) and 5.0% (95% CI 2.4-9.0) for females. Odds ratio (OR) of AL in females vs. males was 0.25 (95% CI 0.12-0.51). The use of at least three firings when transecting the rectum was associated with OR of 2.71 (95% CI 1.17-6.26) for AL. The 5-year survival for patients with vs. those without AL was 76.1% (95%CI 65.1-84.0) and 83.6% (95%CI 79.8-86.7), corresponding to adjusted hazard ratio of 1.43 (95%CI 0.84-2.41). CONCLUSION: Symptomatic AL is still a challenge in a standardized setting using minimally invasive surgery in rectal cancer patients undergoing RRR, especially in men. Multiple firings should be avoided in transection of the rectum with an endoscopic stapler. AL had a statistical non-significant negative impact on survival.

Anastomotic leakage following restorative rectal cancer resection: treatment and impact on stoma presence 1 year after surgery-a population-based study.

PURPOSE: Anastomotic leakage (AL) continues to be a challenge after restorative rectal resection (RRR). Various treatment options of AL are available; however, their long-term outcomes are uncertain. We explored the impact of AL on the risk of stoma presence 1 year after RRR for rectal cancer and described treatment of AL after RRR including impact on the probability of receiving adjuvant chemotherapy and stoma presence following different treatment options of AL. METHODS: We included 859 patients undergoing RRR in Central Denmark Region between 2013 and 2019. Stoma presence was calculated as the proportion of patients with stoma 1 year after RRR. Multivariable logistic regression was conducted to estimate the impact of AL on stoma presence adjusting for potential predictors. Descriptive data of outcomes were stratified for various treatment options of AL. RESULTS: The risk of stoma presence 1 year after surgery was 9.8% (95% CI 7.98-12.0). Predictors for having stoma 1 year after RRR were AL (OR 8.43 (95% CI 4.87-14.59)) and low tumour height (OR 3.85 (95% CI 1.22-13.21)). For patients eligible for adjuvant chemotherapy, the probability of receiving it was 42.9% (95% CI 21.8-66.0) if treated with endo-SPONGE and 71.4% (95% CI 47.8-88.7) if treated with other anastomosis preserving treatment options. The risk of having stoma 1 year after RRR was 33.9% (95% CI 21.8-47.8) for patients treated with endo-SPONGE and 13.5% (95% CI 5.6-25.8) for patients treated with other anastomosis preserving treatment options (p = 0.013). CONCLUSION: AL is a strong predictor for stoma presence 1 year after RRR. Patients treated with endo-SPONGE seem to have worse outcomes compared to other anastomosis preserving treatment options.

Adenoma and serrated lesion detection with distal attachment in screening colonoscopy: a randomized controlled trial.

BACKGROUND: Adenoma detection rate (ADR) is the single most important measure of quality in colonoscopy, but little is known about the detection rate of serrated lesions (SLDR). To improve ADR, Endocuff Vision (EV) can be used. Studies have shown differing results as to the effect on ADR; an effect on SLDR has not been shown. To investigate the effect of Endocuff Vision on ADR in a screening population, this randomized controlled open label trial with concealed allocation was performed. Randomization to trial group was carried out by the endoscopist using prepared numbered envelopes. METHODS: Patients referred as part of the national bowel screening program at Regional Hospital Herning, Denmark were recruited and allocated to one of two groups: Endocuff Vision colonoscopy (EVC) and standard colonoscopy (SC). Outcomes were ADR, mean number, site, and size of lesions per procedure. SLDR as outcome was added after inclusion had begun. RESULTS: A total of 1178 participants were included, with 1166 (EVC 583 and SC 583) available for analysis. There was no clinical relevant difference in ADR (59.2% [CI 55.1; 63.1] v 60.5% [CI 56.5; 64.4]) or SLDR (13.0% [CI 10.5; 16.0] v 10.3% [CI 8.0; 13.0]) between groups. More serrated lesions were found per procedure (MSP) (0.2 v 0.1, IRR 57% [CI 17; 109]. Removal rate of EV was similar in the two study groups. CONCLUSION: We found no significant effects of the use of Endocuff Vision on ADR, when compared to standard colonoscopy, but more serrated lesions were detected in the Endocuff group. TRIAL REGISTRATION: Clinical Trials NCT04651062.

How can surgical skills in laparoscopic colon surgery be objectively assessed?-a scoping review.

BACKGROUND: In laparoscopic colorectal surgery, higher technical skills have been associated with improved patient outcome. With the growing interest in laparoscopic techniques, pressure on surgeons and certifying bodies is mounting to ensure that operative procedures are performed safely and efficiently. The aim of the present review was to comprehensively identify tools for skill assessment in laparoscopic colon surgery and to assess their validity as reported in the literature. METHODS: A systematic search was conducted in EMBASE and PubMed/MEDLINE in May 2021 to identify studies examining technical skills assessment tools in laparoscopic colon surgery. Available information on validity evidence (content, response process, internal structure, relation to other variables, and consequences) was evaluated for all included tools. RESULTS: Fourteen assessment tools were identified, of which most were procedure-specific and video-based. Most tools reported moderate validity evidence. Commonly not reported were rater training, assessment correlation with variables other than training level, and validity reproducibility and reliability in external educational settings. CONCLUSION: The results of this review show that several tools are available for evaluation of laparoscopic colon cancer surgery, but few authors present substantial validity for tool development and use. As we move towards the implementation of new techniques in laparoscopic colon surgery, it is imperative to establish validity before surgical skill assessment tools can be applied to new procedures and settings. Therefore, future studies ought to examine different aspects of tool validity, especially correlation with other variables, such as patient morbidity and pathological reports, which impact patient survival.

Correlation between incidental focal colorectal FDG uptake on PET/CT and colonoscopic and histopathological results.

OBJECTIVE AND AIMS: The primary aim of this study was to evaluate the correlation between incidental focal colorectal foci on fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) with colonoscopic and histopathological results. The secondary aim was to determine to what extent these findings led to a change in patient management. MATERIALS AND METHODS: A retrospective study was performed among 5850 patients who had an FDG-PT/CT scan from July 2015 to July 2018. Among these patients, we identified patients with a PET/CT description of incidental colorectal FDG uptake, and a colonoscopy within 90 days from the PET/CT scan. PET/CT findings were compared with colonoscopy-detected lesions and eventually histopathology on a per-lesion analysis and a per-person analysis. RESULTS: A total of 145 patients were included in the study. A total of 180 foci of colorectal FDG uptake were detected on FDG-PET/CT. Of these, 86 foci corresponded to advanced colorectal neoplasia (ACRN), positive predictive value (PPV) 47.8%; 95% CI: 40.5-55.1%). On a per-patient analysis 81 patients had a least one ACRN at colonoscopy (PPV 55.9%; 95% CI: 47.6-63.8), this group included 20 patients (13.8%) diagnosed with cancer. There was a small positive correlation between focal FDG-uptake and the finding of ACRN at the same colonic segment at colonoscopy, which was statistically significant, rho = 0.2565, p = .002. The findings changed patient management in 67 (46.2%) cases. CONCLUSIONS: Incidental focal colorectal FDG uptake on PET/CT is associated with a high risk of ACRN and is affecting subsequent patient management. Further evaluation with colonoscopy is recommended when the patient is considered suitable for further treatment.

Identifying technical skills and clinical procedures in surgery for a simulation-based curriculum: a national general needs assessment.

BACKGROUND: The efficacy of simulation-based training in surgical education is well known. However, the development of training programs should start with problem identification and a general needs assessment to ensure that the content is aligned with current surgical trainee needs. The objective of the present study is to identify the technical skills and clinical procedures that should be included in a simulation-based curriculum in general surgery. METHODS: A national, three-round Delphi process was conducted to achieve consensus on which technical skills and clinical procedures should be included in a simulation-based curriculum in general surgery. In total, 87 key opinion leaders were identified and invited to the study. RESULTS: Round 1 of the Delphi process had a response rate of 64% (56/87) and a total of 245 suggestions. Based on these suggestions, a consolidated list of 51 technical skills or clinical procedures was made. The response rate in Delphi round 2 was 62% (54/87) resulting in a pre-prioritized order of procedures for round 3. The response rate in Delphi round 3 was 65% (35/54). The final list included 13 technical skills and clinical procedures. Training was predominantly requested within general open surgical skills, laparoscopic skills, and endoscopic skills, and a few specific procedures such as appendectomy and cholecystectomy were included in the final prioritized list. CONCLUSION: Based on the Delphi process 13 technical skills and clinical procedures were included in the final prioritized list, which can serve as a point of departure when developing simulation-based training in surgery.

Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences.

PURPOSE: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. EXPERIMENTAL DESIGN: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. RESULTS: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7-13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4-167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.See related commentary by Morris and George, p. 438.

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum.

BACKGROUND: Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH. METHODS: Multiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors). RESULTS: Overall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data identified large ITH at protein level; as the multiregional biopsies clustered together for only 9 out of 29 tumors. CONCLUSION: Our transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.

Long-term follow-up on shoulder and arm morbidity in patients treated for early breast cancer.

Background: A prospective study on shoulder and arm morbidity was conducted in Denmark in 2003-2005. This study demonstrated that sentinel lymph node biopsy was associated with better outcomes than axillary lymph node dissection 18 months after surgery. We here aimed to describe subjective symptoms and objective findings in these patients 10+ years after they underwent breast cancer surgery and to assess how symptoms and findings developed during this period.Material and methods: Participants in the prospective study completed a questionnaire and underwent an objective, bilateral examination of their shoulder and arm morbidity, which included measurement of arm volume, range of motion, and sensibility.Results: Seventy participants completed follow-up. Thirty-four (49%) had one or more functional impairments, and 64% had one or more subjective loco regional symptoms like pain, swelling of the arm, and decreased shoulder mobility. Objective evaluation showed 34 ml's of increased arm volumes and 3-25% had severe reduced shoulder mobility on the operated side. Compared to the findings at 18 months postoperatively, small but significant differences in occurrence of subjective findings were observed. A significant progression regarding most objective findings was revealed.Conclusion: More than 11 years after breast cancer surgery, the majority of participants complained of one or more subjective symptoms of shoulder and arm morbidity. Objective findings were mild or modest in most cases. During the prolonged follow-up period of 10 years, a worsening in symptoms and objective findings was observed.HIGHLIGHTSShoulder and arm morbidity in relation to breast cancer treatment seems to progress beyond 10 years.The most frequent symptoms were pain, swelling or heaviness of the arm, and decreased shoulder mobility.The objective evaluation showed higher arm volumes and reduced shoulder mobility on the operated side.Objective findings are mild and modest but may affect activities of daily living, and most participants with late symptoms stated that this was a daily problem.

Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer-a clinical biomarker discovery and validation study.

BACKGROUND: Early detection plays an essential role to reduce colorectal cancer (CRC) mortality. While current screening methods suffer from poor compliance, liquid biopsy-based strategies for cancer detection is rapidly gaining promise. Here, we describe the development of TriMeth, a minimal-invasive blood-based test for detection of early-stage colorectal cancer. The test is based on assessment of three tumour-specific DNA methylation markers in circulating cell-free DNA. RESULTS: A thorough multi-step biomarker discovery study based on DNA methylation profiles of more than 5000 tumours and blood cell populations identified CRC-specific DNA methylation markers. The DNA methylation patterns of biomarker candidates were validated by bisulfite sequencing and methylation-specific droplet digital PCR in CRC tumour tissue and peripheral blood leucocytes. The three best performing markers were first applied to plasma from 113 primarily early-stage CRC patients and 87 age- and gender-matched colonoscopy-verified controls. Based on this, the test scoring algorithm was locked, and then TriMeth was validated in an independent cohort comprising 143 CRC patients and 91 controls. Three DNA methylation markers, C9orf50, KCNQ5, and CLIP4, were identified, each capable of discriminating plasma from colorectal cancer patients and healthy individuals (areas under the curve 0.86, 0.91, and 0.88). When combined in the TriMeth test, an average sensitivity of 85% (218/256) was observed (stage I: 80% (33/41), stage II: 85% (121/143), stage III: 89% (49/55), and stage IV: 88% (15/17)) at 99% (176/178) specificity in two independent plasma cohorts. CONCLUSION: TriMeth enables detection of early-stage colorectal cancer with high sensitivity and specificity. The reported results underline the potential utility of DNA methylation-based detection of circulating tumour DNA in the clinical management of colorectal cancer.

Validation of computational determination of microsatellite status using whole exome sequencing data from colorectal cancer patients.

BACKGROUND: Microsatellite instability (MSI), resulting from a defective mismatch repair system, occurs in approximately 15% of sporadic colorectal cancers (CRC). Since MSI is associated with a poor response to 5-fluorouracile based chemotherapy and is a positive predictive marker of immunotherapy, it is routine practice to evaluate the MSI status of resected tumors in CRC patients. MSIsensor is a novel computational tool for determining MSI status using Next Generation Sequencing. However, it is not widely used in the clinic and has not been independently validated in exome data from CRC. To facilitate clinical implementation of computational determination of MSI status, we compared MSIsensor to current gold standard methods for MSI testing. METHODS: MSI status was determined for 130 CRC patients (UICC stage I-IV) using immunohistochemistry, PCR based microsatellite stability testing and by applying MSIsensor to exome sequenced tumors and paired germline DNA. Furthermore, we investigated correlation between MSI status, mutational load and mutational signatures. RESULTS: Eighteen out of 130 (13.8%) patients were microsatellite instable. We found a 100% agreement between MSIsensor and gold standard methods for MSI testing. All MSI tumors were hypermutated. In addition, two microsatellite stable (MSS) tumors were hypermutated, which was explained by a dominant POLE signature and pathogenic POLE mutations (p.Pro286Arg and p.Ser459Phe). CONCLUSION: MSIsensor is a robust tool, which can be used to determine MSI status of tumor samples from exome sequenced CRC patients.