Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel. METHODS: Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses. RESULTS: ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson's R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10-4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28-5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53-16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31-12.75; p = 0.016). CONCLUSION: Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.

Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: There is no validated magnetic resonance imaging (MRI) index for assessment of perianal fistulas in patients with Crohn's disease (CD). We developed and internally validated a new instrument. METHODS: We used paired baseline and week-24 MRI scans from 160 participants in a randomized placebo-controlled trial of stem cell therapy for patients with perianal fistulizing CD. Four radiologists scored disease activity using index items identified during previous studies and exploratory items. Reliability was assessed using intraclass correlation coefficients. We developed an index using backward elimination linear regression analysis, in which potential independent variables were items having intraclass correlation coefficients of at least 0.4 and the dependent variable was perianal fistulizing disease activity, measured on a 100-mm visual analogue scale. The final model was internally validated using the .632 bootstrap method to correct model optimism and quantify calibration accuracy. We evaluated responsiveness of the index by assessing longitudinal validity and estimating standardized effect sizes. RESULTS: We developed the magnetic resonance novel index for fistula imaging in CD (MAGNIFI-CD) using 6 items. The optimism-corrected R2 of the model was 0.71, which was comparable to R2 for the original sample (0.74). The calibration slope for the model was 0.98. Compared with the original and modified versions of the Van Assche Index, the MAGNIFI-CD had improved operating characteristics. Estimates of intraclass correlation coefficients for MAGNIFI-CD, the modified Van Assche Index, and Van Assche Index were 0.85 (95% confidence interval [CI], 0.77-0.90), 0.81 (95% CI, 0.74-0.86), and 0.81 (95% CI, 0.71-0.86) for intra-rater reliability, and 0.74 (95% CI, 0.63-0.80), 0.67 (95% CI, 0.55-0.75) and 0.68 (95% CI, 0.56-0.77) for inter-rater reliability. Corresponding standardized effect size estimates were 1.02 (95% CI, 0.65-1.39), 0.84 (95% CI, 0.48-1.21), and 0.68 (95% CI, 0.33-1.03). CONCLUSIONS: We developed an index called the MAGNIFI-CD, which is based on 6 items. It assesses MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to previous indices. This index may be used as an outcome measure in clinical trials comparing treatment effects in patients with perianal fistulizing CD. Although the performance of the MAGNIFI-CD indicates its stability and reasonable external validity, external validation is needed.

Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1-14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

Comparison of contrast-enhanced and diffusion-weighted MRI in assessment of the terminal ileum in Crohn's disease patients.

PURPOSE: The purpose of the study was to compare the performance of contrast-enhanced (CE)-MRI and diffusion-weighted imaging (DW)-MRI in grading Crohn's disease activity of the terminal ileum. METHODS: Three readers evaluated CE-MRI, DW-MRI, and their combinations (CE/DW-MRI and DW/CE-MRI, depending on which protocol was used at the start of evaluation). Disease severity grading scores were correlated to the Crohn's Disease Endoscopic Index of Severity (CDEIS). Diagnostic accuracy, severity grading, and levels of confidence were compared between imaging protocols and interobserver agreement was calculated. RESULTS: Sixty-one patients were included (30 female, median age 36). Diagnostic accuracy for active disease for CE-MRI, DW-MRI, CE/DW-MRI, and DW/CE-MRI ranged between 0.82 and 0.85, 0.75 and 0.83, 0.79 and 0.84, and 0.74 and 0.82, respectively. Severity grading correlation to CDEIS ranged between 0.70 and 0.74, 0.66 and 0.70, 0.69 and 0.75, and 0.67 and 0.74, respectively. For each reader, CE-MRI values were consistently higher than DW-MRI, albeit not significantly. Confidence levels for all readers were significantly higher for CE-MRI compared to DW-MRI (P < 0.001). Further increased confidence was seen when using combined imaging protocols. CONCLUSIONS: There was no significant difference of CE-MRI and DW-MRI in determining disease activity, but the higher confidence levels may favor CE-MRI. DW-MRI is a good alternative in cases with relative contraindications for the use of intravenous contrast medium.

Feasibility of CT radiomics to predict treatment response of individual liver metastases in esophagogastric cancer patients.

In this study we investigate a CT radiomics approach to predict response to chemotherapy of individual liver metastases in patients with esophagogastric cancer (EGC). In eighteen patients with metastatic EGC treated with chemotherapy, all liver metastases were manually delineated in 3D on the pre-treatment and evaluation CT. From the pre-treatment CT scans 370 radiomics features were extracted per lesion. Random forest (RF) models were generated to discriminate partial responding (PR, >65% volume decrease, including 100% volume decrease), and complete remission (CR, only 100% volume decrease) lesions from other lesions. RF-models were build using a leave one out strategy where all lesions of a single patient were removed from the dataset and used as validation set for a model trained on the lesions of the remaining patients. This process was repeated for all patients, resulting in 18 trained models and one validation set for both the PR and CR datasets. Model performance was evaluated by receiver operating characteristics with corresponding area under the curve (AUC). In total 196 liver metastases were delineated on the pre-treatment CT, of which 99 (51%) lesions showed a decrease in size of more than 65% (PR). From the PR set a total of 47 (47% of RL, 24% of initial) lesions were no longer detected in CT scan 2 (CR). The RF-model for PR lesions showed an average training AUC of 0.79 (range: 0.74-0.83) and 0.65 (95% ci: 0.57-0.73) for the combined validation set. The RF-model for CR lesions had an average training AUC of 0.87 (range: 0.83-0.90) and 0.79 (95% ci 0.72-0.87) for the validation set. Our findings show that individual response of liver metastases varies greatly within and between patients. A CT radiomics approach shows potential in discriminating responding from non-responding liver metastases based on the pre-treatment CT scan, although further validation in an independent patient cohort is needed to validate these findings.

Hypothermic perfusion with retrograde outflow during right hepatectomy is safe and feasible.

BACKGROUND: In situ hypothermic perfusion during liver resection performed under vascular inflow occlusion decreases hepatic ischemia-reperfusion injury, but technical limitations have restricted its widespread use. In situ hypothermic perfusion with retrograde outflow circumvents these impediments and thus could extend the applicability of in situ hypothermic perfusion. The safety and feasibility of in situ hypothermic perfusion with retrograde outflow were analyzed in selected patients undergoing right (extended) hepatectomy and compared to intermittent vascular inflow occlusion, the gold standard method, in this randomized pilot study. METHODS: Patients were first screened for parenchymal liver disease (exclusion criteria: steatosis ≥30%, cirrhosis, or cholestasis). Study participants were randomized intraoperatively to undergo in situ hypothermic perfusion with retrograde outflow (n = 9) or intermittent vascular inflow occlusion (n = 9). The target liver core temperature during in situ hypothermic perfusion with retrograde outflow was 28°C. The primary end point was ischemia-reperfusion injury (expressed by peak postoperative transaminase levels). Secondary outcomes included functional liver regeneration (assessed by hepatobiliary scintigraphy) and clinical outcomes. RESULTS: Peak transaminase levels, total bilirubin, and the international normalized ratio were similar between both groups, although a trend toward more rapid normalization of bilirubin levels was noted for the in situ hypothermic perfusion with retrograde outflow group. Functional liver regeneration as evaluated by hepatobiliary scintigraphy was improved on postoperative day 3 fafter in situ hypothermic perfusion with retrograde outflow but not after intermittent vascular inflow occlusion. Furthermore, in situ hypothermic perfusion with retrograde outflow (requiring continuous ischemia) was comparable to intermittent vascular inflow occlusion for all clinical outcomes, including postoperative complications and hospital stay. CONCLUSION: The use of in situ hypothermic perfusion with retrograde outflow appears to be safe and feasible in selected patients with healthy liver parenchyma and may benefit early functional liver regeneration. Future applications of in situ hypothermic perfusion with retrograde outflow include patients with damaged liver parenchyma who would require major hepatic resection with a prolonged vascular inflow occlusion duration.

MRI characteristics of proctitis in Crohn's disease on perianal MRI.

PURPOSE: Multiple features have been described for assessing inflammation in Crohn's disease (CD) in MR enterography, but have not been validated in perianal magnetic resonance imaging (MRI). Retrospectively, we studied which MRI features are valuable in assessing proctitis. MATERIALS AND METHODS: CD patients (≥18 years) who underwent colonoscopy (reference standard) and perianal fistula MRI within 8 weeks were included. Seventeen MRI features were blindly scored by three observers and correlated to endoscopy (regression analysis). Reproducibility (multirater kappa, intraclass correlation coefficient) was determined for all three observer pairs. MRI features were considered relevant when significantly correlated to endoscopy for ≥2 observers, and reproducibility was ≥0.40 for ≥2 observer pairs. RESULTS: Perianal MRI of 58 CD patients were included. Wall thickness, rectal mural fat, creeping fat, and size of mesorectal lymph nodes showed a significant correlation with endoscopy for ≥2 observers (p = 0.000-0.023, p = 0.011-0.172, p = 0.007-0.011 and p = 0.000-0.005, respectively) with a kappa/intraclass correlation coefficient of ≥0.60 for ≥2 observer pairs. Perimural T2 signal and perimural enhancement significantly correlated to endoscopy (all p values ≤0.05) for all three observers and the reproducibility was ≥0.40 for ≥2 observer pairs. Mural T2 signal and degree and pattern of T1 enhancement showed significant correlation to endoscopy for two observers, but with poor to moderate reproducibility. CONCLUSION: Wall thickness, mural fat, and mesorectal features (perimural T2 signal, perimural enhancement, creeping fat, and size of mesorectal lymph nodes) had significant correlation to endoscopy and were reproducible in diagnosing proctitis. Some established luminal features in MRE were considered not useful.

Disappointing interobserver agreement among radiologists for a classifying diagnosis of pancreatic cysts using magnetic resonance imaging.

OBJECTIVES: To assess the degree of interobserver agreement of MRI in the diagnostic assessment of pancreatic cysts (PCs). METHODS: Magnetic resonance imaging sets of images of 62 patients with PCs (32 with histological confirmation and 30 with clinical diagnosis) were reviewed by 4 experienced radiologists. Features scored included septations, nodules, solid components, pancreatic duct communication, and wall thickening (>2 mm). Radiologists were asked whether they considered the PC mucinous and if the PC was suspicious for malignancy. Furthermore, they had to choose a classifying diagnosis. Intraclass correlation coefficient (ICC) was used to measure agreement within the group. RESULTS: Interobserver agreement for septations and nodules was fair (ICC, 0.36 and 0.23, respectively). Agreement for the presence of solid components was fair (ICC, 0.23), agreement for communication with the pancreatic duct was moderate (ICC, 0.53), and agreement for wall thickening was moderate (ICC, 0.44). There was fair agreement for the discrimination between mucinous and nonmucinous PC (ICC, 0.36). Agreement was fair (ICC, 0.26) for a classifying diagnosis and fair for the presence of malignant features (ICC, 0.33). CONCLUSIONS: Interobserver agreement was poor to moderate for individual PC features, and there was fair agreement for a classifying diagnosis. Magnetic resonance imaging morphology alone did not allow for a reliable discrimination between different types of PC.

Retrospective comparison of magnetic resonance imaging features and histopathology in Crohn's disease patients.

PURPOSE: To retrospectively compare histopathological findings of surgically resected bowel segments with magnetic resonance imaging (MRI) findings on Crohn's disease activity. MATERIALS AND METHODS: Patients who underwent a MR enterography or enteroclysis before surgery were included after informed consent. MRI features (T1-enhancement, T1 and T2 stratification, T2 signal intensity, bowel wall thickness, presence of ulcerations, comb sign, creeping fat, and disease activity) were assessed by three experienced abdominal radiologists. An acute inflammatory score based on histopathology (parameters: mucosal ulceration, edema, depth and degree of neutrophils) was calculated. Interobserver variability for subjective MRI features was also assessed. RESULTS: Thirty-nine segments in 25 patients (mean age 38 years) were included. Of the MRI features, disease activity per segment and bowel wall thickness had a positive association with the acute inflammatory score (p<0.05). T1-enhancement had a positive correlation with disease chronicity. All other MRI features did not have an association with the acute inflammatory score. Interobserver agreement between the three observers was weak to moderate. CONCLUSION: MR features bowel wall thickness and disease activity per-segment reflect disease activity in Crohn's disease patients.

Computer-aided detection of lung cancer on chest radiographs: effect on observer performance.

PURPOSE: To assess how computer-aided detection (CAD) affects reader performance in detecting early lung cancer on chest radiographs. MATERIALS AND METHODS: In this ethics committee-approved study, 46 individuals with 49 computed tomographically (CT)-detected and histologically proved lung cancers and 65 patients without nodules at CT were retrospectively included. All subjects participated in a lung cancer screening trial. Chest radiographs were obtained within 2 months after screening CT. Four radiology residents and two experienced radiologists were asked to identify and localize potential cancers on the chest radiographs, first without and subsequently with the use of CAD software. A figure of merit was calculated by using free-response receiver operating characteristic analysis. RESULTS: Tumor diameter ranged from 5.1 to 50.7 mm (median, 11.8 mm). Fifty-one percent (22 of 49) of lesions were subtle and detected by two or fewer readers. Stand-alone CAD sensitivity was 61%, with an average of 2.4 false-positive annotations per chest radiograph. Average sensitivity was 63% for radiologists at 0.23 false-positive annotations per chest radiograph and 49% for residents at 0.45 false-positive annotations per chest radiograph. Figure of merit did not change significantly for any of the observers after using CAD. CAD marked between five and 16 cancers that were initially missed by the readers. These correctly CAD-depicted lesions were rejected by radiologists in 92% of cases and by residents in 77% of cases. CONCLUSION: The sensitivity of CAD in identifying lung cancers depicted with CT screening was similar to that of experienced radiologists. However, CAD did not improve cancer detection because, especially for subtle lesions, observers were unable to sufficiently differentiate true-positive from false-positive annotations.

Autoimmune hepatitis: CT and MR imaging features with histopathological correlation.

BACKGROUND: To describe the CT and MRI features of autoimmune hepatitis (AIH) and correlate them with histological grade and stage. Observed changes associated with treatment are also described. METHODS: A retrospective analysis of the initial CT scans (n = 22) and MRI exams (n = 12) of 27 patients with pathologically-proven AIH was conducted. Multiple objective and subjective imaging features were evaluated. Correlation of imaging features with histological inflammatory grade and fibrotic stage was performed using the Fisher exact test and Spearman's rank correlation coefficient. In eight patients serial CT and MR imaging during treatment was used to describe the changes associated with treatment. RESULTS: The presence of ascites, expanded gallbladder fossa, spleen size, and enlarged preportal space had significant positive correlations with fibrotic stage. No significant positive correlations existed between imaging features and portal or lobular inflammatory grade. Seven patients (25.9%) were normal. The most common abnormal finding was surface nodularity: CT (n = 11 [50%]) and MRI (n = 8 [66.7%]). There was a wide variability in imaging appearances of patients who had serial scans on treatment. CONCLUSIONS: There is a wide spectrum of CT and MR imaging features in patients with AIH. Several MRI features demonstrate a significant positive correlation with fibrotic stage.

Gastric motility: comparison of assessment with real-time MR imaging or barostat measurement initial experience.

Measurements of gastric volume and motility with magnetic resonance (MR) imaging were compared with simultaneously performed measurements with a barostat in six healthy volunteers. Three-dimensional volume and two-dimensional dynamic MR images and barostat measurements were obtained at rest. Alterations in gastric volume and motility were induced by means of infusion of glucagon and erythromycin, respectively. There is strong evidence to have the opinion that MR imaging is as accurate as barostat measurement in determining changes in gastric volume, and it yields additional information about gastric contractions.