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Background and Aims Since there are no accurate methods for fibrosis identification or quantification, the purpose is to investigate the utility of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images for intestinal fibrosis assessment in a mouse model of gut fibrosis. Methods Chronic colitis was obtained in 16 C57BL/6 mice by cyclic administration of dextran sodium sulphate (DSS) inducing early phase inflammation and progressive bowel fibrosis. Mice underwent 7.0 T MR imaging at various timepoints. MT ratio (MTR) in the bowel wall was calculated. Textural features (skewness, kurtosis, entropy) were extracted by a filtration histogram technique. Resected colonic tissue was scored for inflammation and fibrosis. Performance of MT-MRI and TA was validated in a consecutive experiment in mice using antifibrotic therapy. Finally, a retrospective study was conducted in five CD patients who underwent bowel surgery. Results MTR and texture entropy both correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in presence of coexisting inflammation (linear regression R² = .93 versus R2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan; Δ mean = 0.128, p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (1.29 in inflammation; 1.40 and 1.48 in mixed strictures; 1.73 and 1.90 in fibrosis). Conclusion Texture analysis of T2-weighted MR images outperforms magnetization transfer imaging in detecting the fibrotic component in mixed inflammatory-fibrotic bowel tissue and can be used for monitoring antifibrotic treatment response.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT. ispartof: JOURNAL OF CLINICAL ONCOLOGY vol:40 issue:29 pages:3377-+ ispartof: location:United States status: published

A common and untreatable complication of Crohn’s disease (CD) is the development of intestinal fibrosis for which no adequate noninvasive tools for fibrosis progression monitoring exist. For this purpose, we assessed the performance of magnetization transfer (MT) magnetic resonance imaging (MRI) and texture analysis (TA) on T2-weighted images by correlating them with histology in a fibrosis mouse model. MT-MRI and TA performance was validated during antifibrotic therapy in mice and on MR enterography images of CD patients undergoing bowel surgery. The MT-MRI and TA entropy correlated with histological fibrosis (r = .85 and .81, respectively). However, TA entropy was superior to MT-MRI for quantifying fibrosis progression during coexisting inflammation (linear regression R² = .93). TA entropy could efficiently monitor anti-fibrotic therapy efficacy and correlated with the grade of intestinal fibrosis in CD. In conclusion, MT-MRI and TA entropy are highly promising surrogate markers of intestinal fibrosis, but TA entropy performed better in the presence of concomitant inflammation.

5025 Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.