Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).

Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

MR imaging of iron phagocytosis in intraluminal thrombi of abdominal aortic aneurysms in humans.

PURPOSE: To prospectively determine if superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging could help visualize leukocyte phagocytic activities in human abdominal aortic aneurysms (AAAs). MATERIALS AND METHODS: This study was approved by the institutional ethics committee; all patients gave informed consent. Preoperative MR imaging data, including unenhanced and SPIO-enhanced T1-, T2*-, and T2-weighted transverse images of the entire AAA, obtained 1 hour after contrast enhancement from 15 patients (mean age, 72.7 years +/- 8.2; range, 60-83 years), 10 men (mean age, 73.5 years +/- 7.9; range, 60-83 years) and five women (mean age, 71.2 years +/- 9.4; range 60-82), were retrospectively evaluated. Morphologic appearance and semiquantitative and contrast-to-noise ratio (CNR) analyses of the thrombi were performed. Thrombi were analyzed semiquantitatively at microscopy after staining with hematoxylin-eosin, CD68, and CD66b. Levels of promatrix metalloproteinase (pro-MMP)-2 and pro-MMP-9, MMP-2 and MMP-9, and their mRNA located in the thrombus were assessed by using zymography and quantitative reverse transcriptase polymerase chain reaction analysis. Nonparametric statistics of the Spearman rank correlation were calculated to evaluate correlations between the aneurysm thrombus signal level decrease after SPIO and the levels of CD68(+), CD66b(+) cells, pro-MMP-2 and pro-MMP-9, MMP-2 and MMP-9, and MMP-9 mRNA. RESULTS: The pre-SPIO CNRs in the luminal sublayer of the thrombus and the deeper thrombus were -10.20 +/- 12.69 and -5.68 +/-10.38, respectively. After SPIO, the CNRs decreased to -21.34 +/-13.07 (P < .001) and -12.44 +/- 14.56, respectively (P < .012). There was a significant linear correlation between the thrombus signal level decrease and the levels of CD68(+) and CD66b(+) cells, pro-MMP-9, and MMP-9 mRNA (P < .05). CONCLUSION: MR imaging allows in vivo demonstration of SPIO uptake at the luminal interface of the thrombus. This uptake is correlated to the abundance of leukocytes. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.09090657/-/DC1.

Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases.

BACKGROUND: The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM). METHODS: One hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed. RESULTS: Bevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively). CONCLUSIONS: The routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications.

TTC7A mutations disrupt intestinal epithelial apicobasal polarity.

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain­7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.