[en] Purpose: To examine dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a macromolecular contrast agent (P792) to visualize effects of radiotherapy (RT) on microvascular leakage in a colorectal cancer model. Methods and Materials: CC531 tumors were induced in WAG/Rij rats. DCE-MRI was performed before and 5 days after 5 x 5 Gy of RT and parametric maps generated of the endothelial transfer constant (K^trans ) and the fractional interstitial space (V_e ) according to the Tofts model. Tissue pO₂ mapping was performed in each tumor core and rim before and after RT. Microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and pimonidazole hypoxia staining were compared with a control group of tumor-bearing rats. Results: Mean K^trans and v_e were significantly reduced after RT in all tumor regions. Mean pO₂ was 6.8 mm Hg before RT vs. 7.7 mm Hg after RT (p < 0.001) in the tumor rim and 3.5 mm Hg before RT vs. 4.4 mm Hg after RT (p < 0.001) in the tumor core. Mean MVD in the tumor rim was 10.4 in the RT treated group vs. 16.9 in the control group (p = 0.061). VEGF expression was significantly higher in RT-treated rats. After RT, no correlation was found between DCE-MRI parameters and histologic parameters. A correlation was seen after RT between pO₂ and K^trans (r -0.57, p = 0.08) and between pO₂ and v_e (r = -0.65, p = 0.04). Conclusions: Dynamic contrast-enhanced-MRI with P792 allows quantification of microvascular changes in this colorectal model. RT significantly reduces neovascular leakage and enhances tissue oxygenation and VEGF expression. After RT, DCE-MRI parameters are related to tumor pO₂, but not to MVD or VEGF expression

[en] Objectives: To investigate the added value of fusion of high b-value diffusion-weighted images (DWI) and T2-weighted (T2) MR images for the detection of pancreatic neuroendocrine tumors (PNT). Methods: 18 patients with 18 histologically proven PNT were included. Two radiologists independently and retrospectively reviewed four randomized images sets (T2+T1, DWI, T2+DWI, and DWI+T2 fusion). Lesion detection confidence level was assessed using a three grade score (no lesion; uncertain lesion and certain lesion); lesion size and signal intensity were recorded. Apparent diffusion coefficients (ADC) of tumor and adjacent pancreas were measured. Results: Readers 1 and 2 respectively detected 14/18 and 16/18 lesions on T2+T1, 13/18 and 12/18 on DWI, 16/18 and 15/18 on T2+DWI and 17/18 and 16/18 on DWI+T2 fusion. Lesion median size was 16 mm (range: 7 mm–40 mm), 22% were hyperfunctioning (all insulinomas) and 72% were low-grade (Rindi 1). All tumors except one (with cystic component) showed lower ADC than adjacent pancreatic parenchyma. Fusion imaging had significantly better detection score by both authors (p < 0.005) and provided the higher inter-reader agreement (kappa 0.7). DWI alone had the worst score for both readers. Conclusions: Fusion images improve the detection of PNT, especially in patients with small isointense lesions on conventional MR sequences.

[en] Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown. We assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56⁺ cells. ADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56⁺ cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56⁺ cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56⁺ cells failed to predict PFS and response in the control group. CD56⁺ cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56⁺ cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy

[en] With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas. Formalin fixed, paraffin-embedded tissues from anal and tonsil carcinoma were used. EGFR protein expression and EGFR gene copy number were analysed by means of immunohistochemistry and fluorescence in situ hybridisation. The somatic status of the EGFR gene was investigated by PCR using primers specific for exons 18 through 21. For the K-RAS gene, PCR was performed using exon 2 specific primers. EGFR immunoreactivity was present in 36/43 (83.7%) of anal canal and in 20/24 (83.3%) of tonsil squamous cell carcinomas. EGFR amplification was absent in anal canal tumours (0/23), but could be identified in 4 of 24 tonsil tumours. From 38 anal canal specimens, 26 specimens were successfully analysed for exon 18, 30 for exon 19, 34 for exon 20 and 30 for exon 21. No EGFR mutations were found in the investigated samples. Thirty samples were sequenced for K-RAS exon 2 and no mutation was identified. From 24 tonsil specimens, 22 were successfully analysed for exon 18 and all 24 specimens for exon 19, 20 and 21. No EGFR mutations were found. Twenty-two samples were sequenced for K-RAS exon 2 and one mutation c.53C > A was identified. EGFR mutations were absent from squamous cell carcinoma of the anus and tonsils, but EGFR protein expression was detected in the majority of the cases. EGFR amplification was seen in tonsil but not in anal canal carcinomas. In our investigated panel, only one mutation in the K-RAS gene of a tonsil squamous cell carcinoma was identified. This indicates that EGFR and K-RAS mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in anal canal and tonsil squamous cell carcinoma