Cytokine/chemokine profiles in squamous cell carcinoma correlate with precancerous and cancerous disease stage.

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes

Influence of diffusion weighted imaging and contrast enhanced T1 sequences on the diagnostic accuracy of magnetic resonance enterography for Crohn's disease

OBJECTIVES: To evaluate the additional diagnostic benefit of diffusion weighted imaging (DWI) and contrast enhanced (CE) images during MR enterography (MRE) of Crohn's disease.METHODS: Datasets from 73 patients (mean age 32; 40 male) (28 new-diagnosis, 45 relapsed) were read independently by two radiologists selected from a pool of 13. Radiologists interpreted datasets using three sequential sequence blocks: (1) T2 weighted and steady state free precession gradient echo (SSFP) images alone (T2^); (2) T2 weighted and SSFP images with DWI (T2 + DWI^) and; (3) T2 weighted images, SSFP, DWI and post-contrast enhanced (CE) T1 images (T2 + DWI + CE^), documenting presence, location, and activity of small bowel disease. For each sequence block, sensitivity and specificity (readers combined) was calculated against an outcome-based construct reference standard.RESULTS: 59/73 patients had small bowel disease. Per-patient sensitivity for disease detection was essentially identical (80 % [95 % CI 72, 86], 81 % [73,87], and 79 % [71,86] for T2^, T2 + DWI^and T2 + DWI + CE^respectively). Specificity was identical (82 % [64 to 92]). Per patient sensitivity for disease extent was 56 % (47,65), 56 % (47,65) and 52 % (43 to 61) respectively, and specificity was 82 % (64 to 92) for all blocks. Sensitivity for active disease was 97 % (90,99), 97 % (90,99) and 98 % (92,99), and specificity was also comparable between all sequence combination reads. Results were consistent across segments and newly diagnosed/relapse patients.CONCLUSION: There is no additional diagnostic benefit of adding either DWI or CE to T2 FSE and SSFP sequences for evaluating small bowel Crohn's disease, suggesting MRE protocols can be simplified safely.</p

An ex vivo human tumour assay reveals distinct patterns of EGFR trafficking in squamous cell carcinoma correlating to therapeutic outcomes

EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in 3D culture. These studies have been completed via genetic sequencing, cell line or 3D in vitro and in vivo murine models. Here we describe an imaging method that allows ex-vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumours. We analyzed sets of tumour samples from advanced cutaneous squamous cell carcinoma and Head and Neck squamous cell carcinoma, actinic keratosis, intra-epidermal carcinoma and cutaneous squamous cell carcinoma. We demonstrate that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intra-epidermal carcinoma and well-differentiated cutaneous squamous cell carcinoma different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex-vivo human tumours confirm that endocytosis dysregulation is a physiological event in human tumours and has therapeutic implications

Observer agreement for small bowel ultrasound in Crohn’s disease:results from the METRIC trial

Purpose: To prospectively evaluate interobserver agreement for small bowel ultrasound (SBUS) in newly diagnosed and relapsing Crohn’s disease. Methods: A subset of patients recruited to a prospective trial comparing the diagnostic accuracy of MR enterography and SBUS underwent a second SBUS performed by one of a pool of six practitioners, who recorded the presence, activity and location of small bowel and colonic disease. Detailed segmental mural and extra-mural observations were also scored. Interobserver variability was expressed as percentage agreement with a construct reference standard, split by patient cohort, grouping disease as present or absent. Prevalence adjusted bias adjusted kappa (PABAK), and simple percentage agreement between practitioners, irrespective of the reference standard, were calculated. Results: Thirty-eight patients (11 new diagnosis, 27 relapse) were recruited from two sites. Overall percentage agreement for small bowel disease presence against the consensus reference was 82% (52–95% (95%CI)), kappa coefficient (κ) 0.64, (substantial agreement) for new diagnosis and 81%, κ 0.63 (substantial agreement) for the relapsing cohort. Agreement for colonic disease presence was 64%, κ 0.27 (fair agreement) in new diagnosis and 78%,κ 0.56 (moderate agreement) in the relapsing cohort. Simple agreement between practitioners was 84% and 87% for small bowel and colonic disease presence respectively. Practitioners agreed on small bowel disease activity in 24/27 (89%) where both identified disease. Kappa agreement for detailed mural observations ranged from κ 0.00 to 1.00. Conclusion: There is substantial practitioner agreement for small bowel disease presence in newly diagnosed and relapsing CD patients, supporting wider dissemination of enteric US.</p

Observer agreement for small bowel ultrasound in Crohn’s disease:results from the METRIC trial

Purpose: To prospectively evaluate interobserver agreement for small bowel ultrasound (SBUS) in newly diagnosed and relapsing Crohn’s disease. Methods: A subset of patients recruited to a prospective trial comparing the diagnostic accuracy of MR enterography and SBUS underwent a second SBUS performed by one of a pool of six practitioners, who recorded the presence, activity and location of small bowel and colonic disease. Detailed segmental mural and extra-mural observations were also scored. Interobserver variability was expressed as percentage agreement with a construct reference standard, split by patient cohort, grouping disease as present or absent. Prevalence adjusted bias adjusted kappa (PABAK), and simple percentage agreement between practitioners, irrespective of the reference standard, were calculated. Results: Thirty-eight patients (11 new diagnosis, 27 relapse) were recruited from two sites. Overall percentage agreement for small bowel disease presence against the consensus reference was 82% (52–95% (95%CI)), kappa coefficient (κ) 0.64, (substantial agreement) for new diagnosis and 81%, κ 0.63 (substantial agreement) for the relapsing cohort. Agreement for colonic disease presence was 64%, κ 0.27 (fair agreement) in new diagnosis and 78%,κ 0.56 (moderate agreement) in the relapsing cohort. Simple agreement between practitioners was 84% and 87% for small bowel and colonic disease presence respectively. Practitioners agreed on small bowel disease activity in 24/27 (89%) where both identified disease. Kappa agreement for detailed mural observations ranged from κ 0.00 to 1.00. Conclusion: There is substantial practitioner agreement for small bowel disease presence in newly diagnosed and relapsing CD patients, supporting wider dissemination of enteric US.</p