EGFR Expression Is Unreliable to Decide for Cetuximab Treatment in Patients with Metastatic Colorectal Cancer: Results from “ERBITUX-OUEST”

Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.

Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease

AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse(ARFI) in determining fibrosis stage in patients with alcoholic liver disease(ALD) undergoing alcoholic detoxification in relation to biopsy.METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy onthe same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient.RESULTS: Sixty-nine males and thirteen females(one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4%(0.70-0.95) and 83.3%(0.73-0.94)(AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4%(0.64-1.00) and 78.5%(0.69-0.89)(AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3%(0.78-1.00] and 81.6%(0.72-0.90)(AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s.CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification.

Pathology of hepatic iron overload

Although progress in imaging and genetics allow for a noninvasive diagnosis of most cases of genetic iron overload, liver pathology remains often useful （1） to assess prognosis by grading fibrosis and seeking for associated lesions and （2） to guide the etiological diagnosis, especially when no molecular marker is available. Then, the type of liver siderosis （parenchymal, mesenchymal or mixed） and its distribution throughout the Iobule and the liver are useful means for suggesting its etiology： HLA-linked hemochromatosis gene （HFE） hemochromatosis or other rare genetic hemochromatosis, nonhemochromatotic genetic iron overload （ferroportin disease, aceruloplasminemia）, or iron overload secondary to excessive iron supply, inflammatory syndrome, noncirrhotic chronic liver diseases including dysmetabolic iron overload syndrome, cirrhosis, and blood disorders.

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

AIM： TO study the implication of prokineticin 1 （PKI/EGVEGF） and prokineticin 2 （PK2/13v8） in hepatocellular carcinoma angiogenesis.METHODS： The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF （an angiogenesis marker）, vWF （an endothelial cell marker） and to CD68 （a monocyte/macrophage marker）. Furthermore, the rnRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochernistry and immunocytochemistry.RESULTS： PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/13v8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC,as expected. In addition, out of all isolated liver cells examined, only Kupffer cells （liver resident macrophages） express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2.CONCLUSION： In normal liver PK2/Bv8 and its receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves towards cancer and did not correlate with HCC angiogenesis.