Bortezomib, a proteasome inhibitor, has been clinically approved for the treatment of myeloma and lymphoma. Here, we report a differential effect of bortezomib on apoptosis in four hepatocellular carcinoma (HCC) cell lines and identify the major molecular event that determines sensitivity. Although bortezomib inhibited proteasome activity to a similar extent in all HCC cell lines, it showed differential effects on their viability: Huh-7 (IC 50 196 nmol/L), Sk-Hep1 (IC 50 180 nmol/L), Hep3B (IC 50 112 nmol/L), and resistant PLC5 (IC 50 >1,000 nmol/L). Bortezomib caused cell cycle arrest at G 2 -M phase in all HCC cells tested whereas apoptotic induction was found only in sensitive cells but not in PLC5 cells. No significant bortezomib-induced NF-KB changes were noted in Huh-7 and PLC5. Bortezomib down-regulated phospho-Akt (P-Akt) in a dose-and time-dependent manner in all sensitive HCC cells whereas no alterations of P-Akt were found in PLC5. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in PLC5 cells, but a constitutively activated Akt1 protected Huh-7 cells from bortezomib-induced apoptosis. Furthermore, bortezomib showed suppression of tumor growth with downregulation of P-Akt in Huh-7 tumors but not in PLC5 tumors. Down-regulation of P-Akt represents a major molecular event of bortezomib-induced apoptosis in HCC cell lines and may be a biomarker for predicting clinical response to HCC treatment. Targeting Akt signaling overcomes drug resistance to bortezomib in HCC cells, which provides a new approach for the combinational therapy of HCC. [Cancer Res 2008; 68(16):6698-707]

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We were interested to read the paper on survival after resection of non-small-cell lung cancer (NSCLC) in relation to 'tumour volume' by Jefferson et al (1996).By multiplying together the three dimensions of each tumour, the authors have assumed that the carcinomas are box shaped. The accuracy of this assumption was not validated. In a study of 54 resected lung cancers (Binks et al, 1996), we found that the most appropriate measures of tumour volume were to assume that the tumours were ellipsoidal or boxes. These measurements compared well with our gold standard methods (R = 0.887 and R = 0.910 respectively) of sequential 1-mm or 1-cm slices, for which the tumour area was measured and the volume derived from the sum of the areas. In contrast, measurement of the maximum dimension and assuming a spherical shape grossly overestimated the volume of some tumours (R = 0.632).Although we expected ellipsoidal measurements to be more accurate than boxes, this was not the case. We support the authors statement that tumour volume is a useful piece of information that is easily collected, but three dimensions should always be measured for solid tumours.

The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.

The t(11;18)(q21;q21) translocation is a specific marker for Helicobacter pyloriindependent status of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, there are no reliable markers to predict tumor response to H pylori eradication in patients without t(11;18)(q21;q21). Nuclear expression of BCL10 and nuclear factor kappa B (NF-B) was recently found to be closely associated with H pylori-independent status of the high-grade counterpart of gastric MALT lymphoma, which usually lacks t(11;18)(q21;q21). This study examined whether these 2 markers can also predict H pylori-independent status of low-grade gastric MALT lymphomas without t(11; 18)(q21;q21). Sixty patients who underwent successful H pylori eradication for low-grade gastric MALT lymphomas were included. Forty-seven (78.3%) patients were negative for t(11;18)(q21;q21); among them, 36 (76.6%) were H pylori dependent and 11 (23.4%) were H pylori independent. Nuclear expression of BCL10 was significantly higher in H pylori-independent than in H pylori-dependent tumors (8 of 11 [72.7%] vs 3 of 36 [8.3%]; P < .001). Nuclear expression of NF-B was also significantly higher in H pylori-independent than in H pyloridependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-B was observed in 12 of the 13 patients with t(11;18)(q21;q21), and all these 12 patients were H pylori independent. In summary, nuclear expression of BCL10 or NF-B is predictive of H pylori-independent status of low-grade gastric MALT lymphoma with or without t(11;18)(q21; q21).