[Show abstract][Hide abstract] ABSTRACT: Hepatitis B virus (HBV) reactivation is one unique pathogenesis in Asian carriers with liver toxicity after radiotherapy for hepatobiliary malignancies. This study attempts to delineate the biological mechanism of radiation-induced HBV reactivation.
Primary cultures of hepatocytes (PCC) were prepared from the noncancerous liver tissue removed perioperatively from 12 HBV carriers with hepatocellular carcinoma (HCC). The conditioned medium of irradiated PCCs, HCC, and endothelial cells from patients was transferred to PCCs or HepG2.2.15 cells (a human hepatoblastoma cell line transfected with HBV DNA) before subsequent irradiation. Forty-eight hours after irradiation, HBV DNA was measured by real-time quantitative PCR. Specific cytokines were determined by cytokine array and ELISA analysis. Preradiotherapy and postradiotherapy sera from 10 HBV carriers and 16 non-HBV carriers were analyzed for viral loads and cytokine activities.
Radiation induced HBV DNA replication in (a) irradiated PCCs cultured with the conditioned medium from irradiated PCCs (2.74-fold; P=0.004) and endothelial cells (9.50-fold; P=3.1x10(-10)), but not from HCCs (1.07-fold), and in (b) irradiated HepG2.2.15 cells (17.7-fold) cocultured with human umbilical vascular endothelial cells. Cytokine assay revealed increased expression of interleukin-6 (IL-6) in conditioned medium from irradiated human umbilical vascular endothelial cells. All 16 patients with liver irradiated had the increased serum IL-6 compared with 3 of 10 patients with irradiation excluding liver (P<0.001). All nine HBV carriers with liver irradiated had postradiotherapy increases in both HBV DNA and IL-6.
Radiation-induced liver toxicity with HBV reactivation is from a bystander effect on irradiated endothelial cells releasing cytokines, including IL-6.
Clinical Cancer Research 03/2007; 13(3):851-7. DOI:10.1158/1078-0432.CCR-06-2459 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whether diffuse large B-cell lymphoma (DLBCL) of primary central nervous system origin (PCNSL) is biologically different from DLBCL of peripheral nodal origin (NL) remains unclear. The purpose of this study was to compare the expression frequencies and prognostic significance of a panel of cell differentiation markers between these two disease entities.
This study included HIV-unrelated patients with PCNSL (n = 51) and NL (n = 72) treated at four hospitals in Taiwan for whom archival tumor tissue was available. Immunohistochemistry for CD10, BCL-6, MUM-1, vs38c, CD138, and BCL-2 was done. CD10, BCL-6, and MUM-1 expression results were used to classify all cases into the germinal center B-cell (GCB) or the non-GCB subgroup. The prognostic significances of clinical and immunophenotypic markers were evaluated.
Nuclear MUM-1 expression was significantly higher in PCNSL than in NL (P < 0.001; 84% versus 53%). PCNSL tumors were more frequently classified into the non-GCB subgroup than NL tumors (P = 0.020; 78% versus 62%). For patients with PCNSL, univariate analysis showed that patients with BCL-6 expression had a trend towards longer survival (P = 0.073; median survival, 25.3 versus 7.3 months), and multivariate analysis showed BCL-6 was an independent prognostic factor (P = 0.026). For patients with NL, both of univariate (P = 0.003) and multivariate analyses (P = 0.002) showed that GCB was significantly associated with favorable survival.
The higher frequency of non-GCB subclassification, which was mainly contributed by nuclear MUM-1 expression in PCNSL implies that it has a more differentiated cellular origin than NL. BCL-6 expression in patients with PCNSL and GCB subgroup in patients with NL were favorable prognostic factors.
Clinical Cancer Research 02/2006; 12(4):1152-6. DOI:10.1158/1078-0432.CCR-05-1699 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The t(11;18)(q21;q21) translocation is a specific marker for Helicobacter pylori-independent 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-kappaB) 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-kappaB was also significantly higher in H pylori-independent than in H pylori-dependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-kappaB 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-kappaB is predictive of H pylori-independent status of low-grade gastric MALT lymphoma with or without t(11;18)(q21; q21).
[Show abstract][Hide abstract] ABSTRACT: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori (H pylori)-dependent. However, unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict H pylori-dependent status of high-grade gastric MALT lymphoma.
Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage I(E) high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade II or less after H pylori eradication were classified as H pylori-dependent; others were classified as H pylori-independent. The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry.
There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8+/-1.4% vs 1.1+/-0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9+/-1.1% vs 1.4+/-1.3%; P = 0.005).
These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.
World Journal of Gastroenterology 08/2005; 11(28):4357-62. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H. pylori-independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-kappaB) is useful in predicting H. pylori-independent status in patients with stage IE high-grade gastric MALT lymphomas.
Twenty-two patients who had participated in a prospective study of H. pylori eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-kappaB in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript.
Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H. pylori-independent and in none of 14 H. pylori-dependent high-grade gastric MALT lymphomas (P <.001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kappaB, compared with only two of 15 patients without nuclear BCL10 expression (P =.002). As a single variable, the frequency of nuclear expression of NF-kappaB was also significantly higher in H. pylori-independent tumors than in H. pylori-dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P =.002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H. pylori-independent lymphomas.
Nuclear expression of BCL10 or NF-kappaB is highly predictive of H. pylori-independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.
[Show abstract][Hide abstract] ABSTRACT: Reactivation of HBV replication is a clinically significant complication in HBV(+) patients receiving chemotherapy. We recently found that nearly half of the HBV reactivation in lymphoma patients occurred within 2 weeks of the first dose of chemotherapy. We hypothesized that mechanisms other than immunosuppression, such as direct stimulation of HBV replication by anticancer drugs, might be involved in this type of HBV reactivation.
2.2.15 cells, which secrete HBV particles constitutively, were used in the experiments. Real-time quantitative polymerase chain reaction was used to quantitate HBV DNA, and microparticle enzyme immunoassay to measure HBV surface antigen (HBsAg).
HBV DNA secretion in culture medium was dose- dependently increased by doxorubicin, one of the most commonly used anticancer drugs for lmphoma. One-hour exposure of cells to 1 microM doxorubicin induced a 15.4+/-5.9-fold and a 3.05+/-0.09-fold increase of HBV DNA and HBsAg on the 4th culture day, respectively. Lamivudine suppressed the doxorubicin-induced increase of HBV DNA.
Our data suggest that cytotoxic agents may stimulate the replication of HBVand thereby contribute to the reactivation of HBV during systemic chemotherapy. Importantly, this adverse effect of cytotoxic agents may be preventable by co-administration of lamivudine.
Anticancer research 09/2004; 24(5A):3035-40. · 1.83 Impact Factor