Tsai Yun Chen

Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports

BACKGROUND Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. METHODS We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. RESULTS One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0-12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9-34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4-31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01-16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ(2) = 2.12, P = 0.5473). CONCLUSIONS The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.

Intramyocardial Peptide Nanofiber Injection Improves Postinfarction Ventricular Remodeling and Efficacy of Bone Marrow Cell Therapy in Pigs

Background— Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. Methods and Results— A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1×108 isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and −dP/dt (1214.5±91.9 and −1109.7±91.2 mm Hg/s in MI+NS, 1693.7±84.7 and −1809.6±264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3±4.5 cells/mm2 in MI+MNCs and 229.4±41.4 cells/mm2 in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area. Conclusions— We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future.

A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis

BACKGROUND The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING Samsung Biomedical Research Institute.

Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes Bcr-AblT315I Mutant Cells to Imatinib

The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-xs and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib.

Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis

Inactivation of glycogen synthase kinase (GSK)‐3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK‐3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr‐Abl tyrosine kinase. In Bcr‐Abl signaling, the role of GSK‐3 is not well defined. Here, we report that enforced expression of constitutively active GSK‐3 reduced proliferation and increased Bcr‐Abl inhibition‐induced apoptosis by nearly 1‐fold. Bcr‐Abl inhibition activated GSK‐3 and GSK‐3‐dependent apoptosis. Inactivation of GSK‐3 by Bcr‐Abl activity is, therefore, confirmed. To reactivate GSK‐3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor‐suppressor sphingo‐lipid and a potent GSK‐3 activator. We found that either PDMP or silence of GCS increased Bcr‐Abl inhibition‐induced GSK‐3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drug‐resistant CML T315I mutant to Bcr‐Abl inhibitor GNF‐2‐, imatinib‐, or nilotinib‐induced apoptosis by >5‐fold. Combining PDMP and GNF‐2 eliminated transplanted‐CML‐T315I‐mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF‐2‐induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr‐Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK‐3‐mediated apoptosis. This study suggests a feasible novel anti‐CML strategy by accumulating endogenous ceramide to reactivate GSK‐3 and abrogate drug resistance.—Huang, W.‐C., Tsai, C.‐C., Chen, C.‐L., Chen, T.‐Y., Chen, Y.‐P., Lin, Y.‐S., Lu, P.‐J., Lin, C.‐M., Wang, S.‐W., Tsao, C.‐W., Wang, C.‐Y., Cheng, Y.‐L., Hsieh, C.‐Y., Tseng, P.‐C., Lin, C.‐F. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr‐Abl inhibitor and cooperatively induces glycogen synthase kinase‐3‐regulated apoptosis. FASEB J. 25, 3661–3673 (2011). www.fasebj.org

Chemotherapy with cisplatin and continuous infusion of 5-fluorouracil and bleomycin for recurrent and metastatic nasopharyngeal carcinoma in Taiwan.

Twenty-five patients with metastatic and/or recurrent nasopharyngeal carcinoma were treated with cisplatin 20 mg/m2/day on days 1-5 i.v. with hydration; 5-fluorouracil (5-FU) 1,000 mg/m2/day by continuous infusion (CI); and bleomycin 15 mg/m2 on day 1 also by CI. These cycles were repeated every 4 weeks. Twenty-three (92%) had distant metastases. Bone was the most frequently involved site (72%), followed by lungs (44%) and liver (40%). More than half the patients (14/25) presented with at least 3 organ sites involved or had local T3/T4 or N3 lesions with a distant metastasis. The median time from relapse to start of chemotherapy was 7.5 months. We observed 1 (4%) complete response (CR), and 9 (36%) partial responses (PR). The objective response rate (CR + PR) was 40%. Hematologic toxicities were frequently encountered. Twenty (80%) patients experienced leukopenia during the treatment courses and 9 (36%) had severe (grade 3 or 4) leukopenia. Eight patients had grade 3 or 4 infections. Two of them died of sepsis and 1 succumbed to uncontrolled pneumonia. The objective response rate was inferior to other series. Possible explanation included longer delay before initiation of definitive treatment, larger tumor burdens, higher severe hematologic toxicity and lower dosage of bleomycin. The results suggested metastatic and/or recurrent nasopharyngeal carcinoma is chemosensitive, however, for patients with large tumor burdens, more intensive chemotherapy regimens with support of hematopoietic growth factors may be required to achieve a better control.

Combined intrapleural and intravenous chemotherapy, and pulmonary irradiation, for treatment of patients with lung cancer presenting with malignant pleural effusion. A pilot study.

Objectives: Patients with non-small-cell lung cancer (NSCLC) and malignant pleural effusion (MPE) are difficult to manage clinically and have a short life expectancy. In this pilot study, we designed a protocol of combined intrapleural (i.p.) and intravenous (i.v.) chemotherapy and pulmonary irradiation to enhance local as well as systemic control of the disease. Methods: From April 1998 to April 2000, 27 patients with NSCLC and symptomatic MPE were eligible for the study. Patients received pre-radiation chemotherapy (cisplatin 60 mg/m2 i.p. on day 1; gemcitabine 1,000 mg/m2 i.v. on days 1, 8, and 15, q4week × 3) after surgical implantation of i.p. and i.v. port-A, followed by radiotherapy (7,020 cGy/39fr), and, finally, post-radiation chemotherapy (docetaxel 60 mg/m2 q3week × 3–6 i.v.). Results: Grade 1/2 nausea/vomiting and impaired renal function were more common from pre-radiation than post-radiation chemotherapy; however, grade 3/4 toxicities from pre-radiation chemotherapy were minimal. Conversely, grade 3/4 leukopenia and grade 1/2 alopecia, diarrhea, elevation of SGOT/SGPT, and sensory impairment were more common following post-radiation chemotherapy. Only two patients experienced recurrence of pleural effusion. The overall response rate was 55% with 7% complete remission, 48% partial remission, 22% stable disease, and 22% progressive disease. The median failure-free and overall survival was 8 and 16 months, respectively. The one-year survival rate was 63% (95% confidence interval, 45–80%). Conclusions: We conclude that the combination of i.p. and i.v. chemotherapy and pulmonary irradiation is feasible and should be tested in a larger clinical trial to determine whether survival can be improved for this cohort of patients.

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells.

Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.

Large B cell lymphoma presenting initially in bone marrow, liver and spleen: An aggressive entity associated frequently with haemophagocytic syndrome

Yeh Y‐M, Chang K‐C, Chen Y‐P, Kao L‐Y, Tsai H‐P, Ho C‐L, Wang J‐R, Jones D & Chen T‐Y
(2010) Histopathology57, 785–795

Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma

A phase II trial was conducted to evaluate the therapeutic efficacy and safety profiles of frontline concurrent chemoradiotherapy (CCRT) plus consolidation chemotherapy for patients with stage I/II nasal natural killer/T‐cell lymphoma (NKTCL).