Dasatinib-related chylothorax.

Dasatinib is a potent second-generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia. The most common adverse event associated with dasatinib therapy is fluid retention, including pleural effusion. Dasatinib-related chylothorax has rarely been reported. The clinical manifestations, pathophysiology, management, and prognosis are not fully understood. Here we report a 40-year-old woman presenting with chylothorax following dasatinib use. We propose the hypothesis of its mechanism as well as offering a review of the relevant literature.

Pretreatment performance status and nutrition are associated with early mortality of locally advanced head and neck cancer patients undergoing concurrent chemoradiation.

Unexpected fatal events in patients with head and neck cancers undergoing concurrent chemoradiation therapy are a clinical concern. Malnutrition, which is reported frequently in head and neck cancer patients, are associated with immunity derangement. The purpose of this study was to identify risk factors for early death of patients undergoing chemoradiation. We retrospectively analyzed the records of 194 stage III, IVA, and IVB head and neck cancer patients who were treated with chemoradiation between 2007 and 2009. We defined early death as death while receiving chemoradiation or within 60 days of treatment completion. Risk factors for early death were tested using univariate and multivariate analyses. Fourteen patients (7.2 %) experienced early death, 78.6 % of whom died of infection. Univariate analysis revealed significant correlations between early death and several pretreatment variables, including Eastern Cooperative Oncology Group performance status (PS) >1, hemoglobin <10 g/dL, albumin <3 g/dL, body mass index (BMI) <19 kg/m(2), and peripheral blood total lymphocyte count <700/µL. Multivariate analysis showed that PS >1, BMI <19 kg/m(2), and peripheral blood total lymphocyte count <700/µL were independent variables associated with early death. Poor performance status and malnutrition before chemoradiation independently predict early death in locally advanced head and neck cancer patients undergoing chemoradiation. Cautious management of head and neck cancer patients with these risk factors is required throughout chemoradiation period.

Developmental silencing of human zeta-globin gene expression is mediated by the transcriptional repressor RREB1.

The mammalian embryonic zeta-globin genes, including that of humans, are expressed at the early embryonic stage and then switched off during erythroid development. This autonomous silencing of the zeta-globin gene transcription is probably regulated by the cooperative work of various protein-DNA and protein-protein complexes formed at the zeta-globin promoter and its upstream enhancer (HS-40). We present data here indicating that a protein-binding motif, ZF2, contributes to the repression of the HS-40-regulated human zeta-promoter activity in erythroid cell lines and in transgenic mice. Combined site-directed mutagenesis and EMSA suggest that repression of the human zeta-globin promoter is mediated through binding of the zinc finger factor RREB1 to ZF2. This model is further supported by the observation that human zeta-globin gene transcription is elevated in the human erythroid K562 cell line or the primary erythroid culture upon RNA interference (RNAi)(2) knockdown of RREB1 expression. These data together suggest that RREB1 is a putative repressor for the silencing of the mammalian zeta-globin genes during erythroid development. Because zeta-globin is a powerful inhibitor of HbS polymerization, our experiments have provided a foundation for therapeutic up-regulation of zeta-globin gene expression in patients with severe hemoglobinopathies.

Late-outgrowth endothelial cells attenuate intimal hyperplasia contributed by mesenchymal stem cells after vascular injury.

OBJECTIVE: Mesenchymal stem cells (MSCs) are one of a number of cell types undergoing extensive investigation for cardiac regeneration therapy. It has not yet been determined whether this cell therapy also substantially contributes to vascular remodeling of diseased vessels. METHODS AND RESULTS: Human MSCs and a variety of progenitor and vascular cells were used for in vitro and in vivo experiments. Wire-induced vascular injury mobilized MSCs into the circulation. Compared with human aortic smooth muscle cells, MSCs exhibited a 2.8-fold increase in the adhesion capacity in vitro (P<0.001) and a 6.3-fold increase in vivo (P<0.001). In all animal models, a significant amount of MSCs contributed to intimal hyperplasia after vascular injury. MSCs were able to differentiate into cells of endothelial or smooth muscle lineage. Coculture experiments demonstrated that late-outgrowth endothelial cells (OECs) guided MSCs to differentiate toward an endothelial lineage through a paracrine effects. In vivo, cell therapy with OECs significantly attenuated the thickness of the neointima contributed by MSCs (intima/media ratio, from 3.2+/-0.4 to 0.4+/-0.1, P<0.001). CONCLUSIONS: Tissue regeneration therapy with MSCs or cell populations containing MSCs requires a strategy to attenuate the high potential of MSCs to develop intimal hyperplasia on diseased vessels.

Eltrombopag enhances platelet adhesion by upregulating the expression of glycoprotein VI in patients with chronic immune thrombocytopenic purpura.

Eltrombopag, a thrombopoietin receptor agonist, has been approved for the treatment of patients with immune thrombocytopenia because of its abilities to enhance platelet production and reduce hemorrhage. Both platelet count and platelet adhesion are crucial to stop bleeding. Although eltrombopag is known to improve platelet counts, its effects on platelet adhesion are not yet known. This study aimed to assess the efficacy of eltrombopag on platelet production and platelet adhesive affinity. To evaluate the efficacy of low-dose eltrombopag (25 mg) for patients with chronic refractory immune thrombocytopenic purpura (ITP) and to determine the ex vivo platelet adhesion ability before and after treatment with eltrombopag, we conducted an open-label, multicenter study in which 25 Taiwanese patients with chronic ITP were enrolled. During the 6-month evaluation, the starting and maximum doses of eltrombopag were 25 and 50 mg, respectively, to maintain the platelet count of ≥50,000 per µL. Flow-based adhesion assay was used to detect the percentage of platelets adhering to immobilized von Willebrand factor-collagen on microslides. Of the enrolled patients, 48% achieved a platelet count of ≥50,000 per µL. Interestingly, 83% of all responders required 25 mg of eltrombopag daily to achieve the target platelet count. In addition, the percentage of bleeding patients was significantly reduced in both responders and nonresponders by 50% from the baseline level throughout the treatment period. The ex vivo platelet adhesion capacity was elevated after the 6-month eltrombopag treatment in both responders and nonresponders. Furthermore, glycoprotein VI (GPVI) expression was significantly upregulated after treatment with eltrombopag. Low-to-intermediate dose of eltrombopag showed good efficacy to expedite platelet production and augment platelet adhesion. These 2 factors might explain the efficacy of eltrombopag in ameliorating hemorrhage in patients with ITP.

Guidelines for treating iron overload in myelodysplastic syndromes: a Taiwan consensus statement.

Iron overload is common in myelodysplastic syndrome (MDS) patients, and an accumulation of evidence shows that iron chelation may have benefits in these patients. However, discussion and consensus about iron chelation therapy (ICT) for MDS patients is lacking in Taiwan and other Southeast Asian countries. An Expert Panel in Taiwan was organized in 2011 to develop iron overload guidelines and provide a uniform reference for physicians treating MDS patients with iron overload, with specific regard to when to initiate ICT, in which patients, and the clinical and scientific rationale behind its use.

Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia.

OBJECTIVE: To evaluate whether an oral nutritional supplement enriched with omega-3 fatty acids, micronutrients, and probiotics affected body weight (BW) changes, serum albumin and prealbumin levels in patients with head and neck cancer (HNC) cachexia. STUDY DESIGN: Sixty-eight HNC patients were randomly assigned to receive either an Ethanwell/Ethanzyme (EE) regimen enriched with omega-3 fatty acids, micronutrients, and probiotics, or control (Isocal) for a 3-month period. Analysis of covariance was used to examine the association between BW change and variables. RESULTS: Patients with body mass index (BMI) <19 and those receiving the EE regimen consumed fewer daily calories but showed significantly increased BW and maintained higher serum albumin and prealbumin levels than other patients (P<.05). Their BW changes were significantly associated with changes in serum albumin and prealbumin levels. CONCLUSIONS: EE regimen improved BW as well as serum albumin and prealbumin levels in HNC patients with BMI <19.

Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure.

Some chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI) do not respond or relapse. BCR-ABL1 mutations are the principal cause of TKI resistance, but the kinetics of emerging mutations in CML patients treated with imatinib remain to be determined. To investigate the emergence dynamics of mutations and their effects on outcomes, we conducted a systematically longitudinal study of BCR-ABL1 mutation dynamics during TKI therapy. Seminested polymerase chain reaction followed by denaturing high-performance liquid chromatography with sequence confirmation were used to detect BCR-ABL1 mutations in 202 CML patients with imatinib resistance at different CML phases. We detected 68 mutations in 58 imatinib-failure patients. Mutations were present in 27.6% of patients who failed front-line imatinib therapy and in 68.1% with advanced disease. Mutations were not detected in patients before commencing imatinib treatment. Pyrosequencing was then used to quantitatively monitor the mutant levels sequentially and also traced back for their earlier appearance. The mutants differed in rapidity of emergence which appeared to arise in different time frame as well as in speed of rising mutant levels. In the 78 front-line imatinib-failure patients, mutation positive patients had significantly higher risk of disease progression or relapse and inferior progression-free survival compared to those without mutations (p=0.006). Our study demonstrates kinetics of different BCR-ABL1 mutant emergence and an association between BCR-ABL1 mutations and disease progression.

Cyclosporine increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system.

Cyclosporin A (CsA) improves the success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57BL/6 mice were divided into control and CsA-treated groups. Before and after hindlimb ischemia was induced, circulating EPC number and serum levels of different cytokines were measured. Compared with the controls, CsA treatment significantly increased the blood levels of stroma-derived factor-1alpha and stem cell factor after ischemic stress (P < 0.001). The CsA group displayed a significant increase in the number of circulating EPCs (sca-1+KDR+ and c-kit+CD31+ EPCs, both P < 0.05). In vivo, CsA caused a significant increase in the numbers of EPCs incorporated into the Matrigel and ischemic limbs (P < 0.05). In the peripheral blood, CsA significantly decreased CD26+ cell numbers and attenuated the plasma CD26/DPP IV activity (P < 0.001). Furthermore, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In summary, CsA manipulates the mobilization of EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogenesis of ischemic tissues.

Leukapheresis and cranial irradiation in patients with hyperleukocytic acute myeloid leukemia: no impact on early mortality and intracranial hemorrhage.

To assess the role of leukapheresis and cranial irradiation in reducing the incidence of intracranial hemorrhage (ICH) and early death in patients with hyperleukocytic acute myeloid leukemia (AML) and the impact of such treatment on survival. This study retrospectively analyzed the records of 75 patients with hyperleukocytic AML who had a white cell count over 100,000/microL. All patients had de novo AML except for two with therapy-related AML. Various factors were assessed for their impact on morbidity and mortality, particularly the role of pre-induction leukapharesis and cranial irradiation. The most significant risk factors for ICH were the presence of two or more symptoms of leukostasis (odds ratios [OR] 10.6, 95% CI: 2.67-42.02; P = 0.001) and respiratory distress (OR 5.41, 95% CI: 1.44-20.32, P = 0.012). The most significant risk factors for early death were age >or= 65 (OR 4.21, 95% CI: 1.45-12.21, P = 0.008), respiratory failure (OR 3.34, 95% CI: 1.24-9.50, P = 0.018), and two or more symptoms (OR 3.50 95% CI: 1.16-10.52, P = 0.026). Neither leukapheresis nor cranial irradiation were significantly associated with a decreased incidence of ICH (P = 0.349 and 0.378, respectively). Leukapheresis had no significant influence on early death (P = 0.367). The median survival patients receiving no pretreatment was 10.50 months (range 2.58-18.42) and for those receiving pretreatment 1.50 months (range 0.10-3.16; log-rank test, P = 0.062). Leukapheresis and cranial irradiation do not improve survival or decrease the incidence of ICH in adults with hyperleukocytic AML.

Decreasing dosage of irinotecan, 5-flurouracil (5-FU) and leucovorin (LV) in the treatment of advanced and/or metastatic colorectal cancer: a phase II study.

BACKGROUND: In this study, we attempted to determine the efficacy and toxicity of decreasing dosage of irinotecan plus 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of advanced colorectal cancer. METHODS: A total of 250 mg/m2 Irinotecan (CPT-11) intravenous infusion for 90 minutes was administered every 3 weeks. A 24-hour intravenous infusion with 2000 mg/m2 5-FU and 200 mg/m2 LV was administered through a port-A catheter system weekly for 2 consecutive weeks. Each treatment cycle was repeated every 3 weeks. Progression-free survival and survival curves were drawn according to Kaplan-Meier method. Tumor responses were determined according to the RECIST guidelines. Toxicities were evaluated using the WHO criteria. RESULTS: Thirty-eight patients were enrolled from September 2001 through October 2004. The median number of treatment courses was 8.1 (range, 1-14). Based on the intent-to-treat principle, the response rate was 39.5% (95% CI: 25.4-54.4%) which included 5.3% complete response (CR) and 34.2% partial response (PR). The time to tumor progression was 8.4 months (range, 2-12 months). The median time of survival was 18.4 months (range, 4-26 months). The major toxicities were grade 1 neutropenia and grade 2 diarrhea. Toxic death was not found in this study. The efficacy of this regimen was compatible with the reports of the clinical trials in the United States and European countries but fewer incidence of toxicity was found in our results. CONCLUSION: The results revealed that our combination regimen of 5-FU/LV + CPT-11 is a highly effective and acceptable protocol. This treatment is easily performed in an outpatient clinic. The biggest advantage is that all patients were intensively cared by the physicians to maintain a quality of life, and only 26.3% of patients showed progressive disease. Therefore, this regimen may be considered to be used in the treatment of patients with terminal cancer. A further randomized study comparing this regimen with oral fluoropyrimidines plus irinotecan is warranted.

Hypercalcemia in prostate cancer with positive neuron-specific enolase stain.

Hypercalcemia is a common complication of malignant diseases with or without bone metastasis. Hypercalcemia in prostate cancer is rarely seen. The exact mechanism of prostate cancer-related hypercalcemia is still uncertain. Secretion of parathyroid hormone-related peptides (PTH-rP) is thought to be one of the possible mechanisms. We reported a rare case of prostate cancer with hypercalcemia (13 mg/dL). Bone marrow biopsy showed metastatic adenocarcinoma. The cells were also positive for neuron-specific enolase, which is the specific marker for neuroendocrine cell. The finding suggested that the prostate cancer cell derived from the neuroendocrine cell, which might synthesize PTH-rP and be responsible for the observed hypercalcemia.

A randomized trial comparing intravesical instillations of mitoxantrone and doxorubicin in patients with superficial bladder cancer.

BACKGROUND: This randomized trial was conducted to compare the efficacy and side effects of intravesical mitoxantrone instillation with those of doxorubicin in superficial bladder cancer following transurethral resection. METHODS: Sixty-three patients were randomized into mitoxantrone and doxorubicin groups. Most of the patients enrolled were elderly people (mean age, 71 years). The instilled doses of doxorubicin and mitoxantrone were 30 and 14 mg, respectively. Disease recurrence and side effects were compared using Fisher's exact test. The interval to recurrence was shown by Kaplan-Meier survivorship curves, and the log-rank test was used to compare the time to recurrence. RESULTS: The median follow-up period was 36 months. Thirty-three patients received mitoxantrone, whereas 30 patients used doxorubicin. The recurrence rate in the doxorubicin group was 30% (95% CI: 19.8%-38.8%), while it was 27.3% (95% CI: 17.5%-36.8%) in the mitoxantrone group. The median recurrence-free survival in the mitoxantrone group and in the doxorubicin group was 22 and 20 months, respectively (p=0.580). Higher recurrence rates were found for Grade III and multiple primary tumors. There was no significant difference in response rates (p=0.784). The incidence of side effects was 20% in the doxorubicin group and 21.2% in the mitoxantrone group. However, the difference was not significant (p>0.99). CONCLUSIONS: The results revealed that the efficacy and side effects of mitoxantrone were similar to those of doxorubicin. Especially for patients with pulmonary tuberculosis or aged patients with primary bladder tumors, mitoxantrone and doxorubicin may be the tolerable and effective intravesical agents.