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1.  The Osteoblastogenesis Potential of Adipose Mesenchymal Stem Cells in Myeloma Patients Who Had Received Intensive Therapy 
PLoS ONE  2014;9(4):e94395.
Multiple myeloma (MM) is characterized by advanced osteolytic lesions resulting from the activation of osteoclasts (OCs) and inhibition of osteoblasts (OBs). OBs are derived from mesenchymal stem cells (MSCs) from the bone marrow (BM), however the pool and function of BMMSCs in MM patients (MM-BMMSCs) are reduced by myeloma cells (MCs) and cytokines secreted from MCs and related anti-MM treatment. Such reduction in MM-BMMSCs currently cannot be restored by any means. Recently, genetic aberrations of MM-BMMSCs have been noted, which further impaired their differentiation toward OBs. We hypothesize that the MSCs derived from adipose tissue (ADMSCs) can be used as alternative MSC sources to enhance the pool and function of OBs. Therefore, the purpose of this study was to compare the osteogenesis ability of paired ADMSCs and BMMSCs in MM patients who had completed intensive therapy. Fifteen MM patients who had received bortezomib-based induction and autologous transplantation were enrolled. At the third month after the transplant, the paired ADMSCs and BMMSCs were obtained and cultured. Compared with the BMMSCs, the ADMSCs exhibited a significantly higher expansion capacity (100% vs 13%, respectively; P = .001) and shorter doubling time (28 hours vs 115 hours, respectively; P = .019). After inducing osteogenic differentiation, although the ALP activity did not differ between the ADMSCs and BMMSCs (0.78 U/µg vs 0.74±0.14 U/µg, respectively; P = .834), the ADMSCs still exhibited higher calcium mineralization, which was determined using Alizarin red S (1029 nmole vs 341 nmole, respectively; P = .001) and von Kossa staining (2.6 E+05 µm2 vs 5 E+04 µm2, respectively; P = .042), than the BMMSCs did. Our results suggested that ADMSCs are a feasible MSC source for enhancing the pool and function of OBs in MM patients who have received intensive therapy.
doi:10.1371/journal.pone.0094395
PMCID: PMC3983165  PMID: 24722177
2.  Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma 
Annals of Hematology  2014;93:1371-1380.
Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.
doi:10.1007/s00277-014-2063-7
PMCID: PMC4082140  PMID: 24687382
Cereblon; Immunohistochemistry; Immunomodulatory drugs; Multiple myeloma; Prognosis
3.  Clinical and Microbiological Characteristics of Perianal Infections in Adult Patients with Acute Leukemia 
PLoS ONE  2013;8(4):e60624.
Background
Perianal infection is a common problem for patients with acute leukemia. However, neutropenia and bleeding tendency are relatively contraindicated to surgical intervention. The epidemiology, microbiology, clinical manifestations and outcomes of perianal infection in leukemic patients are also rarely discussed.
Method
The medical records of 1102 adult patients with acute leukemia at a tertiary medical center in Taiwan between 2001 and 2010 were retrospectively reviewed and analyzed.
Result
The prevalence of perianal infection was 6.7% (74 of 1102) in adult patients with acute leukemia. Twenty-three (31%) of the 74 patients had recurrent episodes of perianal infections. Patients with acute myeloid leukemia had higher recurrent rates than acute lymphoblastic leukemia patients (p = 0.028). More than half (n = 61, 53%) of the perianal infections were caused by gram-negative bacilli, followed by gram-positive cocci (n = 36, 31%), anaerobes (n = 18, 15%) and Candida (n = 1, 1%) from pus culture. Eighteen patients experienced bacteremia (n = 24) or candidemia (n = 1). Overall 41 (68%) of 60 patients had polymicrobial infection. Escherichia coli (25%) was the most common micro-organism isolated, followed by Enterococcus species (22%), Klebsiella pneumoniae (13%), and Bacteroides species (11%). Twenty-five (34%) of 74 patients received surgical intervention. Acute leukemia patients with surgically managed anal fistulas tended to have fewer recurrences (p = 0.067). Four (5%) patients died within 30 days after diagnosis of perianal infection. Univariate analysis of 30-day survival revealed the elderly (≧ 65 years) (p = 0.015) and patients with shock (p<0.001) had worse outcome. Multivariate analysis showed septic shock to be the independent predictive factor of 30-day crude mortality of perianal infections (p = 0.016).
Conclusion
Perianal infections were common and had high recurrence rate in adult patients with acute leukemia. Empirical broad-spectrum antibiotics with anaerobic coverage should be considered. Shock independently predicted 30-day crude mortality. Surgical intervention for perianal infection remains challenging in patients with acute leukemia.
doi:10.1371/journal.pone.0060624
PMCID: PMC3618431  PMID: 23577135
4.  Intracranial hemorrhage in adult patients with hematological malignancies 
BMC Medicine  2012;10:97.
Background
Clinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited.
Methods
A total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed.
Results
A total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%, P = 0.001). ICH was more common among patients with central nervous system (CNS) involvement of lymphoma than among patients with CNS involved acute leukemia (P <0.001). Sites of ICH occurrence included the cerebral cortex (60 patients, 83%), basal ganglia (13 patients, 18%), cerebellum (10 patients, 14%), and brainstem (5 patients, 7%). A total of 33 patients (46%) had multifocal hemorrhages. In all, 56 patients (77%) had intraparenchymal hemorrhage, 22 patients (31%) had subdural hemorrhage, 15 patients (21%) had subarachnoid hemorrhage (SAH), and 3 patients (4%) had epidural hemorrhage. A total of 22 patients had 2 or more types of ICH. In all, 46 (64%) patients died of ICH within 30 days of diagnosis, irrespective of the type of hematological malignancy. Multivariate analysis revealed three independent prognostic factors: prolonged prothrombin time (P = 0.008), SAH (P = 0.021), and multifocal cerebral hemorrhage (P = 0.026).
Conclusions
The incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies.
doi:10.1186/1741-7015-10-97
PMCID: PMC3482556  PMID: 22931433
central nervous system (CNS) involvement; cerebral hemorrhage; hematological malignancy; prognosis; neuroimage
5.  Clinical characteristics and outcomes of Mycobacterium tuberculosis disease in adult patients with hematological malignancies 
BMC Infectious Diseases  2011;11:324.
Background
Diseases caused by Mycobacterium tuberculosis (TB) among adult patients with hematological malignancies have rarely been investigated.
Methods
Adult patients with hematological malignancies at National Taiwan University Hospital between 1996 and 2009 were retrospectively reviewed. Patients with positive serology for HIV were excluded. TB disease is diagnosed by positive culture(s) in the presence of compatible symptoms and signs. The demographics, laboratory and, microbiological features, were analyzed in the context of clinical outcomes.
Results
Fifty-three of 2984 patients (1.78%) were diagnosed with TB disease. The estimated incidence was 120 per 100,000 adult patients with hematological malignancies. Patients with acute myeloid leukemia had a significantly higher incidence of TB disease than other subtypes of hematological malignancies (2.87% vs. 1.21%, p = 0.002, odds ratio, 2.40; 95% confidence interval, 1.39-4.41). Thirty-eight patients (72%) with non-disseminated pulmonary TB disease presented typically with mediastinal lymphadenopathy (53%), pleural effusion (47%) and fibrocalcific lesions (43%) on chest imaging. The 15 (28%) patients with extra-pulmonary disease had lower rates of defervescence within 72 h of empirical antimicrobial therapy (13% vs 45%, p = 0.03) and a higher 30-day in-hospital mortality (20% vs. 0%, p = 0.004) compared to those with disease confined to the lungs.
Conclusions
TB disease is not uncommon among patients with hematological malignancies in Taiwan. Patients who received a diagnosis of extra-pulmonary TB suffered higher mortality than those with pulmonary TB alone. Clinicians should consider TB in the differential diagnoses of prolonged fever in patients with hematological malignancies, particularly in regions of high endemicity.
doi:10.1186/1471-2334-11-324
PMCID: PMC3241214  PMID: 22111760
Mycobacterium tuberculosis (TB); Hematological malignancy; Febrile neutropenia
6.  Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan 
BMC Infectious Diseases  2011;11:250.
Background
Risk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era.
Method
A retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009.
Results
Clinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm3 for more than 10 days) (p < 0.001). Aspergillus flavus was the most common pathogen isolated (44%). Serum Aspergillus galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS.
Conclusions
Patients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS.
doi:10.1186/1471-2334-11-250
PMCID: PMC3196720  PMID: 21939544
Invasive fungal sinusitis (IFS) ; hematological disease;  Aspergillus galactomanan
7.  Extramedullary plasmacytoma masquerading as Tolosa–Hunt syndrome: a case report 
BMJ Case Reports  2009;2009:bcr08.2008.0804.
Painful ophthalmoplegia due to extramedullary plasmacytoma is a rare initial manifestation of multiple myeloma. The present report describes a 48-year-old man who suffered an acute onset of retro-orbital pain, left abducens palsy and left facial hypoesthesia. In addition, he exhibited an elevated erythrocyte sedimentation rate and partial responsiveness to corticosteroid treatment, all of which resemble the features of Tolosa–Hunt syndrome. Imaging studies revealed a multilobulated tumour invading the left sphenoid bone and sphenoid sinus, later confirmed as a plasmacytoma at pathology. Multiple myeloma was also diagnosed by bone marrow examination. After completion of chemotherapy and radiotherapy, the patient has been free of symptoms for 10 months. Although cranial neuropathies with any combination of oculomotor, abducens, trochlear, ophthalmic and maxillary nerves may indicate a cavernous sinus lesion, neuropathies exclusive to the abducens and maxillary nerves may raise the possibility of extracavernous sinus origin. Cranial imaging is crucial in diagnosing painful ophthalmoplegia with additional minimal cranial nerve signs.
doi:10.1136/bcr.08.2008.0804
PMCID: PMC3029032  PMID: 21686622

Results 1-8 (8)