Risk of hemophagocytic lymphohistiocytosis in adults with fevers of unknown origin: the clinical utility of a new scoring system on early detection.

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naïve fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100 × 103 /µL), leukoerythroblastosis, hyperbilirubinemia (total bilirubin > 2 × upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355-1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883-0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH.

Risk of stroke in patients with newly diagnosed multiple myeloma: a retrospective cohort study.

Cerebrovascular events are a common complication among patients with cancer, increasing morbidity and mortality. However, the association between multiple myeloma and cerebrovascular events remains unclear. We therefore investigated multiple myeloma patients' risk factors for stroke to devise a better stroke-prevention strategy. This study includes consecutive patients 20 years and older who were newly diagnosed with symptomatic multiple myeloma at Taipei Veterans General Hospital, a tertiary medical center, between January 1, 2002 and December 31, 2014. The primary outcome was stroke development. Patients with head injuries, brain tumors, brain parenchymal invasions, or antecedent malignancies were excluded. Hazard ratios (HRs) of stroke risk factors for multiple myeloma patients were estimated by Cox proportional regression analysis. Overall, 395 patients with a median age of 70 years were investigated. In the median follow-up period of 18 months, cerebrovascular events occurred in 16 patients, including 10 ischemic strokes and 6 hemorrhagic strokes. The 5-year estimated cumulative incidence rate was 7.45%. In the multivariate analysis, the κ light chain isotype (adjusted HR, 8.37; 95% confidence interval [CI], 1.91-39.8), previous cerebrovascular accidents (adjusted HR, 5.16; 95% CI, 1.48-17.9), and serum creatinine > 2 mg/dL (adjusted HR, 4.21; 95% CI, 1.10-16.0) were identified as independent risk factors for stroke. Subgroup analysis showed that atrial fibrillation (adjusted HR, 8.07) and previous cerebrovascular accident (adjusted HR, 4.89) are significant risk factors for ischemic stroke. Serum creatinine > 2 mg/dL (adjusted HR, 30.6) and previous cerebrovascular accident (adjusted HR, 13.9) are significant for hemorrhagic stroke. Moreover, therapeutic strategies for multiple myeloma were not associated with stroke in our study. This study demonstrates that risk of stroke increases in myeloma patients with a κ light chain isotype, previous cerebrovascular events, and renal impairment. Further prospective clinical studies to clarify the relationship between multiple myeloma and stroke are warranted.

Clinical-associated characteristics and microbiological features of bloodstream nontyphoidal salmonella infection in adult patients receiving allogeneic hematopoietic stem cell transplantation.

Bloodstream nontyphoidal salmonella (NTS) infection is rare, but its associated characteristics and microbiological features in immunocompromised patients are worth paying attention to, particularly for those receiving allogeneic hematopoietic stem cell transplantation (SCT). No studies so far have analyzed post-transplant bloodstream NTS infection. Therefore, we reviewed 423 adult patients undergoing allogeneic hematopoietic SCT from 2003 to 2014. Nine out of four hundred twenty-three patients (2.13%) developed post-transplant bloodstream NTS infection, including two patients who had subsequent or combined metastatic infections. The median age at SCT was 35 years (interquartile range, 29-46) among the nine patients with bloodstream NTS infection. Male patients were predominant (78%). The median onset of bloodstream NTS infection was at 315 days after SCT (range, 207-629). Multivariate analysis revealed that extensive chronic graft-versus-host disease (GVHD) (OR 8.054, p = 0.003) and nonmyeloablative transplant conditioning (OR 4.604, p = 0.037) were significant associated characteristics for NTS infection. Currently, there are no published data analyzing and exploring post-transplant bloodstream NTS infections in adult allogeneic hematopoietic SCT. Our study determined the associated characteristics and microbiological features for this infection.

Risk factors and characteristics of blood stream infections in patients with newly diagnosed multiple myeloma.

BACKGROUND: Patients with multiple myeloma are generally immune-compromised either due to pronounced depression in primary antibody responses or because of anti-myeloma therapy. Infection is a major risk factor for early deaths among these patients. The impact of blood stream infections (BSI) on newly diagnosed myeloma patients has been less studied. We aimed to study the incidence and risk factors of BSI within 3 months after diagnosis of multiple myeloma in a tertiary referral center. METHODS: Between November 2002 and December 2008, consecutive patients with multiple myeloma in Taipei Veterans General Hospital were retrospectively enrolled. Characteristics of patients with or without BSI were collected. Possible factors associated with development of BSI were analyzed by Cox regression. RESULTS: There were a total of 222 patients. The incidence of BSI within 3 months after diagnosis is 11.7%. The patients with BSI had poorer survival outcomes than those without (mortality rate: 50% vs. 20.9%, p < 0.001). Moreover, advanced International Staging System stage (stage III vs. I/II: odds ratio [OR] 2.69, p = 0.049) and poor Eastern Cooperative Oncology Group (ECOG) performance status (ECOG > 2 vs. ≤ 2: OR 3.58, p = 0.005) were the independent risk factors of BSI, whereas immunoglobulin deficiency and low absolute lymphocyte count were not associated with risk of BSI development. CONCLUSIONS: Our study highlights the characteristic of myeloma patients with BSI and the importance of disease and host factors on risk of BSI. Myeloma patients with risks of BSI should be properly managed to reduce early mortality.

Chronic obstructive pulmonary disease associated with increased risk of bipolar disorder.

Epidemiological studies have identified a trend in the development of depressive and anxiety disorders following a diagnosis of chronic obstructive pulmonary disease (COPD). However, the relationship between COPD and subsequent bipolar disorder remains unclear. From January 1, 2000, we identified adult patients with COPD from the Taiwan National Health Insurance Research Database. A nationwide population-based study was conducted; 46,778 COPD patients and 46,778 age-, sex-, and comorbidity-matched subjects between 2000 and 2011 were enrolled. The two cohorts were followed up till December 31, 2011 and observed for occurrence of bipolar disorder. We observed the COPD and comparison cohorts for 263,020 and 267,895 person-years, respectively, from 2000 to 2011. The incidence rate for bipolar disorder was 1.6/1000 person-years in the COPD cohort and 1.2/1000 person-years in the comparison cohort ( p < 0.001). After multivariate adjustment, the hazard ratio (HR) for subsequent bipolar disorder among the COPD patients was 1.42 (95% confidence interval [CI], 1.22-1.64; p < 0.001). In the COPD patients, short-acting beta-agonists (SABAs) was associated with a significantly increased risk of bipolar disorder development (HR = 1.83, 95% CI = 1.25-2.69, p = 0.002). Other COPD medications were not associated with the risk of bipolar disorder development. The study results indicate that COPD may be an independent risk factor for the development of bipolar disorder. The regular use of SABAs might increase the risk of bipolar disorder in COPD patients.

Decision-tree algorithm for optimized hematopoietic progenitor cell-based predictions in peripheral blood stem cell mobilization.

BACKGROUND: Enumerating hematopoietic progenitor cells (HPCs) by using an automated hematology analyzer is a rapid, inexpensive, and simple method for predicting a successful harvest compared with enumerating circulating CD34+ cells. However, the optimal HPC cutoff count and the indicating factors to be considered for improved predicting have not yet been determined. STUDY DESIGN AND METHODS: Between 2007 and 2012, a total of 189 consecutive patients who proceeded to peripheral blood stem cell (PBSC) harvesting were retrospectively recruited. Baseline characteristics were analyzed to identify the risk factors for a failed harvest, which were defined as less than 2 × 10(6) CD34+ cells/kg. Variables identified by multivariate logistic regression and correlation analysis for predicting a successful harvest were subjected to classification and regression tree (CART) analysis. RESULTS: PBSCs were successfully harvested in 154 (81.5%) patients. An age of at least 60 years, a diagnosis of a solid tumor, at least five prior chemotherapy cycles, prior radiotherapy, and mobilization with granulocyte-colony-stimulating factor alone or high-dose cyclophosphamide were independent baseline predictors of poor mobilization. In CART analysis, patients with zero to two host risk factors and either higher HPC (≥28 × 10(6) /L) or mononuclear cell (MNC; ≥3.5 × 10(9) /L) counts were categorized as good mobilizers and their harvest success rate was 92.3%. By contrast, 30.3% of harvests were adequate in the patients with three to five host risk factors and lower HPC and MNC counts. CONCLUSION: A CART algorithm incorporating host predictors and HPC and MNC counts improves predictions in a successful harvest and might reduce the necessity of monitoring peripheral CD34+ cells.

Second primary malignancy risk among patients with gastric cancer: a nationwide population-based study in Taiwan.

BACKGROUND: Several studies have reported an increase in second primary malignancies (SPMs) among gastric cancer patients. METHODS: Patients who were newly diagnosed with gastric cancer between 1997 and 2011 were recruited from the Taiwan National Health Insurance database. Those who had antecedent malignancies or gastrointestinal stromal tumor were excluded. Standardized incidence ratios (SIRs) of SPMs were calculated. Risk factors for cancer development were analyzed by Cox proportional hazards models. Effects of treatments for gastric cancer were treated as time-dependent variables. RESULTS: During the 15-year study period, 47,729 gastric cancer patients were recruited. Overall, 2,110 SPMs developed during a total follow-up of 137,798 person-years. The SIR for all cancers was 1.46. The SIRs for specific follow-up periods were 1.43, 1.41, and 1.21 at >10 years, 5-10 years, and 1-5 years, respectively. After excluding SPMs that developed within 1 year, significantly higher SIRs were seen for cancers of the head and neck (1.34), esophagus (2.16), colon and rectum (1.37), bones and soft tissues (1.95), ovaries (2.89), bladder (1.47), or kidneys (1.44), as well as non-Hodgkin's lymphoma (5.56). Multivariate analysis showed that age ≥70 years [hazard ratio (HR) 1.19], being male (HR 1.37), diabetes mellitus (HR 1.30), chronic obstructive pulmonary disease (HR 1.17), and liver cirrhosis (HR 1.94) were independent risk factors. Radiotherapy (HR 1.24) and chemotherapy (HR 1.87) were independent risk factors, but surgery (HR 0.67) was not. CONCLUSIONS: Patients with gastric cancer are at increased risk of developing SPM. Close surveillance of patients with risk factors over a longer period should be considered.

Risk and impact of tuberculosis in patients with chronic myeloid leukemia: a nationwide population-based study in Taiwan.

The relationship between chronic myeloid leukemia (CML) and tuberculosis (TB) has not been determined. We conducted a national survey including 1,082 CML patients identified from the Taiwan National Health Insurance database covering a period between 1998 and 2011; the matched non-exposed cohort included 10,820 subjects without CML that were matched for age, sex and comorbidities. The impact of TB was measured by the overall mortality, and the risk factors were identified by a multivariate Cox proportional hazards model. We found the risk of TB was higher in the CML cohort, with an adjusted hazard ratio (aHR) of 3.76 (p = 0.001) for both pulmonary (aHR 3.23, p < 0.001) and extrapulmonary (aHR 9.77, p = 0.001) TB. Specific risk factors were: aged ≥ 60 (aHR 3.24, p = 0.022), being male (aHR 13.49, p = 0.012), receiving stem cell transplantation (aHR 10.50, p = 0.001) and interferon-α therapy (aHR 3.34, p = 0.011). CML patients with TB had a higher mortality rate than those without (aHR 2.04, p = 0.043). We conclude that the incidence of TB is significantly higher in CML patients of male sex, aged ≥ 60, having received either stem cell transplantation or interferon-α treatment. Careful screening strategies for TB should be considered for CML patients with high risk of the infection.

Frequency of surveillance computed tomography in non-Hodgkin lymphoma and the risk of secondary primary malignancies: A nationwide population-based study.

With increasing usage of computed tomography (CT) for lymphoma patients receiving curative-intent treatment, development of secondary primary malignancy (SPM) related to radiation from CT scans becomes an emerging issue in these long-term survivors. We conducted a nationwide population-based study analyzing non-Hodgkin lymphoma (NHL) patients receiving curative-intent treatment between January 1997 and December 2010. Patients were divided into two populations by the medium number of CT performed. The cumulative incidence of SPM in these two groups was compared using the Kaplan-Meier method. Propensity score matching was applied to eliminate potential confounders. Group stratification and multivariate analyses calculated by Cox proportional hazard models using competing risk analyses adjusted for mortality were performed to identify independent predictors for SPM. Patients receiving >8 CT scans had a significantly greater risk for developing SPM (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.61-3.13; p < 0.001) than those with ≤8 scans and this difference remained significant even after correction with propensity score matching. Among the 180 SPM identified, those receiving more CT scans had significantly higher SPM incidence in cancers of the breast (HR 11.22), stomach (HR 5.22) and liver and biliary tract (HR 2.18) in comparison to those with less exposure. The risk of SPM was estimated to increase 3% per one more CT scan performed. Our study demonstrated that after curative-intent treatment, patients with NHL receiving more frequent surveillance CT scans would have an increased risk of SPM.

Risk factors for pericardial effusion in adult patients receiving allogeneic haematopoietic stem cell transplantation.

Pericardial effusion (PE) is a rare but potentially life-threatening complication for allogeneic haematopoietic stem cell transplantation (HSCT) recipients. The risk factors, aetiology, incidence and therapy are largely unclear. To investigate this issue, we reviewed 391 adult patients undergoing allogeneic HSCT between January 2003 and December 2013. Twelve out of 391 patients (3·1%) developed PE of moderate to large amounts, including 9 out of 12 patients (75%) identified as late-onset PE. Two out of the nine patients with late-onset PE experienced recurrent effusion. The median age at HSCT was 44·5 years (range: 22-63 years) among the 12 patients with PE and 47 years in the late-onset patients. Multivariate analysis revealed that multiple transplant procedures was a significant risk factor for PE (P = 0·036) and a trend as risk factor in patients aged>50 years (P = 0·066). For late-onset PE, pre-transplant age>50 years (P = 0·032) and extensive chronic graft-versus-host disease (cGVHD) (P = 0·006) remained statistically significant on multivariate analysis. Currently, there are no published data exploring the risk factors for post-transplant PE in adult patients of allogeneic HSCT. Our study determined the risk factors and incidence for the post-transplant PE, especially in the late-onset group.

No increase of JAK2 46/1 haplotype frequency in essential thrombocythemia with CALR mutations: Functional effect of the haplotype limited to allele with JAK2V617F mutation but not CALR mutation.

The true frequency of the JAK2 46/1 haplotype in patients of myeloproliferative neoplasms (MPN) with CALR mutations was unknown. Totally 187 MPN cases with diagnosis of polycythemia vera (PV) and essential thrombocythemia (ET) were recruited. The frequency of 46/1 haplotype was significantly higher in JAK2V617F-positive PV (51%, p < 0.001) and ET (41%, p = 0.005) compared to normal controls. The exact location of JAK2V617F mutation was located at the cis-46/1 haplotype in 86.4% (32/37) PV patients and 87.5% (28/32) ET patients, respectively. Among the 51 patients of ET without JAK2V617F mutation, 38 (75%) patients harbored CALR mutations and 3 patients had MPL mutation. The frequency of 46/1 haplotype in the 38 ET patients with CALR mutations was 27%, which is not significantly different from that of normal control (p value = 0.879). Compared to non-46/1 haplotype, the presence of 46/1 haplotype had a trend to have higher white blood cell count in JAK2V617F-mutated PV and ET patients but not in CALR-mutated ET. We conclude that the 46/1 haplotype could have functioning effect but only in the context of JAK2V617F mutation.

Amyloidosis and the risk of cancer: a nationwide population-based study.

BACKGROUND: The association between amyloidosis and cancer remains unclear. PARTICIPANTS AND METHODS: Using the Taiwan National Health Insurance Research Database we conducted a population-based cohort study. Patients newly diagnosed with amyloidosis between 1997 and 2009 were enrolled. Patients with antecedent cancer were excluded. Standardized incidence ratios (SIR) of cancers were calculated for the study cohort and compared with cancer incidence among the general population. We used a multivariate Cox regression model to evaluate the predictors of cancer development for patients with amyloidosis. RESULTS: The study included 1,693 subjects with median follow-up of 5.63 years. A total of 68 patients developed cancer. The incidence of kidney cancer (SIR 3.42; 95 % CI 1.11-7.97; p = 0.034) and hematologic malignancies (SIR 3.88; 95 % CI 1.86-7.14; p < 0.001) were significantly higher for patients with amyloidosis. CONCLUSION: This is currently the largest study to evaluate cancer risk among patients with amyloidosis. The results indicate that amyloidosis may be associated with an increased risk of kidney cancer and hematologic malignancies.

External beam radiation therapy with or without concurrent chemotherapy for patients with unresectable locally advanced hilar cholangiocarcinoma.

BACKGROUND/AIMS: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) compared to radiotherapy (RT) for unresectable, locally advanced hilar cholangiocarcinoma (HCCA). METHODOLOGY: Between 2001 and 2010, 34 patients with unresectable locally advanced HCCA at our institute were reviewed. Eighteen patients received RT and 16 patients received CCRT. Survivals and multivariate analyses were performed to explore potential variables affecting survivals. RESULTS: There were 18 males and 16 females, with a median age of 72 years and median follow-up time 9.4 months. The median overall survival (OS) was 10.4 months (95% CI, 6.7-13.5) with the 1-year survival rates of 41%. The median OS and progression-free survival (PFS) were 13.5 months and 8.8 months for patients receiving CCRT as compared to 6.7 months and 4.4 months for patients receiving RT alone (p = 0.003 and p = 0.005, respectively). On multivariate analysis demonstrated that Karnofsky performance status (KPS) ≥ 80 (p = 0.001), pretreatment carbohydrate antigen 19-9 (CA 19-9) 200 U/ml (p = 0.045) and CCRT were prognostic factors for OS and PFS. CONCLUSIONS: As compared with RT, CCRT provides longer OS and PFS for patients with unresectable HCCA. The efficacy of adding novel chemotherapeutic to RT needs to be further investigated.

Thymosin beta-4 knockdown in IEC-6 normal intestinal epithelial cells induces DNA re-replication via downregulating Emi1.

Thymosin ß4 (Tß4 ) is a multifunctional protein already used clinically to treat various diseases; however, the promoting effect of this protein on tumor malignancy should not be neglected. Here, we assessed whether Tß4 alteration influences normal intestinal epithelial cells because Tß4 is deemed a novel target for treating colorectal cancer (CRC). For this purpose, we examined the consequences of shRNA-mediated knockdown of Tß4 in IEC-6 normal rat small intestinal cells and found that inhibiting Tß4 expression significantly suppressed their growth and induced apoptosis in some cells. Flow cytometric analysis further revealed a marked decrease of G0/G1 population but a drastic increase of polyploid ones in these cells. The increase of polyploidy likely resulted from DNA re-replication because not only the de novo DNA synthesis was greatly increased but also the expression levels of Cdc6 (a replication-licensing factor), cyclin A, and phosphorylated-checkpoint kinase 1 were all dramatically elevated. Moreover, marked reductions in both RNA and protein levels of Emi1 (early mitotic inhibitor 1) were also detected in Tß4 -downregulated IEC-6 cells which might be accounted by the downregulation of E2F1, a transcription factor capable of inducing Emi1 expression, mediated by glycogen synthase-3ß (GSK-3ß). To our best knowledge, this is the first report showing that inhibiting Tß4 expression triggers DNA re-replication in normal intestinal epithelial cells, suggesting that this G-actin sequester may play a crucial role in maintaining genome stability in these cells. More importantly, clinical oncologists should take this novel activity into consideration when design CRC therapy based on targeting Tß4 .

Cancer risk among patients with coal workers' pneumoconiosis in Taiwan: a nationwide population-based study.

This study is aimed to evaluate the cancer risk among patients with coal workers' pneumoconiosis (CWP) using a nationwide population-based dataset. Patients without previous cancer who had been diagnosed with CWP and followed-up for more than 1 year between 1997 and 2006 were recruited from the Taiwan National Health Insurance database. Standardized incidence ratios (SIRs) of cancers in CWP patients were calculated and compared to the cancer incidence in the general population. Risk factors for cancer development were also analyzed. After a median follow-up of 9.68 years, 954 cancers developed among 8,051 recruited CWP patients, with a follow-up of 69,398 person-years. The SIR for all cancers was 1.12 [95% confidence interval (CI) 1.04-1.18]. Males older than 80 years had a SIR of 1.27 (95% CI: 1.06-1.51). The SIRs of esophageal (1.76, 95% CI: 1.24-2.44), gastric (1.42, 95% CI: 1.13-1.76), liver and biliary tract (1.18, 95% CI: 1.01-1.37) and lung and mediastinal (1.45, 95% CI: 1.26-1.66) cancers were significantly higher in the CWP group than in the general population. Multivariate analysis showed that age ≥ 60 years [hazard ratio (HR) 1.70, 95% CI: 1.41-2.05), male gender (HR = 1.79, 95% CI: 1.44-2.23) and liver cirrhosis (HR = 3.99, 95% CI: 2.89-5.51) were significant predictors of cancer development in patients with CWP. We concluded that patients with CWP, especially elderly males, were at increased risk of cancer. Age, male gender and liver cirrhosis were independent risk factors for cancer development.

Risk of ischemic stroke in patients with ovarian cancer: a nationwide population-based study.

BACKGROUND: Cancer patients are at risk of thromboembolism. However, studies investigating the relationship between ovarian cancer and ischemic stroke are lacking. The objectives of this study were to assess the association between ovarian cancer and ischemic stroke, and to determine the predictive risk factors. METHODS: Ovarian cancer patients aged 20 years and older without antecedent cerebrovascular events and who were followed up for more than 1 year between 1 January 2003 and 31 December 2011 were recruited from the Taiwan National Health Insurance database. Hazard ratios (HRs) of stroke risk for ovarian cancer patients compared with an age- and comorbidity-matched cohort were calculated by Cox proportional regression analysis. The difference in cumulative ischemic stroke incidence between ovarian cancer patients and the matched cohort was analyzed with the Kaplan-Meier method and tested with the log-rank test. RESULTS: Each cohort (ovarian cancer and matched cohort) consisted of 8,810 individuals, with a median age of 49 years. After a median follow-up of 2.68 and 3.85 years, respectively, the ischemic stroke incidence was 1.38-fold higher in the ovarian cancer cohort than in the comparison cohort (9.4 versus 6.8 per 1,000 person-years), with an age- and comorbidity-adjusted HR of 1.49 (P <0.001). The ischemic stroke risk imposed by ovarian cancer was more prominent in patients under 50 years old (HR 2.28; P <0.001) compared with patients 50 years and older (HR 1.33; P = 0.005). Significant risk factors predicting stroke development were age 50 years and older (HR 2.21; P <0.001), hypertension (HR 1.84; P <0.001), diabetes mellitus (HR 1.71; P <0.001), and treatment with chemotherapy (HR 1.45; P = 0.017), especially platinum-based regimens. CONCLUSIONS: Ovarian cancer patients were at an increased risk of developing ischemic stroke. Age, hypertension, diabetes, and chemotherapy treatment were independent risk factors.

Absolute lymphocyte count and risk of short-term infection in patients with immune thrombocytopenia.

Patients with immune thrombocytopenia (ITP) may be at increased risk of infection because of the steroids and other immunosuppressive agents used in its treatment. This study aimed to identify events that are associated with infection within 6 months of diagnosis and the impact that infection has on survival. We retrospectively evaluated 239 patients (107 men, 132 women; median age 61 years) diagnosed between January 1997 and August 2011. Every patient received steroid treatment according to the platelet count and the extent of bleeding. Logistic regression analysis was used to identify risk factors associated with the development of infection within 6 months of ITP being diagnosed. Sixty-two patients (25.9 %) developed an infection within 6 months of diagnosis. Multivariate analysis revealed that a lower absolute lymphocyte count (ALC) at diagnosis (<1 × 10(9)/l) was an independent risk factor for infection (P = 0.039; 95 % confidence interval, 1.033-3.599; odds ratio, 1.928). The time to infection event is significant shorter in those of low ALC, compared with those of higher ALC (P = 0.032). Furthermore, the 1-year mortality rate after ITP diagnosis was significantly higher in those patients who developed an infection (P = 0.001). ITP patients with a low absolute lymphocyte count at diagnosis have an increased risk of infection, and those who develop infections have lower 1-year survival.

Amiodarone and the risk of cancer: a nationwide population-based study.

BACKGROUND: In postmarketing surveillance, the US Food and Drug Administration has reported the development of lung masses, thyroid cancer, and skin cancer after amiodarone therapy. METHODS: Using the Taiwan National Health Insurance Research database, the authors conducted a population-based cohort study. Patients who were treated with amiodarone between 1997 and 2008 were enrolled. Those with antecedent cancer were excluded. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort with that of the general population. A multivariate Cox regression model was used to evaluate the association between cumulative defined daily doses (cDDDs) of amiodarone and cancer occurrence. RESULTS: The study included 6418 subjects, with a median follow-up of 2.57 years. A total of 280 patients developed cancer. The risk of cancer increased with borderline significance (SIR, 1.12; 95% confidence interval [95% CI], 0.99-1.26 [P = .067]). Male patients had a higher risk (SIR, 1.18; 95% CI, 1.02-1.36 [P = .022]). The total cohort of patients and the male patients with > 180 cDDDs within the first year were found to have SIRs of 1.28 (95% CI, 1.00-1.61; P = .046) and 1.46 (95% CI, 1.11-1.89; P = .008), respectively. After adjustment for age, sex, and comorbidities, the hazards ratio was 1.98 (95% CI, 1.22-3.22; P = .006) for the high tertile of cDDDs compared with the low tertile. CONCLUSIONS: The results of the current study indicate that amiodarone may be associated with an increased risk of incident cancer, especially in males, with a dose-dependent effect.

Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified. METHODS: The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials. RESULTS: Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit α/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway. CONCLUSIONS: Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA.

Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells.

The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies. Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells. Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Bortezomib increased protein phosphatase 2A activity in sensitive leukemia cells (HL-60 and KG-1), but not in resistant cells (MOLT-3 and K562). Bortezomib's downregulation of cancerous inhibitor of protein phosphatase 2A and phospho-Akt correlated with its drug sensitivity. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity. Ectopic expression of CIP2A up-regulated phospho-Akt and protected HL-60 cells from bortezomib-induced apoptosis, whereas silencing CIP2A overcame the resistance to bortezomib-induced apoptosis in MOLT3 and K562 cells. Importantly, bortezomib exerted in vivo antitumor activity in HL-60 xenografted tumors and induced cell death in some primary leukemic cells. Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib-induced apoptosis in leukemia cells.