To identify prognostic factors for the outcomes of empirical antifungal therapy, we performed a multicenter, prospective, observational study in immunocompromised patients with hematological malignancies.
Materials and Methods
Three hundred seventy-six patients (median age of 48) who had neutropenic fever and who received intravenous (IV) itraconazole as an empirical antifungal therapy for 3 or more days were analyzed. The patients with possible or probable categories of invasive fungal disease (IFD) were enrolled.
The overall success rate was 51.3% (196/376). Age >50 years, underlying lung disease (co-morbidity), poor performance status [Eastern Cooperative Oncology Group (ECOG) ≥2], radiologic evidence of IFD, longer duration of baseline neutropenic fever (≥4 days), no antifungal prophylaxis or prophylactic use of antifungal agents other than itraconazole, and high tumor burden were associated with decreased success rate in univariate analysis. In multivariate analysis, age >50 years (p=0.009) and poor ECOG performance status (p=0.005) were significantly associated with poor outcomes of empirical antifungal therapy. Twenty-two patients (5.9%) discontinued itraconazole therapy due to toxicity.
We concluded that empirical antifungal therapy with IV itraconazole in immunocompromised patients is effective and safe. Additionally, age over 50 years and poor performance status were poor prognostic factors for the outcomes of empirical antifungal therapy with IV itraconazole.
Hematological malignancy; prognosis; itraconazole; empirical antifungal therapy
Only a few patients who experience AML relapse derive lasting benefit from re-induction therapy. The utility of reassessing the disease karyotype at relapse is unclear. The main goals of this study were to identify prognostic factors for AML relapse and to determine the prognostic utility of karyotypic change between diagnosis and relapse as a variable for predicting response to salvage therapy for relapsed AML.
This retrospective study included 58 patients with relapsed AML treated at the Yonsei University College of Medicine between 2005 and 2010. Karyotypes at both diagnosis and relapse were available for 45 patients (77%). A change in karyotype at relapse was observed in 17 of 45 cases (37%), and no change was noted in 28 of 45 cases (62%).
Karyotypic changes between diagnosis and relapse were associated with the response rate (RR) to salvage therapy (P=0.016). Overall survival (OS) and event-free survival (EFS) in the group with karyotypic changes between diagnosis and relapse were significantly different from those with no karyotypic changes (P=0.004 and P=0.010, respectively). We applied multiple multivariate Cox regression analyses to identify independent prognostic factors for overall response (OR), OS, and EFS. A change in karyotype between diagnosis and relapse was significantly associated with OS (P=0.023; RR=2.655) and EFS (P=0.033; RR=2.831).
Karyotypic changes between the diagnosis and relapse of AML could be used to predict outcomes and tailor clinical and biological therapeutic strategies for relapsed AML patients.
Karyotype; Prognosis; Salvage therapy; Acute myeloid leukemia
The overexpression of Aurora A kinase (AurA) has been reported in various malignancies, including acute myeloid leukemia (AML). However, the expression of AurA and the effects of AurA inhibition in cancer stem cells are not yet fully understood. We investigated the expression and inhibition of AurA in AML stem cells (CD34+/CD38-).
Expression of AurA was investigated in cell lines (NB4 and KG1) that express high levels of CD34 and low levels of CD38. Primary AML cells were harvested from 8 patients. The expression of AurA and cell death induced by inhibition of AurA were analyzed in CD34+/CD38- cells.
AurA was shown to be overexpressed in both primary AML cells and leukemia stem cells (LSCs) compared to normal hematopoietic stem cells. Inhibition of AurA plus cytarabine treatment in LSCs resulted in increased cytotoxicity compared to cytarabine treatment alone. Additional stimulation with granulocyte-colony stimulating factor (G-CSF) increased the cell death caused by AurA inhibition plus cytarabine treatment.
To our knowledge, this is the first report describing increased expression of AurA in LSCs. Our results suggest that selective AurA inhibition may be used to reduce LSCs, and this reduction may be enhanced by stimulation with G-CSF. Further exploration of relationship between nuclear factor kappa-B and AurA inhibition and the potential of AurA inhibition for use in leukemia treatment is needed.
Acute myeloid leukemia; Leukemia stem cell; Aurora kinase
Despite extensive study, the use of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (AML) vary considerably. The decision of which of these options to choose is complex and depends on both clinical and molecular variables as well as the availability and histocompatability of donor stem cells. So far there is no clear explanation on whether the expression of myeloperoxidase (MPO) relates to the prognosis of AML.
Materials and Methods
We retrospectively analyzed the prognostic significance of the MPO expression in the 140 patients with diagnosed AML treated at a single institution.
In our study, MPO expression was associated with disease-free survival (DFS) and transplant was beneficial to overcome a negative prognostic effect of MPO-negative at diagnosis based upon the result that the DFS in patients received transplants are not significant between the MPO-positive group and MPO-negative group although DFS in all patients was different according to MPO expression.
MPO expression at diagnosis helps to choose therapy for each AML patient and can differentiate AML patients who need transplantation.
Myeloperoxidase; acute myeloid leukemia; prognostic factor; transplant
BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) are members of the tumor necrosis factor family and promote B cell survival and proliferation. We evaluated the correlation between serum concentration of BAFF or APRIL and severity of acute graft-versus-host disease (GVHD).
Fifteen patients who received allogeneic hematopoietic stem transplantation for leukemia and developed acute GVHD were enrolled. We determined serum concentrations of BAFF and APRIL at the onset of the first clinical manifestation of GVHD by enzyme-linked immunosorbent assay.
Nine patients had grade 2 acute GVHD, and 6 had grade 3-4 acute GVHD. The BAFF serum concentration was higher in patients with grade 3-4 acute GVHD (1,093.42 in grade 2 vs. 2,171.99 pg/mL in grade 3-4), although the difference was not significant (P=0.077). However, the ratio of BAFF serum concentration to absolute lymphocyte count (ALC) (BAFF/ALC) was significantly higher in patients with grade 3-4 acute GVHD (P=0.045). The APRIL serum concentration and APRIL/ALC ratio showed similar results (P=0.077 and P=0.013, respectively).
Patients with grade 3-4 acute GVHD had higher BAFF/ALC and APRIL/ALC ratios than patients with grade 2 acute GVHD. These findings suggest that B cells might play an important role in the development of acute GVHD, and that the BAFF and APRIL concentrations in serum might be significant predictive factors for estimating the severity of acute GVHD. Their clinical significance should be further evaluated in a larger patient population.
B cell-activating factor (BAFF); A proliferation-inducing ligand (APRIL); Acute graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation
The modified Glasgow Prognostic Score (mGPS) consisting of serum C-reactive protein and albumin levels, shows significant prognostic value in several types of tumors. We evaluated the prognostic significance of mGPS in 285 patients with diffuse large B cell lymphoma (DLBCL), retrospectively.
Materials and Methods
According to mGPS classification, 204 patients (71.5%) had an mGPS of 0, 57 (20%) had an mGPS of 1, and 24 (8.5%) had an mGPS of 2.
Our study found that high mGPS were associated with poor prognostic factors including older age, extranodal involvement, advanced disease stage, unfavorable International Prognostic Index scores, and the presence of B symptoms. The complete response (CR) rate after 3 cycles of R-CHOP chemotherapy was higher in patients with mGPS of 0 (53.8%) compared to those with mGPS of 1 (33.3%) or 2 (25.0%) (p=0.001). Patients with mGPS of 0 had significantly better overall survival (OS) than those with mGPS=1 and those with mGPS=2 (p=0.036). Multivariate analyses revealed that the GPS score was a prognostic factor for the CR rate of 3 cycle R-CHOP therapy (p=0.044) as well as OS (p=0.037).
mGPS can be considered a potential prognostic factor that may predict early responses to R-CHOP therapy in DLBCL patients.
Modified Glasgow Prognostic Score; diffuse large B cell lymphoma; prognostic factor
Identification of biomarkers that predict responses to hypomethylating agents (HMAs) will allow optimal strategies for epigenetic therapy in myelodysplastic syndromes (MDS) to be established. Serum miR-21 was quantitatively measured in 58 MDS patients treated with HMAs and 14 healthy controls. Serum miR-192 was an internal control, and diagnostic performance was evaluated according to receiver operating characteristics (ROCs). ROC analysis indicated that serum miR-21 levels differentiated responders from non-responders with an area under the curve of 0.648 (95% confidence, 0.49 to 0.72). The baseline level of serum miR-21 was significantly lower in the responder group than in the non-responder group (P = 0.041). The overall response rate (ORR) of the high miR-21 group was significantly lower than that of the low miR-21 group (41.2 vs. 73.2%, P = 0.021). Progression-free survival (PFS) was significantly inferior in the high group versus the low group (14.0 vs. 44.5 months, P = 0.001). Multivariate analyses revealed that the initial serum miR-21 level (P = 0.001) and circulating blasts (P = 0.007) were prognostic factors for PFS. Serum miR-21 level was significantly associated with ORR and PFS in MDS patients treated with HMAs. Although validation with a large prospective study is required, serum miR-21 is a potential biomarker of epigenetic therapy in MDS patients.
We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462)
Hematological Malignancy; Itraconazole; Empirical Antifungal Therapy; Galactomannan Test
This study aimed to survey the clinical spectrum of diffuse large B-cell lymphoma (DLBCL) in terms of epidemiology, pathologic subtypes, stage, and prognostic index as well as treatment outcomes.
In 2007-2008, 13 university hospitals evenly distributed in the Korean peninsula contributed to the online registry of DLBCL at www.lymphoma.or.kr and filed a total of 1,665 cases of DLBCL recorded since 1990.
Our analysis showed a higher prevalence of DLBCL in male than in female individuals (M:F=958:707), and extranodal disease was more common than primary nodular disease (53% vs. 47%). Among the 1,544 patients who had been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP (R-CHOP) therapy with or without radiation, 993 (63.9%) were alive, with 80% free of disease, 417 were dead (26.8%), with 13% free of disease, and 144 (9.3%) were lost to follow-up, with 23% free of disease. Age below 60 years, stage at diagnosis, international prognostic index (IPI) score regardless of age, and addition of rituximab to CHOP therapy in low- and low-intermediate-risk groups according to IPI scores significantly increased survival duration.
The epidemiology, clinical spectrum, and biological behavior of DLBCL in Korea are similar to those observed in Western countries, and the advent of rituximab improved survival.
Diffuse large B-cell lymphoma; Epidemiology; Survival; Rituximab; CHOP regimen
Non-small cell lung cancer (NSCLC) is the most deadly type of cancer worldwide. Although a number of therapies are used in NSCLC treatment, their therapeutic efficacy remains low. Lenalidomide was originally approved for use in patients with myelodysplastic syndromes, which are associated with 5q deletions, and multiple myeloma. Recently, lenalidomide was investigated as a new NSCLC treatment, and it exerted anticancer effects. However, the primary cellular mechanism of its effects in NSCLC is largely unknown. Therefore, we attempted to elucidate a molecular portrait of lenalidomide-mediated cellular events in NSCLC. Lenalidomide reduced the viability of several NSCLC cell lines in a concentration-dependent manner. In addition, array-based gene expression analysis revealed that lenalidomide regulated the expression of several genes associated with cell survival, apoptosis and development, including BH3-interacting domain death agonist (BID), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) and NK2 homeobox1 (NKX2-1). BID and FOS, which are known apoptosis activators, were upregulated by lenalidomide treatment, whereas NKX2-1, which is used as an immunohistochemistry marker for NSCLC, was downregulated. These results provide evidence that lenalidomide directly induces antiproliferative effects by altering the expression of genes associated with cell proliferation and apoptosis.
lenalidomide; non-small cell lung carcinoma cell; cell growth inhibition; gene expression profiles
Resveratrol is a plant phenolic phytoalexin that has been reported to have antitumor properties in several types of cancers. In particular, several studies have suggested that resveratrol exerts antiproliferative effects against A549 human non-small cell lung cancer cells; however, its mechanism of action remains incompletely understood. Deregulation of microRNAs (miRNAs), a class of small, noncoding, regulatory RNA molecules involved in gene expression, is strongly correlated with lung cancer. In this study, we demonstrated that resveratrol treatment altered miRNA expression in A549 cells. Using microarray analysis, we identified 71 miRNAs exhibiting greater than 2-fold expression changes in resveratrol-treated cells relative to their expression levels in untreated cells. Furthermore, we identified target genes related to apoptosis, cell cycle regulation, cell proliferation, and differentiation using a miRNA target-prediction program. In conclusion, our data demonstrate that resveratrol induces considerable changes in the miRNA expression profiles of A549 cells, suggesting a novel approach for studying the anticancer mechanisms of resveratrol.
A549; human non-small cell lung cancer cells; microRNA; resveratrol
The objective of this study was to identify prognostic factors for survival in patients with primary diffuse large B-cell lymphoma (DLBCL) of the adrenal gland.
Thirty one patients diagnosed with primary adrenal DLBCL from 14 Korean institutions and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were analyzed.
Complete remission (CR) and overall response rate after R-CHOP chemotherapy were 54.8% and 87.0%. The 2-year estimates of overall survival (OS) and progression-free survival (PFS) were 68.3% and 51.1%. In patients achieving CR, significant prolongations of OS (P = 0.029) and PFS (P = 0.005) were observed. Ann Arbor stage had no influence on OS. There was no significant difference in OS between patients with unilateral involvement of adrenal gland and those with bilateral involvement. When staging was modified to include bilateral adrenal involvement as one extranodal site, early stage (I or II) significantly correlated with longer OS (P = 0.021) and PFS (P <0.001).
Contrary to prior reports, our data suggests that outcomes of primary adrenal DLBCL are encouraging using a regimen of R-CHOP, and that achieving CR after R-CHOP is predictive of survival. Likewise, our modified staging system may have prognostic value.
Primary adrenal lymphoma; Diffuse large B-cell lymphoma; Prognostic factor; R-CHOP
Anaphylactic transfusion reactions are rare complications of blood transfusions. Anhaptoglobinemia, a condition that has high incidence in Asia, can cause allergic transfusion reactions or anaphylaxis in severe cases. A 50-yr-old Korean woman was diagnosed with relapsed acute promyelocytic leukemia. She developed thrombocytopenia during chemotherapy and an anaphylactic transfusion reaction on the 4th and 5th platelet transfusions immediately after the transfusion of the platelet concentrates was initiated. Blood analysis showed no detectable serum haptoglobin. We examined her genetic phenotype and detected anhaptoglobinemia, which occurs because of an allelic deletion in the Hp gene cluster. The presence of an antibody against haptoglobin was detected by performing ELISA. To prevent anaphylactic reactions, apheresis platelets were transfused after washing. Consequently, anaphylactic transfusion reactions did not develop. Here, we report the first case of anhaptoglobinemia causing anaphylactic transfusion reaction in Korea.
Platelet transfusion; Anaphylaxis; Haptoglobin
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with poor treatment outcomes. The aim of this study was to evaluate whether lymphopenia at diagnosis would have an adverse effect on survival in patients with PTCL-NOS treated with anthracycline-containing chemotherapy.
A total of 118 patients with PTCL-NOS treated with anthracycline-containing chemotherapy from 4 Korean institutions were included.
Thirty-six patients (30.5%) had a low absolute lymphocyte count (ALC, < 1.0 × 109/L) at diagnosis. Patients with lymphopenia had shorter overall survival (OS) and progression-free survival (PFS) rates compared with patients with high ALCs (P = 0.003, P = 0.012, respectively). In multivariate analysis, high-intermediate/high-risk International Prognostic Index (IPI) scores and lymphopenia were both associated with shorter OS and PFS. Treatment-related mortality was 25.0% in the low ALC group and 4.8% in the high ALC group (P = 0.003). In patients considered high-intermediate/high-risk based on IPI scores, lymphopenia was also associated with shorter OS and PFS (P = 0.002, P = 0.001, respectively).
This study suggests that lymphopenia could be an independent prognostic marker to predict unfavorable OS and PFS in patients with PTCL-NOS treated with anthracycline-containing chemotherapy and can be used to further stratify high-risk patients using IPI scores.
peripheral T-cell lymphoma; not otherwise specified; lymphopenia; international prognostic index; prognostic factor
Invasive aspergillosis (IA) is a leading cause of infectious mortality in patients who have undergone a hematopoietic stem cell transplant (HSCT); the mortality due to IA ranges from 70% to 93% in HSCT patients. Early diagnosis and treatment are the cornerstones for the good prognosis of IA. Primary renal aspergillosis is an extremely rare presentation in patients who have undergone HSCT, and the risk factor for this uncommon presentation is not well known. We report a patient who developed primary renal aspergillosis and renal stones in both the kidneys after HSCT. Invasive renal aspergillosis was diagnosed after a nephrectomy, which was performed to treat massive renal hematoma.
Primary renal aspergillosis; Hematopoietic stem cell transplant; Renal stones
The prognosis for patients with primary central nervous system (CNS) lymphoma (PCNSL) who relapse after the initial response is usually poor. A standard treatment for relapsed PCNSL has not yet been identified because of the heterogeneity of the therapies employed and the lack of large, prospective clinical trials. We describe a 46-year-old relapsed PCNSL patient who was successfully treated with intraventricular applications of rituximab to minimize neurotoxicity, 2 cycles of salvage chemotherapy with etoposide, ifosfamide, and cytarabine (VIA) regimen and high-dose chemotherapy with autologous stem cell rescue. The high-dose chemotherapy consisted of bischloroethylnitrosourea, etoposide, cytarabine, and melphalan (BEAM) regimen. Partial remission was detected after intraventricular rituximab therapy and the patient has been in complete remission without evidence of neurotoxicity for 28 months after high-dose chemotherapy with autologous stem cell rescue. This case indicates a new appropriate treatment guideline in relapsed PCNSL patient after initial intensive chemo-radiotherapy.
Primary central nervous system lymphoma; salvage therapy; rituximab; high-dose chemotherapy with autologous stem cell rescue
Laparoscopic splenectomy (LS) has been reserved for intractable and relapsing immune thrombocytopenic purpura (ITP) despite medical treatment. With further experiences of LS in ITP, we investigated long term outcomes of LS, especially newly developed morbidities, and tried to find predictive factors for favorable outcomes. From August 1994 to December 2004, fifty-nine patients whose follow-up period was more than 12 months after LS were investigated. After a long-term follow-up (median 54 months, range 12.5-129 months), a complete response (CR) was found in 28 patients (47.5%), partial response in 24 (40.7%), and no response in 7 (11.9%). The relapse rate during follow-up periods was 15.2%. The rapid response group (p=0.017), in which the platelet count increased more than twice of the preoperative platelet count within 7 days after LS, relapsing after medical treatment (p=0.02), and the satisfactory group as the initial result of LS (p=0.001) were significant for predicting CR in univariate analysis, but only the initial satisfactory group was an independent predictive factor for CR in multivariate analysis (p=0.036, relative risk=6419; 95% CI, 1.171-35.190). Infections were the most frequent morbidities during the follow-up period, which were treated well without mortality. LS is a safe and effective treatment modality for ITP. Active referral to surgery might be required, considering complications and treatment results related to long-term use of steroid-based medications.
Laparoscopic Splenectomy (LS); Immune Thrombocytopenic Purpura (ITP); Follow-up
Hepatitis B virus (HBV) reactivation is the frequent complication after cytotoxic chemotherapy in HBsAg-positive non-Hodgkin's lymphoma (NHL) patients. Pre-chemotherapy viral load may be a risk factor and HBeAg-positive status is associated with increased viral load. The aim of this study was to investigate the long-term treatment outcome of lamivudine in preventing HBV reactivation and its associated morbidity according to HBeAg status. Twenty-four adult HBsAg-positive NHL patients were taken 100 mg of lamivudine daily before the initiation of chemotherapy. The median duration of lamivudine therapy was 11.5 months (range: 1-54 months) and the median number of chemotherapy cycles was 6 (range: 1-16 cycles). The steroid containing chemotherapy regimens were used in 18 patients (75%), and the anti-CD20 monoclonal antibody containing chemotherapy regimen was used in 6 patients (25%). Four patients received autologous peripheral blood stem cell transplantation without resultant HBV reactivation. Hepatitis related to HBV reactivation was developed in 1 patient among 14 HBeAg-positive patients and no one among 10 HBeAg-negative. One patient developed HBV reactivation after lamivudine withdrawal, and 4 patients developed the YMDD (tyrosine-methionine-aspartate-aspartate) mutation during lamivudine therapy. There were no statistical differences in HBV reactivation rate during chemotherapy according to the HBeAg status. Our results demonstrate that lamivudine should be considered preemptively before the chemotherapy for all HBsAg-positive NHL patients to prevent HBV reactivation, regardless of pre-chemotherapy HBeAg status. Finally, compared with the chronic hepatitis B patients, similar rate of HBV reactivation after lamivudine withdrawal and development of YMDD mutation was observed in NHL patients.
HBV reactivation; lamivudine; non-Hodgkin's lymphoma; chemotherapy; HBeAg