Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients.
Materials and Methods
RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed.
Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05).
Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.
Burkitt lymphoma; Recurrence; Children
We assessed the feasibility and effectiveness of reduced-dose craniospinal (CS) radiotherapy (RT) followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in reducing late adverse effects without jeopardizing survival among children with high-risk medulloblastoma (MB).
From October 2005 through September 2010, twenty consecutive children aged >3 years with high-risk MB (presence of metastasis and/or postoperative residual tumor >1.5 cm2) were assigned to receive 2 cycles of pre-RT chemotherapy, CSRT (23.4 or 30.6 Gy) combined with local RT to the primary site (total 54.0 Gy), and 4 cycles of post-RT chemotherapy followed by tandem HDCT/autoSCT. Carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens were used for the first and second HDCT, respectively.
Of 20 patients with high-risk MB, 17 had metastatic disease and 3 had a postoperative residual tumor >1.5 cm2 without metastasis. The tumor relapsed/progressed in 4 patients, and 2 patients died of toxicities during the second HDCT/autoSCT. Therefore, 14 patients remained event-free at a median follow-up of 46 months (range, 23−82) from diagnosis. The probability of 5-year event-free survival was 70.0% ± 10.3% for all patients and 70.6% ± 11.1% for patients with metastases. Late adverse effects evaluated at a median of 36 months (range, 12−68) after tandem HDCT/autoSCT were acceptable.
In children with high-risk MB, CSRT dose might be reduced when accompanied by tandem HDCT/autoSCT without jeopardizing survival. However, longer follow-up is needed to evaluate whether the benefits of reduced-dose CSRT outweigh the long-term risks of tandem HDCT/autoSCT.
autologous stem cell transplantation; high-dose chemotherapy; late effect; medulloblastoma; radiotherapy
Previous studies conducted cell expansion ex vivo using low initial plating densities for optimal expansion and subsequent differentiation of mesenchymal stem cells (MSCs). However, MSC populations are heterogeneous and culture conditions can affect the characteristics of MSCs. In this study, differences in gene expression profiles of adipose tissue (AT)-derived MSCs were examined after harvesting cells cultured at different densities. AT-MSCs from three different donors were plated at a density of 200 or 5,000 cells/cm2. After 7 days in culture, detailed gene expression profiles were investigated using a DNA chip microarray, and subsequently validated using a reverse transcription polymerase chain reaction (RT-PCR) analysis. Gene expression profiles were influenced primarily by the level of cell confluence at harvest. In MSCs harvested at ∼90% confluence, 177 genes were up-regulated and 102 genes down-regulated relative to cells harvested at ∼50% confluence (P<0.05, FC>2). Proliferation-related genes were highly expressed in MSCs harvested at low density, while genes that were highly expressed in MSCs harvested at high density (∼90% confluent) were linked to immunity and defense, cell communication, signal transduction and cell motility. Several cytokine, chemokine and growth factor genes involved in immunosuppression, migration, and reconstitution of damaged tissues were up-regulated in MSCs harvested at high density compared with MSCs harvested at low density. These results imply that cell density at harvest is a critical factor for modulating the specific gene-expression patterns of heterogeneous MSCs.
In order to clarify the optimal timing for peripheral blood stem cell (PBSC) collection, PBSC collection records of 323 children who were scheduled to undergo autologous stem cell transplantation from two study periods differing in the timing of PBSC collection were analyzed. In the early study period (March 1998 to August 2007, n=198), PBSC collection was initiated when the peripheral WBC count exceeded 1,000/µL during recovery from chemotherapy. Findings in this study period indicated that initiation of PBSC collection at a higher WBC count might result in a greater CD34+ cell yield. Therefore, during the late study period (September 2007 to December 2012, n=125), PBSC collection was initiated when the WBC count exceeded 4,000/µL. Results in the late study period validated our conclusion from the early study period. Collection of a higher number of CD34+ cells was associated with a faster hematologic recovery after transplant in the late study period. Initiation of PBSC collection at WBC count > 4,000/µL was an independent factor for a greater CD34+ cell yield. In conclusion, PBSC collection at a higher WBC count is associated with a greater CD34+ cell yield, and consequently a faster hematologic recovery after transplant.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; Peripheral Blood Stem Cell Collection
The mouse model is an important research tool in neurosciences to examine brain function and diseases with genetic perturbation in different brain regions. However, the limited techniques to map activated brain regions under specific experimental manipulations has been a drawback of the mouse model compared to human functional brain mapping. Here, we present a functional brain mapping method for fast and robust in vivo brain mapping of the mouse brain. The method is based on the acquisition of high density electroencephalography (EEG) with a microarray and EEG source estimation to localize the electrophysiological origins. We adapted the Fieldtrip toolbox for the source estimation, taking advantage of its software openness and flexibility in modeling the EEG volume conduction. Three source estimation techniques were compared: Distribution source modeling with minimum-norm estimation (MNE), scanning with multiple signal classification (MUSIC), and single-dipole fitting. Known sources to evaluate the performance of the localization methods were provided using optogenetic tools. The accuracy was quantified based on the receiver operating characteristic (ROC) analysis. The mean detection accuracy was high, with a false positive rate less than 1.3% and 7% at the sensitivity of 90% plotted with the MNE and MUSIC algorithms, respectively. The mean center-to-center distance was less than 1.2 mm in single dipole fitting algorithm. Mouse microarray EEG source localization using microarray allows a reliable method for functional brain mapping in awake mouse opening an access to cross-species study with human brain.
A microarray analysis was performed to investigate whether ex vivo culture conditions affect the characteristics of MSCs. Gene expression profiles were mainly influenced by the level of cell confluence rather than initial seeding density. The analysis showed that 276 genes were upregulated and 230 genes downregulated in MSCs harvested at ~90% versus ~50% confluence (P < 0.05, FC > 2). The genes that were highly expressed in MSCs largely corresponded to chemotaxis, inflammation, and immune responses, indicating direct or indirect involvement in immunomodulatory functions. Specifically, PTGES and ULBP1 were up-regulated in MSCs harvested at high density. Treatment of MSCs with PTGES or ULBP1 siRNA reversed their inhibition of T-cell proliferation in vitro. The culture conditions such as cell confluence at harvest seem to be important for gene expression profile of MSCs; therefore, the results of this study may provide useful guidelines for the harvest of MSCs that can appropriately suppress the immune response.
Because of the heterogeneity of human mesenchymal stem cells (MSCs), methods for cell expansion in culture and the effects on gene expression are critical factors that need to be standardized for preparing MSCs. We investigated gene expression patterns of MSCs with different seeding densities and culture times.
Bone marrow-derived MSCs were plated at densities from 200 cells/cm2 to 5,000 cells/cm2, and the gene expression patterns were evaluated over time using a reverse-transcription polymerase chain reaction assay.
The mRNA levels of factors that play a critical role in cell migration and tissue regeneration, such as podocalyxin-like protein (PODXL), α4-integrin, α6-integrin, and leukemia inhibitory factor (LIF), were higher in MSCs plated at 200 cells/cm2 than in MSCs plated at 5,000 cells/cm2. The mRNA levels of these factors gradually increased for 10 days and then decreased by day 15 in culture. MSCs seeded at 200 cells/cm2 that were cultured for 10 days expressed high levels of Oct-4 and Nanog. Indoleamine 2,3-dioxygenase, cyclooxygenase-1, and hepatocyte growth factor expression were upregulated in the presence of the proinflammatory cytokine interferon-γ in these cells.
We found differences in the gene expression patterns of MSCs under different culture conditions. MSCs from 10-day cultures seeded at a low density were efficiently expanded, expressed PODXL, α6-integrin, α4-integrin, and LIF, and maintained properties like stemness and immunomodulation. Therefore, ex vivo expansion of MSCs maintained for an adequate culture time after plating at low cell density can provide an effective regenerative medicinal strategy for cell therapies using MSCs.
Mesenchymal stem cell; Gene expression pattern; Seeding density; Culture time; Cell therapy
Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea.
The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients.
Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months).
In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
Therapy-related neoplasms; Myelodysplastic syndrome; Acute myeloid leukemia; Cytogenetics; Korea
Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34+ cells transplanted during the first and second HDCT/autoSCT were 4.3 × 106/kg (range 0.6-220.2) and 4.1 × 106/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34+ cells was lower, especially if it was < 2 × 106/kg. A lower CD34+ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34+ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; CD34+ Cells; Hematologic Recovery; Iron Overload
Some strains of plant growth-promoting rhizobacteria (PGPR) elicit induced systemic resistance (ISR) by emission of volatile organic compounds (VOCs) including short chain alcohols, acetoin, and 2,3-butanediol. The objective of this study was to evaluate whether species-specific VOCs from PGPR strain Paenibacillus polymyxa E681 can promote growth and induce resistance in Arabidopsis.
The efficacy of induction was strain-specific, with stronger protection against Pseudomonas syringae pv. maculicola ES4326 in plants exposed to VOCs from P. polymyxa E681 versus Arabidopsis plants exposed to VOCs from a reference strain Bacillus subtilis GB03, which was previously shown to elicit ISR and plant growth promotion. VOC emissions released from E681 primed transcriptional expression of the salicylic acid, jasmonic acid, and ethylene signaling marker genes PR1, ChiB, and VSP2, respectively. In addition, strain E681 produced more than thirty low molecular-weight VOCs, of which tridecane was only produced by E681 and not found in GB03 or IN937a volatile blends. These strain-specific VOCs induced PR1 and VSP2 genes.
These results provide new insight into the existence of a long chain VOC signaling molecule produced by P. polymyxa that can serve as a bacterial trigger of induced systemic resistance in planta.
Through this study, we aimed to validate several biomarkers that have been known to possibly predict the outcomes of the trastuzumab and paclitaxel (TP). Human epidermal growth factor 2 (HER2) positive metastatic breast cancer (MBC) patients who had been treated with TP in single institute from 2006 to 2009 were included in this study. For procured formalin fixed paraffin embedded tumor tissues, HER2 amplification index (AI) and polymorphisms of the immunoglobulin G fragment C receptors (FCGR) were assessed as biomarkers to the trastuzumab and expression of class III beta tubulin (bTubIII) was evaluated as a predictive factor to the paclitaxel. Of 46 patients treated with TP, 27 patients could be evaluated for HER2 AI, 31 for bTubIII, and 26 for FCGR gene polymorphism. The median of the HER2 AI was 5.0 (range, 1.4−15.5) and a higher HER2 AI (≥5.0) was significantly correlated with better response rate (RR) (80% vs. 42%, P = 0.049) and longer progression-free survival (PFS) (13.6 vs. 6.9 months, P = 0.023). High bTubIII expression showed higher RRs than did low expression (81% vs. 40%, P = 0.040) in addition to longer PFS (16.2 months vs. 8.8 months, P = 0.04). However, polymorphisms in FCGR 2A-H131R or FCGR 3A-V158F were not predictive of RR or PFS. Our results suggest that a high HER2 AI and high bTubIII expression could be predictive of the outcomes to TP therapy but no evidence was found in terms of FCGR polymorphisms.
MYC rearrangement, a characteristic cytogenetic abnormality of Burkitt lymphoma and several subsets of other mature B-cell neoplasms, typically involves an immunoglobulin gene partner. Herein, we describe a case of precursor B-cell lymphoblastic leukemia harboring a MYC rearrangement with a novel non-immunoglobulin partner locus. The patient was a 4-yr-old Korean boy with ALL of the precursor B-cell immunophenotype. At the time of the second relapse, cytogenetic analyses revealed t(4;8)(q31.1;q24.1) as a clonal evolution. The MYC rearrangement was confirmed by FISH analysis. He died 3 months after the second relapse without achieving complete remission. To our knowledge, this is the first report of a case of MYC rearrangement with a non-immunoglobulin partner in precursor B-cell lymphoblastic leukemia.
Precursor B-cell acute lymphoblastic leukemia; MYC gene rearrangement; Non-immunoglobulin partner
TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is a promising agent for clinical use since it kills a wide range of tumour cells without affecting normal cells. We provide evidence that pretreatment with etoposide significantly enhanced TRAIL-mediated apoptosis via up-regulation of DR5 (death receptor 5 or TRAIL-R2) expression in the caspase 8 expressing neuroblastoma cell line, SK-N-MC. In addition, sequential treatment with etoposide and TRAIL increased caspases 8, 9 and 3 activation, Mcl-1 cleavage and Bid truncation, which suggests that the ability of etoposide and TRAIL to induce apoptosis is mediated through activation of an intrinsic signalling pathway. Although TRAIL-R2 expression increased in IMR-32 cells in response to etoposide treatment, cell death was not increased by concurrent treatment with TRAIL compared with etoposide alone, because the cells lacked caspase 8 expression. Restoration of caspase 8 expression by exposure to IFNγ (interferon γ) sensitizes IMR-32 cells to TRAIL. Moreover, pretreatment with etoposide increased TRAIL-induced apoptosis in caspase 8 restored IMR-32 cells through activation of a caspase cascade that included caspases 8, 9 and 3. These results indicate that the etoposide-mediated sensitization of neuroblastoma cells to TRAIL is associated with an increase in TRAIL-R2 expression and requires caspase 8 expression. These observations support the potential use of a combination of etoposide and TRAIL in future clinical trials.
caspase 8; death receptor; etoposide; inferferon γ; mitochondrial cascade; TRAIL; AzaC, 5-aza-2′ deoxycytidine; BCA, bicinchoninic acid; DD, death domain; DcR, decoy receptor; DR5, death receptor 5; FADD, Fas-associated death domain; FBS, fetal bovine serum; IFNγ, interferon γ; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand
Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; Iron Overload; Deferasirox; Iron Chelation Treatment; Neuroblastoma
This study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD).
This retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41).
Neutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD (P<0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; P=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; P<0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; P<0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; P<0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; P=0.04).
Survival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative.
Umbilical cord blood; Hematopoietic stem cell transplantation; Stem cell donor
Churg-Strauss syndrome (CSS) is a multisystem granulomatous vasculitis that is characterized by peripheral eosinophilia and the infiltration of eosinophils into systemic organs. The skin lesions of CSS consist mainly of palpable purpura and nodules. Wells' syndrome (WS) is a rare inflammatory dermatosis that is associated with recurrent granulomatous dermatitis and eosinophilia. Since these two diseases are rare, any overlap between them is very unusual. Herein, we report a patient with CSS, who initially presented a skin eruption of erythematous urticarial-plaques, vesicles, and blisters. Upon biopsy, the histology of these plaques indicated eosinophilic infiltration and "flame figures" within the dermis, which was consistent with a diagnosis of WS. Although the association between WS and CSS that was observed in our patient may be purely coincidental, it could also suggest a common pathogenetic background of these two distinct diseases, as both share several many common features.
Churg-Strauss syndrome; Flame figures; Wells' syndrome
Long-term survivors of childhood cancer appear to have an increased risk for the metabolic syndrome, subsequent type 2 diabetes and cardiovascular disease in adulthood compared to healthy children. The purpose of this study was to investigate the frequency of the metabolic syndrome and associated factors in childhood cancer survivors at a single center in Korea.
We performed a retrospective review of medical records of 98 childhood cancer survivors who were diagnosed and completed anticancer treatment at Samsung Medical Center, Seoul, Korea between Jan. 1996 and Dec. 2007. Parameters of metabolic syndrome were evaluated between Jan. 2008 and Dec. 2009. Clinical and biochemical findings including body fat percentage were analyzed.
A total of 19 (19.4%) patients had the metabolic syndrome. The median body fat percentage was 31.5%. The body mass index and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.00, respectively). Sixty-one (62.2%) patients had at least one abnormal lipid value. The triglyceride showed significant positive correlation with the body fat percentage (r=0.26, P=0.03). The high density lipoprotein cholesterol showed significant negative correlation with the percent body fat (r=-0.26, P=0.03).
Childhood cancer survivors should have thorough metabolic evaluation including measurement of body fat percentage even if they are not obese. A better understanding of the determinants of the metabolic syndrome during adolescence might provide preventive interventions for improving health outcomes in adulthood.
Cancer survivor; Metabolic syndrome; Body composition; Fat percentage
The risk of invasive fungal infection is greater for allogeneic hematopoietic stem cell transplantation (HSCT) than for autologous transplantation. Therefore, many transplantation centers use antifungal prophylaxis for allogeneic HSCT, however, there exists no standard guidelines or consensus regarding autologous HSCT.
Materials and Methods
A prospective double-blind randomized study was conducted in autologous HSCT recipients who were divided into prophylaxis and empirical treatment groups, and we investigated the efficacy of itraconazole prophylaxis in pediatric autologous HSCT.
Total 87 autologous HSCT episodes in 55 children with high-risk solid tumors were studied. No invasive fungal infections occurred in either group. However, patients in the prophylaxis group had a significantly shorter duration of fever (p < 0.05) and received antibacterial treatment of shorter duration (p < 0.05) with fewer numbers of antibiotics (p < 0.05 for the use of second line antibiotics) than those in the empirical group. No significant additional adverse events were found with itraconazole prophylaxis.
Although beneficial effects such as a shorter duration of fever and reduced need for antibiotic use were observed in the prophylaxis group, the results were not sufficient to draw a definite recommendation about the routine use of antifungal prophylaxis in pediatric autologous HSCT recipients with high-risk solid tumors (Trial registration: NCT00336531).
Itraconazole; autologous transplantation; antifungal prophylaxis; solid tumor
Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs). However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy.
We examined 35 patients (27 men and 8 women) diagnosed with IC-GCTs between August 2004 and April 2008 and received risk-adapted carboplatin-based chemotherapy at the Samsung Medical Center. Patients were divided into either low-risk (LR) or high-risk (HR) groups and a retrospective analysis was performed using information from the medical records.
Although hematological complications were common, hearing difficulties or grade 3 or 4 creatinine level elevation were not observed in patients who underwent carboplatin-based chemotherapy. The frequency of febrile neutropenia did not differ between the risk groups. The overall survival was 100% and event-free survival (EFS) was 95.7%. The EFS rate was 100% in the LR group and 90% in the HR group, respectively.
Despite their common occurrence in high-risk patients, no lethal hematological complications were associated with carboplatin-based treatment. The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs.
Intracranial germ cell tumor; Carboplatin; Adverse effects
With their prolonged survival and malnutrition, cancer patients, and especially gastrointestinal (GI) tract cancer patients, can develop Wernicke's encephalopathy (WE). The aim of this study is to remind physicians of the importance of WE and prompt management in patients with GI tract cancer.
Materials and Methods
This study is a retrospective review of 2 cases of WE in advanced gastric cancer (AGC) patients, and we review the literature for cases of GI tract cancer related to WE.
A 48-year-old female with AGC presented dizziness and diplopia for 5 days and a 20 kg weight loss. Neurologic exam showed nystagmus and gaze disturbance. Her symptoms improved after daily parenteral injection of thiamine 100 mg for 17 days. A 58-year-old female with AGC presented with sudden disorientation, confusion and 15 kg weight loss. Neurologic exam showed gaze limitation and mild ataxia. Despite daily parenteral injection of thiamine 100 mg for 4 days, she died 5 days after the onset of neurologic symptoms. Combining the cases noted in the literature review with our 2 cases, the 7 gastric cancer cases and 2 colorectal cancer cases related to WE showed similar clinical characteristics; 1) a history of long-period malnutrition and weight loss, 2) relatively typical neurologic signs and symptoms and 3) specific magnetic resonance image findings. Except for 2 patients who had irreversible neurologic symptoms, the other 7 patients were improved with prompt thiamine treatment.
It is important to consider WE in GI tract cancer patients with acute neurologic symptoms and who are in a state of malnutrition. Thiamine should be given as soon as possible when WE is suspected.
Wernicke's encephalopathy; Advanced gastric cancer; Thiamine
To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3 (n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.
Neoplasms, Germ Cell and Embryonal; Central Nervous System; Drug Therapy; Survival
Transplantation of marrow-derived mesenchymal stem cells (MSCs), expanded by culture in addition to whole bone marrow, has been shown to enhance engraftment of human hematopoietic stem cells (HSCs). Our hypothesis was that there might be an optimum ratio range that could enhance engraftment. We examined the percent donor chimerism according to the ratio of HSCs to MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We tested a series of ratios of co-transplanted CD34+-selected bone marrow cells, and marrow-derived MSCs into sublethally irradiated NOD/SCID mice. In all experiments, 1×105 bone marrow derived human CD34+ cells were administered to each mouse and human MSCs from different donors were infused concomitantly. We repeated the procedure three times and evaluated engraftment with flow cytometry four weeks after each transplantation. Serial ratios of HSCs to MSCs were 1:0, 1:1, 1:2 and 1:4, in the first experiment, 1:0, 1:1, 1:2, 1:4 and 1:8 in the second and 1:0, 1:1, 1:4, 1:8 and 1:16 in the third. Cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased. Our results suggest that the optimal ratio of HSCs and MSCs for cotransplantation might be in the range of 1:8-1:16; whereas, an excessive dose of MSCs might decrease engraftment efficiency.
Hematopoietic Stem Cells; Mesenchymal Stem Cells; Transplantation; Mice, SCID; Engraftment
We wanted to compare the transaxial source images with the optimized three plane, thin-slab maximum intensity projection (MIP) images from electrocardiographic (ECG)-gated cardiac CT for their ability to detect hemodynamically significant stenosis (HSS), and we did this by means of performing a receiver operating characteristic (ROC) analysis.
Materials and Methods
Twenty-eight patients with a heart rate less than 66 beats per minute and who were undergoing both retrospective ECG-gated cardiac CT and conventional coronary angiography were included in this study. The contrast-enhanced CT scans were obtained with a collimation of 16×0.75-mm and a rotation time of 420 msec. The transaxial images were reconstructed at the mid-diastolic phase with a 1-mm slice thickness and a 0.5-mm increment. Using the transaxial images, the slab MIP images were created with a 4-mm thickness and a 2-mm increment, and they covered the entire heart in the horizontal long axis (4 chamber view), in the vertical long axis (2 chamber view) and in the short axis. The transaxial images and MIP images were independently evaluated for their ability to detect HSS. Conventional coronary angiograms of the same study group served as the standard of reference. Four radiologists were requested to rank each image with using a five-point scale (1 = definitely negative, 2 = probably negative, 3 = indeterminate, 4 = probably positive, and 5 = definitely positive) for the presence of HSS; the data were then interpreted using ROC analysis.
There was no statistical difference in the area under the ROC curve between transaxial images and MIP images for the detection of HSS (0.8375 and 0.8708, respectively; p > 0.05). The mean reading time for the transaxial source images and the MIP images was 116 and 126.5 minutes, respectively.
The diagnostic performance of the MIP images for detecting HSS of the coronary arteries is acceptable and this technique's ability to detect HSS is comparable to that of the transaxial source images.
Computed tomography (CT), maximum intensity projection; Coronary vessels; CT Coronary vessels, stenosis or obstruction; Diagnostic radiology, observer performance
Multiple births in Korea have been increased recently as a consequence of increased infertility due to advancing maternal age at first birth, and increased use of assisted reproductive technology. Multiples suffer higher mortality and morbidity than singletons. However, it is not clear whether preterm multiple very low birth weight infants (VLBWI) suffer higher mortality and morbidity than comparable singletons. We evaluated 266 singleton and 113 multiple VLBWI to determine whether mortality and morbidity in multiple VLBWI were higher than those in comparable singletons. The rate of in vitro fertilization and cesarean section were significantly higher in multiples than singletons. The total and the adjusted mortality with gestational age and birth weight were not significantly different between the two groups. Maternal age and the incidence of respiratory distress syndrome, patent ductus arteriosus, bronchopulmonary dysplasia, intracranial hemorrhage (grade> or =3), cystic periventricular leukomalacia, and retinopathy of prematurity (stage> or =3) were not significantly different between the two groups, and the incidence of abnormal brainstem auditory evoked potential was higher among the singletons. These results suggest that multiple VLBWI do not suffer higher mortality or morbidity than comparable singletons.