AIM: To investigate the therapeutic efficacy and mechanisms of action of oncolytic-herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor (HSVGM-CSF) in pancreatic carcinoma.
METHODS: Tumor blocks were homogenized in a sterile grinder in saline. The homogenate was injected into the right armpit of each mouse. After vaccination, the mice were randomly assigned into four groups: a control group, a high dose HSVGM-CSF group [1 × 107 plaque forming units (pfu)/tumor], a medium dose HSVGM-CSF group (5 × 106 pfu/tumor) and a low dose HSVGM-CSF group (5 × 105 pfu/tumor). After initiation of drug administration, body weights and tumor diameters were measured every 3 d. Fifteen days later, after decapitation of the animal by cervical dislocation, each tumor was isolated, weighed and stored in 10% formaldehyde solution. The drug effectiveness was evaluated according to the weight, volume and relative volume change of each tumor. Furthermore, GM-CSF protein levels in serum were assayed by enzyme-linked immunosorbent assays at 1, 2, 3 and 4 d after injection of HSVGM-CSF.
RESULTS: Injection of the recombinant mouse HSV encoding GM-CSF resulted in a significant reduction in tumor growth compared to the control group, and dose-dependent effects were observed: the relative tumor proliferation rates of the low dose, medium dose and high dose groups on 15 d after injection were 45.5%, 55.2% and 65.5%, respectively. The inhibition rates of the tumor weights of the low, middle, and high dose groups were 41.4%, 46.7% and 50.5%, respectively. Furthermore, the production of GM-CSF was significantly increased in the mice infected with HSVGM-CSF. The increase in the GM-CSF level was more pronounced in the high dose group compared to the other two dose groups.
CONCLUSION: Our study provides the first evidence that HSVGM-CSF could inhibit the growth of pancreatic cancer. The enhanced GM-CSF expression might be responsible for the phenomenon.
Pancreatic carcinoma; Gene therapy; Animal test; Herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor
Few studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2–6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.
Results of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.
The available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004–1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232–14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.
Immediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.
Pneumonitis is a complication of high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) regimens containing BCNU. Our goal was to define the incidence and risk factors for pneumonitis in lymphoma patients receiving a uniform conditioning regimen in the modern era. We studied 222 patients who received HDC-ASCT using cyclophosphamide, BCNU, and VP-16 (CBV). Pneumonitis incidence was 22%, with 19% receiving systemic corticosteroid treatment, and 8% requiring inpatient hospitalization for pneumonitis. Three patients died secondary to pneumonitis-related complications. The following variables were independently associated with pneumonitis: prior mediastinal radiation (odds ratio 6.5, 95%CI 2.3–18.9, P=0.0005), total BCNU dose above 1000 mg (OR 3.4, 95%CI 1.3–8.7, P=0.012), and age less than 54 (OR 3.0, 95%CI 1.4–6.5, P=0.0037). Increased vigilance for symptoms of pneumonitis is warranted for patients with prior mediastinal radiation and for younger patients, and dose reduction may be considered for patients who would receive greater than 1000 mg of BCNU.
This study aims to investigate the clinicopathologic significance of lymphatic vessel invasion (LVI) labeled by D2-40 monoclonal antibody in esophageal squamous cell carcinoma (ESCC).
Immunohistochemical assay was used to detect the expression of D2-40 and LVI in 107 ESCC patients. Then, the correlation between the clinicopathologic feature and the overall survival time of the patients was analyzed.
The lymph node metastasis rates were 70% and 21% in the LVI-positive and LVI-negative groups, respectively. The nodal metastasis rate was higher in the LVI-positive group than in the LVI-negative group. Multivariate regression analysis showed that LVI was related to nodal metastasis (P<0.001). The median survival time of the patients was 26 and 43 months in the LVI-positive and LVI-negative groups, respectively. Although univariate regression analysis showed significant difference between the two groups (P=0.014), multivariate regression analysis revealed that LVI was not an independent prognostic factor for overall survival in the ESCC patients (P=0.062). Lymphatic node metastasis (P=0.031), clinical stage (P=0.019), and residual tumor (P=0.026) were the independent prognostic factors.
LVI labeled by D2-40 monoclonal antibody is a risk factor predictive of lymph node metastasis in ESCC patients.
Esophageal squamous cell carcinoma; lymphatic vessel invasion; D2-40; lymph node metastasis; prognosis
Double umbilical cord blood (DUCB) transplantation is an accepted transplantation strategy for patients without suitable human leukocyte antigen (HLA)-matched donors. However, DUCB transplantation is associated with increased morbidity and mortality due to slow recovery of immunity and a high risk of infection. To define the differences in immune reconstitution between DUCB transplantation and HLA-matched unrelated donor (MUD) transplantation, we performed a detailed, prospective analysis of immune reconstitution in 42 DUCB recipients and 102 filgrastim-mobilized unrelated peripheral blood stem cell recipients. Reconstitution of CD3 T cells was significantly delayed in the DUCB cohort compared with the MUD cohort for 1–6 months post-transplantation (p<0.001), including naive (CD45RO−) and memory (CD45RO+) CD4 T cells, regulatory (CD4CD25) T cells, and CD8 T cells. In contrast, CD19 B cells recovered more rapidly in the DUCB cohort and numbers remained significantly greater from 3–24 months after transplantation (p=0.001). CD56CD16 natural killer (NK) cells also recovered more rapidly in DUCB recipients and remained significantly greater from 1–24 months after transplantation. B cell activating factor (BAFF) levels were higher in the DUCB cohort at 1 month (p<0.001), were similar in both cohorts at 3 and 6 months, and were lower in the DUCB cohort at 12 months (p=0.002). BAFF/CD19 B cell ratios were lower in the DUCB cohort at 3 (p=0.045), 6 (p=0.02), and 12 months (p=0.002) after transplantation. DUCB recipients had more infections within the first 100 days after transplantation (p<0.001), and there was less chronic graft-versus-host disease (cGVHD) (p<0.001), but there were no differences in cumulative incidence of relapse, non-relapse death, progression-free survival or overall survival between the two groups. These results suggest that increased risk of infections is specifically associated with delayed reconstitution of all major T cell subsets, but the increased risk is limited to the first 3 months after DUCB transplantation. There is no increased risk of relapse suggesting that graft-versus-leukemia (GVL) activity is maintained. Early reconstitution of B cells and NK cells may, in part, account for these findings.
Mammography screening rates among Chinese American women have been reported to be low. This study examines whether and how culture views and language ability influence mammography adherence in this mostly immigrant population. Asymptomatic Chinese American women (n = 466) aged 50 and older, recruited from the Washington, D.C. area, completed a telephone interview. Regular mammography was defined as having two mammograms at age-appropriate recommended intervals. Cultural views were assessed by 30 items, and language ability measured women’s ability in reading, writing, speaking, and listening to English. After controlling for risk perception, worry, physician recommendation, family encouragement, and access barriers, women holding a more Chinese/Eastern cultural view were significantly less likely to have had regular mammograms than those having a Western cultural view. English ability was positively associated with mammography adherence. The authors’ results imply that culturally sensitive and language-appropriate educational interventions are likely to improve mammography adherence in this population.
breast cancer screening; culture; minority health
New developments in the treatment of patients with relapsed/refractory Hodgkin's lymphoma undergoing autologous stem cell transplantation are summarized including modern prognostic markers, the role of functional imaging, the role of newer drugs, different conditioning regimens, and maintenance therapy.
Despite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ∼20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ∼50%–60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas.
Autologous stem cell transplant; Hodgkin's lymphoma; High-dose chemotherapy
This study investigated the hypothesis that adherence to colon cancer screening guidelines among Chinese women was associated with Eastern cultural views and anxiety about developing colon cancer.
Cross-sectional data from a community-based longitudinal study were used to examine the hypothesis of this study. Measures of sociodemographics, medical access factors, cultural views of health care, cancer worry, and practices of colon cancer screening were administered by a computer assisted telephone interview.
Four hundred and thirty-three Chinese-American women from Metropolitan Washington, DC age 50 years and older and without a history of colon cancer completed the telephone interview.
Main Outcome Measure
Adherence to utilization of either fecal occult blood test (FOBT) within a year, sigmoidoscopy within five years, or colonoscopy within 10 years was used to define two outcome categories: current screeners and noncurrent screeners.
Controlling for covariates, this study found that: 1) women with more Eastern cultural views were less likely to be current screeners; 2) women who thought about the chance of getting colon cancer had approximately three-fold greater odds of being current screeners than women who never thought about colon cancer; and 3) women receiving physician recommendation for colon cancer screening had more than three-fold increased odds of being current screeners than those who had not received a recommendation.
In addition to the lack of physician recommendation, older Chinese women face cultural and psychological barriers to obtaining timely colon cancer screening. These barriers may be reduced through culturally sensitive intervention studies.
Cancer Worry; Chinese-American Women; Colon Cancer Screening; Colonoscopy; Cultural Views of Health Care; FOBT; Physician Recommendation; Sigmoidoscopy
Bronchofiberscopy, a widely used procedure for the diagnosis of various pulmonary diseases within intensive care units, has a history of association with nosocomial infections. Between September and November 2009, an outbreak caused by multidrug-resistant Acinetobacter baumannii (MDR-Ab) was observed in the intensive care unit of a tertiary care hospital in Beijing, China. This study is aimed to describe the course and control of this outbreak and investigate the related risk factors.
Clinical and environmental sampling, genotyping with repetitive extragenic palindromic polymerase chain reaction (REP-PCR), and case–control risk factor analysis were performed in the current study.
During the epidemic period, 12 patients were infected or colonized with MDR-Ab. Sixteen (72.7%) of twenty-two MDR-Ab isolates from the 12 patients and 22 (84.6%) of 26 MDR-Ab isolates from the bronchofiberscope and the healthcare-associated environment were clustered significantly into a major clone (outbreak MDR-Ab strain) by REP-PCR typing. Seven patients carrying the outbreak MDR-Ab strain were defined as the cases. Six of the seven cases (83%) received bronchofiberscopy versus four of the 19 controls (21%) (odds ratio, 22.5; 95% confidence interval, 2.07–244.84; P = 0.005). Several potential administrative and technical problems existed in bronchofiberscope reprocessing.
Bronchofiberscopy was associated with this MDR-Ab outbreak. Infection control precautions including appropriate bronchofiberscope reprocessing and environmental decontamination should be strengthened.
Outbreak; Bronchofiberscopy; Multidrug-resistant Acinetobacter baumannii
Yellow seed is a desirable quality trait of the Brassica oilseed species. Previously, several seed coat color genes have been mapped in the Brassica species, but the molecular mechanism is still unknown. In the present investigation, map-based cloning method was used to identify a seed coat color gene, located on A9 in B. rapa. Blast analysis with the Arabidopsis genome showed that there were 22 Arabidopsis genes in this region including at4g09820 to at4g10620. Functional complementation test exhibited a phenotype reversion in the Arabidopsis thaliana tt8-1 mutant and yellow-seeded plant. These results suggested that the candidate gene was a homolog of TRANSPARENT TESTA8 (TT8) locus. BrTT8 regulated the accumulation of proanthocyanidins (PAs) in the seed coat. Sequence analysis of two alleles revealed a large insertion of a new class of transposable elements, Helitron in yellow sarson. In addition, no mRNA expression of BrTT8 was detected in the yellow-seeded line. It indicated that the natural transposon might have caused the loss in function of BrTT8. BrTT8 encodes a basic/helix-loop-helix (bHLH) protein that shares a high degree of similarity with other bHLH proteins in the Brassica. Further expression analysis also revealed that BrTT8 was involved in controlling the late biosynthetic genes (LBGs) of the flavonoid pathway. Our present findings provided with further studies could assist in understanding the molecular mechanism involved in seed coat color formation in Brassica species, which is an important oil yielding quality trait.
p28GANK (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28GANK mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28GANK is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28GANK expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28GANK expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28GANK-mediated activation of β-catenin. p28GANK overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28GANK resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28GANK, and a correlation between p28GANK overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28GANK expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.
p28GANK; β-catenin; E-cadherin; positive feedback loop; hepatocellular carcinoma
Gut-associated dendritic cells (DC) synthesize all-trans retinoic acid (RA), which is required for inducing gut-tropic lymphocytes. Gut-associated DC from MyD88-/- mice, which lack most TLR signals, expressed low levels of retinal dehydrogenases (Raldh, critical enzymes for RA biosynthesis) and were significantly impaired in their capacity to induce gut-homing T cells. Pre-treatment of extra-intestinal DC with a TLR1/2 agonist was sufficient to induce Raldh and to confer these DC with the capacity to induce gut-homing lymphocytes via a mechanism dependent on MyD88 and JNK/MAPK. Moreover, gut-associated DC from TLR2-/- mice or from mice in which JNK was pharmacologically blocked were impaired in their education to imprint gut-homing T cells, which correlated with a decreased induction of gut-tropic T cells in TLR2-/- mice upon immunization. Thus, MyD88-dependent TLR2 signals are necessary and sufficient to educate DC with gut-specific imprinting properties and contribute in vivo to the generation of gut-tropic T cells.
7365AB, a recessive genetic male sterility system, is controlled by BnMs3 in Brassica napus, which encodes a Tic40 protein required for tapetum development. However, the role of BnMs3 in rapeseed anther development is still largely unclear. In this research, cytological analysis revealed that anther development of a Bnms3 mutant has defects in the transition of the tapetum to the secretory type, callose degradation, and pollen-wall formation. A total of 76 down-regulated unigenes in the Bnms3 mutant, several of which are associated with tapetum development, callose degeneration, and pollen development, were isolated by suppression subtractive hybridization combined with a macroarray analysis. Reverse genetics was applied by means of Arabidopsis insertional mutant lines to characterize the function of these unigenes and revealed that MSR02 is only required for transport of sporopollenin precursors through the plasma membrane of the tapetum. The real-time PCR data have further verified that BnMs3 plays a primary role in tapetal differentiation by affecting the expression of a few key transcription factors, participates in tapetal degradation by modulating the expression of cysteine protease genes, and influences microspore separation by manipulating the expression of BnA6 and BnMSR66 related to callose degradation and of BnQRT1 and BnQRT3 required for the primary cell-wall degradation of the pollen mother cell. Moreover, BnMs3 takes part in pollen-wall formation by affecting the expression of a series of genes involved in biosynthesis and transport of sporopollenin precursors. All of the above results suggest that BnMs3 participates in tapetum development, microspore release, and pollen-wall formation in B. napus.
BnMs3; Brassica napus; exine development; gene expression; microspore release; recessive genetic male sterility; suppression subtractive hybridization; tapetum
Sucrose is the primary photosynthesis product and the principal translocating form within higher plants. Sucrose transporters (SUC/SUT) play a critical role in phloem loading and unloading. Photoassimilate transport is a major limiting factor for seed yield. Our previous research demonstrated that SUT co-localizes with yield-related quantitative trait loci. This paper reports the isolation of BnA7.SUT1 alleles and their promoters and their association with yield-related traits.
Two novel BnA7.SUT1 genes were isolated from B. napus lines 'Eagle' and 'S-1300' and designated as BnA7.SUT1.a and BnA7.SUT1.b, respectively. The BnA7.SUT1 protein exhibited typical SUT features and showed high amino acid homology with related species. Promoters of BnA7.SUT1.a and BnA7.SUT1.b were also isolated and classified as pBnA7.SUT1.a and pBnA7.SUT1.b, respectively. Four dominant sequence-characterized amplified region markers were developed to distinguish BnA7.SUT1.a and BnA7.SUT1.b. The two genes were estimated as alleles with two segregating populations (F2 and BC1) obtained by crossing '3715'×'3769'. BnA7.SUT1 was mapped to the A7 linkage group of the TN doubled haploid population. In silico analysis of 55 segmental BnA7.SUT1 alleles resulted three BnA7.SUT1 clusters: pBnA7.SUT1.a- BnA7.SUT1.a (type I), pBnA7.SUT1.b- BnA7.SUT1.a (type II), and pBnA7.SUT1.b- BnA7.SUT1.b (type III). Association analysis with a diverse panel of 55 rapeseed lines identified single nucleotide polymorphisms (SNPs) in promoter and coding domain sequences of BnA7.SUT1 that were significantly associated with one of three yield-related traits: number of effective first branches (EFB), siliques per plant (SP), and seed weight (n = 1000) (TSW) across all four environments examined. SNPs at other BnA7.SUT1 sites were also significantly associated with at least one of six yield-related traits: EFB, SP, number of seeds per silique, seed yield per plant, block yield, and TSW. Expression levels varied over various tissue/organs at the seed-filling stage, and BnA7.SUT1 expression positively correlated with EFB and TSW.
Sequence, mapping, association, and expression analyses collectively showed significant diversity between the two BnA7.SUT1 alleles, which control some of the phenotypic variation for branch number and seed weight in B. napus consistent with expression levels. The associations between allelic variation and yield-related traits may facilitate selection of better genotypes in breeding.
Cytoplasmic male sterility (CMS) is a widespread phenomenon in higher plants, and several studies have established that this maternally inherited defect is often associated with a mitochondrial mutant. Approximately 10 chimeric genes have been identified as being associated with corresponding CMS systems in the family Brassicaceae, but there is little direct evidence that these genes cause male sterility. In this study, a novel chimeric gene (named orf288) was found to be located downstream of the atp6 gene and co-transcribed with this gene in the hau CMS sterile line. Western blotting analysis showed that this predicted open reading frame (ORF) was translated in the mitochondria of male-sterile plants. Furthermore, the growth of Escherichia coli was significantly repressed in the presence of ORF288, which indicated that this protein is toxic to the E. coli host cells. To confirm further the function of orf288 in male sterility, the gene was fused to a mitochondrial-targeting pre-sequence under the control of the Arabidopsis APETALA3 promoter and introduced into Arabidopsis thaliana. Almost 80% of transgenic plants with orf288 failed to develop anthers. It was also found that the independent expression of orf288 caused male sterility in transgenic plants, even without the transit pre-sequence. Furthermore, transient expression of orf288 and green fluorescent protein (GFP) as a fused protein in A. thaliana protoplasts showed that ORF288 was able to anchor to mitochondria even without the external mitochondrial-targeting peptide. These observations provide important evidence that orf288 is responsible for the male sterility of hau CMS in Brassica juncea.
Brassica juncea; cytoplasmic male sterility; cytotoxic protein; mitochondrial-anchored protein; orf288; transgenic plants
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.
B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as “double-hit” lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathological features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathological spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we performed case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32-91). Six patients had a history of grade 1-2 follicular lymphoma (FL); review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 months) was inferior to both BL (p=0.002) and IPI-matched DLBCL (p=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (p<0.0001), Mum1/IRF4 (p=0.006), Ki-67 <95% (p<0.0001), and absence of EBV-EBER (p=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen in most BL controls (p=0.001), and exhibited a higher number of chromosomal aberrations (p=0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multi-agent chemotherapy, and clinical and pathological features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches.
MYC; BCL2; diffuse large B-cell lymphoma; Burkitt lymphoma; cytogenetics; high-grade B-cell lymphoma
Double umbilical cord blood transplantation with a reduced intensity regimen is an effective strategy for adult patients without matched donors. However, the risk of second cancers is not yet established. Ninety-eight adults with hematologic malignancies received a double umbilical cord blood transplant. Seventy patients received the reduced intensity regimen of fludarabine 30 mg/m2/day × 6 days, melphalan 100 mg/m2/day × 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day × 4 days, and 28 patients received an ablative total body radiation containing conditioning regimen. Sixty-three patients received sirolimus-based graft versus host disease prophylaxis and 35 patients received non-sirolimus based graft versus host disease prophylaxis. Median age was 48 (range 19-67) years. Eighteen patients developed a second malignancy at a median of 134 days after transplant. Sixteen patients had lymphoma and two patients had myelodysplasia/myeloproliferative disorder. Sixteen of these second cancers (both MDS/MPD and fourteen of the lymphomas) were donor derived; the origin of the others was not determined. GVHD prophylaxis, HLA matching, primary disease, age, total nucleated cell dose, and CD34+ cell dose were not associated with a higher rate of second malignancy. Second myeloid malignancies of donor origin occur after double umbilical cord blood transplantation, suggesting that a search for donor origin should be performed in all patients with suspected relapse.
Our previous studies showed that ZBTB20, a new BTB/POZ-domain gene, could negatively regulate α feto-protein and other liver-specific genes, concerning such as bio-transformation, glucose metabolism and the regulation of the somatotropic hormonal axis. The aim of this study is to determine the potential clinical implications of ZBTB20 in hepatocellular carcinoma (HCC).
Quantitative real-time RT-PCR and Western blot analyses were used to detect expression levels of ZBTB20 in 50 paired HCC tumorous and nontumorous tissues and in 20 normal liver tissues. Moreover, expression of ZBTB20 was assessed by immunohistochemistry of paired tumor and peritumoral liver tissue from 102 patients who had undergone hepatectomy for histologically proven HCC. And its relationship with clinicopathological parameters and prognosis was investigated.
Both messenger RNA and protein expression levels of ZBTB20 were elevated significantly in HCC tissues compared with the paired non-tumor tissues and normal liver tissues. Overexpressed ZBTB20 protein in HCC was significantly associated with vein invasion (P = 0.016). Importantly, the recurrence or metastasis rates of HCCs with higher ZBTB20 expression were markedly greater than those of HCCs with lower expression (P = 0.003, P = 0.00015, respectively). Univariate and multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. The disease-free survival period and over-all survival period in patients with overexpressed ZBTB20 in HCC was significantly reduced.
The expression of ZBTB20 is increased in HCC and associated with poor prognosis in patients with HCC, implicating ZBTB20 as a candidate prognostic marker in HCC.
The influence of rural-urban disparities in children's health on neonatal death in disadvantaged areas of China is poorly understood. In this study of rural and urban populations in Gansu province, a disadvantaged province of China, we describe the characteristics and mortality of newborn infants and evaluated rural-urban differences of neonatal death.
We analyzed all neonatal deaths in the data from the Surveillance System of Child Death in Gansu Province, China from 2004 to 2009. We calculated all-cause neonatal mortality rates (NMR) and cause-specific death rates for infants born to rural or urban mothers during 2004-09. Rural-urban classifications were determined based on the residence registry system of China. Chi-square tests were used to compare differences of infant characteristics and cause-specific deaths by rural-urban maternal residence.
Overall, NMR fell in both rural and urban populations during 2004-09. Average NMR for rural and urban populations was 17.8 and 7.5 per 1000 live births, respectively. For both rural and urban newborn infants, the four leading causes of death were birth asphyxia, preterm or low birth weight, congenital malformation, and pneumonia. Each cause-specific death rate was higher in rural infants than in urban infants. More rural than urban neonates died out of hospital or did not receive medical care before death.
Neonatal mortality declined dramatically both in urban and rural groups in Gansu province during 2004-09. However, profound disparities persisted between rural and urban populations. Strategies that address inequalities of accessibility and quality of health care are necessary to improve neonatal health in rural settings in China.
The role of IL-17 producing cells in tumors is controversial. In the present study, we investigated the prognostic value of measuring tumor-infiltrating IL-17 producing cell levels in human esophageal squamous cell carcinoma (ESCC).
Immunohistochemical staining was performed to investigate the levels of IL-17+ tumor infiltrating lymphocytes (TILs), as well as CD8+ cytotoxic T lymphocytes (CTLs) and CD57+ natural killer (NK) cells from 181 ESCC patients. The prognostic value of measuring the densities of IL-17+TILs and the correlation with CTLs and NK was evaluated. IL-17 producing cells were detected in esophageal squamous cell carcinoma tissues. The IL-17 producing cells were major CD4 positive, but Foxp3 negative. The median level of IL-17+TILs was 3.90 cells/high power microscopic field (HPF). The density of IL-17 producing cells correlated negatively with T stage (P = 0.042). The higher densities of tumor infiltrating IL-17+ lymphocytes were associated with better overall survival (P = 0.031). Furthermore, we found that there were positive correlations between levels of IL-17 producing cells and the densities of CD8+cells, as well as CD57+cells (r = 0.198, P = 0.008 for CD8+ cells and r = 0.261, P<0.001 for CD57+ cells, respectively). The prognosis analysis also showed that the higher levels of CD8+ CTLs and CD57+ NK cells correlated with better overall survival of ESCC patients.
Our study suggests that tumor infiltrating IL-17 producing cells in ESCC patients may have protective roles in the tumor microenvironment and may be treated as a prognostic marker for ESCC patients.
Herb-drug interactions are an important issue in drug safety and clinical practice. The aim of this epidemiological study was to characterize associations of clinical outcomes with concomitant herbal and antipsychotic use in patients with schizophrenia.
Methods and Findings
In this retrospective, cross-sectional study, 1795 patients with schizophrenia who were randomly selected from 17 psychiatric hospitals in China were interviewed face-to-face using a structured questionnaire. Association analyses were conducted to examine correlates between Chinese medicine (CM) use and demographic, clinical variables, antipsychotic medication mode, and clinical outcomes. The prevalence of concomitant CM and antipsychotic treatment was 36.4% [95% confidence interval (95% CI) 34.2%–38.6%]. Patients using concomitant CM had a significantly greater chance of improved outcomes than non-CM use (61.1% vs. 34.3%, OR = 3.44, 95% CI 2.80–4.24). However, a small but significant number of patients treated concomitantly with CM had a greater risk of developing worse outcomes (7.2% vs. 4.4%, OR = 2.06, 95% CI 2.06–4.83). Significant predictors for concomitant CM treatment-associated outcomes were residence in urban areas, paranoid psychosis, and exceeding 3 months of CM use. Herbal medicine regimens containing Radix Bupleuri, Fructus Gardenia, Fructus Schisandrae, Radix Rehmanniae, Akebia Caulis, and Semen Plantaginis in concomitant use with quetiapine, clozapine, and olanzepine were associated with nearly 60% of the risk of adverse outcomes.
Concomitant herbal and antipsychotic treatment could produce either beneficial or adverse clinical effects in schizophrenic population. Potential herb-drug pharmacokinetic interactions need to be further evaluated.
Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens for diffuse large B-cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, many patients develop refractory or recurrent DLBCL and then receive autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes following AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n=176, “+R” group) or was not (n=818, “ −R” group) administered with front-line or salvage therapy prior to AuHCT. The +R group had superior progression-free survival (50% versus 38%, p=0.008) and overall survival (57% versus 45%, p=0.006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Non-relapse mortality (NRM) did not differ significantly between the +R and −R groups. In multivariate analysis, the +R group had improved progression-free survival (relative risk of relapse/progression or death 0.64, p<0.001) and improved overall survival (relative risk of death of 0.74, p=0.039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival following AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM.
autologous hematopoietic stem cell transplantation; lymphoma; rituximab
Chinese-American women have much lower mammography screening rates than the general population. This study examined the collective impact of knowledge, cultural views, and health beliefs on intentions to obtain mammography among Chinese women who had not had a mammogram in the previous year.
Five-hundred, sixty-six immigrant Chinese women from the Washington, DC and New York metropolitan areas completed baseline assessments for a longitudinal intervention study. Validated surveys were used to measure variables of interest. The outcomes were 1) past mammography use (ever versus never) and 2) future screening intention.
Only 35% of the participants reported intentions to obtain mammograms, with approximately 19% of the never users reporting intentions (vs. 44% ever users). Ever users had higher knowledge (OR 1.13, 95% CI 1.03–1.25), less Eastern cultural views (OR 0.78, 95% CI 0.70–0.87), and perceived fewer barriers (OR 0.78, 95% CI 0.70–0.87) than never users, controlling for covariates. Never users were more likely to be recent immigrants, have low income and English ability, and lack regular sources of care than ever users (all p<.001). Multivariate models showed that ever users who were employed, received physician recommendations, had less Eastern views, and perceived higher susceptibility were more likely to have intentions. Among never users, only being ages 40–49 and perceiving fewer barriers led to increased intention.
Understanding cultural patterns and health beliefs in Chinese women is critical to changing their screening behaviors. Interventions that address their common beliefs and specific group barriers are optimal for promoting mammography adherence.
Mammography adherence; Chinese-American women; Cultural views; Health Belief Model