bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Tryptase Levels in AML at Diagnosis: A Multicenter Retrospective Study.
Authors: Cairoli Roberto , Ripamonti Carla B. , Granata Simonetta , Beghini Alessandro , Colapietro Patrizia , Grillo Giovanni , Nadali Gianpaolo , Viola Assunta , Cattaneo Chiara , Intropido Liliana , Ravelli Erika , Bertani Gianbattista , Pezzetti Laura , Nichelatti Michele , Veronese Silvio , Marocchi Alessandro , Rossi Giuseppe , Pizzolo Giovanni , Ferrara Felicetto , Nosari Annamaria , Morra Enrica 
Published: October 2019

Abstract
α and β-tryptase genes cluster on the short arm of human chromosome 16 and encode lineage-associated serine proteases that are abundantly expressed in mast-cells and, in trace amounts, in basophils. Under physiologic conditions no other myeloid cells express tryptases. However, in several myeloid leukemia cell lines and in AML blasts, the level of tryptase is elevated. In an attempt at correlating the levels of tryptase with cytogenetic features and the KIT and FLT3 mutational status, we analyzed serum samples collected at diagnosis from 150 AML and 57 ALL adult patients. The total serum concentration was determined by UniCAP 100 and UniCAP Tryptase Fluorenzyme Immunoassay Kit (Pharmacia-Upjohn, Uppsala, Sweden). The median value of tryptase level in the control group (50 healthy people; mean age 35 y, range 20–50; M/F= 26/24) amounted to less than 5 ng/ml, ranging from 1 to 15 ng/ml. We detected elevated tryptase levels (more than 15 ng/ml) in 66 out of 150 AML-patients (44%) and in 1 out of 57 ALL-patients (1.75%; median value 1.2 ng/ml) (p = < 0.0005, Fisher’s exact test ). In AMLs data showed that elevated tryptase values are significantly bound to patients with t(8;21) (n = 26, p = <0.0001) and inv(16) (n = 17, p = 0.035). Furthermore, we found a strong correlation between tryptase < 15 ng/ml and normal karyotype (n = 58 ; p = <0.0001). By contrast, we didn’t find any correlation between the levels of tryptase and t(15;17) (n = 12, p = 0.227), abnormal chr 5 or 7 (n = 9, p = 0.507), +8 (n = 6, p = 0.229), complex karyotype (n = 9, p = 1.000) or other abnormalities (n = 14, p = 0.778). A mutational screening for KIT (exon 2,8,10,11,and 17) and FLT3 (exon 14,15 and 20) was performed on 67/150 (45%) and 82/150 (55%) patients with AML, respectively. We recorded a significant association between high tryptase levels and the presence of KIT mutation (Fisher’s exact test: p = 0.012). No correlation was found between levels of tryptase and FLT3 mutational status (Fisher’s exact test: p = 0.803).In conclusion, data suggest that elevated serum tryptase levels at diagnosis are frequently associated with Core Binding Factor and with KIT mutated AML’s.
Role of Huntingtin Interacting Protein HIP-1 in Non-Hodgkin’s Lymphoma.
Authors: Smith Mitchell R. , Joshi Indira , Jin Fang , Bradley Sarah V. , Ross Theodora S. 
Published: October 2019

Abstract
We have developed a murine model for mantle cell lymphoma (muMCL) that occurs after pristane injection of Eμ-cyclin D1 transgenic mice that are > 1 year of age (Leukemia 20:891, 2006). Eμ-cyclin D1 transgenic mice are healthy, implying that cyclin D1 may be necessary, but not sufficient, for MCL decvelopment. We are using this model to identify genes that coooperate with cyclin D1 in lymphomagenensis. Comparing gene expression in B cells from spleens of these muMCL with B cells from non-pristane injected age-matched Eμ-cyclin D1 transgenic mice by differential gene expression, we identified up-regulation of RNA for the Huntingtin interacting protein HIP-1 in the muMCL. We confirmed that this translated into up-regulation at the protein level by Western blot. HIP-1 is an inositol lipid, clathrin and actin binding protein that can directly transform fibroblasts. HIP-1, located on 7q, was previously found in a fusion protein with PDGFRβ in a case of CMML with t(5;7), suggsting a role in hematopoietic malignancies. To test the generalizability of the finding of HIP-1 overexpression in lymphoma, we performed immunohistochemistry using the monoclonal anti-HIP-1 antibody 4B10 on a lymphoma tissue microarray (Cybridi). Positive antibody staining was found in 79 of 116 (68.1%) non-Hodgkin’s lymphomas (NHL). Based on:
our identification of HIP-1 as a potential cooperating gene in MCL development; overexpression of HIP-1 in many NHL; and that the presence of antibodies to HIP-1 in serum correlates with overexpression of the protein, we tested serum samples from lymphoma patients.
We found circulating HIP-1 antibodies in sera from 23 of 39 (59%) lymphoma patients. The highest antibody titer was in serum from a patient with T-ALL in remission during maintenance chemotherapy who had a cytogenetic abnormality of 7q near the site of the HIP-1 gene. Studies are ongoing to expand this data set to see if HIP-1 antibodies correlate with disease type or outcome. In summary, HIP-1 appears to be involved in lymphoma development in a murine model of MCL and is frequently overexpressed in other types of NHL. Its role in lymphomagenesis, and potentially in treatment response and prognosis needs to be further explored.
Novel Diagnostic Scheme for Follicular Dendritic Cell Neoplasm: Clinicopathologic Analysis of 146 Cases.
Authors: Kim Tae-Jung , Moon Yeonsook , Lee Kyungji , Park Gyeongsin , Lee Youn-Soo , Kang Chang-Suk , Shim Sang-In , Lee Kyo-Young 
Published: October 2019

Abstract
Follicular dendritic cell neoplasm(FDCN), a rare tumor exhibiting a broad histopathological spectrum and unpredictable biologic behavior, has been classified into follicular dendritic cell tumor(FDCT) and follicular dendritic cell sarcoma(FDCS) regarded as borderline lesion and malignant tumor, respectively, by World Health Organization. But still no definite diagnostic criteria distinguishing FDCT from FDCS was established. Here in, as an approach to the differential diagnostic criteria, we performed clinicopathological analysis for 146 cases of FDCN, documented in English literature from January 1986 to May 2006. Through PubMED search with key words of FDC or dendritic cell tumor, we collected and reviewed 73 articles out of more than six thousands candidates, which contained 146 FDCNs with clinicopathological informations. We analyzed the carefully selected cases with parameters including age, gender, tumor location, tumor size, tumor margin, EBV association, mitosis, nuclear atypism, hemorrhage, necrosis and Castleman’s disease association. Recurrence, metastasis and death of disease were referred as event. Kaplan-Meier model was used for overall event-free survival analysis and the log-rank test was used to assess statistical significance.
Mitotic Index (MI, ≥ 5/10HPF vs <5/10HPF, P=0.0182) and tumor location (intraabdominal vs extraabdominal, P=0.007) showed significant association with event-free survival. But the other parameters have failed to achieve statistical significance as predictors of adverse events. For proposing diagnostic scheme, the risk groups were designated as follows: high risk group(n=7), MI ≥ 5/10HPF and intraabdominal; low risk group(n=26), MI <5/10HPF and extraabdominal; intermediate risk group(n=35), all others. These three risk groups had distinctly different median event-free survivals, 11 months, 24 months and 96 months for high, intermediate and low risk groups, respectively. And each group showed significantly different overall event-free survivals(P=0.0007). In conclusion, this novel diagnostic scheme might be a useful tool for predicting biologic behavior of FDCN.
Adult Weight Gain and Risk of Developing Non-Hodgkin Lymphoma (NHL): Results from a Large Prospective Cohort Study of Older Women.
Authors: Bardia Aditya , Habermann Thomas M. , Vierkant Robert A. , Wang Alice H. , Cerhan James R. 
Published: October 2019

Abstract
Background: Obesity has been associated with risk of non-Hodgkin lymphoma (NHL) in several recent studies. However, the effect of weight gain during adulthood, a potentially modifiable risk factor, on the incidence of NHL is not clear. We therefore examined the association of weight gain since age 18 years with the risk of NHL among older women.
Methods: We examined this association in the Iowa Women’s Health Study, a prospective study of 37,762 Iowa women aged 55 to 69 years at enrollment in 1986. Lifestyle and other risk factors, including weight at age 18 and at enrollment, were self-reported on a mailed questionnaire. We defined stable weight as no increase in weight or up to a 10% weight loss from age 18 to enrollment, while percent weight gain was divided into tertiles based on the distribution observed in the cohort. NHL incidence through 18 years of follow-up was ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) of percent weight gain with NHL incidence, adjusting for age (Age-adjusted model) and age, marital status, farm residence, transfusion history, diabetes, use of hormone replacement therapy, alcohol use, smoking, and intake of red meat and fruits (Multivariate model).
Results: The mean age of the women in the cohort in 1986 was 62.1 years. During 593,474 person-years of follow-up, 379 incident cases of NHL were observed. The mean age at diagnosis was 72.6 years (range 58–87 years). The main results are reported in the table. Similar results were found for absolute weight gain. Stratification of these results on body mass index at age 18 (using a cutpoint of 21 kg/m2) showed similar results, with the exception of >10% weight loss for women with a BMI of <21 at age 18 where we could not estimate a RR (no cases observed).
Conclusions: Weight gain or large weight loss (>10% of body weight) during adulthood were both associated with increased risk of NHL, although the RRs for percent weight gain were not statistically significant and there was no dose-response. This study suggests another potential benefit of avoiding adult weight gain, although further studies are needed to confirm these novel findings.
Association of percent weight change during adulthood (age 18 to age 55–69 years) and risk of NHL % Weight Change NHL Cases Person-years Age-Adjusted RR(95% CI) Multivariate RR (95% CI) >10% weight loss 15 17053 2.06 (1.05–4.02) 2.02 (1.03–3.95) Stable 20 45973 1 (reference) 1 (reference) 0–18.2% gain 115 175883 1.50 (0.94–2.42) 1.50 (0.93–2.41) 18.3–34.8% gain 119 176258 1.54 (0.96–2.47) 1.53 (0.95–2.47) >34.8% gain 110 178308 1.40 (0.87–2.25) 1.32 (0.82–2.14).
Induction of RKIP and Inhibition of the Transcription Repressor YY1 in B-NHL by the Novel Proteasome Inhibitor NPI-0052 and Sensitization to TRAIL-Induced Apoptosis.
Authors: Suzuki Eriko , Huerta-Yepez Sara , Baritaki Stavroula , Palladino Michael , Bonavida Benjamin 
Published: October 2019

Abstract
Proteasome inhibitors have been shown to exert multiple effects including direct cytotoxic activity in sensitive cancer cells. In addition, proteasome inhibitors have recently been used therapeutically for certain cancers such as multiple myeloma and mantle cell lymphoma. We have recently reported that the novel proteasome inhibitor, NPI-0052 (Nereus Pharmaceuticals), can sensitize drug-resistant B-NHL tumor cells to apoptosis by various chemotherapeutic drugs. Also, NPI-0052 inhibits the NF-κB survival pathway and inhibition of NF-κB sensitizes tumor cells to TRAIL-induced apoptosis. We hypothesized that inhibition of NF-κB by NPI-0052 may also lead to sensitization of TRAIL-resistant B-NHL cells to TRAIL-mediated apoptosis. Human Burkitt’s lymphoma,Ramos cells, were treated with various concentrations of NPI-0052 (0–10ng/ml for 24h) and were then treated with recombinant human TRAIL (0–100ng/ml for 24h). The cells were examined for apoptosis by Annexin V/PI. The combination treatment resulted in significant potentiation of cytotoxicity and synergy in apoptosis was achieved. We have then examined a potential underlying mechanism of NPI-0052-mediated sensitization. The transcription repressor YY1 was recently shown to negatively regulate the transcription of the TRAIL death receptor DR5 and thus overexpression of YY1 is a resistant factor for TRAIL-induced apoptosis. Hence, treatment of Ramos cells with NPI-0052 resulted in significant inhibition of YY1 expression and upregulation of surface DR5 expression. We have also examined the effect of NPI-0052 on RKIP (Raf-kinase inhibitor protein) (Yeung et al., Molecular Cellular Biology; 21:7207, 2001) expression. Since both NPI-0052 and RKIP inhibit the NF-κB pathway, we hypothesized that treatment of Ramos cells with NPI-0052 may result in significant upregulation of RKIP expression. The findings, indeed, demonstrate that NPI-0052 significantly induced RKIP expression in Ramos cells. Overall, the findings show, for the first time, that NPI-0052 sensitizes B-NHL tumor cells to TRAIL-mediated apoptosis. Sensitization by NPI-0052 was correlated with both the induction of RKIP expression and inhibition of YY1 and upregulation of DR5 expression. Currently, TRAIL or agonist monoclonal antibodies against DR4 or DR5 are being examined clinically for anti-tumor activity. Therefore, our findings suggest the potential application of the combination of NPI-0052 and TRAIL or agonistic monoclonal antibodies against DR4 or DR5 in the treatment of tumor cells that are resistant to drugs and TRAIL.
Host Immunogenetic Single Nucleotide Polymorphisms (SNPs) Predict Overall Survival in Small Lymphocytic Lymphoma.
Authors: Thompson Carrie A. , Wang Sophia , Maurer Matthew J. , Habermann Thomas M. , Severson Richard K. , Rothman Nathaniel , Lynch Charles F. , Davis Scott , Morton Lindsay M. , Cozen Wendy , Hartge Patricia , Geyer Susan M. , Chanock Stephen , Cerhan James R. 
Published: October 2019

Abstract
Small lymphocytic lymphoma (SLL) is an incurable indolent lymphoma, and there are relatively few prognostic biomarkers for this important NHL subtype. We evaluated the hypothesis that inherited variability in cytokine and immune-related genes was associated with overall survival in SLL. We genotyped 73 SNPs in 44 candidate genes in 140 SLL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. DNA was extracted from a venous blood sample or mouthwash buccal cell sample. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) and 95% confidence interval for the association between individual SNPs and overall survival, adjusted for age, demographic and clinical factors. Multiple simultaneous modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At last follow-up, there were 45 deaths in 140 patients (32%). The median follow-up of the 95 surviving patients was 58 months (range 24–75 months). In multivariate modeling, SNPs in IL13 (rs1800925; HRCC=2.36, 1.24–4.49), IL7R (rs1494555; HRGG =2.20, 0.84–5.76), and TNF-alpha (rs1800630; HRAC/AA=1.73, 0.95–3.17) were the strongest and most robust predictors of survival. Two or more deleterious genotypes from these three SNPs increased the risk of death (HR=2.2, 1.2–4.1) compared with one or fewer deleterious genotypes (p=0.009). Three groups (low, intermediate, and high risk) were defined by combining the SNP score and a clinical/demographic score. The 5-year Kaplan-Meier survival estimates for these groups were 85%, 65%, and 11%, respectively. Compared to patients with a low risk score, patients with intermediate (HR=2.5, 1.2–5.1) or high (HR=11, 4.3–27.7) risk scores had poorer overall survival (p=3.9 x 10−8). Our preliminary results suggest that SNPs in IL13, IL7R, and TNF-alpha alone and in combination predict overall survival in SLL, lending support to the hypothesis that host genetic background is a promising class of prognostic biomarkers in SLL.
Clinical Usefulness and Therapeutic Plan with Interim PET/CT Analysis in Malignant Lymphoma.
Authors: Yang Deok-Hwan , Lee Je-Jung , Min Jung-Joon , Lee Se-Ryeon , Kim Yeo-Kyeoung , Bom Hee-Seung , Kim Hyeoung-Joon 
Published: October 2019

Abstract
FDG-PET, a functional imaging modality used for staging and monitoring response to treatment of malignant lymphoma, has a higher sensitivity and specificity than conventional imaging. PET/CT may be more accurate than conventional imaging in assessing treatment effects to correctly identify patients with residual disease and predict therapy outcomes. We prospectively investigated that PET/CT may provide additional prognostic information in mid-response assessment prior to completion of chemotherapy.
Patients and Method: Eighty-six newly diagnosed patients with malignant lymphoma were enrolled from Aug. 2004 to July 2006. Both CT and PET/CT analysis were performed at the time of diagnosis and after the 3rd or 4th chemotherapy. The clinical stage of the patients was assessed according to International Workshop Criteria (IWC). PET/CT imaging was analyzed according to the combination of morphology using the CT portion and by the uptake and location of the FDG-PET portion. The cut off value of the positive in PET/CT was more than max SUV 3.0. We divided them into four different response groups using IWC and PET/CT (CRu-negative, Cru-positive, PR-negative, PR-positive). The limited-stage patients were treated with chemotherapy and involved field radiation therapy and the advanced-stage patients were treated with eight cycles of chemotherapy. However, advanced-stage patients who were older than sixty, if they had CRu-negative in interim analysis, were treated with only six cycles.
Results: Median age was 53.5 years (range: 19 – 85). Seventy five patients had Non-Hodgkin’s lymphoma [Indolent-11 (12.8%), Aggressive-64 (74.4%)] and eleven patients (12.8%) had Hodgkin’s lymphoma. Forty-two patients (48.8%) achieved CRu-negative, 6 patients (7.0%) achieved CRu-positive, 20 patients (23.3%) achieved PR-negative and 18 patients (20.9%) showed PR-positive by interim IWC and PET/CT. The relapse rate is significantly different between PET-positive (58.3%) and PET-negative (8.1%) (P=0.000), especially when 12 of 18 patients in PR-positive group (66.7%) relapsed after or during chemotherapy. Figures showed the Kaplan-Meier estimates of overall and progression free survival of 86 patients depending on the combined evaluation of interim IWC and PET/CT.
Conclusion: Interim PET/CT analysis was a significantly predictive value of disease progression and survival. The patients with PR-positive according to interim IWC and PET/CT analysis should be considered for an intensive therapeutic plan.
Figure Figure
Aberrant Somatic Hypermutation of Follicular Lymphoma Transformed To Diffuse Large B-Cell Lymphoma.
Authors: Fruehwirth Margareta , Deutsch Alexander J.A. , Staber Philipp B. , Aigelsreiter Ariane , Linkesch Werner , Beham-Schmid Christine , Neumeister Peter 
Published: October 2019

Abstract
Follicular Lymphoma (FL) accounts for approximately 20–30% of all malignant lymphomas and the frequency of histological transformation (HT) into diffuse large B-cell lymphomas (DLBCL) varies from 10% to 70%. Many genetic lesions have already been described in histological transformation, but a mechanism of genome-wide instability during histological transformation (HT) has not been reported. We have shown that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature 412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in histological transformation of follicular lymphoma in DLBCL we studied the mutational profile of these genes in a total of 26 cases consisting of 10 paired samples of follicular lymphoma together with the corresponding DLBCL and 6 single cases of transformed DLBCL. Genomic DNA from histologically confirmed, macrodissected tissue obtained from formalin fixed and paraffin embedded tissue or cryoconserved samples was directly sequenced. Mutations in one or more genes were detected in 6 of 10 (60%) cases of pre-HT follicular lymphoma and in 13 of 16 (81.2%) post-HT cases. Two ore more genes were affected in 1 of 10 (10%) of FL and in 7 of 16 (43.7%) cases with DLBCL. Mutations in PIM-1 occurred in 3 of 10 (30%) cases of follicular lymphoma and in 9 of 16 (56.2%) in DLBCL. For PAX-5, the distribution of the mutated cases between FL and DLBCL was 2 of 10 (20%) and 7 of 16 (43.7%), for RhoH/TTF 2 of 10 (20%) and 3 of 16 (18.7%) and for c-MYC none of 10 (0%) FL and 2 of 16 (12.5%) DLBCL. A total of 38 single base pair substitutions were found in 19 cases, 10 sequence variants in 6 FL cases and 28 sequence variants in 13 DLBCL cases. The mutations were of somatic origin and share features of the IgV SHM process including bias for transition over transversion, elevated ratio of G+C over A+T substitutions and restriction to the first 1-2Kb from the promoter initiation site. The mean mutation frequency in mutated follicular lymphoma was with 0.024 ×10−2/bp 1.4 fold lower compared to 0.032 ×10−2/bp in the transformed DLBCLs. Further in PIM-1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data support a role of aberrant SHM in the histological transformation of FL to overt DLBCL.