bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of ZAP-70 Expression in Chronic Lymphocytic Leukemia (CLL) Using Kolmogorov-Smirnov (KS) Statistics.
Authors: Gibbs Graham , Bromidge Teresa , Howe Denise , Johnson Stephen 
Published: November 2019

Abstract
ZAP-70 is a prognostic marker in CLL and has been shown to correlate closely with VH mutational status in most studies. Assays that require the setting of markers using either T-cells, or a matched isotype control to determine ZAP-70 expression in CLL are subjective and prone to analytical and inter-operator variability. We examined the use of the KS statistical test to analyze histogram overlays as an objective approach to the assessment of ZAP-70 expression in 18 CLL patients with known VH mutational status (VH mutated; n=11, VH unmutated; n=7). Use of the KS statistical test to compare ZAP-70 expression of T cells with B cells in CLL has been recently described by Van Bockstaele et al.(Cytometry Part B 70B:302-308. 2006). In contrast to this approach we used a B cell gating assay with a pre-conjugated alexa-fluor 488 ZAP-70 antibody clone 1E7.2 and an alexa-fluor 488 matched isotype control manufactured by Caltag Laboratories (Burlingame, CA) as previously described by our group. Modifications were made to allow the determination of KS ‘D’values. Statistical analysis of our resulting KS data using a t-test demonstrated a significant difference in ZAP-70 KS ‘D’ values between the two VH mutational groups (p=0.0001). All patients with a KS ‘D’ value of 0.5 or below were VH mutated, whilst all patients with a KS ‘D’ value of 0.7 or above were VH unmutated, with some cross-over between these values. At a threshold KS ‘D’ value of 0.6, 10 of the 11 VH mutated patients were correctly classified (1 patient had a ‘D’ value of 0.68), whilst 6 of the 7 VH unmutated patients were correctly classified (1 patient had a ‘D’ value of 0.59) The sensitivity and specificity of using a threshold KS ‘D’ value of 0.6 was 86% and 91% respectively. Analysis of ZAP-70 expression using the KS statistic is operator independent and thus provides a means for a more reproducible analytical approach in the laboratory. We acknowledge that our initial sample size was small and requires further investigation using a larger sample size to fully validate the diagnostic value of using KS ‘D’ values to determine ZAP-70 expression in CLL.
Survival Patterns among Chronic Lymphocytic Leukemia and Other Lymphoma Patients with Family History of Lymphoma.
Authors: Anderson Lesley A. , Pfeiffer Ruth M. , Rapkin Joshua S. , Gridley Gloria , Mellemkjaer Lene , Hemminki Kari , Bjorkholm Magnus , Goldin Lynn R. , Caporaso Neil E. , Langren Ola 
Published: November 2019

Abstract
Background. A role for genetic factors in chronic lymphocytic leukemia (CLL) is unequivocal based on evidence from multiply affected families, from case series, twin and case-control studies, and population-based registry studies. Similar characteristics have been observed for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Population-based studies have found CLL, NHL and HL to co-occur in families. A few hospital-based series have explored survival outcomes in familial vs. sporadic CLL patients based on the hypothesis that genetic mechanisms involved in the causation of familial lymphomas might influence survival, however these have been based on small numbers with inconsistent findings. We have conducted a large study in Scandinavia including more than 41,000 lymphoma patients to quantify survival outcomes among familial vs. sporadic patients.
Methods. We used the population-based central Cancer and Multigenerational Registries in Sweden and Denmark to identify all CLL (n=7749), NHL (n=25801), and HL (n=7476) patients diagnosed 1958–2001, with linkable first-degree relatives. All relatives were linked with the Cancer Registries to obtain information on CLL, NHL, and HL. Using Cox proportional hazard models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of overall survival for CLL, NHL, and HL patients with vs. without family history of lymphoma.
Results. We found 85 (1.1%) CLL, 207 (0.8%) NHL, and 96 (1.3%) HL patients with family history of lymphoma. Overall survival was similar for CLL (HR=1.24, 95% CI 0.93–1.67), NHL (HR=0.97, 95% CI 0.80–1.16), and HL (HR=0.78, 95% CI 0.51–1.19) patients with vs. without family history of lymphoma. Risk-estimates were similar when we calculated overall survival by age at lymphoma diagnosis (above vs. below median age), year at diagnosis (before vs. after 1987), and by sex. Consistent with the literature, including all CLL, NHL and HL patients, older age (p<0.001) and male gender (p<0.001) was associated with poorer survival. However, when analyses were restricted to patients with family history of lymphoma, only older age (p<0.005) remained significant.
Conclusions: Survival patterns were similar for CLL, NHL, and HL patients with vs. without family history of lymphoma, suggesting that familial lymphomas do not have an altered clinical course. Overall, there is no evidence at this time to modify therapeutic strategies for patients with CLL, NHL, or HL based solely on family history.
Translocation t(14;19)(q32;q13) Is a Rare Abnormality in CLL and Associated with Trisomy 12, an Unmutated IgVH Status and a Distinct Gene Expression Profile.
Authors: Haferlach Claudia , Rauhut Sonja , Merk Sylvia , Dicker Frank , Schnittger Susanne , Kern Wolfgang , Dugas Martin , Haferlach Torsten 
Published: November 2019

Abstract
Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease. Recently, several genetic aberrations have been identified that allow to distinguish different biological subgroups within CLL. Translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 is a rare but recurrent abnormality in CLL and still poorly described. Based on karyotype data we identified 12 cases with t(14;19)(q32;q13) in a cohort of 1051 CLL (1.1%). In all these cases 1 to 10 chromosomal aberrations were observed in addition to t(14;19) (median: 3). Recurring accompanying aberrations were: +12 (n=8), loss of 18p (n=2), and gain of 10q (n=2). Interestingly, trisomy 12 is also the most frequent additional abnormality in CLL with t(14;18)(q32;q21). Remarkably, neither 13q deletions nor 11q deletions which are frequently observed in CLL overall, were found in addition to t(14;19). A TP53-deletion and a 6q21 deletion were observed in one case each. In 8/12 cases the mutation status of the immunoglobulin variable heavy chain gene (IgVH) was available. All 8 cases showed an unmutated IgVH status. Gene expression analysis (Affymetrix, HG U133 Plus 2.0) was performed in 9 cases with t(14;19) and compared to 44 cases with CLL comprising various chromosome aberrations excluding t(14;19). Using 10fold cross validation resulted in an assignment of 7 out of 9 cases with t(14;19) into the correct class, none of the cases without t(14;19) was classified into the t(14;19) group (accuracy 96%, sensitivity 78%, specificity 100%). Classification based on an independent test set led to comparable results (median accuracy 94%, sensitivity 67%, specificity 100%). The 10 most differentially expressed genes showing a higher expression in t(14;19)+ CLL were: TUBB6, CPSF6, RFC5, MAP3K8, CUGBP2, BCAT1, BCAT1, LOC647135, TSPAN13, SIGLEC6 and are involved in transition of mitotic cell cycle, DNA replication and RNA processing. The 10 most differentially expressed genes showing a lower expression in t(14;19)+ CLL were: LSR, APLP2, C2orf10, HS3ST1, LRRC32, PALM2-AKAP2, DFNB31, PDE4A, CTLA4, PDCD4 and are involved in signal transduction, apoptosis and immune response. In conclusion:
t(14;19)(q32;q13) is a rare, recurrent chromosome abnormality in CLL. It is very frequently accompanied by additional chromosomal aberrations. The most frequent additional aberration is trisomy 12. t(14;19) is associated with an unmutated IgVH status. Comparable to other translocations leading to fusion genes it is associated with a distinct gene expression profile.
Chromosomal Abnormalities Detected by FISH in CLL May Be Influenced by Ethnic Origin: Preliminary Data from a Multicenter Study in Israel for the Israel CLL Study Group (ICLLSG).
Authors: Ruchlemer Rosa , Shvidel Lev , Baester Andre A. , Bairey Osnat , Berrebi Alain , Polliack Aaron 
Published: November 2019

Israel has a variety of distinct ethnic groups and a high incidence of CLL, particularly in patients of European origin (Ashkenazi Jews). Recently we have examined 82 CLL patients who had FISH performed in 4 centers from different areas in Israel in an attempt to see if the results varied by ethnic origin. The patients were divided into 4 ethnic groups:
- Asheknazi Jews -North African Jews (including Spanish origin, Bulgaria, Western Turkey and Greece), Eastern Jews (Iraq, Iran, Azberjian, India, Kurdistan, Eastern Turkey, Yemen and Egypt) and - Arab descent (this group was too small to further divide).
Ashkenazi Jews comprised 65.8% of the patients, North Africans 15.8%, Eastern Jews 14.6%, Arabic patients 3.7%. Variations of clinical and biological parameters by ethnic groups are recorded in table 1, and the distribution of FISH aberrations by ethnic groups in table 2. Seventy four percent of patients had FISH abnormalities. Trends suggestive of ethnic variations of FISH abnormalities were observed, but none reached statistical significance due to the small number of patients. These initial results warrants continuation of this ongoing multicenter study.
Variations of clinical and biological parameters of CLL patients by ethnic groups Ashkenazi N African Eastern Arabic Total No. patients 54 (65.8%) 13 (15.8%) 12(14.6%) 3(3.7%) 82 Median age (range) 67 67 60.5 57 65(35–82) Male:Female 1.7:1 1.6:1 3:1 2:1 1.86:1 Time from diagnosis 59.4(1–170)m 99.3m 80.5(9–202) 32(17–177)m 60.4 m Splenomegaly 55% 46% 40% 100% 39/75(52%) Lymphadenopathy 56% 31% 70% 100% 40/75(53%) Treated 73% 60% 60% 100% Zap70≥ 20% 11/25(44%) 1/7(14%) 33% 100% 17/42(40.5%) CD38>30 12/32(37.5%) 1/8(12.5%) (1/9)11% 100% 17/65(26%) FISH 13q del 21(38.9%) 4/12(33%) 42% 33 36% Trisomy 12 24% 2/12(16.7%) 16.7% 0 22% 11q23 del (ATM) 17% 0 16.7% 0 13% 17p13 del (p53) 13% 2/13(15%) 33% 33% 16% Normal 24% 38% 15% 33% 26% ≥ 2 abnormalities by FISH 9 (16.7%) 0 33% 0 12/81(15%) The distribution of FISH abnormalities in CLL patients by ethnic groups 13q− 12+ 11q− 17p− Normal No. patients 82 31 16 11 15 21 Ashkenazi 65.8% 21(68%) 11(69%) 9(82%) 6(40%) 13(62%) N Africans 15.8% 4(13%) 2(13%) 0 3(20%) 5(24%) Eastern Jews 14.6% 5(16%) 2(13%) 2(18%) 5(33%) 2(10%) Arabic 3.7% 1(3%) 0 0 1(7%) 1(5%) ≥ 2 abnormalities 12 (15%) 9 (29%) 3 (19%) 7(64%) 5(33%) 0
Rituximab in Combination with High-Dose Steroids in Advanced, Refractory Chronic Lymphocytic Leukaemia.
Authors: Quinn John , Mohamedbhai Sajir , Treacey Marilyn , D’Sa Shirley , Nathwani Amit 
Published: November 2019

Abstract
High-dose methlyprednislone (HDMP) is active in refractory chronic lymphocytic leukaemia (CLL), and rituximab, although showing limited efficacy as a single agent, is effective when used in combination with other cytotoxic agents. Early relapse (<12 months) after purine-analogue based treatment poses a difficult management problem as older patients may be unable to tolerate treatment intensification. This retrospective audit examines the outcome in patients with advanced, refractory/relapsed CLL treated with a combination of high-dose steroids and rituximab. Eleven patients with CLL were treated with rituximab (375mg/m2) and high-dose steroids between 2003 and 2007. Ten patients had advanced and/or refractory disease and one patient had severe autoimmune haemolytic anaemia complicating early-stage CLL. Median age was 70 (range 54–82) and there were 7 male and 4 female patients. Nine patients had Binet stage C disease. Six of the 7 patients for whom results were available had germ-line variable heavy chain immunoglobuliun genes. Median number of prior treatments was 2 (range 1–6) with 9 patients having already received a fludarabine based-regimen. Six patients received a combination of rituximab and high-dose methylprednisolone (1gm/m2 on days 1–5) and 5 patients received a combination of rituximab and high-dose dexamethasone (40mg daily on days 1–4) and. Cycles were repeated every 28 days and the median number of cycles received was 4 (3–6). Antiviral and anti-PCP prophlaxis with aciclovir and co-trimoxazole was routinely prescribed. Response was assessed according to the NCI working group criteria. There was one complete response (CR) and 7 partial responses (PR). Furthermore, 2 of the patients who achieved a PR were successfully salvaged prior to reduced-intensity allogeneic stem-cell transplant and both remain in complete remission (CR) post-transplant. The other 3 patients had minor responses that did not meet NCI response criteria. Median duration of response was 13 months (6–35), excluding the 2 patients who received allogeneic transplants. Three patients required hospital admission with infective complications during treatment. No other significant toxicity was observed. 3 patients have died, none of whom had attained a PR. In conclusion, we found that rituximab in combination with high-dose steroids is a safe and well-tolerated combination in patients with advanced refractory CLL. One patient achieved a CR and we observed a PR in 7/11 patients. Importantly, 2 of these patients were successfully salvaged prior to reduced-intensity conditioning allogeneic stem-cell transplant and both remain in CR at 4 and 12 months respectively post-transplant.
Expression of Bruton’s Tyrosine Kinase in Multiple Myeloma.
Authors: Zhou Guangbiao , Liu Ying , Zhang Bo , Meng Fanyi , Liu Xiaoli 
Published: November 2019

Abstract
Bruton’s tyrosine kinase (BTK), a member of the Tec family of nonreceptor protein tyrosine kinases, is critical for early B cell development and mature B cell activation and survival, and is downregulated in plasma cells. Mutation of BTK leads to human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). Here we investigate BTK function in multiple myeloma (MM) cells. Although rare mutations were found in the promoter and coding sequence of the BTK gene, elevated BTK at mRNA level was detected in MM cell lines and CD138 positive primary cells from 3 out of 8 cases of patients with MM. At protein level, BTK was upregulated in some of MM as well as myeloid leukemia cell lines. Specific inhibitor of BTK also suppressed proliferation of MM cells. These data suggest a role for BTK to play in MM pathogenesis.
Biclonal Multiple Myeloma with Monoclonal Free IgG3 Heavy Chain and kappa Free Light Chains.
Authors: Richter Alex G. , Harding Stephen , Rimmer Steve , Pratt Guy , Huissoon Aarnoud , Drayson Mark 
Published: November 2019

Abstract
Background: Heavy chain disease (HCD) is a rare lymphoproliferative disorder characterized by a monoclonal heavy chain (HC) unattached to a light chain (LC). IgGHCD or γHCD typically presents as a lymphoproliferative disorder with lymphadenopathy and hepatosplenomegaly. Myeloma has been described associated with γHCD but only with a second intact Ig paraprotein. This report describes a unique presentation of multiple myeloma with monoclonal free γ3HC and kappa free light chains.
Case: A 34 year old gentleman presented with mild persistent neutropenia following two episodes of pneumonia, 18 months previously. He admitted to persistent night sweats but no other significant history. Baseline investigations revealed a mild anaemia, neutropenia and a large IgG paraprotein with no associated light chain. Bone marrow aspirate and trephine confirmed myeloma. The patient was treated with cyclophosphamide, thalidomide and dexamethasone and has had a very good partial remission. He is awaiting a sibling allogeneic peripheral blood stem cell transplant.
Investigations and results: Serum Electrophoresis confirmed a large IgG paraprotein (23g/l) with no associated light chain in the serum and identified as γ3 subclass by radial immunodiffusion. Western blot showed the γ3HC was truncated with a large deletion. Markedly elevated free kappa (κ) LC (503.58 mg/l [3.30–19.4]) were found in the serum with gross skewing of the kappa/lambda ratio. Urine electrophoresis revealed separate γHC and κ LC paraproteins. Western blot of the fractionated urine protein demonstrated different sized κLC aggregates. Flow cytometry of the marrow aspirate revealed an unusual staining pattern; CD5,19,38,45+ve and CD20,22,23,34,56,138 –ve plasma cells. Cytoplasmic staining revealed 2 distinct populations of plasma cells, the first producing γ3HC and the second only free κLC. Cytogenetics and FISH analysis for 14q, p53 and c-myc abnormalities were normal.
Discussion: This is the first description of a Biclonal Myeloma with separate plasma cell populations producing γ3HC and κLC paraproteins. The biclonality confirms the free HC occurs as a result of abnormal synthesis not cleavage. The clinical and immunological findings are clearly different to typical findings in both γ3HCD and Myeloma. HCD has an appalling prognosis and this case is likely to have been ‘smouldering’ for 18 months, evidenced by the 2 pneumonias and persistent night sweats. There is no lymphadenopathy or organomegaly associated with γ3HCD. The immunophenotype of the malignant plasma cells is unique. Other atypical features include frank proteinuria, with a HC in the urine, but normal renal function and no radiological or biochemical evidence of bone involvement. We propose that this unique biclonal myeloma has distinct immunological and clinical features.
DKK1-Specific Cytotoxic T Lymphocytes Are Potent Effector Cells for the Treatment of Multiple Myeloma in SCID-hu Model.
Authors: Qian Jianfei , Zhang Liang , Hong Sungyoul , Wang Ji , Kwak Larry , Yi Qing 
Published: November 2019

Abstract
Dickkopf-1 (DKK1), a secreted protein and Wnt signaling pathway inhibitor, is highly expressed by the tumor cells of most multiple myeloma (MM) patients and contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. DKK1 has been targeted as a myeloma-associated antigen by immunotherapeutical approaches based on DKK1-directed monoclonal antibodies and DKK1-specific cytolytic T lymphocytes (CTLs). The present study was conducted to develop a treatment strategy through adoptive transfer of DKK1-specific CTLs in a SCID-hu system. Using DKK1 peptide-pulsed dendritic cells (DCs), we successfully generated DKK1-specific CTL lines and clones from HLA-A2+ MM patients in vitro. These CTLs not only had cytolytic activity against DKK1 peptide-pulsed T2 cells, but also significantly lysed autologous myeloma tumor cells, HLA-A2+ and DKK1+ MM cell lines U266 and IM-9, and primary tumor cells in vitro. No killing was observed against HLA-A2+ normal lymphocytes, including B cells and HLA-A2+ DKK1- XG1 or HLA-A2- myeloma cell lines or primary myeloma cells from patients. To determine the in vivo antitumor activity, SCID-hu mice were engrafted with primary MM cells expressing high levels of DKK1 from patients and treated with DKK1-specific CTLs after one month of tumor injection. Control mice were treated with naïve CD8+ T cells or PBS alone. All mice were examined by X-ray, tumor burden was measured according to levels of circulating human IgG, and survival rates were determined. All mice established human myeloma within one month after tumor inoculation, at which time the level of circulating human IgG was greater than 600 ng/ml in mouse serum. After another 3 weeks, the level of circulating human IgG was greater than 2,500 ng/ml in the serum of all control mice, while only 40% mice treated with DKK1-specific CTLs had high levels of circulating human IgG. X-ray examination showed that osteolytic bone disease and a large tumor burden were found in all control mice, while the established tumor was eradicated in 60% mice treated with DKK1-specific CTLs. Results of immunofluorescence studies showed that only tumor-reactive DKK1-specific CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. All control mice succumbed to myeloma within one month of establishment of the myeloma, while 9 out of 15 mice treated with DKK1-specific CTLs were macroscopically disease-free at the end of the experiment. These results suggest that DKK1-specific CTLs are able to eradicate established patient-derived primary myeloma in the host and that adoptive transfer of DKK1-specific CTLs may be used for myeloma therapy.
The Clinical Significance Of Activated p-AKT Expression In Peripheral T-Cell Lymphomas
Authors: Hong Jung Yong , Hong Min Eui , Kim Seok Jin , Jang Jun Ho , Kim Kihyun , Jung Chul Won , Ko Young Hyeh , Kim Won Seog 
Published: November 2019

Abstract

Background
The oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway mediates diverse prosurvival signals and promotes the malignant phenotype of cancer cells through multiple downstream pathways. We aimed to define the prognostic role and clinical significance of p-AKT expression in peripheral T-cell lymphomas (PTCLs).

Methods
We evaluated the p-Akt expression in patients with PTCLs using tissue microarray(TMA) technology. The intensity of p-AKT staining was scored as 0, 1, 2, and 3 and the proportion of p-AKT positive cells was scored from 0% to 100%. p-AKT expression score was expressed as arbitrary units (AUs), calculated by multiplying the intensity score by the proportion score.

Results
A total of 63 PTCL patients were analyzed (PTCL not otherwise specified [PTCL-NOS, n=16], angioimmunoblastic T-cell lymphoma [AITL, n=19], and anaplastic large cell lymphoma [ALCL, n=11] and natural killer T-cell lymphoma [NKTCL, n=17]). The upper limit of the third quartile (Q3) of the AU values was 120. High p-AKT group (AU>Q3) included a higher proportion of NKTCL (41.7%) and ALCL (33.3%) subtypes, while low p-AKT group (AU≤Q3) included higher proportion of AITL (37.3%) and PTCL-NOS (25.0%) subtypes. High p-AKT group showed substantially poorer overall survival (OS) (median OS, 2.3 months vs. 25.2 months, P< 0.001) compared with the low p-AKT group. Multivariate analysis showed that high p-AKT group retained its significance as an independent prognostic factor for poor OS (hazard ratio [HR] 6.5; 95% confidence interval [CI], 2.7 – 15.9; P< 0.001) and poor PFS (HR 4.7, 95% CI; 2.1 – 10.6, P< 0.001).< 0.001) compared with the low p-AKT group.

Conclusion
PTCLs having high p-AKT expression showed a significantly worse survival than patients with low p-AKT expression. Thus, more effective treatment approaches are needed for this subset of patients with PTCLs, and we suggest inhibition of PI3K/AKT pathway may be a promising therapeutic strategy in PTCLs.

Disclosures:
No relevant conflicts of interest to declare.