bluuebunny/crossref_metadata_2025 huggingface dataset:
Avascular Necrosis of Femoral Head in Childhood Acute Lymphoblastic Leukemia.
Authors: Tang JingYan
Published: October 2019

Purpose This study was to determine the frequency of avascular necrosis of femoral head(AVNFH), clinical manifestation, following up results and risk factors in children with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Method Acute non-lymphoblastic leukemia and solid tumor as the background, to assess AVNFH in ALL and NHL between October 1998 and June 2003. Glucocorticoid was included in ALL and T-NHL therapy, but not in B-NHL and other diseases. The criteria of AVNFH is clinical hip pain and/or limp with avascular necrosis sign at MR imaging of the femoral head, but no sign of cancer relapse in clinical and laboratory checking. Results We treated ALL 164 cases, T-NHL 28, B-NHL 20, and solid tumor 126 between October 1998 and June 2003. Forty-three patients with ALL and T-NHL are older than 10 years, including 29 boys and 14 girls. Five cases were diagnosed as AVNFH through MR imaging, including 3 with ALL and 2 with T-NHL. No AVNFH happened in B-NHL and other groups. All of AVNFH are older than 14, average 15 years, and presented with hip pain and/or limping after 1 year glucocorticorid contained chemotherapy. It is 2.6%(5/192) in all ALL and T-NHL cases, but 11.6%(5/43) in the group of older than 10 years. Of those 5 patients, 4 girls and 1 boy. So in the group of older than 10 years girls with ALL and T-NHL, AVNFH happened as high as 28.5%(4/14). After medical interfering, 3 recovered, 2 remained slightly limping but no surgical replacement. Conclusion AVNFH incidence in childhood ALL and T-NHL under our therapy protocol is at least 2.6%. Girls, old than 10, with glucocorticoid contained chemotherapy, are the risk factors of AVNFH. Early detection and interfering may make most of them recover. So, regular MR imaging of the hips for girls who are older than 10 years with glucocorticoid contained chemotherapy longer than 1 year, is reasonable if financially tolerated.

Clinical data of AVNFH in childhood ALL and T-NHL No sex disease chemo-time AVNFH predinision* status of cancer status of AVNFH * or equile to predinision 45mg/m2.d 1 F LR-ALL 42 months left 150 days CR stable, limp 2 M HR-ALL 12 months right 65 days CR stable, limp 3 F T-NHL 17 months right 90 days CR recover 4 F T-NHL 22 months both sides 105 days CR recover 5 F HR-ALL 42 months both sides 150 days CR recover
Detection of 24 TCR Vβ-Dβ1 sjTRECs in T Cells from Cord Blood, Peripheral Blood of Normal Individuals and Patients with AML-M2.
Authors: Li Yangqiu , Yin Qingsong , Chen Shaohua , Yang Lijian
Published: October 2019

Thymic function is characterized its importance of thymus to T-cell diversity in the periphery of both children and adults during both health and disease. The generation of TCR diversity occurs in the thymus through recombination of gene segments encoding the variable parts of the TCRα and β chains. During these processes, by-products of the rearrangements are generated in the form of signal joint T-cell receptor excision circles (sjTRECs). As sjTRECs are stable extrachromosomal DNA fragments, are not replicated during mitosis and thus diluted with each round of cell division, and are therefore most frequent in naïve T cells that have recently left the thymus, their quantification is actually considered as a very valuable tool to estimate thymic function. Quantitative of δRec-ψJα sjTRECs can direct evaluate the recent thymic output function, but it is unable to analyze the particular thymic output function of different TCR Vβ subfamily naive T cells. The complexity of TCR Vβ repertoire is an important factor for immune reconstitution, it should be established the quantitative analysis of series TCR Vβ-Dβ sjTRECs to evaluate the levels of different Vβ subfamily naive T cells. In the present study, analysis of 24 TCR Vβ-Dβ sjTRECs was established by semi-nested PCR using 24 Vβ subfamily antisense primers and 2 Dβ1 sense primers. TCR Vβ-Dβ sjTRECs were amplified in genomic DNA from mononuclear cells of 10 cord blood samples, 10 cases of peripheral blood from normol individuals and 11 cases with AML-M2. Different amounts of DNA (corresponding to 2*105, 5*104, 1*104 and 1*103 cells respectively) from all samples were amplified to estimate the frequency of TCR Vβ-Dβ sjTRECs. The results showed that most Vβ subfamily sjTRECs could be detected in all samples from cord blood and peripheral blood at 2*105 or 5*104 cells level, some of Vβ subfamily sjTRECs could be detected in 1*103 cells level. Whereas the frequency of Vβ subfamily sjTRECs were lower in peripheral blood T cells from patients with AML-M2 than in normal individuals (p<0.05). Vβ19, Vβ23 and Vβ24 subfamily sjTRECs could not be detected in all samples at 5*104 cells level. The results indicated that Vβ subfamily naive T cells could be detected with different frequency in peripheral blood of normaol individuals as well as in some patients with AML-M2. Lower frequency of Vβ subfamily naive T cells was found in most AML-M2 patients.
The delta Assay - A Suitable Tool To Detect the Cellular Immune Response Against Acute Myeloid Leukemia Blasts.
Authors: Kaiser Sabine E. , Mautner Josef , Schmid Christoph , Schmetzer Helga , Gaeta Antonia , Kolb Hans-Jochem
Published: October 2019

Adoptive immunotherapy with donor T-cells has been used successfully for the treatment of both relapsed chronic and acute myeloid leukemia after hematopoietic stem cell transplantation. Here we describe a method for the detection of T cell immunity by the inhibition of cytokine driven growth of blasts. According to the heterogeneous growth pattern of various cases of acute myeloid leukemia (AML) the culture requirements had to be determined individually. The basic cytokine cocktail consisted of SCF (50 ng/mL), GM-CSF (100 ng/mL), IL3 (50 ng/mL), G-CSF (100 ng/mL) and EPO (2 U/mL); this cocktail succeeded to induce blast-proliferation in 15 out of 16 AML samples tested. In a first step we determined optimal growth conditions regarding cell density and the day of linear growth. The peak proliferation was measured by the incorporation of tritium labeled thymidine at various time points. It ranged between days 2 and 5. In a second step, donor cells were stimulated for 10 days with irradiated AML-cell lines (MonoMac6, THP1) or patient derived AML blasts. After harvesting, the donor cells were irradiated (15 Gy) and co-cultured with the AML-cell lines, or the patients cytokine stimulated blast suspensions. Inhibition of growth was measured by the incorporation of tritium labeled thymidine at the previously determined day of linear proliferation of the AML-blasts. A significant inhibition of blast proliferation was observed in the co-culture of normal T cells with both AML-cell lines. In HLA-identical combinations T cells were primed by dendritic cells derived from AML blasts and re-stimulated on days 6 and 10. T cells primed by this method inhibited the growth of AML blasts in higher effector target ratios, in lower ratios no inhibition or even stimulation was observed. In summary, the delta-assay is a suitable tool to monitor specific anti-leukemic immune responses of donor lymphocytes even against very heterogeneous blast populations, if individualized culture conditions are considered.
Familial Acute Myeloblastic Leukemia with a Dominant Negative Mutation in the CEBPA Gene.
Authors: Nanri Tomoko , Kawakita Toshiro , Hoshino Koyu , Mitsuya Hiroaki , Asou Norio , Uike Naokuni
Published: October 2019

Transcription factors involved in myeloid cell differentiation are frequent targets of chromosomal translocations or point mutations in patients with acute myeloblastic leukemia (AML). Familial AML harboring a mutation of a transcription factor should provide an association with clinical features and functions of the transcription factor. Recently, two pedigrees of AML carried a germ-line mutation in the CEBPA, the gene encoding transcription factor C/EBPα. have been reported. We here present clinical and molecular features of a Japanese family in whom two members affected by AML had an identical CEBPA mutation. Father had received the diagnosis of AML M2 in 1988 at the age of 39 years. His blast cells contained Auer rods and aberrantly expressed CD7 antigen. Following a relapse, he received autologous stem cell transplantation, after which he has been in a lasting complete remission (CR). His son was diagnosed to have M2Eo in 2004 at the age of 26 years. His marrow showed blasts including Auer rods and 6.8% eosinophils. He has achieved a continuous CR. Bone marrow cells at the time of diagnosis in both patients showed a 4-base pair insertion in the CEBPA (350_351insCTAC). The corresponding protein is predicted to terminate prematurely at codon 107 (I68fsX107). Therefore, this heterozygous mutation causes truncation of the 42-kD C/EBPα protein and overproduction of a 30-kD isoform, which functions in a dominant negative fashion, causing a decrease in C/EBPα activities. Peripheral blood cells obtained during CR in both patients also had the same mutation. Interestingly, the germ-line mutation identified in the affected individuals we present is almost identical to those in the familial AMLs carrying a C/EBPα mutation, 212delC or 217insC. N-terminal C/EBPα mutations in sporadic AML patients are associated with M1/M2, presence of Auer rods, CD7 expression, normal karyotype, and favorable prognosis. Familial AMLs with a C/EBPα mutation demonstrate links of these unique features to a dominant negative C/EBPα mutation. Although the mechanism underlying the development of AML is yet unclear, carriers of the CEBPA mutation appear to have a large population of undifferentiated myeloid cells associated with an increased risk of a second genetic hit, leading to AML over a long latency.
The Role of Leukemia Derived B7-H1 in Tumor-T-Cell Interactions in Humans.
Authors: Krusch Matthias , Wintterle Sabine , Chen Lieping , Kanz Lothar , Wiendl Heinz , Salih Helmut R.
Published: October 2019

Objective: Expression of the B7-homologue B7-H1 (PD1-Ligand) has been proposed to enable tumor cells to evade immune surveillance. Recently, B7-H1 on murine leukemia cells was reported to mediate resistance to cytolytic T-cell destruction. In this study we investigated the expression and functional role of the B7-homologue B7-H1 in human leukemia.

Patients and Methods: Leukemia cells from 20 patients and 9 human leukemia cell lines were investigated for B7-H1 expression by flow cytometry. Functional relevance of B7-H1 for tumor-immune interactions was assessed by coculture experiments using purified, alloreactive CD4 and CD8 T-cells in the presence of a neutralizing anti-B7-H1 antibody.

Results: Significant B7-H1 expression levels on leukemia cells were detected in 13 of 20 patients and in 8 of 9 cell lines. In contrast to various other tumor entities and the data reported from a murine leukemia system we did not observe any significant inhibitory effect of leukemia-derived B7-H1 on CD4 and CD8 cytokine production (IFN-g, IL-2) or expression of T-cell activation markers (ICOS, CD69). In the presence of a neutralizing B7-H1 antibody (mAb 5H1) no significant changes in T cell IFN-g or IL-2 production were observed.

Conclusions: Our data demonstrate that leukemia-derived B7-H1 seems to have no direct influence on T-cell activation and cytokine production in humans. Further experiments are warranted to delineate factors and characterize yet unidentified B7-H1 receptor(s) that determine inhibitory and stimulatory functions of B7-H1 in human leukemia.
Early Intervention in Minimal Residual Disease after Allogeneic Transplant for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Prolonged Survival by Imatinib.
Authors: Miyamura Koichi , Yoshihisa Kodera , Skamaki Satoshi , Nakao Shinji , Sasaki Satoshi , Yokozawa Toshiya , Kato Chiaki
Published: October 2019

Minimal residual disease (MRD) was examined using quantitative polymerase chain reaction in 34 patients with Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were divided into two groups according to the time of transplant (Group A; n=17, – 2000 and Group B; n=17, 2001-). Group B had a significantly higher overall survival rate than Group B (74.2% vs 29.4%, P<0.01). In Group A, MRD+ after HSCT indicated imminent hematological relapse with subsequent death. On the contrary, in Group B, 8 patients showed MRD after HSCT. However, only one died of leukemia during the observation. Among the MRD+ patients after HSCT, the probability of hematological relapse was higher in group A than in group B (100% vs 20%, P<0.05). MRD-based clinical interventions such as Imatinib administration, donor lymphocyte infusion, or second HSCT may contribute to longer survival. In particular, imatinib introduce MRD-negativity in most patients, resulting better performance status and time for preparing next strategies. Two patients who became MRD-negative after imatinib treatment developed molecular relapse after imatinib discontinuation. Thus, Imatinib may contribute to the improvement of overall survival, however, an allogeneic power may be required for the cure of leukemia.
CXCR4 Antagonists Mobilize Acute Lymphoblastic Leukemia Cells into the Peripheral Blood and Inhibit Engraftment in Mice.
Authors: Juarez Julius , Hewson John , Cisterne Adam , Baraz Rana , Bradstock Kenneth F. , Bendall Linda J.
Published: October 2019

The role of CXCL12 in the growth of B cell progenitor acute lymphoblastic leukemia (ALL) and the homing of these cells to the bone marrow has been well established. However the effect of modulating CXCL12/CXCR4 interactions on the growth of ALL cells in vivo has not been examined. In this study we used specific peptide and small molecule antagonists of CXCR4 to examine the importance of CXCL12/CXCR4 interactions in the development of leukemia in an in-vivo murine model of ALL. CXCR4 antagonists induced mobilization of human and murine B cell progenitor ALL cells into the peripheral blood, with a 3.8±1.9 and 6.5±3.3 fold increase in leukemic cells/ml one hour after administration of the antagonist respectively, similar to that observed for normal progenitors. Daily administration of AMD3100 commencing the day following the injection of cells and continuing for 21 days resulted in a mean reduction in peripheral blood white cell count of 50±12% and the leukemic cell count of 63±4%. There was also a significant reduction in both the total cells in the spleen of 58±1% and the leukemic cell number in this organ of 75±11%. A significant reduction in leukemic cell numbers in the bone marrow was observed in one (44% reduction) case. There was reduced infiltration of other organs including kidney, liver and skeletal muscle. This study demonstrates that disrupting the CXCL12/CXCR4 axis in B cell progenitor ALL reduces the tumor burden. Whether this is due to direct inhibitory effects on proliferation and survival, or results from disruption of the leukemic cell interactions within the bone marrow remains to be determined.
Expression of CD25+ Cell Subsets after Induction Chemotherapy in Adult Patients with Acute Myeloid Leukemia.
Authors: Min Woo-Sung , Kim Hee-Je , Choi Young , Kim Sung-Yong , Eom Ki-Sung , Kim Yoo-Jin , Lee Seok , Min Chang-Ki , Lee Jong-Wook , Kim Chun-Choo
Published: October 2019

An attempt was made to correlate clinical outcomes with specific patterns of the expression of CD25+ cells after induction chemotherapy (IC) in adult patients with acute myeloid leukemia (AML). Seventy-five newly diagnosed AML patients received the same initial IC and serial bone marrow (BM)- or peripheral blood (PB)-samples were taken. The gated CD45/CD25/CD4 cell populations were used to compare for the intensity of immunophenotypic signals and the different cell subsets, according to the treatment timeline. As one of the best predictive prognostic parameters, patients who responded poorly to IC showed exceptionally higher levels of PB CD45+CD25+ cells on days 7 (P=0.002) and 21 (P=0.05) post-IC. The results of patients in complete remission (CR)(n=61), as well as those of the patients who showed continuous CR, showed relatively lower levels of PB CD45+CD25+ and higher CD4+CD25+ regulatory T cells in the steady PB after the standard IC, which was accurately discernible in every patient and in normal healthy individuals (n=21). We found considerably lower expression levels of BM/PB CD4+CD25+ regulatory T cells in the patients. These results suggest that this tool can be used to predict the outcome of adult AML patients at an early period in treatment.
Retroviral Gene Therapy of RAG-1-/- Mice: Balance between Efficiency and Toxicity.
Authors: Lagresle-Peyrou Chantal , Yates Frank , Malassis-Seris Michele , Hue Christophe , Morillon Estelle , Garrigue Alexandrine , Liu Allen , Hajdari Philippe , Stockholm Daniel , Danos Olivier , Lemercier Brigitte , Gougeon Marie-Lize , Rieux-laucat Frederic , de Villartay Jean-Pierre , Fischer Alain , Cavazzana-Calvo Marina
Published: October 2019

Patients affected by severe combined immunodeficiency (SCID) have a profound defect in T cell development and the only curative treatment is hematopoietic stem cell transplantation (HSCT). When an HLA-identical family related donor exists, the success rate of HSCT is 90% while in all others cases, it ranges between 40 and 70%. In SCID patients also presenting B cell differentiation defects, such as in RAG-1 and RAG-2 deficiencies, the survival rate is significantly reduced. We have thus been interested in the development of a potential alternative treatment by using retroviral gene transfer of a normal copy of RAG-1 cDNA. To this end, murine RAG-1 deficient hematopoietic stem cells were transduced with a retroviral modified Moloney leukemia virus vector containing the RAG-1cDNA and transplanted into RAG-1-deficient mice. B and T cell development was achieved in all the recipient mice and the reconstitution is stable over time, attesting for a selective advantage of transduced progenitors. The T cell compartment was found to be diverse and functional as shown by Va and Vb TCR immunoscope analysis as well as proliferation assays in the presence of mitogens. The mature circulating B lymphocytes were not abundant but functional as the serum immunoglobulin levels and specific antibody response against the T cell dependent KLH antigen were always within normal range. Noteworthy, a high transgene copy number was detected in all lymphoid organs and this was associated with a risk of insertional mutagenesis as observed in one mouse. Altogether, these results demonstrate that RAG-1 gene transfer can correct immunodeficiency associated with RAG-1 defect but that human application would require the use of lentivirus vectors with self inactivating long terminal repeats in order to decrease the risk of lymphoproliferative diseases.
A Deletion 7q in a M0 Adult Acute Myeloid Leukemia (AML) with a Complete Cytogenetic Response to Idarubicin.
Authors: Domke Lewis , Anderson Norwood R.
Published: October 2019

The alteration of chromosome 7 is associated with a reported unfavorable prognosis in acute myeloid leukemia. The deletion of the 7q is seen alone in approximately 1% of AML cases. This finding is associated with an AML M0, M1, and M2 FAB classification. Treatment with idarubicin is thought to be equivalent to other anthracyclines in the induction of a complete remission in acute myeloid leukemia. In previous studies younger patients have responded with improved complete remission rates, when idarubicin is used. A unique case with a 7q single aberration and an AML M0 FAB classification is reported with a complete and rapid response of less than 32 days after one cycle of idarubicin at a dose of 12 mg /m2/day for three days accompanied by a cytosine arabinoside intravenous infusion at a dose of 100 mg/m2/day for seven days. A complete cytologic and genetic remission was obtained after one cycle of induction. The patient received high dose cytosine arabinoside consolidation and will be considered for autologous stem cell transplant. The patient remains in a complete genetic and cytologic remission. In this 25 year old african american female a complete cytologic and genetic remission by FISH is obtained in a rare acute myeloid leukemia genotype with a reportedly unfavorable prognosis using idarubicin as the anthracycline in the 3+7 combination.

Conclusion: Further studies are required to better define the appropriate anthracycline in acute myeloid leukemia by using age and cytogenetic markers. In this rare case presentation, idarubicin is shown to be effective in inducing a complete and rapid cytogenetic remission in a young adult patient with a chromosome 7 cytogenetic aberration and an unfavorable prognosis.
Detection of Aspergillus Species in Blood of Malignant Hemotopoietic Tumor Patients by Two-Step PCR.
Authors: Qian Wenbin , Liu Junqing , Jin Jie
Published: October 2019

Objective To investigate the sensitivity and specificity of two-step PCR in detection of aspergillus species in blood from malignant hemotopoietic tumor patients. Methods Forty-one blood samples from patients at high-risk for invasive fungal disease were detected by two-step PCR. The clinic applicability of two-step PCR for systemic aspergillosis diagnosis was assessed by analyzing computed tomography, aspergillus culture, neutropenia and outcome after anti-fungal therapy. Results Specific band of PCR was obtained from aspergillus strains and the products of PCR had a high homogeneous in sequence with aspergillus species. Sixteen of 41 patients were PCR positive, aspergillosis was proven in 4 of these patients by the results of culture. The controls (12 healthy) were all PCR negative. The eight patients (of the 16 PCR positive patients) had characteristic high-resolution computed tomography findings that suggested invasive aspergillosis. The minimum value of white blood cell (WBC) was 0.3×109/L±0.14×109/L in PCR positive patients, whereas, was 0.5×109/L ±0.26×109/L in PCR negative patients (p=0.0326). The duration with WBC count less than 1.0×109/L was 19±8.313 days and 12.69±6.945 days respectively between two groups (p=0.0472). After antifungal therapy, one of the patients with PCR positive died of chemotherapy-related early death. Conclusions The two-step PCR assays allows for the highly sensitive and specific detection of aspergillus pathogens in vitro and in vivo. A specific two-step PCR assay for the rapid detection of the aspergillus species in blood samples improves early diagnosis for systemic aspergillosis and helps us to make decision for antifungal therapy.
Essential Role of Jun Family Transcription Factors in PU.1-Induced Leukemic Stem Cell Transformation.
Authors: Steidl Ulrich , Rosenbauer Frank , Verhaak Roel G.W , Gu Xuesong , Otu Hasan H. , Kolia Shakir , Owens Bronwyn M. , Klippel Steffen , Wagner Katharina , Aivado Manuel , Passegue Emmanuelle , Libermann Towia A. , Delwel Ruud , Tenen Daniel G.
Published: October 2019

Knockdown of the expression of the myeloid master regulator PU.1 leads to the development of an immature acute myeloid leukemia (AML) in mice. Recent reports suggest that functional inactivation of PU.1 might also play a role in human AML. However, the molecular mechanisms underlying PU.1-mediated malignant transformation are unknown. We examined leukemic PU.1 knockdown mice and found a 3-fold expansion of lin-, c-kit+, Sca1+ (KLS) hematopoietic stem cells (HSC) as compared to wildtype controls, which was not observed during the preleukemic phase. When we transplanted double-sorted leukemic KLS-HSC into NOD-SCID mice the recipients developed AML after 9–12 weeks indicating that the leukemic stem cells derive from the HSC compartment. This finding prompted us to examine the transcriptome of PU.1 knockdown preleukemic HSC to identify early transcriptional changes underlying their malignant transformation. After lineage-depletion and FACS sorting of preleukemic KLS-HSC we performed linear amplification of RNA by 2 cycles of RT-IVT and hybridized the cRNA with Affymetrix Mouse Genome 430 2.0 arrays. Principal component analysis as well as hierarchical cluster analysis clearly distinguished PU.1 knockdown and wildtype HSC. Several in-vitro targets of PU.1 such as c-Fes, BTK, TFEC, CSF2R, and Ebi3 were downregulated demonstrating that those are also affected in HSC in vivo. Differential expression of 16 genes was corroborated by qRT-PCR. Strikingly, several Jun family transcription factors including c-Jun and JunB were downregulated. Retroviral restoration of c-Jun expression in bone marrow cells of preleukemic mice rescued the PU.1-initiated myelomonocytic differentiation block in this early phase. To target cells in the leukemic stage we applied lentiviral vectors expressing c-Jun or JunB. While c-Jun did not affect leukemic proliferation, lentiviral restoration of JunB led to an 80% reduction of clonogenic growth and a loss of leukemic self-renewal capacity in serial replating assays. Expression analysis of 285 patients with AML confirmed the correlation between PU.1 and JunB downregulation and suggests its relevance in human disease. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1 knockdown HSC and demonstrate that downregulation of c-Jun and JunB contribute to the development of PU.1-induced AML by blocking differentiation (c-Jun) and increasing self-renewal (JunB). Therefore, examination of disturbed gene expression in preleukemic HSC can identify genes whose dysregulation is essential for leukemic stem cell function and are potential targets for therapeutic interventions.
Common Variable Immunodeficiency Presenting with Hodgkin’s Disease.
Authors: Ellwood Amanda , Hamm Caroline
Published: October 2019

We report a case of a 32 year old man with classic Common Variable Immunodeficiency Disease (CVID) and Hodgkin’s disease. Repeated immunoglobulin studies as a child showed hypogammaglobulinemia and decreased mitogen responses, with the suggestion of CVID. He presented to the oncology clinic with nearly three decades of recurrent reactive lymphadenopathy and multiple lymph node biopsies throughout his lifetime, recurrent pulmonary infections, and multiple autoimmune manifestations including diabetes mellitus onset at age 4, autoimmune hemolytic anemia and autoimmune thrombocytopenia. He developed Hodgkin’s disease at the age of 30, which has not previously been described in CVID. We also report two other cases of CVID with the diagnosis of non-Hodgkin’s lymphoma in the same oncology practice. CVID is a relatively common and yet rarely identified syndrome. Specific treatment is recommended. We suggest that oncologists should be aware of this unusual and yet relatively common disorder that carries up to 400 times the risk for the development of lymphoma (Cunningham-Rundles, C, et al. J Clin Immunol1987; 7:294–299).
Tumor Burden Related Immunodeficiency in Lymphoma Patients and Clinical Course.
Authors: Jentsch-Ullrich Kathleen , Gerber Annegret , Reppin Regina , Koenigsmann Michael , Mohren Martin , Franke Astrid
Published: October 2019

The association of lymphoma with a plethora of secondary immune defects is well established. However, most investigations were performed many years ago and little is known about disease specific alterations of the immune system. From January 2003 to August 2004 50 patients with newly diagnosed malignant lymphoma were analyzed and compared with 50 healthy volunteers Corresponding in age and gender. Parameters of cellular and humoral immunity, including CBC, FACS analysis of lymphocyte subpopulations, cytokines (sIL2-R, IL-6, IL-10, TNF-a), serum complement components C3c, C4, CH50 and total concentrations of serum immunoglobulin IgG, IgM, IgA were measured. The median number of CD3+ and CD4+ lymphocyte subsets (p≤0.01) were significantly lower in lymphoma patients compared with matched healthy volunteers. The number of CD8+ T-cells was decreased in patients with bulky disease (p≤0.01). High-intermediate/high risk lymphoma (IPI 3-4 or aaIPI 2-3) had significantly higher CH50 (p=0,02), C3c (p≤0,01), sIL2-R (p≤0,01) and TNF-a levels (p=0,05) than patients with low/low-intermediate risk lymphoma. Infectious complications after chemotherapy (n=14) occurred frequently in patients with high initial LDH (p=0,04), low number of CD4+ (p=0,02) or CD8+ T-cells (p=0,04) and high levels of sIL2-R (p=0,02) or TNF-a (p=0,03). Relapse (n=6) was also observed in patients with decreased CD8+ T-cells (p=0,04) and in patients with high C4 levels (p=0,02). These results indicate that tumor burden in lymphoma patients significantly influenced the number of lymphocyte subsets, serum cytokine levels (sIL2R, TNF- a) and complement components (CH50, C3c). IPI-score and clinical course (infections and relapse) were related to the immunodeficiency. We conclude that measurement of peripheral blood lymphocyte subsets, cytokines and complement factors can be expected to improve existing methods of risk assignment in lymphoma.
Trends in AIDS-Associated Cancers among Patients Attending a Palliative Care Service in Uganda in the ’Pre-HAART’ Era, 1994–2002.
Authors: Ddungu Henry , Crowther Mark A.
Published: October 2019

Objectives: To describe the pattern of AIDS-associated cancers among patients referred to a palliative care service in the absence of HAART therapy.

Design: A systematic review of patient records as part of an ongoing quality assurance project.

Setting: A primary palliative care service centre for cancer and/or AIDS patients in Kampala district, Uganda.

Participants: All patient charts from 1994 to 2002 that met inclusion criteria (positive HIV test, or an AIDS diagnosing condition and AIDS-associated cancer) were selected.

Results – 657 out of 3,706 (17.7%) patients met inclusion criteria. Fifty-two percent were female and the median age was 33 years. Thirty-nine percent were referred for pain and symptom control, 51.9% for pain control only, 7.0% for symptom control only; and 2.3% were referred for other reasons. Ninety-six percent were in pain and 95% of these had moderate-to-severe pain. Kaposi’s sarcoma was the most common AIDS associated malignancy, accounting for 73.2% of cases followed by invasive cancer of the cervix (15.1%), non-Hodgkin’s lymphoma (6.4%) and squamous cell carcinoma of the conjunctiva (1.8%). 83.4% had their pain well controlled at the time of death.

Conclusions: The number and proportion of patients with Kaposi’s sarcoma declined over the study period. Pain control was achievable in most patients despite restrained resources.
Expression of X-Linked Inhibitor of Apoptosis Protein in Reactive Lymphoid Tissues, Non-Hodgkin’s Lymphomas, and Hodgkin’s Disease.
Authors: Strauchen James A. , Burstein David
Published: October 2019

X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of apoptosis which binds to and inhibits caspases-3, -7 and -9, blocking the caspase 9-mediated apoptosis pathway. This pathway is activated by p53 and DNA damage and may be an important determinant of responsiveness to chemotherapy. Apoptosis also plays a major role in the regulation of follicle center B-cell proliferation and BCL2-mediated inhibition of apoptosis is a key factor in B-cell lymphomagenesis. In this study we examined the expression of XIAP in 65 reactive and neoplastic lymphoid proliferations utilizing a monoclonal antibody to XIAP (#610763 BD Biosciences, San Jose, CA) and immunohistochemistry with avidin-biotin-complex immunoperoxidase technique on formalin-fixed, paraffin-embedded sections. In reactive lymph nodes and tonsils, expression of XIAP was limited to large noncleaved cells in follicle centers (5 of 6 cases). XIAP was absent in plasmacytoma (3 cases) and small lymphocytic lymphoma/chronic lymphocytic leukemia (1 case). XIAP was expressed in follicular lymphoma, predominantly in large noncleaved cells (6 of 9 cases) and in diffuse large B cell lymphoma (11 of 16 cases), including cases of T-cell/histiocyte-rich diffuse large B cell lymphoma (2 cases), primary mediastinal large B cell lymphoma (1 case), and posttransplantation diffuse large B cell lymphoma (1 case). XIAP was consistently expressed in Burkitt and Burkitt-like lymphoma (3 of 3 cases) and anaplastic large cell lymphoma (3 of 3 cases) and in one case of adult T cell leukemia/lymphoma. XIAP was variably expressed in marginal-zone B cell lymphoma, predominantly in large blasts (2 of 4 cases) and in mantle cell lymphoma (2 of 3 cases). XIAP was not detected in peripheral T cell lymphoma, unspecified (1 case), extranodal NK/T cell lymphoma, nasal type (1 case), precursor B cell lymphoblastic leukemia (1 case), or granulocytic sarcoma (1 case). XIAP was consistently expressed in the Reed-Sternberg and mononuclear Reed-Sternberg-variant cells of classical Hodgkin disease (9 of 9 cases) and the L+H Reed-Sternberg-variant cells of nodular lymphocyte predominance Hodgkin disease (3 of 3 cases). XIAP is expressed across a broad range of lymphoproliferative disorders, including classical and nodular lymphocyte predominance Hodgkin disease, diffuse large B cell lymphoma, follicular lymphoma, Burkitt lymphoma, marginal-zone and mantle cell lymphoma, and anaplastic large cell lymphoma. XIAP appears to be selectively expressed in the proliferating elements of these lymphomas. The possible prognostic and therapeutic significance of XIAP expression needs to be determined.
Characterization of New Aberrations in 25 Splenic Marginal Zone B-Cell Lymphomas (SMZBCL) Using Spectral Karyotyping Technique (SKY).
Authors: Baro C. , Astier L. , Salido M. , Espinet B. , Domingo A. , Granada I. , Costa D. , Hernandez J.M. , Florensa L. , Salar A. , Serrano S. , Sole F.
Published: October 2019

BACKGROUND/INTRODUCTION

Splenic Marginal Zone B-Cell Lymphoma (SMZBCL) is a specific low grade small B-cell lymphoma described by the World Health Organization (WHO). SMZBCL has distinct features from other B-cell malignancies, but few studies include a large series of patients. Previous reports suggest that SMZBCL constitute a genetically heterogeneous disease being 7q22-q32 deletions and gains of 3q the most frequent cytogenetic aberrations. Karyotypes are often complex and difficult to interpret. Other recurrent chromosomes involved are 1 and 8. Nevertheless, at this cytogenetic level few studies have been reported and the possible chromosome markers are not still well defined.

OBJECTIVES

The aim of this study is to define karyotypes from patients with SMZBCL by SKY technique.

PATIENTS AND METHODS

Among a series of 138 patients we have selected 25 with undefined karyotype. The diagnosis of SMZBCL was confirmed by morphology, histology, phenotype and clinical data. All samples were obtained from peripheral blood, bone marrow or spleen. The current SKY protocol has been used with minor modifications to improve the spectral image. We analyzed a minimum of ten metaphases per karyotype and they were described according to the International System for Human Cytogenetic Nomenclature (ISCN).

RESULTS

All the studied karyotypes were complex with chromosome aberrations which, in most cases, were not fully characterized by G-banding. SKY has allowed to refine chromosomal aberrations and revealed new translocations which were not defined by conventional cytogenetics. In nine cases, the karyotype remained unchanged after SKY analysis and in the remaining cases, new aberrations were described.

We observed that the most common involved chromosomes in translocations were 14, 6, 13 and 17.

CONCLUSIONS

SKY provides a useful complementary technique to routine conventional cytogenetics in the analysis of lymphomas with complex karyotypes. SKY will permit to reveal new translocations associated with SMZBCL. The following new translocations involving 14q32 were found: t(1;14)(p22;q32), t(1;14)(q21;q32), t(9;14)(?;q32), t(9;14)(9pter-9p21::14q32-14q11::9p24-9qter), t(9;14)(p21;q32), t(10;14)(p12;q32), t(14;19)(q32;q13).
High Expression of Human Leukocyte Formin Protein in T Non-Hodgkin’s Lymphomas and in CD19− Cell Population of Normal Tonsils.
Authors: Favaro Patricia M.B. , Traina Fabiola , Crespo Marta , Bosch Francesc , Brousset Pierre , Delsol George , Costa Fernando F. , Saad Sara T.O.
Published: October 2019

We recently described a new gene, denominated human leukocyte formin (hlf), which was overexpressed in lymphoid malignancies and cancer cell lines. In contrast, a low expression of the hlf protein was observed in lymph node and peripheral blood leukocytes in normal tissues. Interestingly, the hlf protein associates with Akt, a protein kinase of an important pathway for cell survival. In order to better characterize the expression of the hlf protein we performed Western blotting in the lymphocytes isolated from 4 tonsils from adult patients obtained during routine tonsillectomy, at the Department of Hematology, Clinic Hospital, Barcelona. Results demonstrated that the CD19− cell population of the tonsil displayed a higher expression of this protein when compared with CD19+ cells. In addition, CD19+ cells were separated into two subpopulations: CD27+ (memory cells) and CD27− (naïve cells), and the CD19+/CD27+ cell presented a higher expression when compared with naïve B cells. Furthermore, we performed Western blotting analysis in frozen biopsies of non-Hodgkin’s lymphoma (NHL) patients obtained from the Department of Pathology, Purpan Hospital (Toulouse, France). The lymph node biopsies were performed at the time of clinical diagnosis and the initial diagnosis was confirmed by immunohistochemical analysis and classified according to REAL classification. Fifty-four patients were studied with ages ranging between 28 and 93 years (median 57 years). The histologic types were: 22 follicular NHL, 15 diffuse large B-cell NHL, 17 T cell NHL (non-otherwise specified). Five reactive lymph nodes were also studied. The expression of the hlf protein was detected in all lymphoma samples studied and also in the 5 reactive lymph nodes. The hlf expression, however, was higher in T cell NHL when compared with the others NHL and reactive lymph nodes (T cell NHL vs reactive lymph node, p=0.002; T cell NHL vs follicular NHL, p=0.0001; T cell NHL vs diffuse large B-cell, p=0.012; Mann Whitney test). The hlf protein may be involved in the anti-apoptosis mechanisms, as it is expressed in all types of lymphoproliferative samples and it is associated with Akt, a pathway that is constitutively activated in some hematologic malignancies. Indeed, the ortholog protein described in mice, presents a role in the protection of the cells from apoptosis, but the pathway is unknown. This report provides a more detailed description of the expression of hlf protein in normal lymphocytes and supports the hypothesis that the hlf protein has a role in the cancer molecular pathology of hematologic malignancies.
Bcl2 Expression Predicts Better Overall Survival in 90 Patients with Mantle Cell Lymphoma.
Authors: Schrader Carsten , Klapper Wolfram , Janssen Dirk , Riis Paul , Meusers Peter , Brittinger Guenter , Siebmann Jens U. , Kneba Michael , Parwaresch Reza
Published: October 2019

The expression of bcl2 was typically observed in follicular lymphoma with a t(14;18) but also in CLL and mantle cell lymphoma (MCL). Up to now no study investigated the expression of bcl2 in correlation with the clinical outcome in a large collective of patients with MCL. We investigated immunohistochemically the expression of the apoptotic marker bcl2 in relation to the clinical course. 90 biopsy specimens were investigated immunohistochemically with antibodies against CD20, CD5, CD3, CD23, cyclin D1 and bcl2. The expression was analyzed in three groups: negative, 5–50% positive cells (weak positive) and more than 50% positive cells (strong positive). The expression profils were compared with the overall survival data analysed according to Kaplan and Meier. In none of thae cases a negative staining was found. 16 cases (18%) had a weak and 74 cases (82%) a strong bcl2 expression. Patients with mantle cell lymphoma that had a weak positive expression (n=16) had a median overall survival time of 21 months compared to 32 months for patients with a strong expression (n=74) (p=0.0402). In contrast to DLBL high levels of bcl2 expression had a better prognosis than pathients with low levels.
Correlation between Angiogenic and Coagulation-Fibrinolysis Factors and Stage of Disease in Non Hodgkin’s Lymphoma Patients.
Authors: Mazur Grzegorz , Poreba Malgorzata , Wrobel Tomasz , Poreba Rafal , Pyszel Angelika , Beck Boguslaw , Steinmetz-Beck Aleksandra , Andrzejak Ryszard , Kuliczkowski Kazimierz
Published: October 2019

BACKGROUND: Angiogenesis and activation of coagulation system in cancer patients are common and are thought to be unfavorable clinical parameters. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (bFGF) are well-known angiogenic cytokines. The elevations of plasma fibrinogen and D-dimer level indicate coagulation and fibrinolysis activation. There may be links between angiogenic cytokines and coagulation - fibrinolysis factors in cancer. Possible specific interactions include releasing angiogenic factors, such as VEGF by activated platelets and binding of VEGF and bFGF to fibrin and fibrinogen resulting in an increase in endothelial cell proliferation.

AIM: The purpose of our study was: (a) to analyze relations of VEGF, bFGF serum levels and fibrinogen, D-dimer plasma levels with stage of disease according to Ann Arbor Staging System (AASS); (b) to evaluate correlation between serum levels of angiogenic cytokines and plasma levels of coagulation-fibrinolysis factors in non Hodgkin’s lymphoma patients.

MATERIAL AND METHODS: 52 non Hodgkin’s lymphoma patients (31 men, 21 women; median age 52,1 ± 14,7 years) in II, III or IV stage of disease according to AASS were assessed. In stage II were 15, in stage III- 10 and in stage IV- 27 persons. Serum VEGF, bFGF and plasma D-dimer levels were measured by enzyme-linked immunosorbent assay (ELISA). Plasma levels of fibrinogen were determined using Behring Coagulation System (BCS) equipment.

RESULTS: Plasma level of D-dimer was elevated in majority of patients, mean plasma D-dimer levels [ng/ml] were in stage II: 1654,3 ± 1301,5, in stage III: 1816,6 ± 1370,7, in stage IV: 2747,1 ± 1410,8. There was significantly higher D-dimer level in IV stage of disease in comparison to stage II and III. p<0,01. The mean serum VEGF levels [pg/mL] in following stages of disease were: in II: 387,4 ± 219,8, in III: 399,2 ± 235,0, in IV: 406,9 ± 308,8; mean serum bFGF levels [pg/mL] were: in II: 4,3 ± 2,9, in III: 4,6 ± 2,5, in IV: 4,4 ± 3,4; mean plasma fibrinogen levels [mg%] were: in II: 514,3 ± 198,7, in III: 518,0 ± 209,2, in IV: 495,4 ± 155,3). Differences in levels of VEGF, bFGF and fibrinogen between II, III and IV stage of disease were not statistically significant We observed positive linear correlation between VEGF and fibrinogen (r = 0,45; p<0,01) and between bFGF and fibrinogen (r = 0,52; p<0,05) and negative linear correlation between VEGF and D-dimer (r = −0,69; p<0,001) and between bFGF and D-dimer (r = −0,72; p<0,001).

CONCLUSIONS: Our study indicates that D-dimer level correlates with Ann Arbor Staging System in non Hodgkin’s lymphoma patients. Significant correlations between levels of VEGF/bFGF and fibrinogen/D-dimer suggest specific interactions between angiogenic and coagulation-fibrinolysis system.
Evidence for Disease Specific Immunophenotypic Abnormalities in Blood from Patients with Mantle Cell Lymphoma.
Authors: Narvaez Amy B. , Gascon Ronnie L. , Zhang Rongzhen , Kaplan Lawrence , McGrath Michael S.
Published: October 2019

Immune dysfunction is known to contribute to lymphomagenesis in the context of immunosuppressive therapy and infection with HIV. The current study was undertaken to test whether low grade but progressive forms of lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma (FL), might be associated with systemic immunologic dysfunction as evaluated by flow cytometry. Because of recent studies suggesting a tumor initiating function for infiltrating macrophages in AIDS lymphoma (Zenger et al, Cancer Research62:5536–42,2002), we investigated the immunophenotype of both monocytes and T cells in blood from patients with recurrent MCL and FL. Heparinized blood was taken from 13 individuals with MCL and 6 with FL, both sets of patients previously treated with an average of 4 cycles of combination chemotherapy +/− Rituxan. No patient had received any therapy during the 3 months prior to the current study. Cell surface antigens CD14, CD16, HLA-DR, CD4, CD8, and CD38 were studied in the two diseases and results were compared to age matched controls. Blood from MCL patients showed an immunophenotypic pattern, similar to blood phenotypes described for patients infected with HIV. The %CD4 population was significantly lower than normal controls (p<0.05). The %CD8 T-cell population was elevated when compared to normal (p<0.001) as was the median level of CD38 expression on CD8 T-cells (p<0.01). The CD4/CD8 ratio was inverted (<0.85). Significant elevation of monocyte activation markers was observed in MCL blood when compared to normal controls. Mean fluorescence of HLA-DR on CD14+ cells was elevated (p<0.0001) as was the %CD14+ cells co-expressing CD16 (p<0.0003). By comparison, FL blood showed evidence for both CD4 and CD8 T cell activation with normal CD4/CD8 ratios, however there was no evidence for CD14 cell activation as observed in MCL blood. Taken together, these data suggest that MCL, as a lymphoma subset, shows significant evidence for systemic immune dysfunction and as an acknowledged T cell independent process, shows evidence for macrophage activation, shown recently to potentially play a role in AIDS lymphomagenesis. Further studies on MCL will be required to determine what “factors” might contribute to the persistently abnormal immunophenotype including investigating this class of lymphoma for viral like factors.