bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteosome Inhibitor Treatment Down-Regulates S-Phase Kinase-Associated Protein 2 Causing Inhibition of Proliferation and Induces Apoptosis in Primary Effusion Lymphoma.
Authors: Hussain Azhar R. , Al-Jomah Naif A. , Sultana Mehar , Pulicat Manugaran S. , Al-Kuraya Khawla S. , Uddin Shahab
Published: April 2020

Proteosome inhibition is a novel approach for treating malignancy and has been approved for clinical use. The proteosome is the primary proteolytic mechanism in eukaryotic cells and inhibition of its catalytic activity initiates a cascade of events affecting cell cycle and apoptotic activities. These activities ultimately lead to cell cycle arrest and apoptosis in malignant cells however, the normal counterpart of these cells are spared. In this study, we used a panel of primary effusion lymphoma cell lines (BC1, BC3, BCBL1 and HBL6) to study the effects of proteosome inhibitor, MG132 on cell proliferation and apoptosis. Our data showed that proteosome inhibitor MG132 decreased cell viability as well as induced apoptosis in a dose dependent manner ranging from 0.5–10μM. Furthermore, treatment with 2.5μM MG132 for 24hours induced 41% apoptosis in BC1, 51% in BC3, 41% in BCBL1 and 48% in HBL6 cell lines as detected by annexinV/PI dual staining. S-phase kinase-associated protein 2 (skp-2) is a proto-oncogene and over expressed in various types of tumors. We sought to determine the role of Skp-2 following proteosome inhibition in PELs. MG132 treatment of PEL cell lines resulted in down-regulation of SKP-2 protein in a dose dependent manner whereas the expression of p-27 was up-regulated demonstrating an inverse relationship between these two proteins. Furthermore, MG132 treatment of PELs led to conformational changes in Bax protein and translocation to the mitochondria leading to the loss of mitochondrial membrane potential with subsequent release of cytochrome c from mitochondria into cytosol. Cytochrome c release caused activation of caspase-3 followed by polyadenosin-5′-diphosphate-ribose polymerase (PARP) cleavage. In addition, proteosome inhibitor treatment also caused down-regulation of inhibitor of apoptosis protein, XIAP. Taken together, our findings show that proteosome inhibition causes down-regulation of skp-2, up-regulation of p-27, inhibition of proliferation as well as caspase-dependent apoptosis in primary effusion lymphoma cells suggesting a role of proteosome inhibitors in the treatment of these aggressive cancers.
Detection of Clonality in Lymphoproliferations Using PCR of the Antigen Receptor Genes: Does Size Matter?.
Authors: Rothberg Paul G. , Vargas Roberto L. , Felgar Raymond E. , Polochock Susan L. , Frazier Sharon D.
Published: April 2020

A biopsy of a nasal mass was received from another institution for a hematopathology consultation. The specimen had morphologic and immunostaining features consistent with a B-cell lymphoma, histologically low-grade, and suggestive for an extranodal marginal cell lymphoma of mucosa associated lymphoid tissue (MALT) type. We used PCR of the IgH gene to evaluate clonality on DNA derived from this specimen. The primers were from the BIOMED-2 report (van Dongen et al. 2003, Leukemia17:2257) and the amplicons were subjected to heteroduplex formation prior to PAGE. A homoduplex of approximately 140 bp was obtained reproducibly from the FR2 and JH primers, which is below the usually acceptable size limits of 250–295 bps. No homoduplex was obtained using FR3 and JH primers. We sequenced the FR2/JH amplicon using the PCR primers as sequencing primers. The amplicon was 137 bps, with 92 bps between the primers. After the upstream VH3 FR2 primer there were approximately 25 bps from the FR2 region of several members of the VH3 family, with VH3-49 (allele *03) being the best match. Adjacent to the downstream consensus JH primer there were approximately 30 bp from the J6 segment. Between the identifiable sequences there were 37 bp that we could not identify. Blast searches turned up several matches of 18 bp, but nothing that gave convincing evidence for its origin. We interpret these results as indicating a clonal IgH rearrangement followed by a deletion that removed most of the downstream portion of the V segment, including the FR3 region. It is likely that the 37 bp in between the identified IgH segments consists of randomly inserted nucleotides and IgH sequence that has been somatically mutated beyond recognition, although other interpretations are possible. However, the amplicon does appear to be derived from an IgH rearrangement, which is consistent with derivation from a monoclonal population of B-lymphocytes. This work illustrates that DNA fragments outside of the size range expected from PCR of the antigen receptor genes may still be consistent with a monoclonal result. Thus, this type of result should not be dismissed, but should be subjected to further analysis.
Involvement of the Lyn Interactome in the Regulation of Erythropoiesis.
Authors: Ingley Evan , McCarthy David J. , Samuels Amy L. , Schneider Jessica R. , Payne Christine J. , Klinken Svend Peter
Published: April 2020

Src family kinases, such as Lyn, are involved in signalling pathways regulating a myriad of cellular processes. We have shown previously that Lyn is involved in differentiation signals emanating from activated erythropoietin (Epo) receptors. We have highlighted the importance of Lyn to red cell maturation in vivo with Lyn−/ − mice, which develop anaemia and display extramedullary stress erythropoiesis. Here, we show that ex vivo cultures of primary Lyn−/ − erythroblasts display an imbalance between proliferation and differentiation. In addition we have identified several new Lyn pathways. One centres on Cbp (Csk binding protein), an adaptor protein that recruits negative regulators Csk/Ctk. Our data show that Lyn phosphorylates Cbp, which then recruits Csk/Ctk to suppress Lyn kinase activity. Intriguingly, through the use of a phosphotyrosine-specific yeast two-hybrid assay that we developed, phosphorylated Cbp also binds SOCS1, another well-characterised negative regulator of cell signalling - this results in elevated ubiquitination and degradation of Lyn in Epo-stimulated erythroid cells. Altering Cbp expression in primary erythroblasts significantly affected their ability to transmit Epo-receptor signals and differentiate correctly. Another Lyn pathway we have identified centres on a novel molecule we termed LACM, which transmits Lyn signals to Vav2 and Nckβ via phospho-tyrosine-specific interactions. These novel associations regulate the cytoskeleton/cell shape, which lead to changes in cell attachment and migration. Significantly, primary erythroblasts from Lyn−/ − mice display altered subcellular localization of LACM. Another novel Lyn interactor (LIAR) regulates nuclear import/export of signalling molecules - impairing LIAR’s normal function inhibits primary erythroblast development. Taken together, these results illustrate that Lyn is intimately involved in multiple signalling complexes, which play crucial roles in regulating numerous aspects of red blood cell biology.
Primary Systemic Anaplastic Large Cell Lymphoma in Korean Adults; Retrospective Analysis of 36 Patients.
Authors: Park Soo Jung , Kim Shin , Lee Dae Ho , Jeong Yong Pil , Bae Yunjeong , Huh Jooryung , Han Eun Mee , Suh Cheolwon
Published: April 2020

Anaplastic large cell lymphoma (ALCL) is a CD30+ T-cell non-Hodgikin’s lymphoma and represents only 2–8% of lymphoma overall. Information on clinical finding and response to treatment of primary systemic ALCL is still limited in Korea. The aim of this study was to report our experience thirty-six cases with focusing on the clinical feature, treatment response, survival, and prognosis. We retrospectively reviewed the medical records of the patients who were diagnosed as primary systemic ALCL at the Asan Medical Center from February 1995 through December 2005. The median follow up period was 47 months. The median age was 39 years (range, 17–67). The ratio of male to female was 4.14. Patients with primary systemic ALCL had high frequency of advanced-stage disease and extranodal involvement. Seventy-two percent of patients showed Ann Arbor stage III and IV. The most common involved extranodal sites were bone (19%) and soft tissue (17%). Thirty-two (89%) patients were treated by anthracycline-based regimen (CHOP) as induction chemotherapy. Sixteen patients (44%) obtained CR and 14 patients (39%) attained PR, with overall response rate of 83%. The overall survival and disease-free survival was 49 and 17 months. In ALK-positive patients, median overall survival was not reached in follow up period and 3-year overall survival was 61%. In ALK-negative patients, median overall survival was 53 months and 1-year and 3-year overall survival was 75% and 40% respectively. On univariate analysis, international prognostic index (IPI) was significant prognostic factor for overall survival (p = .03). But ALK expression did not affect overall survival in Korea (p = .78). There was no independent prognostic factor for overall survival in multivariate analysis. This retrospective analysis contributes to our understanding of clinical aspects for patients with primary systemic ALCL in Korea. Overall survival is 49 months and overall response to CHOP chemotherapy is 83%. IPI is important predictor of overall survival, but ALK expression may not provide prognostic information for primary systemic ALCL in Korea.
Immunohistochemical Expression Pattern of Germinal Center and Non-Germinal Center Markers Correlates with Prognosis in Diffuse Large B-Cell Lymphoma.
Authors: Chiattone Carlos , Carvalho Marineide P. , Paes Roberto P. , Ribeiro Karina C.B. , Soares Fernando
Published: April 2020

Recent studies have shown correlations between diffuse large B-cell lymphoma (DLCBL) prognosis and molecular features using genome profiles by cDNA microarrays. Since this analysis is not routinely used, immunohistochemical tests for prediction of DLBCL survival are gaining major importance, using markers as, CD10, BCL-6 and MUM-1 to identify germinal center B-cell (GCB) and non-GCB, respectively. The goal of this study was to evaluate the significant effect on survival within GCB and non-GCB subgroup.

Patients and Methods: Seventy-four untreated pts (median age: 58 yrs: 38M/36F) with DLBCL de novo diagnosed in a single institution, treated with CHOP-like regimens. Tissue microarrays (TMA) blocks were created from paraffin-embedded, formalin-fixed block and stained with antibodies to CD20 (clone L26, Dako), CD10 (clone 56C6; Novocastra; NCL-CD10-270), BCL-6 (clone GI 191E/A8; Cell Mark; CMC 798) and MUM1 (clone MUM1p; Dako, CA; M7259). Results. Cases were subclassified using CD10, BCL-6, and MUM1 expression, and 25 cases (33.8%) were considered GCB and 49 cases (66.2%) non-GCB. The 2-year overall survival (OS) for the GCB group was 80% compared with only 38.9% for the non-GCB (p<0.001). In the multivariate analysis, only the International Prognostic Index score (IPI 3-4 HR=2.6, p=0.013) and the GCB phenotype (Non-GCB HR=2.7, p=0.054) were independent prognostic factors. In summary, immunohistochemical expression of CD10, BCL-6 and MUM1 are able to determine the GCB and non-GCB subtypes of DLBCL and predict survival.
CCR5 Chemokine Receptor Expression Can Promote Disease Progression in Non-Hodgkin’s Lymphoma.
Authors: Mazur Grzegorz , Kryczek Ilona , Wrobel Tomasz , Dlubek Dorota , Klimczak Aleksandra , Jaskula Emilia , Jelen Michal , Lange Andrzej , Kuliczkowski Kazimierz
Published: April 2020

Background: Non-Hodgkin’s lymphomas (nHL) represent heterogenous group of lymphoid malignancies derived from B and T lymphocytes, NK cells or histiocytes. Most of lymphomas are B-cell origin. Lymphoma cells can migrate to other organs and their migration could be linked to chemokines and their receptors. Chemokine receptors are expressed by many cell populations, including lymphoid cells, and their function is mediation of trafficking and localization particularly lymphocytes. CCR5 is predominantly expressed on Th1 cells, but also on dendritic cells, fibroblasts, endothelial and epithelial cells. Up-regulation of CCR5 expression is typical for nonneoplastic leukocytic infiltrates of nodal Hodgkin lymphoma. Its expression has been shown in hairy cell leukemia (HCL) and mantle cell lymphoma (MCL).

Aim: The purpose of this study was to determine CCR5 expression in lymph nodes derived from patients with nHL comparing to control reactive lymph nodes and if there was any correlation between CCR5 expression and proliferation marker Ki-67 and international prognostic index (IPI).

Material and methods: CCR5 gene expression was determined in 37 lymph nodes of lymphoma patients (26 B-cell lymphoma: 12 females and 14 males aged 26–73 years; 4 T-cell lymphoma: males aged 41–81 years; 7 Hodgkin’s lymphoma: 4 females and 3 males aged 21–58 years) and 25 reactive lymph nodes (15 females, 10 males, aged 18–59 years, median age 32 years). Gene expression was determined by the reverse transcription (RT)-polymerase chain reaction method. Scale of expression was 0–3 AU. Statistical analysis was performed using Kruskall-Wallis and Mann-Witney tests (p<0,05).

Results: Most of lymphoma lymph nodes (25/37) showed low CCR5 expression (0–1 AU). In reactive lymph nodes 18/25 had also low CCR5 expression. In B-cell lymphomas high CCR5 expression characterized HCL, Burkitt’s lymphoma and diffuse large B-cell lymphoma nodes. In pts with higher CCR5 expression there was positive correlation with Ki-67 proliferation marker (p=0,016; coefficient = 0,34) and IPI (p=0,047; coefficient = 0,298).

Conclusions: As there is a positive correlation between CCR5 expression and Ki-67 proliferation marker and IPI in non-Hodgkin’s lymphoma lymph nodes CCR5 may be associated with lymphoma progression.
Childhood Crowding, Atopy and Risk of Non-Hodgkin Lymphoma.
Authors: Cozen Wendy , Eric Engels A. , Cerhan James R. , Linet Martha , Bernstein Leslie , Colt Joanne S. , Davis Scott S. , Severson Richard K. , Martinez-Maza Otoniel , Hartge Patricia
Published: April 2020

Subtle differences in immune response may play a role in non-Hodgkin lymphoma (NHL) etiology. Because adult immune response may be influenced by early childhood exposures, we examined the role of childhood crowding, history of atopic disease, and other childhood immune-related exposures on the risk of non-Hodgkin lymphoma in a multi-center case-control study. Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Health Care Financing Administration (HCFA) database. The association between NHL risk in relation to atopy and other exposures was assessed using multivariable logistic regression methods. Most types of allergy were associated with protection from NHL, with hay fever especially protective against all NHL combined (Odds Ratio [OR] = 0.71, 95% confidence interval [CI]= 0.54–0.94), diffuse large B-cell lymphoma [DLBCL] (OR=0.61, 95% CI=0.41–0.91), and follicular lymphoma (OR=0.70, 95% CI=0.45–1.09). A history of eczema increased risk of follicular lymphoma (OR=1.92, 95% CI= 1.08–3.41) but not DLBCL (OR=1.06, 95% CI= 0.55.2.04). Asthma in childhood was not associated with risk of NHL. Risk of DLBCL (OR =1.72, 95% CI=1.17–2.52), but not follicular lymphoma (OR=1.15, 95% CI=0.75–1.76) was elevated for the youngest compared to the oldest of siblings. Neither number of siblings nor years between births of siblings were significantly associated with risk. These results suggest that some immune-related exposures may affect NHL risk.
Penumbra Encodes a New Tetraspanin Critical to Effective Erythropoiesis.
Authors: Cao Thai M. , Heikens Marc J. , DeHart Sarah L. , Morita Chikako , Tsai Schickwann
Published: April 2020

To search for new genes that might be involved in the regulation of erythropoiesis, we performed cDNA representational difference analysis on a multipotent murine hematopoietic cell line, EML C1. Penumbra was identified based on its predominant, high-level expression in TER119+ erythroblasts. It is not expressed or is expressed at very low levels in Gr1+ or CD3+ or B220+ or CD11c or NK1.1+ bone marrow or spleen cells. The full-length murine Penumbra mRNA contains 2017 nucleotides and encodes a new membrane protein characterized by four transmembrane domains, a small extracellular domain between the first and second transmembrane domains and a large extracellular domain between the third and fourth transmembrane domains. It is a member of the evolutionarily conserved tetraspanin membrane protein superfamily that includes CD63, CD81, CD151 and Peripherin. Using the murine Penumbra as a probe, we identified the human Penumbra from a human bone marrow cDNA library. The human Penumbra also encodes a protein of 283 amino acids and is 97% identical to the murine Penumbra. The human Penumbra gene is mapped to chromosome 7q32, a hotspot for interstitial deletions in myelodysplastic syndromes and acute myelogenous leukemias. Immunofluorescence microscopy indicated that Penumbra is targeted to the cell surface. Immunoprecipitation-Western analysis showed that Penumbra formed disulfide bond-linked homodimers. To study the possible effects of Penumbra deletions, a knockout mouse model was created by homologous recombination. To avoid any pathology that might result from the Neo selectable marker, the targeting vector employed a self-excising Cre-Neo cassette driven by a testis-specific promoter. At 3 months of age, Penumbra−/− mice had similar numbers of RBC, hematocrits, WBC and platelets as the WT littermates. At 1 year of age, Penumbra−/− mice as a group had significantly lower RBC numbers and hematocrits than the WT littermates. Furthermore, about 40–60% of the Penumbra−/− mice had increased percentages of basophilic or polychromatophilic macrocytic RBC. As a group, these mice had even lower numbers of RBC (6.24 ± 1.87 vs. 8.88 ± 0.51 x 106/microliter in WT; p = 0.0002) and hematocrits (36.63 ± 8.28 vs. 46.21 ± 3.62% in WT; p = 0.002). Many such mice had massive splenomegaly due to increased extramedullary hematopoiesis. A multipotent hematopoietic cell line, EMX, was established from the bone marrow of a Penumbra−/−- mouse. EMX exhibits ineffective erythropoiesis in response to erythropoietin, a defect that is reversed by re-expression of Penumbra. These findings indicate that Penumbra plays an important role in erythropoiesis and suggest that Penumbra may be one of the genes that are often deleted during the evolution of myelodysplastic syndromes and acute myelogenous leukemias.
Dexamethasone, Etoposide, Ifosfamide and Cisplatin (DVIP) as Salvage Therapy in Non-Hodgkin’s Lymphoma and Hodgkin’s Disease.
Authors: Chubar Yevgene , Gavish Israel , Yegena Shay , Bennett Michael
Published: April 2020

26 patients (16 male, 10 female; median age 53 years, range 18–77) with relapsed Non-Hodgkin’s Lymphoma or relapsed Hodgkin’s Disease were treated with DVIP combination chemotherapy from July 1999 until February 2006. This consisted of 4 consecutive days of Dexamethsone 20 mg IV twice a day, Etoposide 75mg/m2 IV daily, Ifosfamide 1.2 gm/m2 IV daily with Mesna and Cisplatin 20 mg/m2 IV daily. Cycles were repeated every 3 weeks. 14 (53%) of the patients had an aggressive lymphoma (11 diffuse large B cell lymphoma, 2 anaplastic large T cell lymphoma, 1 immunoblastic lymphoma). 7 (26%) patients had an indolent lymphoma (5 Follicular Lymphoma, 2 splenic lymphoma with villous lymphocytes of which one had a blastic transformation). 5 (19%) patients had Hodgkin’s Disease. 19 (73%) patients received DVIP as a second line of therapy, 5 (19%) as third line therapy and one after 5 previous regimes. The median number of cycles given was 3 (range 1–6).

There was a total response rate of 54% (14) : CR 35% (9) and PR 19% (5). In 11 (42%) of the remaining patients stable disease was documented and one had disease progression with this therapy. 7 of the 9 in CR underwent successful PBSC mobilization and then received consolidation with high dose chemotherapy (HDCT) and autologous stem cell support. All of these are alive and in CR at a median of 55 months (range 2 – 80 months) post DVIP therapy. One patient in PR who underwent this procedure died 12 months later from disease progression.

Overall mean survival (OS) of all 7 patients who achieved CR was 70 months (95%CI = 53-87 months). A significantly lower mean OS of 13.5 months (95%CI = 3.4-23.6) was observed in those who did not achieve CR (p=0.001).

Hematological toxicity such as grade II/IV neutropenia was found in 23 (88%) of patients.

Conclusion : DVIP is an active regimen in relapsed aggressive and indolent non-Hodgkin’s lymphoma and relapsed Hodgkin’s disease. It can be used as cytoreductive treatment prior to PBSC collection and HDCT with autologous stem cell support. Further studies in combination with Rituximab in suitable patients are warranted.
CHOP Every 14 Days in Naïve Patients with Diffuse B-Large Cell Lymphoma.
Authors: Rubio-Martinez Araceli , Palomera Luis , Gonzalez Nicolas , Domingo Jose A. , Arguinano Carlos , Puente Fernando , Perella Matilde , Angos Jose A. , Sancho Ignacio , Herrera Pilar , Recasens Valle , Giraldo Pilar
Published: April 2020

Introduction: Some studies have shown that patients with aggressive lymphoma may benefit from dose intensified schedules as CHOP-14. The addition of rituximab ® improves response rate and survival. The support with G-CSF in dose intensification regimes may provide a good complementation of courses and advantage compared with schedules standard-dose as R-CHOP.

Purpose: To evaluate the efficacy of R-CHOP-14 in naïve patients with diffuse B- large cell lymphoma (DBLC) (REAL classification).

Design: observational, prospective and multicentric in a consecutive and previously untreated patients diagnosed of DBLC CD20+. Exclusion criteria: HIV positive, other malignancies and CNS involvement.

Patients and methods: Since June 2003 to June 2006, 56 patients were included in an R-CHOP regimen administered every 14 days (8 courses). At baseline assessment: clinical and physical exam, blood counts, serum and urine biochemistry, albumin, β2-microglobuline and LDH level, body scan, bone marrow biopsy. Patients were classified according ECOG, clinical stage and IPI. All patients have received prophylaxis with G-CSF. Re-staging studies were performed every 4 cycles. Responses were classified as complete remission (CR), partial remission (PR), and non response (NR).

Statistical analysis: Overall survival (OS), relapsed free survival (RFS). Survival analysis was performed using Kaplan-Meier and Cox regression.

Results: Mean age 50.13 years (20–78), 19M/37V. ECOG 0(24), 1(18), 2(3), 3(11). B symptoms 30 patients (53.5%). IPI score 0–1(21), 2(12), 3(8), 3 4 (15), stage I(4), II(9), III(13), IV(30). Extranodal location 33 (59%): bone marrow 13, lung 8, liver 6, CNS 4. After 4 cycle: 50 evaluable patients; response: 50 (91%), 15 CR (27%), 35 PR (64%), 5 NR. After 8 cycle: 40 valuables patients, 38 CR (95%), 2 PR. 5 patients have relapsed and 12 died (progression 6, infection 6: 5> 70 years). Adverse events 187 episodes: neutropenia III-IV 107 (72%), thrombocytopenia III-IV 21(16%), infection 22 (11.7%): pneumonia 8(4.3%), neutropenia febrile 5(2.7%), gastrointestinal 5 (2.7%). Mean OS was 34.3 months and mean RFS 38.9 months.

Conclusions: A high response rate to R-CHOP 14 in adult’s naïve DBLC patients was observed in this study with acceptable toxicity. No differences in response were observed according to age groups but higher myelotoxicity and adverse events was present in older than seventy
Clinical Features and Treatment Outcomes of Primary Testicular Lymphoma.
Authors: Park Byeong-Bae , Kim Jong Gwang , Eom HyeonSeok , Kim Hyo Jin , Kwon Hyuck Chan , Oh Sung Yong , Kang Jung Hun , Oh Suk Joong , Shin Ho-Jin , Suh Cheolwon , Kim Jung Han , Kim Ho Young , Lee Sang Cheol , Kim Kihyun , Jung Chul W. , Kim Won Seog
Published: April 2020

We investigated clinical features and clinical outcomes of patients with primary testicular non-Hodgkin lymphoma (NHL) between 1996 and 2006. Thirty-eight cases were identified from clinical records. The median age was 59 years (range 41–81). Disease was classified as stages I in 13 cases, stages II in 15 and stages III-IV in 10. Diffuse large B-cell lymphoma was diagnosed in 92% of cases. All patients received orchiectomy. Twenty-three (61%) had orchiectomy and chemotherapy, 13 (34%) had orchiectomy, chemotherapy and involved field radiotherapy. All chemotherapy regimens which were used to patients in this study contained an anthracycline. Central nervous system (CNS) prophylaxis was performed in 6 (16%) patients and 10 (26%) patients were received prophylactic irradiation or surgery on the contralateral testis. In 33 evaluable patients, 4 (12%) had immediate disease progression following orchiectomy or on systemic treatment. A complete response was seen in the remaining 25 (76%) patients, irrespective of treatment modality. The median duration of follow-up was 25 months (range 2.5–122). Recurrence occurred in 18 patients and the most frequent site (45%) was the CNS: 4 in brain parenchyma, 3 in meninges, and 1 in both. Nine (36%) patients relapsed following a complete response and median time to relapse was 10 months. Overall median progression free survival (PFS) was 21 months. Twelve (32%) patients were died during follow-up: 10 died of causes related to their lymphoma and 2 were treatment-related mortality. Estimated median overall survival (OS) was 45 months for the entire patients. Significant survival differences between low/low intermediate and high intermediate/high risk of IPI were observed in OS (p=0.001). Primary testicular NHL was frequent in older patients, and has a poor prognosis although large proportion of this disease was loco-regional stage. Most of patients have died of disease related causes and their frequent relapse site was brain or meninges. Therefore, additional CNS prophylaxis including cranial irradiation and intrathecal chemotherapy to chemotherapy and involved field irradiation after orchiectomy should be considered as an effective treatment modality for improving survival.
Pediatric Hodgkin Lymphoma Patients Treated with ABVD Chemotherapy with or without Low-Dose Radiation Therapy.
Authors: Al-Kofide Amani , Belgaumi Asim F. , Khafaga Yasser , Joseph Nicey , Malik Rubina J. , Mourad Waleed , Mohamed Gamal-Eldin H. , Sabbah Rajeh S.
Published: April 2020

The ABVD protocol is probably the most effective chemotherapy (CTX) regimen for the treatment of Hodgkin Lymphoma (HL), however the dose and volume, and indeed the need for radiation therapy (XRT) in combination remains uncertain. Pediatric patients (0–14 years) at our institution have been treated with ABVD either with or without XRT, based on the treating physician’s decision. Patients receiving XRT were usually given one or two cycles less of CTX than those without. Since 1998 we have used 1500cGy as the dose of XRT, however the field was determined by the radiation oncologist. Between 1990 and 2003, 152 patients were treated according to the ABVD protocol. Of these, 64 were treated with CTX alone, while 88 also received radiation as consolidation therapy (Combined modality therapy; CMT). Of those who received XRT 63 were administered a dose of 1500cGy. The remaining 25 received various higher doses (1655cGy: 1, 2400cGy: 9, 2500cGy: 10, 3500cGy: 3, 3680cGy: 1, 3980cGy:1). Patients who were treated with CMT were older (mean age 9.2 v. 7.4 years; p<0.05), had less B-symptoms (10.2% v. 26.6%; p<0.05), but not more bulky disease (43.2% v. 34.4%; p=0.2). CTX group had more patients with stage III and IV disease, while CMT group had more stage II disease (p<0.05). With a median follow-up of 4 years, the actuarial overall survival (OS) and event free survival (EFS) at 5 years for all the patients is 97.3% and 88.0%, respectively. The OS and EFS for the patients treated with CTX and CMT were 95.3% v. 98.8% (p=0.4) and 85.1% v. 90.2% (p=0.3), respectively. We next looked at the patients who received only 1500cGy of radiation therapy. Of the 63 patients, 29 received extended field radiation (EFXRT) and 34 involved field radiation (IFXRT). Patients who received radiation were administered a median of two cycles of ABVD less than those who did not (median 4 v. 6 cycles; mean 4.3 v. 5.1, p<0.05). OS at 5 years for the patients treated by CTX v. CMT/EFXRT v. CMT/IFXRT is 95.3%, 96.6% and 100%, respectively (p=0.3). The EFS for the same groups is 85.1%, 86.2% and 90.1% (p=0.4).

Conclusion: Pediatric patients with HL can be treated successfully with minimal or no XRT. These results need to be confirmed in a prospective clinical trial.
Prognostic Factors in Hodgkin’s Disease - Analysis of 211 Patients from a Single Institution.
Authors: Grudeva Janet G. , Nenova Ivanka , Mateva Nonka , Ananoshtev Nikola
Published: April 2020

The treatment adaptation to individual risks of patients with Hodgkin’s disease is closely connected to the prognostic factors identification. The goal of the study was to identify prognostic factors related to survival of patients with Hodgkin’s disease in the population of Plovdiv district (South Bulgaria).

Patients and methods: The retrospective study involved 151 patients with Hodgkin’s disease, diagnosed and treated in the University Clinic of Hematology, Plovdiv, Bulgaria, from 1995 to 2005. The prognostic value of several pretreatment parameters with regard to the survival time was analyzed:

Sex, Ann-Arbor clinical staging, ECOG Performance status, Histological type, Extranodal localization, Systemic B symptoms, Abdominal lymphadenopathy and Infradiaphragmatic disease.

The patient’s survival was analyzed by using the Kaplan-Meier method. The log-rank test was used to compare cumulative survival functions.

Results: The mean survival period of patients was 13,35 years (95% C.I. 10,35–16,36). The most important prognostic factors for survival were: ECOG Performance status (P<0,001), Ann-Arbor clinical stages (P=0,0046), extranodal localization (P=0,0009), abdominal lympadenopathy (P=0,0025), B symptoms (P=0,0145) and histological type (P=0,02). The factors with negative impact on survival time were: advanced III/IV clinical stage; poor ECOG performance status 3/4; mixed cellularity/lymphocyte depletion histological type; presence of abdominal lymphadenopathy and B symptoms and more than one extranodal localization. There is a tendency of poorer survival in patients in clinical stage I/II and infradiaphragmatic initial presentation of disease (P=0,185).

Conclusion: Prognostic factors identified in the present study can be easily applied in the routine clinical practice and may be used as a basis for mathematical prognostic models.
Treatment of Peripheral T-Cell Lymphoma (PTCL) with High-Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT).
Authors: Kim Min Kyoung , Kim Shin , Lee Seoung Sook , Sym Sun Jin , Lee Dae Ho , Kim Sang We , Jang Seongsoo , Park Chan Jeong , Chi Hyun Sook , Huh Joo Ryung , Suh Cheolwon
Published: April 2020

Objectives: Although CHOP-type chemotherapy has been the mainstay of therapy, outcome of PTCL has been uniformly disappointing. Despite the poor outcome after conventional chemotherapy, the impact of high-dose chemotherapy (HDCT) and ASCT is not well defined in these patients. The purpose of this study is to evaluate the efficacy of ASCT and the prognostic factors in PTCL with ASCT.

Patients and Methods: We performed a retrospective analysis of 40 PTCL patients from the Asan Medical Center treated between January 1995 to December 2005 with HDCT and ASCT.

Results: A total 40 patients were enrolled. Median age was 39 years (range 18–63). Twenty patients had PTCL-U, 10 extranodal NK/T cell lymphomas, 5 anaplastic large cell lymphomas, 3 angioimmunoblastic, one hepatosplenic γσ T cell lymphoma, and one disseminated mycosis fungoides. Disease status at transplant were CR1 in 3, CR2 or more in 8, partial remission in 25 (PR1 in 8 and PR2 in 17), and refractory in 4 patients.Three (7.5%) therapy-related mortalities occurred. A median follow-up of 16 months (range, 5 to 135 months) for surviving patients, the median overall survival (OS) was 11.5 months and the 1-year probability of survival was 41.5%. Ten patients (25%) were alive without evidence of disease. The median OS of 11 patients with CR at ASCT were not reached and of these, 7 patients (63.6%) were alive with CR. In multivariate analysis, CR status at HDT and BM involvement at ASCT was the most important prognostic factor for event free survival (P=0.032, P=0.031, respectively). A pretransplant IPI ≤1 and infused CD34+ cell dose ≥5×106/kg were the prognostic factors for an improved overall survival (P = 0.04 and P = 0.025, respectively).

Conclusion: The results of HDT with ASCT for the patients with PTCL who did not achieve a CR to first line or salvage chemotherapy are not satisfactory. The patients who did not achieve CR at ASCT and patients with low infused CD34+cell dose, BM involvement or high IPI score at ASCT have poor outcome.
Incidence and Outcome of T-Cell Lymphomas in Malaysia.
Authors: Chang Kian Meng , Lau Ngee Siang , Chew Lee Ping , Tan Sen Mui , Jameela S. , Puru V.
Published: April 2020

The T- and NK-cell neoplasms are a heterogenous group and are relatively uncommon. From the International Non-Hodgkin’s Lymphoma classification study, precursor T-lymphoblastic lymphoma and the mature T- and NK-cell lymphomas account for 1.7% and 12% of all NHLs. T-NHL are in general more common in Asia. The outcome of this disease is poorer with a 5-y overall survival of 20% (excluding anaplastic NHL). Hospital Kuala Lumpur is the major hematology referral centre in Malaysia. A total of 414 new cases of lymphoma was seen during 2000–2005. The majority were DLBCL 46% and follicular grade I/II lymphomas 15.8%. Only 48 cases (12%) were T-NHL. These were PTCL 19 (5%), anaplastic T-NHL 9 (2.2%), cutaneous T-NHL Stage IV 9 (2.2%), T/NK-NHL 5 (1.2%) and angioimmunoblastic NHL 3 (0.7%). Between 2002–2005, 15 patients were treated with HyperCVAD regimen alternating with Mtx/Ara-C. Three had T-lymphoblastic lymphoma, 7 had PTCL and 5 had T/NK cell. The complete remission was 40% with two proceeding to stem cell transplant. One received local DXT. The median duration of remission was 18.5mths(10–30mths) with median follow-up of 30mths(25–35mths). Alemtuzumab(Campth-1H) is a humanised monoclonal antibody that targets the CD 52 antigen including the T-cell. We combined HyperCVAD with Alemtuzumab 30mg sc on day 1 of every chemotherapy cycle. Four patients with relapsed/refractory T-ALL and 1 patient with T/NK NHL were treated. Two patients, one who relapsed six months after chemotherapy and the other after allogeneic transplant achieved complete remission. The patient with T/NK who had progressive disease with enlarging hepatosplenomegaly after 1 pair of HyperCVAD achieved remission after the addition of Campath. The median duration between each chemotherapy cycle was 25 days(23–26d). One patient had CMV reactivation with no evidence of disease. All patients are still undergoing treatment. The addition of Campath 30mg on day 1 of each chemotherapy cycle appears to be a viable option to try to improve the results in aggressive T-NHL. In view of these preliminary findings, we are starting a study protocol using Campath plus HyperCVAD in aggressive T-cell disease.
A Report of AIDS-Related Lymphoma (ARL) in Korea.
Authors: Kim Jin-Soo , Kim Seok Jin , Kim Jin Seok , Min Yoo Hong , Lee Moon Hee , Bang Soo-Mee , Kim Jeong A. , Chi Hyun-Sook , Jang Seong Soo , Park Chan Jeoung , Suh Cheolwon , Kim Chul Soo
Published: April 2020

The prevalence of ARL is thought to be on increase in Korea. The aim of this study is to review cases of ARL in Korea from August 1998 through July 2006. A total of 16 cases of ARL were reported from 6 institutions in Korea. The patients consisted of 14 males and 2 females at a median age of 41 (range, 30–68) on diagnosis of AIDS. ARL developed at their median age of 43 (range, 32–69). The histologic diagnosis was diffuse large B cell lymphoma (n=9), Burkitt lymphoma (n=1), peripheral T cell lymphoma (n=1), NK/T cell lymphoma (n=1), primary CNS lymphoma (n=1), primary effusion lymphoma (n=1), Hodgkin lymphoma (n=1), or plasmablastic lymphoma (n=1). The disease extent was unknown in 4, stage I in 3, stage II in 4, stage III in 1, stage IV in 5. B symptom was noted in 5 at presentation. Seven of 16 (43.8%) was receiving highly active anti-retroviral therapy (HAART) before the diagnosis of ARL. All the patients were given HAART after the diagnosis of ARL. The response to HARRT was evaluable in 9 patients based on CD4+ cell count and HIV viral load, among which 8 (88%) responded. Four of 16 patients did not receive chemotherapy against medical advice. The chemotherapy regimen included CHOP (n=6), CEOP-B (n=3), m-BACOD (n=2), or CODOX-M/IVAC (n=1). Four patients who refused chemotherapy were lost to follow up. Of 12 patients treated with chemotherapy, 7 were alive in remission, 1 alive in disease, 1 died of treatment related complication, 1 died of progressive lymphoma, 2 died of AIDS related causes. The response to chemotherapy included CR in 7 (70%), PR in 2 (20%) and PD 1 (10%). The median follow-up duration was 15.2 months (range, 0.5–53.2) and the median survival time 43.9 months.
Failure of Single-Agent Rituximab for Treatment of Subcutaneous Intravascular Lymphomatosis (IVL): A Case Report.
Authors: Pirog Steven C. , Aboulafia David M.
Published: April 2020

IVL is an uncommon large-cell lymphoma, usually of B-cell origin. Typically, the CD20+ lymphoma cells possess defects in homing receptors. This leads to limited cell migration from the vessel endothelium, resulting in cell crowding and blockage of intravascular lumens. Patients frequently present with skin lesions, fever, and neurological dysfunction, reflecting the ability of malignant cells to infiltrate various organs. The wide spectrum of clinical manifestations of IVL, along with its propensity to afflict elderly patients with multiple comorbidities, presents a diagnostic and therapeutic challenge; most cases are discovered post-mortem. Anthracycline-based chemotherapy is the standard treatment for this malignancy, but outcomes are disappointing, with most patients destined to die from progressive lymphoma and, less commonly, chemotherapy-induced complications. An 86-year-old female underwent a lesion biopsy after bilateral thigh plaques (the largest of which measured 8 × 13 cm) became increasingly erythematous and painful, despite treatment with antibiotics and corticosteroids. She was diagnosed with subcutaneous CD20+ IVL. Laboratory studies were notable for hematocrit 29% with iron indices consistent with inflammatory block, lactate dehydrogenase 950 IU/L (normal < 240 IU/L) and β2-microglobulin 1.8 mg/mL (normal < 2.0mg/mL). Whole-body computed tomography and positron emission tomography fusion studies did not suggest lymphoma elsewhere. She received rituximab (375 mg/m2/week × 8 weeks) and achieved a complete remission (CR), with the disappearance of thigh discomfort and resolution of her medial thigh plaques. Three months after completion of rituximab treatment, a new left posterior chest wall mass was biopsied and proved to be recurrent IVL. She declined further treatment and was referred to hospice care. Through a Medline search we were able to identify 12 additional patients who were treated with multi-agent chemotherapy and rituximab (n=10) or rituximab monotherapy (n=2). The patients’ ages ranged from 42 to 86 years. The most common clinical presentations in these cases included fever (n=5), nervous system involvement (n=3), and skin rash (n=2). Excluding one multi-agent therapy patient who died during treatment, all patients in our search achieved CRs, with a median follow-up duration of 14 months (range, 6–36 months). Among various lymphoma subgroups (including elderly patients with high-risk features and those with IVL), rituximab has been used as a single agent and to augment the anti-lymphoma properties of multi-agent chemotherapy. Our case report is the first to describe IVL recurrence following rituximab monotherapy, and highlights the need for further investigation on the use of rituximab in the treatment of this rare lymphoma.
Initial Treatment of CD20+ Lymphocyte Predominant Hodgkin Lymphoma with Chemotherapy and the Monoclonal Antibody Rituximab-Mabthera Is Effective and Well Tolerated - Case Report.
Authors: Genadieva-Stavrik Sonja G. , Ivkovski Lubomir , Pivkova Aleksandra , Cevreska Lidija
Published: April 2020

Patients with lymphocyte-predominant Hodgkin disease (LPHD) often present at an early stage with slow disease progression. Although 96% of LPHD patients experience a complete remission (CR) upon first line treatment, many relapses occur. CD20+ is strongly expressed by malignant cells in LPHD, but so far there is limited information regarding the efficacy of rituximab in this patient population. We report 46-year-old woman who presented in 2004 with left cervical lymphadenopathy and weight loss.

Case report: Biopsy confirmed a diagnosis of LPHD(stage IIB disease), immunohistochemistry revealed that >30% of malignant cells were CD20+, and a bulky mediastinal mass was observed by computer tomography (CT). Blood counts, erythrocyte sedimentation rate, albumin and lactate dehydrogenate were normal. The patient was treated with rituximab and ABVD (doxorubicin 25mg/m2, bleomycin 10mg/m2, vinbalstine 6mg/m2, dacarbazine 375mg/m2, six cycles). Rituximab was administered (375mg/m2) one day before chemotherapy (50mg/h for one hour and gradually escalated to a maximum of 400mg/h). Treatment was well tolerated and there were no complications. The patient was assessed immediately following treatment and every three months for the following year, by physical examination, CT, bone marrow biopsy and routine analyses. A detectable tumor mass was no observed by CT for the follow up of 2 years, the patient remains in complete remission.

Conclusion: Our case report suggests that Rituximab is both safe and effective in patients with CD20+ LPHD. Further studies with Rituximab are warranted in this patient population.
First Line Treatment with Rituximab and Chlorambucil in the Treatment of Ocular Adnexal Lymphomas.
Authors: Rigacci Luigi , Puccioni Marco , Nassi Luca , Mappa Silvia , Mazzini Cinzia , Alterini Renato , Carrai Valentina , Polito Ennio , Bosi Alberto
Published: April 2020

Ocular adnexal lymphomas (OAL) are malignant neoplasms which develop in the orbit, the conjunctiva and eyelid. The majority of lymphomas occurring in the ocular adnexa are represented by extranodal marginal zone B-cell lymphomas. In patients with stage IE OAL, localized radiotherapy is the therapy of choice. Complications, however, are frequent, including dryness of the eye, corneal ulcerations, cataract and retina damage. Surgical treatment is usually recommended for conjunctival and eyelids lymphomas but fails to control the growth of lymphoma. Contralateral eye or sistemic relapses are reported in about 10–25% of cases. Therefore, a systemic approach is needed. Rituximab is an anti-CD20 monoclonal antibody, and its efficacy has been demonstrated in indolent and aggressive lymphomas in combination with chemotherapy. Since December 2003 to January 2006 we treated 9 patients with OAL with a combination of Rituximab and Chlorambucil according to this schedule: four weekly infusions of Rituximab 375 mg/m2 plus Chlorambucil 0,1 mg/Kg/die for 45 days, followed by Rituximab 375 mg/m2 once a month for four months and Chlorambucil 0,1 mg/Kg/die for two weeks every month. Eight pts had a diagnosis of extranodal marginal zone B-cell lymphoma and one patient a follicular grade I lymphoma. Median age at diagnosis was 78 years (range 56–86). All pts had a stage I disease and no pts presented systemic symptoms. Disease was localized in the conjunctiva in 6 pts (4 right and 2 left), in two pts the disease was observed in the orbit and in one patient it was localized in the eyelid. IPI was evaluable in 7 pts, and all had a low risk. All pts completed the program without delays. Toxicity, both hematological and extrahematological, was mild, in spite of the high median age of the pts. At the end of treatment 8 pts obtained a complete remission (CR), and a patient obtained a partial response. After a median follow-up of 17 months all pts are alive, and 8 out of 9 (89%) are still in CR. No late toxicity of the ocular adnexa was observed. In conclusion, we hypothesize that Rituximab in combination with Chlorambucil should be take into consideration as first line treatment of primary ocular adnexa lymphomas due to its feasibility and the lacking of severe toxicity and local sequelae.
Long Term Follow up of Hairy Cell Leukemia (HCL) Patients (PTS) Treated with Interferon-Alpha (IFN-α). The Importance of Maintenance.
Authors: Sachanas Sotirios , Angelopoulou Maria K. , Anargyrou Konstantinos , Kokoris Styliani I. , Vassilakopoulos Theodoros P. , Galani Zacharoula I. , Dimitriadou Evangelia M. , Siakantaris Marina P. , Dimopoulou Maria N. , Kontopidou Flora N. , Kyrtsonis Marie-Christine , Plata Eleni , Tsaftaridis Panayiotis , Panayiotidis Panayiotis , Pangalis Gerassimos A.
Published: April 2020

HCL is a chronic B-cell lymphoproliferative disorder with a specific morphology and immunophenotype of the malignant lymphocytes. Although purine analoges are the recommended first-line treatment, they are associated with significant immune suppression and secondary neoplasia. IFN-α is an alternative treatment with fewer long term side effects and considerable efficacy.

AIM: The analysis of HCL patients treated with IFN-α as first-line therapy in a single Hematology Unit.

PATIENTS AND METHODS: 75 consecutive pts diagnosed and followed in our Department between 1980 and 2005, treated with IFN-α were analyzed.

RESULTS: 77.3% were males and their median age was 51 years (30–81). 57% had splenomegaly and 12% hepatomegaly at diagnosis. Their median hemoglobin was 11.3g/dL (4.5–14.3), their median leukocyte and absolute neutrophil counts were 3.1×109/L (0.9–26) and 0.77×109/L (0.03–3.9), respectively. Their median platelet count was 79×109/L (20–295). 33% had hypergammaglobulinemia and their median percentage of bone marrow infiltration at diagnosis was 75%. 10% of the pts were splenectomized before IFN-α treatment. The median time from diagnosis to IFN-α initiation was 0.7 months. The majority of pts (68%) received IFN-α induction at a dose of 3MU/day, while 15% 3MU every other day. Median duration of IFN-α induction was 23.5 months. 8% of pts achieved a complete response with a negative bone marrow, while 73% had a partial remission with a >50% reduction of bone marrow infiltration and a complete restoration of all blood counts. The median time to complete hematologic restoration was 10.7 months. 79% of pts received IFN-α maintenance, the majority of whom (58%) at a dose of 3MU/week. 69% of pts never needed a 2d line treatment, while among those who did, 65% were retreated with IFN-α. The 10-year overall survival was 80%. There were 2 cases of secondary neoplasia. At last follow-up 9% of pts were dead due to unrelated causes, 3% due to 2ary neoplasia, while none died due to disease. Two factors were of prognostic significance for freedom from 2d treatment (FF2T). FF2T was significantly longer for pts older than 51 years old (p<0.0004) and for those receiving IFN-α maintenance compared to those who did not (p<0.03).

CONCLUSIONS: IFN-α has significant efficacy in HCL with a slow but sustained response. Continuous maintenance seems to be important in maintaining response. Younger patients might benefit less from IFN-α.