bluuebunny/crossref_metadata_2025 huggingface dataset:
CT and MR imaging in Hodgkin's disease – present and future
Authors: Gossmann Axel , Eich Hans Theodor , Engert Andreas , Josting Andreas , Müller Rolf‐Peter , Diehl Volker , Lackner Klaus‐Jürgen
Published: July 2010

Abstract:  Initial staging of Hodgkin's disease is crucial to determine the location and extent of disease, and is the hallmark for the choice of treatment. At present, the established radiological technique for staging Hodgkin's disease is computed tomography (CT). Modern multidetector row CT scanners allow fast imaging from the scull base to the groins during a single breath hold with a spatial resolution of approximately 1 mm. Both, nodal and extranodal involvement of Hodgkin's disease can be diagnosed with CT. Magnetic resonance (MR) imaging is another useful cross‐sectional imaging modality for staging Hodgkin's disease. The development of fast MR imaging techniques has considerably reduced imaging time without compromising the quality of MR images. As a consequence, MR imaging is now considered to be as diagnostic as CT for staging Hodgkin's disease. The excellent soft‐tissue contrast and the lack of exposure to ionizing radiation are the main advantages of MR imaging. For the detection of extranodal Hodgkin's disease, MR imaging is superior to assess involvement of the brain, the spinal cord and bone marrow; while CT allows excellent evaluation of lung disease. Common major problems in staging Hodgkin's disease are still the detection of nodal involvement in normal sized lymph nodes and residual tumor masses after therapy. In the future, newly developed lymphotropic contrast agents for MR imaging might be helpful to answer these questions.
Transformation in the use of radiation therapy of Hodgkin lymphoma: New concepts and indications lead to modern field design and are assisted by PET imaging and intensity modulated radiation therapy (IMRT)
Authors: Yahalom Joachim
Published: July 2010

Abstract:  The role of radiation therapy (RT) in Hodgkin lymphoma has changed substantially; it has evolved from a first‐line comprehensive single agent into a complementary adjuvant following chemotherapy. Yet, the significant contribution of adding radiotherapy has repeatedly been confirmed by recent information from several prospective randomized trials in early stage patients (CCG, Canada NCIC, and EORTC/GELA H9F). In a recent study that included patients of all stages adding radiotherapy impacted significantly on overall survival. Even in advanced‐stage disease, in patients with less than CR, and/or bulky disease or in programs that use short‐course chemotherapy (e.g. Stanford V) involved‐field radiation therapy (IFRT) remained essential. Randomized studies and most recently the GHSG HD10 and HD11 documented excellent results with low‐dose IFRT of only 20 Gy in both early stage and in intermediate‐stage patients. It is now standard of care to use IFRT rather than the extended radiation fields of the past (mantle, inverted Y, and STLI/TLI). Even smaller volumes than IFRT, such as ‘lymph‐node fields’ are advocated by paediatrics groups and are under consideration for future adults treatment programs. This change in RT concept has been motivated by need to reduce normal tissue exposure in order to markedly lessen the risk of late complications. The small fields of current radiotherapy allow more conformal and innovative approaches that have not been technically feasible in the past. They also mandate better targeting. Both the accuracy and the confirmality of ‘min‐radiation’ are augmented, by using new advances in imaging, treatment planning, and new radiation delivery systems. The PET/CT/Simulator integrated hardware with innovative software allows more accurate PET and CT (or MRI) parallel volume contouring, radiation ‘dose painting’ (dose tailored to PET residual activity) and field ‘sculpting’. Introducing intensity modulated radiotherapy technology (IMRT) – a technology that was originally designed for small tumors treated with very high doses – to the field of lymphoma provides safer and more accurate radiotherapy to selected patients with very bulky residual disease and permits re‐irradiation of relapsed disease.
Lymphocyte‐predominant and classical Hodgkin's lymphoma – comparison of outcomes
Authors: Nogová Lucia , Reineke Thorsten , Josting Andreas , Müller‐Hermelink Hans K. , Eich Hans T. , Behringer Karolin , Müller Rolf‐Peter , Diehl Volker , Engert Andreas
Published: July 2010

Abstract:  Introduction: Lymphocyte predominant Hodgkin's lymphoma (LPHL) differs in histological and clinical presentation from classical Hodgkin's lymphoma (cHL). Treatment of LPHL patients using standard Hodgkin's lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between LPHL and cHL patients were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHL‐cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHL patients. Patients and methods: We retrospectively analyzed 8298 HL patients treated within the GHSG trials (HD4–HD12): 394 LPHL patients and 7904 cHL patients. From 394 LPHL patients 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHL patients analyzed, 22% were in early, 39% in intermediate and 39% in advanced stages. About 9% of LPHL patients had B symptoms compared to 40% in cHL patients. Results: About 91% LPHL vs. 86% cHL patients in early stages, 86% vs. 83% in intermediate and 79% vs. 75% in advanced stages reached CR/CRu. Additional analysis for LPHL IA patients showed 98% CR/CRu after extended field, 100% after involved field (IF) and 98% CR/CRu after combined modality treatment. About 0.3% LPHL patients developed progressive disease (PD) compared to 3.7% cHL patients. The relapse rate of LPHL patients was very similar to cHL (8.1% vs. 7.9%). There were 2.5% secondary malignancies in LPHL and 3.7% in cHL patients. About 4.3% LPHL patients and 8.8% cHL patients died. The FFTF rates for LPHL and cHL patients at a median observation of 41 or 48 months were 92% and 84%, respectively. The OS for LPHL and cHL patients was 96% and 92%, respectively. Conclusion: The cHL patients present more frequently with advanced stages and B symptoms compared to LPHL patients. There was no difference in treatment outcome in terms of CR/CRu, PD and mortality between LPHL and HL. Surprisingly, there were also no differences in patients with relapse.
How to define intermediate stage in Hodgkin's lymphoma?
Authors: Gisselbrecht C. , Mounier N. , André M. , Casanovas O. , Reman O. , Sebban C. , Divine M. , Brice P. , Briere J. , Hennequin C. , Fermé C.
Published: July 2010

Abstract:  Background: Intermediate or unfavourable stage Hodgkin's lymphoma (HL) definition relies upon at least three different scoring systems defined by cooperative groups (EORTC, GHSG and Canadian‐ECOG). We aimed to investigate their efficacy and their correlation with International Prognostic Score (IPS) for advanced HL. Patients and methods: We studied a population of 1156 patients with localized stage HL treated prospectively within GELA centres in H8 (518 patients) and H9 (638 patients) protocols. Median age: 30 yr, 18%, Female 50%; stage I: 25%; stage II: 75%. According to scoring systems 70% had 0–1 EORTC factors; 60% 0–1 GHSG factors and 82% 0–1 Canadian factors. The IPS for advanced stages was available only in H9 study with 64% 0–1 factor. Results: Survival curves according to each of the different scoring systems could significantly discriminate the subgroup populations. When a multivariate Cox analysis was performed for overall survival (OS) including all the scoring system variables: age >45 yr, sex male, Haemoglobin <10.5 g/dL, lymphocytes <600/μL, B symptoms with elevated ESR, extra nodal sites did retain an independent significant value. Probability of OS was 99%, 98%, 92%, 82% and 73% for patients with 1–5 factors, respectively P < 0.0001. Conclusion: These factors are similar for most of them with those described in the IPS when stages III and IV are replaced by extra nodal localization. This new score should be validated in other prospective trials, as it will simplify the Hodgkin prognostic scoring systems for localized and advanced stages.
Is there convincing evidence for the use of chemotherapy alone in patients with limited stage Hodgkin's lymphoma?
Authors: Meyer Ralph M.
Published: July 2010

Abstract:  Standard practices for patients with stages I and IIA non‐bulky Hodgkin's lymphoma have evolved to include combined‐modality therapy consisting of two or three cycles of ABVD and radiation therapy to the involved field. Long‐term disease control can be expected in more than 90% of patients. However, long‐term survival will also be dependent on the occurrence of treatment‐related toxicities (late‐effects) that include second cancers and cardiovascular events; deaths from these causes will outnumber those due to progressive Hodgkin's lymphoma. Data from randomized trials testing the role of chemotherapy alone are now available. These trials are based on the hypothesis that avoidance of radiation therapy will result in fewer deaths from late‐effects, and that long‐term survival will be at least comparable and possibly superior. With intermediate periods of follow‐up, the results of these randomized trials demonstrate that with chemotherapy alone, disease control is reduced by approximately 5–7%, but this difference has not translated into a survival advantage. While further follow‐up is required to evaluate longer term overall survival, current data can be interpreted as showing that a trade‐off exists that requires balancing the advantage of superior disease control achieved with inclusion of radiation therapy and minimization of late‐effects resulting from use of chemotherapy alone. The balance associated with this trade‐off makes chemotherapy alone a legitimate treatment option; patients and clinicians need to be aware of these options in when making treatment decisions.
Clinical trials in North America
Authors: Canellos George P.
Published: July 2010

Abstract:  Majority of patients with Hodgkin lymphoma are cured with current therapy. The short and long‐term toxicity of therapy is a current issue, most especially the radiation‐induced second tumors and cardiac abnormalities. Optimal therapy of advanced disease is being compared to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). More intensive chemotherapy may result in higher response but greater toxicity. Regimens requiring radiotherapy are also at risk of long‐term toxicity. New targeted biologic therapy is under current investigation.
Current treatment strategies of the German Hodgkin Study Group (GHSG)
Authors: Klimm Beate , Diehl Volker , Pfistner Beate , Engert Andreas
Published: July 2010

Abstract:  Hodgkin's Lymphoma (HL) has developed to one of the best curable human cancers and overall about 80% of patients experience long‐term disease free survival. Therefore, current treatment strategies aim at further improving treatment outcome, thereby trying to by minimize therapy‐induced complications, such as infertility, cardiopulmonary toxicity, and secondary malignancies. Ongoing trials investigate a reduction of chemotherapy in terms of dose or cycles given, and the application of lower radiation doses and smaller radiation fields. For patients with a specific high‐risk profile, new approaches with more intense drug combinations are currently being investigated. Moreover, the advent of effective salvage high‐dose therapy for relapsed disease and a better understanding of prognostic factors have further improved the management of HL. Here, we summarize current strategies of the German Hodgkin Study Group (GHSG) in diagnostics and treatment of primary and relapsed HL, together with recent approaches for specific subgroups of HL patients.
Autologous transplantation in relapsed and refractory Hodgkin's disease
Authors: Josting Andreas
Published: July 2010

Abstract:  The current data support the use of high‐dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as standard procedure for the majority of patients with Hodgkin's disease (HD) relapsing or progressing after combination chemotherapy. Prognostic factors reflecting unfavourable prognostic features of the disease as well as resistance to conventional salvage therapy have been identified. Preliminary data suggests a high efficacy of high‐dose sequential chemotherapies in these patients. An ongoing randomized trial is comparing standard HDCT versus sequential HDCT in patients with relapsed HD.
The role of allogeneic stem‐cell transplantation in Hodgkin's disease
Authors: Schmitz N. , Sureda A.
Published: July 2010

Abstract:  The role of allogeneic stem cell transplantation is still controversial. Early results of allogeneic bone marrow transplantation after conventional conditioning indicated high transplant‐related mortality (TRM) (>50%) and disappointing survival (<20%). The introduction of reduced‐intensity conditioning (RIC) prior to transplantation has reduced TRM. Unfortunately graft‐vs.‐host disease, relapse rates and survival have not substantially changed. Modifications of allogeneic transplantation in patients with Hodgkin's disease should be restricted to prospective trials.
Developing new drugs for the treatment of lymphoma
Authors: O'Connor Owen A.
Published: July 2010

Abstract:  Despite the great progress that has been made over the last several decades in the treatment of lymphoma, the prognosis for patients with relapsed disease, and particular sub‐types of lymphoma like mantle cell and T cell lymphoma, remains quite poor. While major advances in the use of combination chemotherapy, monoclonal antibodies, peripheral blood stem cell transplants, and radioimmunotherapy, have provided new opportunities to alter the natural history of these diseases, and even improve cure rates among elected sub‐populations of patients, these ‘traditional‘ approaches have not benefited all patients, or sub‐types of lymphoma. The incredibly rapid pace of understanding the molecular basis for the discrete sub‐types of both non‐Hodgkin's lymphoma and Hodgkin's Disease is beginning to afford exciting new opportunities to both risk stratify patients, and to identify potentially novel ‘drugable’ targets. These advancements in understanding the major molecular defects in lymphoma, have provided a new context in which we can rethink the use of new and old drugs, and design new ones with unique mechanisms of action. The panoply of new targets and drugs now becoming available for the treatment of lymphoma is truly daunting. A plethora of new small molecules that target bcl‐2, mTOR, histone deactylases, and NF‐kB have shown promising preclinical activity, and are now promising early phase activity. In many cases, the empirical observations from early clinical trials have provided invaluable clues to potentially valuable drugs like bortezomib, depsipeptide, and SAHA, These empirical observations, based on the inclusion of patients with lymphoma on these studies, have thus far proven to be as or more valuable than any other ‘rational’ target based approach. In addition, beyond the novel small molecules affecting unique and heretofore unrecognized biological pathways, there continues to be a robust and important effort to identify new derivatives of older generation drugs with hopefully better activity, and less toxicity. For example, new generation anthracenediones and anti‐folates, and new formations of older drugs like doxorubicin, irinotecan, and vincristine afford new opportunities to favourably change the pharmacokinetic profile of these agents, and improve their overall safety profile. While it would not be possible to address each and every new such drug, we hope to touch on some of the major new themes and agents emerging for the treatment of Hodgkin's Disease and non‐Hodgkin's lymphoma.
Immunotherapy of Hodgkin's lymphoma
Authors: Borchmann P. , Schnell R. , Engert A.
Published: July 2010

Abstract:  Many new treatment approaches have given promising results in experimental Hodgkin's lymphoma (HL) models. Early clinical trials evaluating antibody based compounds as immunotoxins (ITs), radioimmunotherapy (RIT), bispecific molecules (BSMs), and recently monoclonal antibodies (MAbs), have demonstrated some clinical efficacy in patients with advanced refractory or relapsed HL. In addition, cellular immunotherapy is evolving. Although it seems unlikely to cure chemotherapy resistant patients with larger tumor masses by either of these approaches alone, the combination with conventional chemotherapy might help to overcome resistance of Hodgkin‐/Reed‐Sternberg (H‐RS) cells. Another rationale for the development of these immunotherapies is to eliminate residual disease and thereby to prevent relapses from the disease. Currently, several clinical studies are running. A murine MAb (Ki‐4) based 131 Iodine conjugate has shown efficacy in refractory HL patients in a phase II study, but less toxic constructs using alternate MAbs or isotopes should be developed. A humanized as well as a fully human anti‐CD30 MAb are being tested in clinical phase I/II studies. These MAbs could engage the human immune system against the H‐RS cells. In addition, these MAbs could be then combined with conventional chemotherapy in order to improve the treatment of HL.
The radiotherapy reference panel – experiences and results of the German Hodgkin Study Group (GHSG)
Authors: Eich Hans Theodor , Müller Rolf‐Peter
Published: July 2010

Abstract:  Objective:  The German Hodgkin Study Group (GHSG) including more than 500 participating centers established a central radiotherapy (RT) reference center to improve quality of treatment. The purpose of the present article is to summarize the experiences and results of the performed and ongoing quality assurance programs (QAP) of RT.

Methods:  A panel of expert radiation oncologists evaluated retrospectively the adequacy of treatment fields, applied radiation doses, treatment time and technical parameters. For the fourth study generation (HD10–12, 1998–2003), the RT reference center moved from Munich to Cologne. New RT QAP were initiated according to the demands of the new trials and former programs were enhanced.

Results:  A strong achievement in the era of extended field RT was to show that major deviations of radiation treatment portals and radiation dose from prospective treatment prescriptions were unfavorable prognostic factors for patients with early‐stage Hodgkin's lymphoma (HL). The central prospective radiation oncological review of all diagnostic imaging showed that corrections of disease involvement in 49% of patients with early stages (HD10) and in 67% for patients with intermediate stages (HD11) were necessary. The introduction of electronic image transfer optimized and simplified the workflow of the QAP.

Conclusion:  Today radiation oncologists in the GHSG perform efficient QAP to improve treatment quality of study patients. For early‐stage HL a central prospective review of all diagnostic imaging is performed to control the disease extension and to define the IF treatment volume. Retrospective analysis of RT portals detects faults in the applied irradiation.
Negative association between type 1 diabetes and HLA DQB1*0602‐DQA1*0102 is attenuated with age at onset
Authors: Graham Jinko , Kockum Ingrid , Sanjeevi Carani B. , Landin‐Olsson Mona , Nyström Lennarth , Sundkvist Göran , Arnqvist Hans , Blohmé Göran , Lithner Folke , Littorin Bengt , Scherstén Bengt , Wibell Lars , Östman Jan , Lernmark Åke , Breslow Norman , Gisela Dahlquist
Published: July 2010

HLA‐associated relative risks of type 1 (insulin‐dependent) diabetes mellitus were analysed in population‐based Swedish patients and controls aged 0–34 years. The age dependence of HLA‐associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201‐A1*0502/B1*0302‐A1*0301 (DQ2/8) genotype (P=0.02) and the negatively associated DQB1*0602‐A1*0102 (DQ6.2) haplotype (P=0.004). At birth, DQ6.2‐positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age‐dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604‐A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301‐A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303‐A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA‐DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8‐positive individuals and inhibited, but not completely blocked, in DQ6.2‐positive individuals.
CD34+ dose‐driven administration of granulocyte colony‐stimulating factor after high‐dose chemotherapy in lymphoma patients
Authors: Todisco Elisabetta , Castagna Luca , Sarina Barbara , Mazza Rita , Magagnoli Massimo , Balzarotti Monica , Nozza Andrea , Siracusano Licia , Timofeeva Inna , Anastasia Antonella , Demarco Monica , Santoro Armando
Published: July 2010

Our goal was to optimize use of granulocyte colony‐stimulating factor (G‐CSF) after high‐dose chemotherapy and autologous peripheral blood stem‐cell transplantation in lymphoma patients, limiting G‐CSF administration to patients infusing a suboptimal CD34+ cell number. Of 124 consecutive patients with histologically proven Hodgkin's and non‐Hodgkin's lymphoma from January 2001 to June 2004, 60 patients (group 1) given ≥5 × 106/kg CD34+ cells received no G‐CSF; 64 patients (group 2) given ≤5 × 106/kg CD34+ cells received G‐CSF from day +5 after stem‐cell reinfusion. The median times to reach 0.5 × 109/L and 1.0 × 109/L neutrophils were, respectively, 3 and 4 d shorter in G‐CSF group and this difference was statistically significant (P = 0.0014; P = 0.0001). In terms of antibiotic and antimycotic requirements, gastrointestinal toxicity, days of hospitalization, and transfusion requirements, no differences were demonstrated between the two groups. No statistically significant difference was demonstrated for the total number of febrile episodes (52 for group 1; 53 for group 2; P = 0.623) and the median number of febrile days (2 d for both groups). Myeloid reconstitution values for both groups agree with published results for autotransplanted patients treated with G‐CSF from 7 to 14 d. Also, major clinical events, antibiotic, antimycotic, and transfusion requirements, and hospital stay were similar to published findings. Our data suggest that G‐CSF administration can be safely optimized, used only for patients infused with a suboptimal CD34+ cell dose.
Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high‐dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas
Authors: Schütt P. , Passon J. , Ebeling P. , Welt A. , Müller S. , Metz K. , Moritz T. , Seeber S. , Nowrousian M. R.
Published: July 2010

High‐dose chemotherapy (HD‐CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high‐grade non‐Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD‐CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD‐CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5‐yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event‐free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment‐related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of ≥2 and resistant disease to first‐line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.
Graft rejection and hyperacute graft‐versus‐host disease in stem cell transplantation from non‐inherited maternal antigen complementary HLA‐mismatched siblings
Authors: Okumura Hirokazu , Yamaguchi Masaki , Kotani Takeharu , Sugimori Naomi , Sugimori Chiharu , Ozaki Jun , Kondo Yukio , Yamazaki Hirohito , Chuhjo Tatsuya , Takami Akiyoshi , Ueda Mikio , Ohtake Shigeki , Nakao Shinji
Published: July 2010

Human leukocyte antigen (HLA)‐mismatched stem cell transplantation from non‐inherited maternal antigen (NIMA)‐complementary donors is known to produce stable engraftment without inducing severe graft‐versus‐host disease (GVHD). We treated two patients with acute myeloid leukemia (AML) and one patient with severe aplastic anemia (SAA) with HLA‐mismatched stem cell transplantation (SCT) from NIMA‐complementary donors (NIMA‐mismatched SCT). The presence of donor and recipient‐derived blood cells in the peripheral blood of recipient (donor microchimerism) and donor was documented respectively by amplifying NIMA‐derived DNA in two of the three patients. Graft rejection occurred in the SAA patient who was conditioned with a fludarabine‐based regimen. Grade III and grade IV acute GVHD developed in patients with AML on day 8 and day 11 respectively, and became a direct cause of death in one patient. The findings suggest that intensive conditioning and immunosuppression after stem cell transplantation are needed in NIMA‐mismatched SCT even if donor and recipient microchimerisms is detectable in the donor and recipient before SCT.
Do cytogenetic abnormalities precede morphologic abnormalities in a developing malignant condition?
Authors: Northup Jill K. , Gadre Swarupa A. , Ge Yimin , Lockhart Lillian H. , Velagaleti Gopalrao V. N.
Published: July 2010

Cytogenetic evaluation of bone marrow and neoplastic tissues plays a critical role in determining patient management and prognosis. Here, we highlight two cases in which the cytogenetic studies challenge the common practice of using hematologic and morphologic changes as key factors in malignant disease management. The first case is that of a lymph node sample from a 40‐yr‐old non‐Hodgkin's lymphoma (NHL) patient sent for determination of disease progress. Hematologic studies showed no evidence of transformation to high‐grade NHL (>15% blasts with rare mitotic figures). Cytogenetic studies of lymph node showed multiple clonal abnormalities, most notably a der(18) from a t(14;18) which is associated with high‐grade NHL. After two cycles of chemotherapy with fludarabine, the patient did not show any clinical response, suggesting possible progression to high‐grade lymphoma. The second case is of a patient with a history of human immunodeficiency virus and blastic natural killer leukemia/lymphoma. Hematologic studies of ascitic fluid classified the patient as having pleural effusion lymphoma whereas bone marrow analysis showed no malignancy. Bone marrow cytogenetic studies showed multiple clonal abnormalities including a t(8;14), which is commonly associated with Burkitt's lymphoma (BL). To our knowledge, this is the first case wherein a morphologically normal bone marrow showed presence of clonal abnormalities consistent with BL or Pleural effusion lymphoma. After two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, the patient's general condition and ascitis improved and she was discharged. These studies clearly demonstrate that genetic changes often precede morphologic changes in a developing malignant condition. Therefore, the critical information needed for care of patients with malignant disorders may be incomplete or inaccurate if cytogenetic evaluation is overlooked.
Intravascular B‐cell lymphoma with leukemic presentation: case report and literature review
Authors: Xanthopoulos Vasilios , Galanopoulos Athanasios G. , Paterakis Georgios , Apessou Dimitra , Argyrakos Theodoros , Goumakou Eleni , Papadhimitriou Stephanos I. , Savvidou Ioanna , Georgiakaki Maria , Anagnostopoulos Nikolaos I.
Published: July 2010

Intravascular lymphoma is an extremely rare, disseminated, and aggressive extranodal CD20+ non‐Hodgkin’s lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels. We report a 72‐year‐old woman with a diagnosis of intravascular lymphoma presented with splenomegaly and leukemic appearance in the peripheral blood smear. Her clinical course was rapidly deteriorated before the initiation of specific chemotherapy and finally died due to multiorgan insufficiency. Bone marrow biopsy revealed a characteristic infiltration of CD5, CD10 B‐cell lymphoma. To our knowledge, this is the first reported case of a CD5, CD10 intravascular B‐cell lymphoma with leukemic presentation in peripheral blood with multiple cytogenetic aberrations.
Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G‐CSF (CLAG‐M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group
Authors: Wierzbowska Agnieszka , Robak Tadeusz , Pluta Agnieszka , Wawrzyniak Ewa , Cebula Barbara , Hołowiecki Jerzy , Kyrcz‐Krzemień Sławomira , Grosicki Sebastian , Giebel Sebastian , Skotnicki Aleksander B. , Piątkowska‐Jakubas Beata , Kuliczkowski Kazimierz , Kiełbiński Marek , Zawilska Krystyna , Kłoczko Janusz , Wrzesień‐Kuś Agata
Published: July 2010

Objectives:  Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2‐CdA) increase cytotoxic effect of Ara‐C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara‐C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi‐center phase II study evaluating the efficacy and toxicity of CLAG‐M salvage regimen in poor risk refractory/relapsed AML patients.

Methods:  The induction chemotherapy consisted of 2‐CdA 5 mg/m2, Ara‐C 2 g/m2, MIT 10 mg/m2, and granulocyte‐colony stimulating factor. In the case of PR, a second CLAG‐M was administered. Patients in CR received consolidation courses based on high doses of Ara‐C and MIT with or without 2‐CdA.

Results:  One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty‐six patients (58%) achieved CR after one or two courses of CLAG‐M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4–23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11–49%). Poor karyotype was the only factor associated with decreased probability of DFS.

Conclusions:  We conclude that CLAG‐M is a well‐tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.
Haematological and clinical features of β‐thalassaemia associated with Hb Dhofar
Authors: Daar Shahina , Gravell David , Hussein Hussein M. , Pathare Anil V. , Wali Yasser , Krishnamoorthy Rajagopal
Published: July 2010

Hb Dhofar is a variant haemoglobin (β29 (GGC–GGT) gly‐gly, β58 (CCT–CGT) pro‐arg) associated with a thalassaemic phenotype and unique to the Sultanate of Oman. We report clinical and haematological data on 54 subjects with Hb Dhofar (37 heterozygotes, 14 homozygotes and three compound heterozygotes with a different β‐thalassaemia mutation). In heterozygotes, the level of Hb Dhofar ranged from 8.8% to 21.5%. All heterozygotes had Hb A2 > 3.5%, consistent with β‐thalassaemia trait. Hb Dhofar in homozygotes and compound heterozygotes ranged from 26% to 59.7%, with a peripheral film consistent with homozygous β‐thalassaemia. Age at presentation in homozygotes ranged between 6 months and 8 yr, with a majority presenting before 5 yr of age. All had splenomegaly and six (43%) had undergone splenectomy. All had some degree of frontal bossing and in particular, two patients with infrequent transfusions had marked thalassaemic facies and stunting of growth. Hb Dhofar can be mistaken for Hb D as the electrophoretic mobility is similar, but differs from it by a variable and reduced quantity of variant Hb in both heterozygotes and homozygotes. Clinical and haematological data suggest that this mutation behaves like a moderately severe β+ thalassaemia allele resulting in a thalassaemia intermedia phenotype.
Quantification of progenitors capable of generating T cells in human cord blood
Authors: Kato Maiko , Masuda Kyoko , Kakugawa Kiyokazu , Kawamoto Hiroshi , Mugishima Hideo , Katsura Yoshimoto
Published: July 2010

Objective:  For transplantation of cord blood (CB) cells, it is important to select a CB sample that can reconstitute not only myelo‐erythropoiesis but also lymphopoiesis in recipients. However, until now the reconstitution ability of CB samples has been assessed by colony forming unit‐culture (CFU‐C) assay or by simply counting CD34+ cells. The present study aims at establishing a method capable of assessing the potential of T lymphopoieses of CB samples.

Methods:  CD34+CD38− cells sorted from CB were cultured on a monolayer of murine stromal cell line TSt‐4, transduced with the human Delta‐like 1 gene.

Results:  Immature T cells expressing CD5 and/or CD7 were generated in the culture. As these immature T cells can easily be discriminated from mature T cells that are included in the mononuclear cell population (MNCs), we can use the MNCs as starting material for quantification of progenitors capable of generating T cells (TGP). By applying a limiting dilution analysis, we succeeded in determining the frequency of TGP in MNCs. It was found that the ratios for the number of TGP vs. that of CFU‐C differ among CB samples maximally by 3.5 times.

Conclusion:  The present assay system provides a novel tool for the evaluation of CB samples, especially for their T‐cell‐generating potential.
Immunoglobulin light chain gene translocations in non‐Hodgkin’s lymphoma as assessed by fluorescence in situ hybridisation
Authors: Fujimoto Yoshiko , Nomura Kenichi , Fukada Shuji , Shimizu Daisuke , Shimura Kazuho , Matsumoto Yosuke , Horiike Shigeo , Nishida Kazuhiro , Shimazaki Chihiro , Abe Masafumi , Taniwaki Masafumi
Published: July 2010

In non‐Hodgkin’s lymphoma (NHL), the majority of translocations involve the immunoglobulin heavy chain gene (IGH) locus, while a few involve the immunoglobulin light chain gene (IGL) locus, consisting of the kappa light chain gene (IGκ) and the lambda light chain gene (IGλ). Although many reports have dealt with the translocation and/or amplification of IGH in NHL, only a few have identified IGL translocations. To identify cytogenetic abnormalities and the partner chromosomes of IGL translocations in NHL, we performed dual‐colour fluorescence in situ hybridisation (DC‐FISH) and spectral karyotyping (SKY) in seven NHL cell lines and 40 patients with NHL. We detected IGL translocations in two cell lines and nine patients: four patients with diffuse large B‐cell lymphoma, three with follicular lymphoma, one with extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue and one with mantle cell lymphoma. Five distinct partners of IGλ translocation were identified by SKY analysis: 3q27 in three patients, and 1p13, 6p25, 17p11.2 and 17q21 in one patient each. Three cases featured double translocations of IGH and IGL. These findings warrant the identification of novel genes 1p13, 6p25, 17p11.2 and 17q21.
GEMOX‐R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large‐cell lymphoma: a phase II study
Authors: López Andrés , Gutiérrez Antonio , Palacios Andrés , Blancas Isabel , Navarrete Maite , Morey Miguel , Perelló Antonia , Alarcón Jesús , Martínez Jordi , Rodríguez José
Published: July 2010

Objectives: The prognosis of old or immunocompromised patients with refractory or relapsing diffuse large‐cell lymphoma (DLCL) is very poor as the current standard of salvage therapy with autologous stem cell transplantation (ASCT) is not feasible for most of them. New active regimens with an acceptable toxicity profile are needed. We aim to report the results of a phase II trial of the GEMOX‐R regimen in DLCL.

Methods: A total of 32 patients received GEMOX‐R regimen in 2‐wk intervals if feasible or every 3 wk for a planned six to eight courses.

Results: Median age of the population was 69 yr. Forty‐one percent of the patients were primary refractory and 59% after relapsing. At GEMOX‐R, 75% of patients had a stage III–IV and an adjusted International Prognostic Index > 1 was observed in 69%. The response rate was 43% with 34% complete response. Neutropenia and thrombopenia grade III–IV were observed in 43% of the patients and neurotoxicity grade III–IV in 7% of cases. Median follow‐up for alive patients was 13 months and the median survival was 9.1 months. At 12 months, the overall survival and progression‐free survival were 41% and 29%, respectively.

Conclusions: GEMOX‐R is a new salvage regimen for DLCL with high activity and relatively safe toxicity profile, which can be offered to elderly patients not candidates of ASCT consolidation. The high efficacy of the regimen in this unfavorable population and also in immunocompromised situations warrant further investigation of this regimen in all salvage situations of this type of lymphomas.
Epidemiology and pathophysiology of immune thrombocytopenic purpura
Authors: Gernsheimer Terry
Published: July 2010

Immune thrombocytopenic purpura (ITP) is characterized by the presence of antiplatelet antibodies and immune platelet destruction. The disorder has been described as having a predilection for young women over men. Bone marrow megakaryocytes appear morphologically and quantitatively normal, and early platelet kinetic studies were consistent with reduced platelet survival as the primary abnormality in ITP. During the last 10–20 yr, understanding of the kinetics of this disorder has evolved with evidence that platelet survival is not as abbreviated as previously thought. Thrombopoietin levels are only minimally elevated, if at all, suggesting marrow stimulation and platelet production may not be maximized. Megakaryocyte physiology appears to be altered in ITP, also suggestive of diminished platelet production. It appears both platelet survival and production are impaired in ITP. The epidemiology of ITP is reviewed here and the pathophysiology of ITP is reconsidered.
New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura
Authors: Kuter David J.
Published: July 2010

Various agents to treat immune thrombocytopenic purpura (ITP) have been developed on the principle that stimulating the thrombopoietin (TPO) receptor would increase platelet production. First‐generation agents—recombinant human thrombopoietin (rHuTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF)—showed promise, but observations of antibody formation to PEG rHuMGDF led to the discontinuation of development of both agents. Second‐generation agents—the TPO peptide mimetics, TPO non‐peptide mimetics, and TPO agonist antibodies—have been developed to reduce or eliminate the problem of antigenicity. Clinical studies for some of these agents, such as AMG 531 (romiplosim, Nplate) and eltrombopag (Promacta), are demonstrating their relative safety and efficacy in increasing platelet counts in patients with ITP; AMG 531 and eltrombopag are in late‐stage clinical development and are able to stimulate platelet production in patients with ITP. Some differences in safety profiles have been described and are undergoing further study. There are currently seven second‐generation TPO receptor agonists that have been reported in the literature, representing the potential advantages—and continuing challenges—with this novel class of platelet‐stimulating therapies for ITP and possibly thrombocytopenia in other disease states as well.
First‐line therapies for immune thrombocytopenic purpura: re‐evaluating the need to treat
Authors: Rodeghiero Francesco
Published: July 2010

Immune thrombocytopenic purpura (ITP) can be challenging to both diagnose and treat: despite the ability to detect anti‐platelet antibodies, the diagnosis of ITP remains one of exclusion. Management of ITP is similarly difficult as many therapies pose potential risks that may be worse than the disease. It has been generally agreed that bleeding – not platelet count – should be the rationale for treatment. Despite the absence of prospective, controlled studies, there is consensus that bleeding risks are significantly greater in patients with platelet counts <20 × 109–30 × 109/L, and therefore treatment is indicated for these patients; for those with platelet counts that are higher, but still <50 × 109/L, treatment is also indicated if accompanied by substantial mucous membrane bleeding. The standard initial treatment for ITP is oral corticosteroids to increase platelet counts. Intravenous immunoglobulin or anti‐D immunoglobulin can also increase platelet counts and are particularly useful for stimulating rapid platelet increases before planned procedures. Splenectomy, which produces a long‐lasting response in a majority of patients, is still commonly used for those who do not have long‐term responses to steroid therapy and it should remain the gold standard therapy. However, splenectomy is an invasive procedure with some patients relapsing even after several years. Very rare cases of life‐threatening or lethal infections may also occur at any time after splenectomy and thus physicians and patients are increasingly reluctant to advise or agree to this treatment approach. Other treatments have been evaluated to prevent or delay splenectomy, including high‐dose dexamethasone, intermittent anti‐D immunoglobulin infusions, and rituximab. There have been few randomized, placebo‐controlled studies of these approaches, and they cannot currently be recommended as their efficacy and safety remain unclear. Thrombopoietin receptor agonists are currently under clinical investigation for the treatment of ITP and may represent an alternative treatment option in the future. The criteria for treating ITP and the benefits and risks of therapies are discussed here. Ongoing and future studies will help define the best strategies for increasing platelet counts and reducing the risk of bleeding in ITP patients.
Emerging strategies to treat chronic immune thrombocytopenic purpura
Authors: Newland Adrian
Published: July 2010

Immune thrombocytopenic purpura (ITP) is a fairly common hematological disorder and is a minor disease for many affected patients; most are in good health, and many can tolerate low platelet counts without the need for treatment. For the majority of patients who do undergo treatment, first‐line therapies, including corticosteroids, are effective in increasing platelet counts, although long‐term use can be associated with adverse effects. Second‐line therapies, such as immunosuppressants, have been largely untested in controlled studies of ITP patients. Like first‐line therapies, splenectomy is effective for many patients; however, it is frequently avoided by physicians who prefer the use of alternative drug therapies due to concerns about safety risks and is often declined by patients reluctant to undergo surgery. Thus, approaches to avoid or defer the use of splenectomy have been actively pursued. An anti‐CD20 antibody, rituximab, can limit the production of autoantibodies, but reactivated viral infections have been reported with its use. Agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor‐binding agents, have shown promise in clinical trials of ITP patients as well as in hepatitis C virus‐infected individuals with thrombocytopenia. Two TPO receptor agonists in advanced clinical development— eltrombopag and AMG 531—are discussed here. Both eltrombopag and AMG 531 appear to be effective in raising platelet counts and both have been well tolerated in clinical trials to date. However, potential safety issues with thrombopoietic growth factors include thrombocytosis, rebound thrombocytopenia, and increased bone marrow fibrosis. Further testing will determine which safety issues—if any—are of clinical concern.
Spontaneous rupture of the spleen as immediate complication in autologous transplantation for primary systemic amyloidosis
Authors: De Larrea Carlos Fernández , Cibeira Maria Teresa , Rovira Montserrat , Rosiñol Laura , Esteve Jordi , Bladé Joan
Published: July 2010

Although splenic rupture is a recognized complication of primary amyloidosis, very few cases have been reported in the context of stem cell transplantation. A patient with systemic primary amyloidosis with renal and cardiac involvement and factor X deficiency, who developed a splenic rupture 24 h after the peripheral blood stem cells infusion during autologous transplantation, is described. This complication has been reported during stem cell mobilization and after post‐transplant hematopoietic recovery, but we have not found a previous report of splenic rupture in the immediate postinfusion period. This case illustrates that splenic rupture can occur at any time during the transplant procedure. Need for close monitoring, particularly in patients with factor X deficiency after receiving granulocyte colony stimulating factor, two recently recognized risk factors for splenic hemorrhage, is highlighted.
The heart in transfusion dependent homozygous thalassaemia today – prediction, prevention and management
Authors: Aessopos Athanassios , Berdoukas Vasilios , Tsironi Maria
Published: July 2010

Cardiac disease remains the major cause of death in thalassaemia major. This review deals with the mechanisms involved in heart failure development, the peculiar clinical presentation of congestive heart failure and provides guidelines for diagnosis and management of the acute phase of cardiac failure. It emphasizes the need for intensive medical – cardiac care and aggressive iron chelating management as, with such approaches, today, the patients outcomes can be favourable in the long term. It covers advances in the assessment of cardiac iron overload with the use of magnetic resonance imaging and makes recommendations for preventing the onset of cardiac problems by tailoring iron chelation therapy appropriate to the degree of cardiac iron loading found.