Showing papers in "Hematological Oncology in 2007"

Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy.

Abstract: Although ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy is infrequently associated with premature amenorrhea, little is known about the success rate of women attempting pregnancy following ABVD. In the present study females treated for HL with ABVD chemotherapy without pelvic radiation therapy (RT) and who were alive without relapse > or =3 years after treatment were identified from a clinical database and screened for inclusion. Using a standardized questionnaire, we determined the pregnancy rate (i.e. time-to-pregnancy, TTP) among survivors who had become pregnant, tried to become pregnant, or who had been sexually active for over 2 months without using contraception at any time following ABVD. The cumulative incidence of pregnancy was calculated using the Kaplan-Meier method. Cox proportional hazards models were constructed to compare the pregnancy rate among HL survivors to that reported by friend or sibling controls. Thirty-six female HL survivors, who had attempted pregnancy after ABVD treatment, and 29 controls, completed the survey. Eighteen patients (50%) received 2-4 cycles of ABVD, 16 (44%) received 4-6 cycles, and 2 (6%) received >6 cycles. The median TTP among both HL survivors and controls was 2.0 months. The 12-month pregnancy rates were 70% and 75%, respectively. The fertility ratio (FR) for HL survivors versus controls was 0.94 (95%CI = 0.53-1.66; p = 0.84) after adjusting for age and frequency of intercourse (where FR or =3 years and who had attempted pregnancy after ABVD did not experience significant sub-fertility.

Rituximab monotherapy is highly effective in splenic marginal zone lymphoma

Abstract: Splenectomy has traditionally been considered as a standard first line treatment for splenic marginal zone lymphoma (SMZL) conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of this retrospective study was to report our experience on the efficacy of Rituximab as first line treatment in 16 consecutive SMZL patients, diagnosed in our department. The diagnosis was established using standard criteria. Patients' median age was 57 years (range, 48-78). Prior to treatment initiation all patients had splenomegaly, nine had anemia, five lymphocytosis, five neutropenia and six thrombocytopenia. Rituximab was administered at a dose of 375 mg/m2/week for 6 consecutive weeks. The overall response rate was 100%. After treatment, all patients had a complete resolution of splenomegaly along with restoration of their blood counts. Eleven patients (69%) achieved a CR, three (19%) unconfirmed CR and two (12%) a PR. Among the complete responders seven patients had also a molecular remission. The median time to clinical response was 3 weeks (range, 2-6). Rituximab maintenance was given to 12 patients. Eleven of them had no evidence of disease progression after a median follow-up time of 28.5 months (range, 14-36), while two out of four patients who did not receive maintenance, relapsed 7 and 24 months after the completion of induction treatment. Median follow-up time for the entire series was 29.5 months (range, 15-81). No deaths were recorded during the follow-up period. Therapy was well tolerated. The present study demonstrates that rituximab is an effective treatment for SMZL and could be considered as a substitute or alternative to splenectomy.

Evidence for the detection of the normal counterpart of hodgkin and sternberg‐reed cells

Abstract: To clarify the origin of Hodgkin (H) and Sternberg-Reed (SR) cells, frozen sections of lymph nodes from 30 patients with Hodgkin's disease were immunostained with a large panel of monoclonal antibodies reactive with cells of lymphoid tissue and granulopoiesis. The results showed that: (a) H and SR cells are devoid of markers specific to, or characteristic of B cells, macrophages, dendritic reticulum cells, interdigitating cells, or cells of erythropoietic or thrombopoietic origin; (b) the vast majority of H and SR cells contain granulocyte-related antigens detectable with the monoclonal antibodies TU9 and 3C4, but constantly lack other granulocytic cell markers (such as peroxidase and chloroacetate esterase). Monoclonal antibodies raised against a Hodgkin's disease-derived cell line included one, Ki-1, that was found to be selectively reactive with H and SR cells and a minute, but distinct cell population in normal lymphoid tissue and bone marrow. The latter, as yet unidentified cell population appears to be the normal equivalent of H and SR cells.

Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells.

Abstract: Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ.

Liposome-encapsulated doxorubicin in combination with cyclophosphamide, vincristine, prednisone and rituximab in patients with lymphoma and concurrent cardiac diseases or pre-treated with anthracyclines.

Abstract: Background To assess the efficacy and safety of the combination of non-pegylated liposome-encapsulated doxorubicin (Myocet®) with cyclophosphamide, vincristine, prednisone and rituximab (R-COMP) in patients with aggressive non-Hodgkin's B-cell lymphomas. Methods Twenty-one patients were selected for the presence of negative concurrent clinical features such as cardiac comorbidity and/or previous treatment with anthracycline-based regimens. Liposome-encapsulated doxorubicin at a dose of 50 mg/m2 was administered in association with cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), prednisone (40 mg/m2) and rituximab (375 mg/m2) every 21 days for four to six cycles unless progression or unacceptable toxicity occurred. Results A complete response (CR) was obtained in 16/21 patients (76%), three patients achieved a partial response (14%), with an overall response rate of 90%. Two patients (10%) did not respond to therapy. After a median follow-up of 13 months (range 2–36 months), 2/16 CR patients relapsed, with a disease-free survival (DFS) of 78%. Conclusions The replacement of doxorubicin with its non-pegylated liposomal pharmaceutical analogue was well tolerated and highly effective in inducing remission in this group of patients at high risk for cardiac toxicity or previously treated with anthracyclines. Its high tolerability and low incidence of cardiac events (only one patient) warrants further studies to confirm the clinical benefits of liposomal doxorubicin in this subset of patients. Copyright © 2007 John Wiley & Sons, Ltd.

Primary mediastinal B-cell lymphoma.

Abstract: Primary mediastinal B-cell lymphoma (PMBCL) is a sub-type of the heterogeneous diffuse large B-cell lymphoma category, and comprises approximately 5% of all non-Hodgkin's lymphomas (NHL). It was first recognized as a distinct clinico-pathologic entity 20 years ago, and recent work has further characterized specific molecular features. Gene expression profiling has suggested a partial overlap with nodular sclerosing Hodgkin lymphoma (HL), with which it shares some clinical features. The optimal management remains a matter of debate. There is uncertainty as to whether weekly alternating chemotherapy regimens may be more effective than CHOP, whether consolidation radiotherapy (RT) to the mediastinum is always required, whether PET scanning can be used to determine this, and whether the use of rituximab as part of initial therapy will change the answers to these questions. The International Extranodal Lymphoma Study Group (IELSG) 26 clinicopathologic study of PMBCL, which has recently opened, represents a first attempt to gather data prospectively on some of these issues. Copyright (c) 2007 John Wiley & Sons, Ltd

Incidence, clinical characteristics and survival of malignant lymphomas: a population-based study from a cancer registry in northern Italy.

Abstract: We conducted a population-based study of peripheral lymphomas (PL) that had been diagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim of providing updated incidence, clinical and survival data for these cancers. We evaluated the incidence patterns and time trends of 1582 cases of PL that had been reclassified according to the WHO classification of hematological malignancies. Data regarding clinical characteristics, treatment and outcome were also collected for each case. The World Age-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 people for B-cell non-Hodgkin's lymphoma (NHL), T-cell NHL and Hodgkin's Lymphoma (HL), respectively, with an increase of 1.62% per year during the study period. The lymphoma subtype showing the highest incidence was found to be diffuse large B-cell lymphoma (DLBCL) with an ASR of 4.8. Compared with reports from other western countries, our series is characterized by a higher incidence of HL and indolent B-NHL in general, and of CLL/SLL (ASR = 3.3) and marginal zone NHL (ASR = 1.5), in particular, and also by a lower incidence of FL (ASR = 2). After a median follow-up of 54 months, the 5-year relative survival for the whole series was found to be 70% with a statistically significant improvement for cases diagnosed during 2002-2003 (from 66 to 74%; p = 0.03). Survival improvement within the study period was also evident for patients with DLBCL, HL and T-NHL. Our study provides a comprehensive description of both the epidemiological and clinical features of PL cases in Modena and our data also reflect the major advances in the curability of some histological subtypes of this disease. The usefulness of a population-based approach to better characterizing different lymphoma subtypes is also demonstrated.

Tartrate-resistant acid phosphatase as a differentiation marker for the human mononuclear phagocyte system.

Abstract: Human blood monocytes (BM) were stimulated with various immune modulators in short-term cultures. Tartrate-resistant acid phosphatase (TAcP) activity was demonstrated with an enzyme cyto-chemical method. Other members of the mononuclear phagocyte system (MPS), such as peritoneal (PM) and alveolar macrophages (AM), were also tested. Unstimulated BM and physiologic functional forms of macrophages, with the exception of AM, were invariably TAcP negative. On appropriate stimulation, particularly with media containing lymphokines, cultured BM became TAcP positive. The results suggest that TAcP is an inducible differentiation marker that indicates transformation of monocytes into cells belonging to a distinct subset of the MPS.

A phase II study of a THP-COP regimen for the treatment of elderly patients aged 70 years or older with diffuse large B-cell lymphoma.

Abstract: Pirarubicin (tetrahydropyranyl adriamycin: THP) is an anthracycline drug that reportedly has fewer cardiotoxic effects than doxorubicin. A phase II study was conducted in order to determine the efficacy of a treatment regimen incorporating THP, namely THP-COP in the treatment of elderly patients aged 70 years or older with diffuse large B-cell lymphoma (DLBCL). The treatment regimens for Group A (aged 70-79 years, n = 45) and Group B (aged 80 years or older, n = 16) consisted of cyclophosphamide, THP, vincristine, and prednisolone, repeated six times, every 3 weeks. The complete remission rate was 72.1%. The 5-year survival rate was 38.1%. For elderly patients with favourable prognostic factors, the 5-year survival rate was significantly better at 77.9% compared with 15.6% for patients with poor prognostic factors (p < 0.01). Death associated with the treatment regimen was not observed. We conclude that the THP-COP treatment regimen has fewer side effects and is very effective in the treatment of DLBCL in elderly patients, especially those with favourable prognostic factors. The present findings indicate the necessity of future studies investigating a combination therapy comprised of rituximab and THP-COP for the treatment of elderly patients with CD20-positive DLBCL.

Primary pulmonary malignant lymphoma, clinical and pathological findings, immunocytochemical and ultrastructural studies in 15 cases

Abstract: Fifteen cases of primary pulmonary malignant lymphoma (M.L.) were studied using strict criteria to distinguish them from secondary pulmonary manifestations. All were M.L.'s of the lymphoid B type. Diagnosis on the basis of non specific clinical, X-ray and endoscopic findings is often difficult but can be facilitated by the systematic use of immunocytochemical and ultrastructural techniques. Their evolution is in good agreement with the prognostic data given by the Kiel-Lennert histopathological classification. 14 of the patients had M.L. of low grade malignancy; the one case of high grade malignancy was quickly fatal. A few cases appeared as a complication of a preexisting dysimmune disease (Pigeon breeder's disease, Gougerot-Sjogren disease, Liebow's lymphomatoid granulomatosis).

The role of MDR-related proteins in the prognosis of adult acute myeloid leukaemia (AML) with normal karyotype.

Abstract: Cytogenetic abnormalities are among the most important factors affecting the outcome of patients with acute myeloid leukaemia (AML), but approximately 40–50% of AML cases display a normal karyotype at diagnosis. Multidrug resistance (MDR) proteins overexpression is associated with worse prognosis in acute leukaemias, but its role in normal karyotype AML is less defined. We analysed the expression of P-glycoprotein (PGP), MDR-related protein (MRP) and lung resistance protein (LRP) in 135 adult patients with normal karyotype AML and its correlation with other biological features of the disease, to evaluate the impact of MDR proteins on response to therapy and on survival. Increased PGP expression was associated with lower rate of complete remission (CR; p = 0.006), similarly to advanced age. Cases overexpressing PGP displayed also a shorter event-free survival (EFS; 4 vs. 10 months, p = 0.035) and the increased expression of at least one MDR protein was associated with a reduced overall survival (OS; p = 0.038). Also age was predictive of worse prognosis. Our data confirm the prognostic role of MDR proteins, in particular of PGP, also in AML patients with normal karyotype at diagnosis. This finding could be used to stratify patients with different prognosis and to design risk-adapted therapeutic strategies. Copyright © 2007 John Wiley & Sons, Ltd.

Therapeutic targets in chronic myeloid leukaemia.

Abstract: Chronic myeloid leukaemia (CML) is a clonal disorder of the haemopoietic stem cell arising as a consequence of the formation of the bcr-abl oncogene. The particular molecular basis of this condition has enabled the development of therapies that selectively target diseased cells. The success of the rationally designed first-line therapy imatinib mesylate (IM) is tempered by the problems of disease persistence and resistance. Novel strategies have been identified to take forward therapy in CML and these will be discussed in this review. This work is generated from a review of published literature and contains particular insight into the work performed by our group in this field.

T Cell-dependent B-Cell proliferation and activation induced by administration of the drug diphenylhydantoin to mice†

Abstract: We have postulated that binding of the hydrophobic anticonvulsant drug diphenylhydantoin (DPH) to lymphoid cells might induce graft-versus-host (GVH)-like cell reactions by T lymphocytes and thus trigger autoimmunization and lymphoma development observed in patients treated with DPH. This hypothesis was studied in mice by means of the popliteal lymph node (PLN) assay. DPH, injected s.c. into the footpads of mice, induced a significant T cell-dependent PLN enlargement. The B cell-derived population comprised the majority of cells in the enlarged PLN. A T cell-dependent activation of Ig-secreting cells in the PLN was induced by DPH. Thymectomy of young adult mice significantly amplified the PLN reaction to DPH and facilitated the activation of Ig-secreting cells. Since injection of the hydantoin rings only completely failed to induce PLN reactions, it is assumed that the observed PLN reactions are caused by the phenyl groups and/or the highly reactive intermediates of DPH. In conclusion, DPH can induce a T cell-dependent proliferation and functional activation of B cells. Conceivably, if such a process persists, it might lead to the GVH-like lymphomagenesis and autoimmunization observed in patients treated with this drug.

Prognostic factors in patients with subdiaphragmatic Hodgkin's disease

Abstract: Between April 1969 and December 1980, 329 patients with pathologically staged IA-IIB Hodgkin's disease were treated at the Joint Center for Radiation Therapy. Twenty-five (7.6 per cent) of these patients presented with inguinal-femoral or superficial iliac adenopathy and had disease limited to below the diaphragm. In addition 11 patients presented with intra-abdominal masses and Hodgkin's disease was diagnosed on laparotomy. The median age, histologic subtypes, and actuarial relapse free and overall survival of patients with peripheral adenopathy limited to below the diaphragm were similar to patients with supradiaphragmatic Hodgkin's disease. Patients with disease limited to the pelvic or inguinal-femoral nodes were treated with pelvic and para-aortic irradiation alone. Staging laparotomy identified those patients with para-aortic or splenic involvement and these patients were treated with total nodal irradiation or combined modality treatment. The small group of patients who presented with intra-abdominal disease without peripheral adenopathy was older, had a predominance of lymphocyte depleted histology, and had a worse prognosis than the other patients described.

Inhibition of Flt3‐activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cells: a possible cause for the limited effectiveness of monotherapy with small‐molecule inhibitors

Abstract: The Flt3 receptor tyrosine kinase is a critical mediator in the pathogenesis of acute myeloid leukaemia (AML). Flt3-activating mutations have been associated with poor prognosis and decreased overall survival of AML patients, thus Flt3 constitutes an ideal target for drug treatment of such disease. Unfortunately, the monotherapy with small-molecule tyrosine kinase inhibitors in clinical trials shows that remission is not permanent, presumably by resistance of Flt3 mutants to inhibitors. An alternative approach for treatment is based on the cooperation between Flt3 and additional intracellular pathways for AML transformation in some patients. Thus, the inhibition of both Flt3 and such pathways may be exploited for successful treatment of the disease. We investigated the importance of Flt3-activating mutations for the constitutive activation of intracellular pathways in primary AML cells, and their effect on cell survival. We found that the main compounds involved in the differentiation, proliferation and survival of AML (MAPK/AKT/STAT) were constitutively activated. However, only four samples showed internal tandem duplications (ITDs) for Flt3. Surprisingly, contrary to previous reports, we found that inhibition of ITD/Flt3 activity did not prevent the phosphorylation of ERK, STAT5 or Akt in some primary AML cells. In parallel, we found that in these cells, Flt3 and ERK or Akt cooperate to regulate cell survival. Our results support the hypothesis that the optimal therapeutic treatment of AML may require not only the oncogenic tyrosine kinase, but also the appropriate combination of different specific inhibitors, thus providing a more effective approach to reverse leukaemogenesis. Thus, we propose that each AML patient should have an individually tailored combination treatment.

Characterization of the expression of cellular retrovirus genes and oncogenes in feline cells

Abstract: Expression of endogenous retrovirus genes and two different cellular oncogenes (c-onc genes) was examined at the transcriptional level in a variety of normal and lymphoma/leukemia tissues of the domestic cat. The two oncogenes, c-myb(related to avian myeloblastosis virus) and c-myc(related to avian myelocytomatosis virus) were selected for their association with the induction of hematopoietic malignancies, when present in the transforming retroviruses. Tissue-specific expression of endogenous feline leukemia virus (FeLV)-related genes was detected in cellular subpopulations of the cat placenta by in situ method of hybridization. Gel blotting analysis of placental poly(A)-selected RNA revealed that the FeLV-related RNA species were primarily subgenomic, representing the env gene region of the endogenous provirus elements. Like the endogenous retrovirus genes, c-myb and c-myc loci of the cat genomic DNA were also transcribed at differential levels in normal tissues of the cat. Dot-blot hybridization analysis showed that the expression of these two oncogenes was linked to growth and development as it varied with the gestational age of the fetus and from fetal to adult tissues. Among the major hematopoietic organs, spleen and bone marrow contained both c-myb and c-myc transcripts, while thymus preferentially expressed the c-myb gene. In contrast to the low level of c-myc expression in fetal thymus tissues, enhanced c-myc expression was detected in all five thymomas tested and also in several other neoplasms including two granulocytic leukemias. The feline c-myb gene was not very active in granulocytic leukemias or in three of the five thymomas. RNA gel blotting analysis of poly(A)-selected RNA of a thymoma and its lymph node metastasis showed identical pattern of c-myc transcripts.

Global correlation of genome and transcriptome changes in classical Hodgkin lymphoma.

Abstract: To identify genes involved in the pathogenesis of classical Hodgkin lymphoma (cHL), we performed serial analysis of gene expression (SAGE) and array-based comparative genomic hybridization (aCGH). Comparison of SAGE libraries of cHL cell lines L428 and L1236 with that of germinal centre B cells revealed consistent overexpression of only 14 genes. In contrast, 141 genes were downregulated in both cHL cell lines, including many B cell and HLA genes. aCGH revealed gain of 2p, 7p, 9p, 11q and Xq and loss of 4q and 11q. Eighteen percent of the differentially expressed genes mapped to regions with loss or gain and a good correlation was observed between underexpression and loss or overexpression and gain of DNA. Remarkably, gain of 2p and 9p did not correlate with increased expression of the proposed target genes c-REL and JAK2. Downregullation of many genes within the HLA region also did not correlate with loss of DNA. FSCN1 and IRAK1 mapping at genomic loci (7p and Xq) that frequently showed gain were overexpressed in cHL cell lines and might be involved in the pathogenesis of cHL. Copyright (c) 2006 John Wiley & Sons, Ltd.

Osteopontin dysregulation and lytic bone lesions in multiple myeloma.

Abstract: Osteopontin (OPN), a secreted phosphoprotein involved in immune regulation and bone homeostasis, is a major component of bone, the natural habitat of long-lived plasma cells and multiple myeloma (MM). We show that only some MM cell lines and primary patient samples express OPN at high levels. High OPN expression inversely correlates with bone disease. When we subdivide MM into molecular subtypes, OPN is significantly upregulated in patients with maf translocations, particularly in the fraction lacking bone disease. OPN is produced in osteolytic lesions: we propose that MM-derived OPN plays a critical role in bone disease by protecting bone from destruction. Copyright © 2006 John Wiley & Sons, Ltd.

Analysis of risk factors predicting thrombotic and/or haemorrhagic complications in 306 patients with essential thrombocythemia.

Abstract: Thrombotic and haemorrhagic complications are the main causes of morbidity in Essential Thrombocythemia (ET). We investigated the clinical and laboratory characteristics associated with the occurrence of these events with the aim of identifying subgroups of patients who might benefit from anti-aggregant and/or cytoreductive therapy. The study involved 306 consecutive ET patients (median age 58 years and median follow-up 96 months); the investigated variables were age, gender, platelet count, previous history of thrombotic or haemorrhagic events, disease duration and cardiovascular risk factors. Forty-six patients (15%) experienced thrombotic complications during the follow-up: 26/64 patients with a previous history of thrombosis (40.6%) and 20/242 patients without (8.3%; p < 0.0001). Thirty-one patients (10%) experienced major haemorrhagic complications, mainly gastrointestinal tract bleeding: 3 with and 28 without a history of haemorrhagic events (p = 0.052). When the patients with a negative history of thrombosis were stratified on the basis of the number of cardiovascular risk factors (none vs. one vs. more than one), there was a significant correlation with the occurrence of thrombotic events (p < 0.05). ET patients with a positive history of thrombosis are at high risk of thrombotic complications, and should receive cytoreductive and anti-aggregant treatment. Asymptomatic patients with a negative thrombotic history and no cardiovascular risk factors are at low risk, and should not be treated. Patients with a negative thrombotic history and one or more cardiovascular risk factors are at intermediate risk, and should be treated with anti-aggregant and/or cytoreductive therapy. The need for treatment should be periodically re-evaluated. Age and platelet count, generally accepted as very important risk factors for thrombosis, did not seem in our series associated with an increased risk for thrombosis. Copyright © 2007 John Wiley & Sons, Ltd.

First and second line imatinib treatment in chronic myelogenous leukemia patients expressing rare e1a2 or e19a2 BCR-ABL transcripts.

Abstract: During the formation of the Philadelphia (Ph) chromosome, in the majority of chronic myelogenous leukemia (CML) patients, the chromosome 22 breakpoint is located in the major breakpoint cluster region of the BCR gene (M-bcr). Minor and micro breakpoint cluster regions (m-bcr with e1a2 transcript and micro-bcr with e19a2 transcript) are rarely affected and have been suggested to be associated with peculiar CML phenotypes. Despite the different clinical characteristics, it is currently not established, whether different therapeutic options are preferably recommended for the treatment of e1a2 or e19a2 CML. Here we report two patients with e1a2 and one patient with e19a2 translocations, treated with different approaches including imatinib. First and second line imatinib treatments induced haematologic response in all of the three patients, and major cytogenetic response in one patient with e1a2, as well as in the patient with e19a2 CML. However, relapse occurred in the patient with e19a2 CML, possibly caused by the presence of additional chromosomal abnormalities such as an extra Ph chromosome, and loss of chromosome Y. Stem cell transplantation (SCT) therapy caused complete haematologic response with molecular remission; however, the patient died of infectious complication. We conclude that in patients with rare BCR-ABL variants, the effectiveness of imatininb treatment may be influenced by the CML stage besides the actual molecular type of the rare transcript. However, this conclusion cannot be generalized to larger patient groups with rare BCR-ABL variants for which further studies may be needed.

Cytogenetic studies in patients with hairy cell leukemia

Abstract: We performed cytogenetic studies on 58 patients with hairy cell leukemia (HCL) from 1975 to 1981. Analysable metaphase cells stained with Q-banding were obtained in 77 samples from 44 patients. Cells with abnormal chromosomes were found in both unstimulated and stimulated cultures of bone marrow and peripheral blood. Patients were classified in 6 groups. Group I, 2 patients with a clonal chromosome abnormality; group II, 13 patients with nonclonal structural abnormalities; group III, 5 patients with nonclonal numerical abnormalities; group IV, 19 patients with only a normal karyotype; group V, 15 patients with no or with fewer than 5 normal metaphase cells; group VI, 4 patients with questionable abnormal chromosomes. Common abnormalities were deletion of the long arm of No. 6 or +3 each in 3 patients, and +Y, +12 or +18 in 2 patients. Actuarial survival for each group was calculated from diagnosis and also from chromosome examination. The two patients with a clonal chromosome abnormality died within one year. Eight of 13 patients with nonclonal structural abnormalities died within 5 years after diagnosis, while none of 5 patients with nonclonal numerical abnormalities and 2 of 19 patients with normal chromosomes died within 5 years. The difference in the 5-year actuarial survival between patients with nonclonal abnormalities (groups II and III) and those with a normal karyotype was significant (p less than 0.05). The difference was more marked between patients with nonclonal structural abnormalities and those with a normal karyotype (p less than 0.01). Patients with nonclonal numerical abnormalities had a longer survival than those patients with nonclonal structural abnormalities (p less than 0.05). Thus, structural chromosome abnormalities in HCL may be a poor prognostic sign even when they are not clonal.

Treatment of non-Hodgkin's lymphoma with chemoradiotherapy and allogenic marrow transplantation.

Abstract: Twenty patients with disseminated non-Hodgkin's lymphoma who failed conventional combination chemotherapy were treated with high-dose chemoradiotherapy and marrow transplantation from an HLA-identical sibling. Four patients remain alive in complete remission from 153 to 784 days after transplant. The reason for failure in eight cases was persistence or relapse of lymphoma. In the other eight cases, death was due to a complication of the transplant procedure including interstitial pneumonia, veno-occlusive disease of the liver, graft-versus-host disease, or infection. These results appear similar to those previously observed in patients with acute leukemia in relapse in that a small but significant proportion of patients with otherwise end-stage disease may achieve prolonged complete remission after intensive chemoradiotherapy and allogeneic marrow transplantation.

Hodgkin's cell lines: characteristics and possible pathogenetic implications.

Abstract: In the last four years we established five long term cultures from tumor material of Hodgkin's disease. The in vitro cells have malignant characteristics and represent the in vivo H- and SR-cells. Common immunological, functional and morphological assays did not characterize the in vitro cells to be a known cell type of lymphoid, myeloid or monocytoid tissue. The in vitro Hodgkin cells are biologically active by producing factors involved in regulation and promotion of immunological response and granulopoiesis. The relevance of the findings for pathogenesis and clinical appearance of Hodgkin's disease is discussed.

Prognostic relevance of circulating matrix metalloproteinase-2 in acute myeloid leukaemia patients.

Abstract: Matrix metalloproteinases (MMPs) were postulated to have important implication in progression and invasiveness of many malignant disorders. On the other hand the biological role of MMP-2 in acute myeloid leukaemia (AML) is not fully clear. Serum samples from 37 adult patients with AML had been taken before chemotherapy was administered. In addition 20 out of the 37 patients were analysed again after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. Total MMP-2 levels were measured using ELISA Kit obtained from R&D system. MMP-2 serum levels were significantly lower in pretreatment AML patients than that in the normal controls (p = 0.000) and in CR (p = 0.007). No significant correlations were detected between pretreatment sMMP-2 levels and FAB subtypes, peripheral blood blast cell counts, peripheral blood WBCs, bone marrow blast cell counts or blast cell distribution ratio. The prognostic value of MMP-2 was evaluated by dividing AML patients into high and low MMP-2 groups using the pretreatment median MMP-2 level of the AML group as the cut-off. The authors found that patients in the high group survived for a significantly shorter time than those patients in the lower MMP-2 group. High pretreatment levels of sMMP-2 among AML patients were associated with poor survival. Prospective studies are recommended to establish the clinical value of longitudinal sMMP-2 measurement. Copyright © 2007 John Wiley & Sons, Ltd.

Monoclonal antibody studies in B-cell chronic lymphocytic leukemia and allied disorders.

Abstract: Lymphocytes from 48 patients with B-cell chronic lymphocytic leukemia (B-CLL) and allied disorders were examined with a panel of monoclonal antibodies and conventional surface marker techniques. Surface immunoglobulin (SIg) and 1a-like antigen were regularly present on B-CLL cells. In addition, 24 of 32 specimens reacted with OKT1, a monoclonal antibody which detects both peripheral and thymic T cells, but reactivity was not observed with anti-T-cell monoclonal antibodies of more restricted specificity (OKT3, OKT4, OKT6, OKT8 or OKT11). Eighteen of 20 samples in which only SIgM was detected were OKT1 –positive, while all 4 with only SIgG were OKT1—negative. Cells from patients with hairy cell leukemia were unreactive with OKT1, but resembled B-CLL lymphocytes in the presence of clonal SIg and 1a-like antigen. Neoplastic plasma cells lacked 1a-like antigen and frequently SIg (2 of 5), but cytoplasmic immunoglobulin was present, cells reacted with OKT 10 (replicating lymphoid cells) and 2 of 5 with OKT9 (transferrin receptor) as well. Cutaneous T-cell lymphoma samples were reactive with the anti-T-cell monoclonal antibodies OKT1, OKT3 and OKT4 even when the sheep cell receptor could not be detected. Monoclonal antibodies can provide more certain diagnosis and superior resolution of cell lineage in these disorders than is possible by morphology alone.

Myeloablative chemotherapy followed by autologous stem cell infusion may overcome the adverse prognostic impact of FLT3 (foetal liver tyrosine kinase 3) mutations in patients with acute myeloid leukaemia and normal karyotype

Abstract: In this study, we analysed the prognostic relevance of foetal liver tyrosine kinase 3 (FLT3) mutations in 73 patients with acute myeloid leukaemia (AML) with normal karyotype, who survived induction and consolidation and received autologous stem cell transplantation (ASCT) after successful mobilization of peripheral blood stem cell (PBSC). There were 44 males and 29 females with a median age of 54 years (range 20-77). Overall, 16 out of 73 autografted patients (22%) had FLT3 mutations. More in detail, FLT3/ITDs were detected in 10 out of 73 patients (14%), while FLT3 D835 mutations were detected in five cases (7%). One patient (1%) was found as having both abnormalities. White blood cell count (p=0.009), serum concentration of lactate dehydrogenase (p=0.01), and percentages of peripheral blood (p=0.002) and bone marrow blasts (p=0.03) were significantly higher in patients showing the FLT3 mutations. On the contrary, overall survival and disease-free survival were similar between patients with or without FLT3 mutations (p=0.73 and 0.78, respectively). In conclusion, our data suggest that myeloablative chemotherapy supported by auto-PBSCT may overcome the adverse prognostic implications of FLT3 mutations in AML. However, it is to consider that autografted patients are highly selected for best response to induction, consolidation and mobilization, as well as for minor non-haematologic toxicity.

Age has no influence on mobilization of peripheral blood stem cells in acute myeloid leukemia

Abstract: The upper age limit for autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) is increasing and peripheral blood (PB) represents the standard source of stem cell (SC). However, no data are available on the impact of age on SC mobilization in AML. We analyzed a cohort of 150 consecutive AML patients in first complete remission in order to make a comparison between patients up to 60 years and above 60 years, by evaluating CD34+ cells mobilization into PB and the number of leukapheresis needed to collect at least one single SC graft. The successful mobilization rate (>2 × 106 CD34+ cells/kg) was comparable between the two groups (87% vs. 80%, p = 0.29). In addition, no statistically significant difference was found in terms of either median number of CD34+ cells collected (p = 0.54) or CD34+ cells peak in PB (p = 0.70). Both groups of patients needed a median of two apheresis and no difference was found in the median number of CD34+ cells collected per single apheresis (p = 0.67). Finally, no correlation was found between age and total number of CD34+ cells collected (r = 0.003, p = 0.58). We conclude that age has no impact on mobilization of PBSCs in AML. Copyright © 2007 John Wiley & Sons, Ltd.

Chronic myelogenous leukemia and genetic events at 9q34.

Abstract: Assessment of cytogenetic patterns associated with chronic myelogenous leukemia (CML) suggests that genetic events at band q34 of chromosome nine are critical in the conversion of benign to malignant hematopoiesis. A break at this band is identified in almost all cases of Philadelphia chromosome (Ph1) positive CML, is also noted in some cases of Ph1 negative CML and cannot be excluded in the remaining cases. The human cellular homolog of the Abelson retrovirus oncogene (c-abl) is situated at band 9q34 and is translocated with the genetic sequences distal to the break point at this site in Ph1 positive disease. This oncogene has been shown experimentally to transform pre-B cells and it is expressed in primitive cells of the granulocytic series which are involved in CML. Although the break in CML chromosomes at 9q34 and the location of c-abl at 9q34 could be unrelated, it seems more likely that the two genetic events are associated with evolution of malignant hematopoiesis of man.

Phenotypic and cytogenetic characteristics of a new epstein‐barr virus negative cell line (SKW 4) derived from A B‐Cell lymphoma

Abstract: A new Epstein-Barr virus nuclear antigen (EBNA) negative cell line SKW 4 has been established in vitro from a patient with diffuse histiocytic lymphoma. The SKW 4 seems to be an authentic human tumour cell line as evidenced by its EBV negativity, monoclonality and aneuploidy tested during early in vitro passage. The cell line expresses surface mu and kappa-chains, HLA-DR antigen, C3 and Fc receptors and B-cell lineage antigens. The karyotypic analyses demonstrated many numerical and structural aberrations. No Burkitt lymphoma associated translocations (t8;14, t2;8, t;22) were detected, but most of the markers found are those commonly associated with various types of human cancer. The SKW 4 thus represents the most common type of 'histiocytic lymphoma', that with a B-lymphoid cell phenotype, but is unique among HL derived lymphoma lines in its strong expression of a Helix pomatia A agglutinin binding surface glycoprotein of an apparent molecular weight of 75 000 daltons.