bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro synergistic activity of PDN‐IFNα and NM + IFNα combinations on fresh bone‐marrow samples from multiple myeloma patients
Authors: Lepri Enrica , Barzi Anna , Menconi Emma , Portuesi Maria Giovanna , Liberati Marina
Published: February 2007

The differential staining cytotoxicity (DiSC) assay was used to evaluate the in vitro sensitivity of tumour and normal bone‐marrow cells from 21 multiple myeloma (MM) patients to antitumour agents methylprednisolone (PDN), nitrogen mustard (NM) and recombinant interferon α‐2b (IFNα) tested singly and in the combinations PDN+IFNα and NM+IFNα. Both the PDN‐IFNα and NM‐IFNα associations were more efficacious than any agents used singly in reducing the percentage of myeloma cell survival. However, whereas NM, alone and in combination with IFNα, provoked a severe reduction in normal bone‐marrow population, PDN and PDN+IFNα induced an increase percentage survival of normal bone‐marrow cells. These findings indicate that, at least in vitro, the PDN‐IFNα combination exerts a great antitumour effect which is not associated with a relevant cytotoxic activity on normal myeloid cells.
Anti‐BLA.36 monoclonal antibody shows reactivity with hodgkin's cells and B lymphocytes in frozen and paraffin‐embedded tissues
Authors: Croce David R. Della , Imam Ashraf , Brynes Russell K. , Nathwani Bharat N. , Taylor Clive R.
Published: February 2007

A newly developed monoclonal antibody, anti‐BLA.36, raised against a Hodgkin cell line, was shown to have reactivity with Reed‐Sternberg cells and activated B lymphocytes and appears to be distinct from other antibodies which identify antigens of hematopoietic cells.

Anti‐BLA.36 was evaluated in B5‐fixed paraffin‐embedded tissue from 16 cases of Hodgkin's disease of various types and 35 cases of non‐Hodgkin's lymphomas representative of the different major subtypes. The specificity of anti‐BLA.36 was compared with other antibodies that have been used to mark Hodgkin's cells and B lymphocytes: namely, L26, LN‐1, Leu‐M1 and Ber‐H2, as well as UCHL‐1, a pan‐T lymphocyte marker. In addition, a subset of the cases was evaluated using frozen tissue in order to validate the staining characteristics of anti‐BLA.36 as observed in fixed paraffin sections. Anti‐BLA.36 was found to react with Hodgkin's cells more consistently than the other antibodies used in this panel. The antibody reacted with an antigen on Reed‐Sternberg cells and their variants (Hodgkin's cells) in all four subtypes of Hodgkin's disease, and with a subset of reactive and malignant B lymphocytes, but not with T lymphocytes. It may, therefore, be useful in the evaluation of non‐Hodgkin's lymphomas.

Finally, this is the first antibody raised to a Hodgkin's cell line which also consistently marks reactive and malignant B cells, but not T cells. The implications of this observation are discussed in relation to the cellular origin of the Reed‐Sternberg cell and the overall nature of Hodgkin's disease.
Ceftazidime and amikacin as empiric antibiotic therapy of febrile granulocytopenic patients with hematological malignancies. Report of 171 consecutive episodes
Authors: Todeschini G. , Veneri D. , Carlini S. , Pizzolo G. , Ambrosetti A. , Bonesi R. , Cassibba V. , Vinante F. , Meneghini V. , Perona G.
Published: February 2007

One hundred and seventy‐one consecutive febrile episodes occurring in 130 neutropenic adult patients with hematological malignancies (mainly acute leukemia) were empirically treated with a combination antibiotic therapy consisting of ceftazidime (100 mg/kg/day) + amikacin (15 mg/kg/day). Of these, 161 were evaluable.

In the majority of episodes (75 per cent) documented infections were identified as a cause of fever. There were 73 bacteremias (34 Gram‐negative, 29 Gram‐positive, 10 polymicrobial). One third of patients had pneumonia. Cure without change of the initial regimen was achieved in 45/73 (62 per cent) bacteremic episodes and in 12/13 episodes of microbiologically documented infections without bacteremia. There were 35 clinically documented infections and 26 (74 per cent) of these were cured. Of the 40 patients presenting with possible infections 26 (65 per cent) were cured.

Overall, cure without modification of the initial antibiotic combination was achieved in 109/161 episodes (68 per cent). In spite of the frequent occurrence of persistent neutropenia (82 per cent), the infectious mortality was low (8–6 per cent), and often due to superinfection. The deaths due to primary infections were 6/161 (3–7 per cent). Side effects were mild and rare.

In our experience ceftazidime+amikacin was an effective and safe empirical regimen for this population of hematologic patients with persistent neutropenia and severe documented infections.
A phase II trial of promace‐cytabom in previously untreated non‐hodgkin's lymphoma of intermediate‐ or high‐grade histology
Authors: Rossi G. , Mariano M. R. , Arcangeli G. , Bonfanti V. , Capucci M. A. , Ferremi P. , Marpicati P. , Meriggi F. , Zaniboni A. , Izzi T. , Marini G.
Published: February 2007

Between November 1985 and June 1989 the aggressive combination chemotherapy programme ProMACE‐CytaBOM was used at a community‐based hospital as primary treatment for non‐Hodgkin's lymphoma (NHL) of intermediate or high‐grade histology in Ann‐Arbor stages IB‐IV. The 53 patients entering the study represented 90 per cent of all consecutive eligible patients with NHL diagnosed during the time period considered. Their median age was 54 years and median observation time was 36 months. Of 50 patients evaluable for response, 35 (70 per cent) achieved complete remission (CR), seven (14 per cent) partial remission, and five (10 per cent) were refractory. Treatment was given on an outpatient basis. Actually delivered drug doses ranged from 88 per cent to 97 per cent of the theoretical doses. Life‐threatening toxicity was experienced by four patients. Treatment was stopped in three cases (6 per cent) because of toxicity and there was one treatment‐related death. Actuarial 2‐year disease‐free survival of patients in CR was 73 per cent. Overall actuarial 3‐year survival and disease‐free survival were 67 per cent and 51 per cent respectively. High LDH level was a significant adverse prognostic factor both for achievement of CR (P < 0·005) and for survival (P < 0·0002). Age was of no prognostic importance. We conclude that ProMACE‐CytaBOM is an effective, easy to administer and well‐tolerated regimen for patients with aggressive NHL.
Polymorphism of the human HA‐RAS oncogene locus in chronic lymphocytic and chronic myelogenous leukemia
Authors: Knauf W. U. , Ho A. D.
Published: February 2007

DNA from white blood cells from healthy controls demonstrates a restriction fragment length polymorphism (RFLP) of the Ha‐ras oncogene locus after cleavage with the restriction enzymes BamH I or MspI plus HpaII, representing frequent and rare alleles. We have studied the RFLP of 15 patients with B‐cell chronic lymphocytic (CLL) and of 16 patients with chronic myelogenous leukemia (CML). As in healthy controls the RFLP in the leukemic cells indicates the occurrence of frequent and rare Ha‐ras alleles. But rare alleles are not more frequent in the patients than in the healthy control group. The frequency of rare Ha‐ras alleles also does not differ between chronic lymphocytic and chronic myelogenous leukemia. While rare alleles of this oncogene locus occur in CML and CLL as frequently as in healthy controls, they do not reflect an inherent increased risk for chronic leukemia in man.
Phase II trial of ifosfamide and mesna in previously treated patients with non‐hodgkin's lymphoma: Cancer and leukemia group b study 8552
Authors: Case Delvyn C. , Anderson James , Ervin Thomas J. , Gottlieb Arlan
Published: February 2007

Ifosfamide (1·25 g/m2 intravenously/day × 5) with mesna (20 per cent of the ifosfamide dose × six doses on each day of ifosfamide therapy) was administered to 46 previously treated patients with non‐Hodgkin's lymphoma of which 31 were eligible and evaluable. A 29 per cent response rate (9/31) was observed (two CR and seven PR) with a median duration of response of 2·5 months. Myelosuppression was dose‐limiting. Hemorrhagic cystitis was observed in three patients (10 per cent). Nausea and vomiting was generally mild or moderate. One patient developed transient neurotoxic symptoms with confusion and disorientation. An additional patient developed an anaphylactic‐type reaction with shortness of breath and respiratory stridor during the fourth course of therapy. Ifosfamide, as a single agent, produces remissions of limited duration in non‐Hodgkin's lymphoma in patients in second or third relapse.
Toxicity and preliminary results with a new eight‐drug regimen (CEOP‐IMVP‐DEXA) in the treatment of aggressive lymphomas
Authors: Fridrik M. A. , Hausmaninger H. , Michlmayr G. , Haidinger R. , Seewann H. L. , Lehnert M.
Published: February 2007

A combination of two non‐cross‐resistant regimens, CEOP and IMVP‐Dexa given every 4 weeks, three to six times according to response was tested in patients with untreated histological proven high and intermediate grade non‐Hodgkin's lymphoma.

To date eight Austrian centres entered 37 patients in this multicentre trial. Data are available from 33 patients, three were excluded, two because of pretreatment, one because of wrong histology. Twenty‐five patients are evaluable for response, 21 had a complete and three a partial remission, two of them entered a complete remission after radiotherapy to residual disease, resulting in a complete remission rate of 92 per cent. Only one patient progressed during therapy. Until now three patients relapsed after achieving a remission. Observation time is 0±4–23±8 months, median 8±8 months.

Toxicity was primarily hematologic with 53·3 per cent of patients having granulocyte nadirs below 0·5 × 109/L and 3·3 per cent below 0·1 × 109/L. Although 60 per cent of patients had infections, there was only one life‐threatening infection in an AIDS patient.

CEOP‐IMVP‐Dexa can be safely given even in smaller hematologic centres and is able to achieve a high rate of complete responses in patients with high and intermediate grade malignant non‐Hodgkin's lymphomas.
Ifosfamide continuous infusion plus etoposide in the treatment of elderly patients with aggressive lymphoma: A phase II study
Authors: Tigaud Jean‐Dominique , Demolombe Sylvie , Bastion Yves , Bryon Paul‐André , Coiffier Bertrand
Published: February 2007

A prospective phase II study was performed to evaluate efficacy and toxicity of continuous infusion ifosfamide plus etoposide combination in elderly patients (older than 70 years) with intermediate or high grade non Hodgkin's lymphoma. Chemotherapy was administered with mesna in order to avoid hemorrhagic cystitis. The 21 patients included were either unable to receive the usual front‐line chemotherapy given in our institution or relapsing after or not responding to conventional chemotherapy. Only one out of 97 courses of chemotherapy was followed by serious complication consisting in non‐lethal pneumonitis. Four out of seven previously untreated patients and five patients treated in first relapse achieved complete response (75 per cent). Out of nine refractory or previously multi‐treated patients, only one achieved complete response. We conclude that combination of continuous infusion ifosfamide plus etoposide deserves to be evaluated on a larger scale so that the optimum doses and schedule may be defined.
IMVP‐16 followed by high dose chemotherapy and autologous bone marrow transplantation as salvage treatment for malignant lymphoma
Authors: Huijgens P. C. , Ossenkoppele G. J. , Van Der Lelie J. , Thomas L. L. M. , Wijngaarden M. J. , Slaper C. M.
Published: February 2007

Thirty patients with high‐grade malignant lymphoma were treated with ifosfamide‐VP16213‐methotrexate (IMVP‐16) combination chemotherapy after failing to respond completely or after relapsing on CHOP‐like therapy. Responders to the salvage therapy subsequently were treated with ablative chemotherapy (BCNU. VP16213, Ara‐C and melphalan) and autografted. Of these 30 patients 11 were in relapse, 11 were partial responders and eight failed CHOP‐like therapy. There were eight complete remissions and 12 partial responses to IMVP‐16. These 20 patients were transplanted, together with one nonresponder. Ten of these 21 patients are disease‐free survivors 16 to 76 months (median 32) after autografting. There were three treatment‐related deaths: one before and two during the autografting procedure.

Using one of the best salvage therapy combinations followed by high dose chemotherapy and autografting is feasible. The results of this study suggest that an appreciable number of patients may be cured by this procedure.
Ifosfamide in the treatment of high‐grade recurrent non‐hodgkin's lymphomas
Authors: Magrath Ian , Adde Melissa , Sandlund John , Jain Vinay
Published: February 2007

We report the results of two phase II trials of ifosfamide in very high risk patients with either partially responsive or recurrent non‐Hodgkin's lymphomas. In the first study, in which patients were extremely heavily pretreated (50 per cent had received a very intensive salvage regimen containing very high dose cyclophosphamide), there were two complete responses, two partial responses and one objective (minimal) response among 14 patients treated. Toxicity was acceptable even in this end‐stage patient group. We concluded that ifosfamide is an active agent even in patients with tumours resistant to cyclophosphamide. The second trial was a pilot study in 13 patients of a regimen incorporating VP16, ifosfamide/mesna, and high dose ara‐C (VIPA). There were four complete responses, five partial responses and two objective responses. Two patients died in complete remission from toxic complications, while a third, with a stably regressed mediastinal mass died after completion of the protocol. While very toxic, we considered that this regimen was highly effective, and have since incorporated a slightly less intensive combination of the same drugs into the primary therapy of high risk patients. Since the primary toxicity of the VIPA combination was myelosupression. the use of a modified protocol incorporating colony stimulating factors to ameliorate the side‐effects and possibly increase dose rate is worthy of further exploration in patients with recurrent B cell tumours.
Prolonged disease‐free survival in pediatric non‐hodgkin's lymphoma using ifosfamide‐containing combination chemotherapy
Authors: Gad‐El‐Mawla Nazli , Hamza M. R. , Abdel‐Hadi S. , El‐Tannir O. , Hussein M. H. , El‐Haddad A. , Adde Melissa , Magrath Ian
Published: February 2007

Pediatric non‐Hodgkin's lymphoma (NHL) constitutes 16 per cent of pediatric malignancies reported to the National Cancer Institute (NCI) in Cairo. The adopted treatment for these cases was, from 1982 to July 1985. a modified St Jude's regimen consisting of: vincristine, cyclophosphamide, adriamycin, prednisone and intrathecal methotrexate for the first 6 weeks for induction, followed by cranial irradiation for cranial prophylaxis. Patients in remission received maintenance therapy for 18 months. Of 32 patients complete remission (CR) was achieved in 24 patients (75 per cent); partial remission (PR) in one patient (3 per cent): five patients showed no response (15 per cent) while two patients died during the induction phase. At 60 + months follow‐up, 60 per cent of cases are still alive, disease‐free, and overall survival is 66 per cent. A new protocol was adopted in 1985, consisting of alternating cycles: A and B, for 4–8 cycles. Cycle A: cyclophosphamide. high dose ara‐C, adriamycin, and vincristine. Cycle B: ifosfamide, methotrexate, VP 16, with intrathecal methotrexate. The response in 39 cases is: CR in 31 cases (82 per cent); PR in four cases (10 per cent): no response in three cases (8 per cent). At 60+ months, the disease‐free survival is 60 per cent, and overall survival 80 per cent. This new protocol has the advantage of: short duration of therapy and so better patient compliance, no maintenance therapy or cranial irradiation with its sequelae in the future. Moreover, it has a better overall survival.
A comparative study of proliferation‐associated parameters in b‐cell non‐hodgkin lymphoma
Authors: Rehn Suzanne , Glimelius Bengt , Sundström Christer
Published: February 2007

The prognostic value of three proliferation‐associated parameters, the frequency of cells in S‐phase, mitotic index (MI) and serum deoxythymidine kinase levels (S‐TK), was examined in 106 primary cases of B‐cell non‐Hodgkin lymphomas (NHL), 76 ‘low grade’ NHL and 30 ‘high grade’ NHL and compared with morphology and clinical variables. All three proliferation factors displayed large differences in the mean values of the two groups ‘low grade’ and ‘high grade’ NHL, and all revealed significant prognostic information. In ‘low grade’ NHL, the information decreased with follow‐up time. A correlation (r=0·7) was noted between S‐phase values and MI but not between S‐TK and the two others. In the entire patient material and in the two prognostic groups defined by morphology, S‐TK gave the best prognostic information. MI gave better prognostic information than S‐phase values in the whole material and in ‘low grade’ NHL, whereas the reverse appeared to be true for ‘high grade’ NHL. In the multivariate analyses, no other parameter apart from S‐TK provided any further prognostic importance in the cases of ‘high grade’ NHL, whereas in that of ‘low grade’ NHL, MI, stage, age and histology had independent importance.
Increased levels of circulating interleukin‐6 in patients with hodgkin's disease
Authors: Gause Angela , Scholz Rotraud , Klein Sigrid , Jung Wolfram , Diehl Volker , Tesch Hans , Hasenclever Dirk , Pfreundschuh Michael
Published: February 2007

Expression of interleukin‐6 (IL‐6) and IL‐6 receptors has been demonstrated in Hodgkin and Reed‐Sternberg (H and RS) cells in vitro and in vivo. In order to evaluate the clinical significance of IL‐6 serum levels in patients with Hodgkin's disease (HD), we tested the sera of 56 untreated patients with HD by means of a sensitive sandwich ELISA. While IL‐6 was only rarely detectable in healthy controls or patients with non‐Hodgkin's lymphoma, 32 of 56 patients (57 per cent) had detectable IL‐6 levels (range 12–32pg/ml). The rates of detectable IL‐6 levels and the median levels were not correlated with age, sex, histological subtype, stage or the presence of B‐symptoms, nor with any of a wide spectrum of laboratory parameters tested, including erythrocyte sedimentation rate, total leukocyte and lymphocyte counts, serum levels of soluble CD8, CD25 or CD30. The rates of complete remissions and freedom from treatment failure were not different in IL‐6‐negative and IL‐6‐positive patients. Except in one of 23 follow‐up sera taken after therapy, IL‐6 was no longer detectable even for patients who suffered from progressing disease, suggesting that the neoplastic H and RS cells are not the major source of circulating IL‐6.
The biological and clinical significance of the KI‐67 growth fraction in multiple myeloma
Authors: Drach Johannes , Gattringer Claus , Glassl Herta , Drach Doris , Huber Heinz
Published: February 2007

We tested the significance of the Ki‐67 plasma cell growth fraction in 49 bone marrow samples from 42 patients with multiple myeloma (MM). As a new approach to study myeloma cell proliferation, strong positivity of the CD38 antigen as plasma cell related feature was simultaneously evaluated with nuclear Ki‐67 expression in a flow cytometric double immunofluorescence assay. Mean Ki‐67 values were significantly higher in MM at relapse (22·4 per cent ± 10·4) as compared with MM at diagnosis (11·9 per cent ± 8·4, p < 0·005) and plateau‐phase (10·0 per cent ± 5·5, p < 0·001), respectively. Serial observations in six patients confirmed this change in cell kinetic behaviour during the course of the disease. Elevated Ki‐67 values correlated significantly with stage III (versus stage I, p < 0·05), beta‐2‐microglobulin serum levels > 6 (p < 0·001), plasmablastic morphology (p < 0·001), and diploid myeloma cell DNA‐content (p < 0·005). No correlation was found between Ki‐67 and immunoglobulin isotypes as well as immunophenotypic features (expression of CD10, CD33, and CD56) of myeloma cells. Clinically, six of seven patients with Ki‐67 > 14 per cent at diagnosis had an unfavourable course (primary resistant disease or early relapse), and three of four patients with elevated Ki‐67 values at plateau‐phase relapsed within 3 months. Our results demonstrate the usefulness of Ki‐67 in determining proliferative activity in MM and emphasize its value in the evaluation of the risk profile of MM patients.
Detection of immunoglobulin gene rearrangement in B‐cell lymphomas by polymerase chain reaction gene amplification
Authors: Liang Raymond , Chan Vivian , Chan T. K. , Wong Thomas , Todd David
Published: February 2007

This is a report on our attempt to use polymerase chain reaction (PCR) to detect rearrangement of the immunoglobulin gene in the tissue specimens obtained from 30 patients with non‐Hodgkin's lymphomas. There were 20 B‐cell lymphomas and 10 T‐cell. All 20 B‐cell lymphomas but none of the 10 T‐cell lymphomas had JH rearrangement by Southern analysis. Two pairs of primers (V670/OL‐4 and VH26/OL‐4) were designed to amplify the CDR3 region of the immunglobulin gene heavy chain. The PCR analysis was positive using either one or both pairs of primers in 11 of the the 20 cases (55 per cent) of B‐cell lymphomas which all had positive rearrangement by Southern analysis. The two pairs of primers seemed to produce complementary results as the specimens may be positive to one pair but negative to the other. The false negative rate of 45 per cent is however much higher than the respective figures of 18 per cent and 0 per cent observed in our patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia in a previous study. Peripheral blood and bone marrow biopsy specimens obtained at the time of initial diagnosis were available from 10 patients with B‐cell lymphomas whose lymph node biopsy specimens at the time of diagnosis were positive by both Southern analysis and PCR. All these peripheral blood and marrow specimens had no microscopic evidence of involvement by lymphoma cells and JH rearrangement was not detected by Southern analysis. However, rearranged bands identical to that of the lymph node biopsy specimen were detected by PCR in the peripheral and marrow blood of one of them. This PCR technique has been shown to have a sensitivity of 0·1 per cent in our previous report and may be more useful than morphology alone or Southern analysis in detecting minimal lymphomatous involvement in the peripheral blood and bone marrow at the time of initial diagnosis. Further clinical correlation is required to confirm the finding.
Proliferation in non‐hodgkin's lymphomas as determined by immunohistochemical double staining for Ki‐67
Authors: Tominaga Kunihiko , Yamaguchi Yoshiko , Nozawa Yoshihiro , Abe Masafumi , Wakasa Haruki
Published: February 2007

The authors have studied proliferation (growth fractions) in non‐Hodgkin's lymphomas (NHL) using an immunohistochemical double staining technique with the monoclonal antibody (MoAb), Ki‐67, in order to clarify the relationships between histologic type, proliferation and prognosis. The percentages of Ki‐67 positive (Ki‐67+) cells in B cell lymphomas were higher for diffuse lymphomas than for follicular lymphomas and increased in order from small to large cell types. In addition, the percentage of Ki‐67+ cells in B cell lymphomas inversely correlated with survival in months (n = 33 r = ‐0·54 p < 0·01). These results indicate that the percentage of Ki‐67+ cells in B cell lymphomas correlates with histologic type and prognosis. Although the prognosis of T cell lymphomas is considered worse than that of B cell lymphomas, the percentage of Ki‐67+ cells was lower, in general, in T cell lymphomas than in B cell lymphomas. These data indicate that proliferation in T cell lymphomas does not correlate with survival.
‘Aggressive’ low grade lymphocytic lymphomas can be identified by flow cytometric s‐phase determinations
Authors: Lindh J. , Jonsson H. , Lenner P. , Roos G.
Published: February 2007

Forty‐five patients with low grade non‐Hodgkin's lymphomas were studied with respect to the fraction of S‐phase cells in fresh tumour material by flow cytometric analysis. Patients with stage I lymphomas were treated with radiotherapy, patients with stage II‐IV lymphomas with Prednimustine (SterecytR). Patients with lymphocytic lymphomas of CLL type were only treated if they had symptoms. Median S‐phase fraction in the samples was 2‐0 per cent. A significantly shorter survival was found for patients with lymphocytic lymphomas with S‐phase fractions >2·0 per cent compared with cases showing lower S‐phase fractions. No significant difference in survival was found in the subgroups of immunocytic or follicular and follicular diffuse centroblastic/centrocytic lymphomas. In a Cox multivariate analysis, in which also age, constitutional symptoms, stage and morphology were included, the fraction of S‐phase cells was found to be a statistically significant, prognostic parameter for low grade lymphomas, mainly due to the result in the subgroup of lymphocytic lymphomas.
In vitro differentiation of a hodgkin's disease derived cell line
Authors: Klein S. , Jones D. B. , Tesch H.
Published: February 2007

We have examined the Hodgkin's disease derived cell line Co in terms of its capacity to differentiate in vitro. Co cells show the characteristics of immature T cells and express CD3 molecules in the cytoplasm. On activation with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) these cells express the CD3 antigen and the T cell receptor αβ (TCRαβ) on the cell surface. Surface expression of the activation marker CD25 (IL2 receptor) was also greatly increased, whereas CD4 and CD8 levels were not altered. Supernatants of TPA‐stimulated Co cells contained the cytokines IL2, IL3, IL4 and IL8, whereas these cytokines were not detected in the supernatants of untreated cells. Different subclones of the Co cell line differed in their response to TPA with respect to the induced CD3 and TCR expression. Our data demonstrate that a Hodgkin's disease derived cell line can be induced to differentiate in vitro from a pre‐T cell phenotype towards a more mature T cell. It is possible that similar processes may occur in Hodgkin's disease in vivo.
The management of acute myelogenous leukemia in the elderly: Ten‐year experience in 118 patients
Authors: Bassan Renato , Buelli Maurizio , Viero Piera , Minotti Clara , Barbui Tiziano
Published: February 2007

This retrospective study was undertaken to analyse the survival pattern of 118 consecutive, unselected patients with acute myelogenous leukemia (AML) aged between 60 and 82 years observed at a single centre over a 10‐year period (1981–1991). Thirty‐two per cent of cases had an antecedent hematological disorder (AHD), and 7 per cent had a secondary AML. Forty patients (39 per cent) were managed with palliative intent with short courses with oral hydroxyurea ±6‐thioguanine. In contrast to 78 patients (61 per cent) selected for remission‐induction treatment, these were significantly older (P< 0·0001), had a greater incidence of AHD (P<0·039) and of hypoplastic AML (P<0·017), and an inferior amount of blast cells in the bone marrow (P<0·003). Patients undergoing remission‐induction chemotherapy were managed with DAT‐like chemotherapy, high‐dose cytosine arabinoside (HD‐ara‐C), and mitoxantrone‐based regimens. The complete response (CR) rate was 29 per cent. Response was higher with the two most intensive HD‐araC and mitoxantrone‐etoposide‐araC programmes (P<0·026), and correlated favourably with no AHD (P<0·04) and lower blast cell count in the peripheral blood (P <0·02). Overall survival of responders was longer than in palliation and nonresponder groups (P<0·025 and P<0·001, respectively). In the active treatment group, survival correlated with performance status (P<0·005) and blast cell count (P<0·05). Infection was the main cause of morbidity during active treatment, accounting for most induction failures (60 per cent), followed by haemorrhage (12 per cent) and resistant disease (12 per cent). These results from an unselected series represent an improvement over those obtained by us in previous years (1971–1980), and show that intensive treatment programmes are applicable to the elderly with AML and that prolonged disease‐free survival is possible for some. Improving further CR rate and duration will depend equally on the optimization of supportive care measures and the introduction of more effective therapeutic modalities.
Large cell lymphoma with initial presentation in the bone marrow
Authors: Wong K. F. , Chan J. K. C. , Ng C. S. , Chu Y. C. , Li L. P. K. , Chan C. H.
Published: February 2007

This report describes 14 cases of large cell lymphoma with initial presentation as marrow involvement in the absence of peripheral lymphadenopathy. The disease affected mainly the middle‐aged and elderly, with male predominance. Most patients presented with swinging fever and peripheral blood cytopenia. Reactive hemophagocytic syndrome was a common finding, causing significant morbidity and mortality. Peripheral lymphadenopathy was absent (by case selection), but involvement of the liver, spleen and paraaortic lymph nodes could be demonstrated in some cases. However, in some patients, the involvement was apparently restricted to the bone marrow. Involvement of the bone marrow was often subtle, and could be missed on casual examination. Immunohistochemical studies on eight cases showed that four exhibited a B‐cell phenotype. three a T‐cell phenotype and one a non‐T non‐B phenotype. The prognosis was poor, with survival being measured in days to weeks in most patients.
Accumulation of p53 protein correlates with tumour proliferative activity in EBV positive Burkitt's lymphoma
Authors: Lehtinen Tuula , Isola Jorma , Aine Risto , Alavaikko Martti , Lehtinen Matti
Published: February 2007

p53 tumour suppressor gene is often found mutated in Burkitt's lymphoma (BL) cell lines and tumours. We analysed 35 BL tumours for the accumulation of p53 protein, and correlated the results with DNA flow cytometric data on the proliferative activity (SPF), and data on the presence or absence of Epstein‐Barr virus (EBV) DNA. More than one‐third (37 per cent) of the tumours showed accumulation of p53, which was considered to be consistent with mutation of the p53 gene. Tumours that were positive both for EBV DNA and p53 had significantly higher mean SPF than corresponding EBV DNA negative and/or p53 negative tumours. The proportions of tumour cells with accumulation of p53 appeared to correlate with tumour SPF only in EBV DNA positive BLs. However, there was no apparent association between accumulation of p53 and the presence or absence of EBV DNA. These findings are suggestive of multiple pathways in BL tumour progression.
A pilot study of chlophepp‐B—A weekly regimen for patients with untreated advanced or recurrent hodgkin's disease
Authors: Smith G. M. , Wright D. , Child J. A. , Simmons A. V. , Norfolk D. R. , Barnard D. L. , Parker D. , Parapia L.
Published: February 2007

Twenty‐five patients with either previously untreated advanced Hodgkin's disease (HD) or with relapsed disease were treated with an intensive weekly chemotherapy regimen (ChlOPhEPP‐B) in which the myelo‐suppressive combinations of epirubicin and chlorambucil, and procarbazine and etoposide alternated at two‐week intervals, interspersed with vincristine and prednisolone and then vincristine, prednisolone and bleomycin in a four‐week cycle. Of the previously untreated patients (n=14), 12 (86 per cent) showed a complete response (CR); in the previously treated patients (n=11), CR was achieved in five (46 per cent). Toxicity was predictable and not evidently more severe than with more standard regimens. Neutropenia leading to treatment delay and/or dose reduction was seen in 11 patients (44 per cent) but severe neutropenia (WHO grade 4) was documented in only six patients (24 per cent) for a cumulative total of nine treatment weeks (1‐8 per cent of the total treatment time). Dose reductions for neutropenia were applied in relation to 11 of the 379 weekly treatment points (2·9 per cent). Delays in treatment, for any reason, averaged 3·65 weeks per patient. The study demonstrated the feasibility of a more intensive weekly multidrug schedule. This approach may be applicable in the treatment of advanced HD and represents a further option in the strategy of treating relapsed disease.
Prognostic significance of karyotype analysis in children with acute lymphoblastic leukemia
Authors: Ankathil Ravindran , Stephen J. , Vasudevan D. M. , Kusumakumary P. , Pillai G. Rajasekharan , Nair M. Krishnan
Published: February 2007

Chromosome studies, using bone marrow samples of 26 pretreated children (below 15 years of age) with Acute Lymphoblastic Leukemia were carried out to explore the potentialities of applying chromosomal findings as a prognostic indicator in these patients. Abnormal karyotype was identified in 15 patients (57·6 per cent). The chromosomes frequently involved in non‐random numerical abnormalities were Nos. 8, 18 and 21. Structural chromosome changes observed consisted of deletion 6q‐ and translocation t (4; 11).

After karyotype analysis, patients were grouped into subsets on the basis of the karyotype pattern observed. They were followed up to evaluate their prognosis and survival period. Patients showing hyperdiploid clone with greater than 51 chromosomes had the best prognosis. Patients with normal karyotype and patients with deletion of the long arm of chromosome 6 showed intermediate prognosis whereas patients showing t (4; 11), trisomy 8, trisomy 18, trisomy 21, and hypodiploid karyotype were associated with worst prognosis. Thus, karyotype analysis before treatment helps to classify ALL patients as poor, intermediate and good prognosis groups and on this basis therapy can be designed accordingly.
Identification of some marker chromosomes in acute leukemias by fluorescence in situ hybridization
Authors: Shi Guangping , Weh Hans Josef , Hossfeld Dieter K.
Published: February 2007

Four patients with acute leukemia are presented in whom conventional karyotypic analysis had revealed complex numerical and structural changes including unidentifiable (marker) chromosomes. It is demonstrated that the application of fluorescence in situ hybridization (FISH) may contribute to the identification of such anomalies.
Pharmacokinetics of high dose methylprednisolone and use in hematological malignancies
Authors: Patel P. M. , Selby P. J. , Graham M. A. , Viner C. , Newell D. R. , McElwain T. J.
Published: February 2007

The pharmacokinetics of oral and intravenous high dose methylprednisolone (Solu‐medrone, Upjohn) were compared in patients with hematological malignancies. The aim of the study was to determine the oral bioavailability of high dose methylprednisolone and to establish whether this is a feasible and more convenient route of administration. The plasma pharmacokinetics were described by a one‐compartment open model with peak plasma levels of 6·9 ± 2·5 μg/ml. Total area under the plasma concentration versus time curve was similar by either route. Mean relative oral bioavailability was generally high (91 ± 27 per cent).

Retrospective analysis of 34 patients with chronic lymphocytic leukemia (CLL), non‐Hodgkin's and Hodgkin's lymphoma treated with high dose methylprednisolone showed 11 responses including two complete remissions among nine patients with CLL. There was significant improvement in platelet counts in thrombocytopenic patients and treatment was well tolerated and toxicity was relatively low. High dose methylprednisolone may therefore be a useful palliative treatment for hematological malignancies, particularly where marrow suppression is a problem.
Evidence of colony suppressor activity and deficiency of hematopoietic growth factors in hairy cell leukemia
Authors: Gasché Christoph , Reinisch Walter , Schwarzmeier Josef D.
Published: February 2007

The cause of myelosuppression in hairy cell leukemia (HCL) has been ascribed to a reduction of the circulating progenitor cell (CPC) compartment and to suppression of hematopoiesis by TNF‐α. The present study was performed to evaluate the inhibitory effect of hairy cells (HCs) and a possible lack of hematopoietic growth factors on the number of autologous CPCs in vitro. In initial experiments the number of circulating BFU‐E, CFU‐GM and CFU‐mix in HCL patients was found decreased. Monocytopenia but not the number of circulating HCs correlated to the degree of colony reduction in our patients. This pointed to a lack of colony stimulating factors (CSFs) in HCL. Actually, the growth of BFU‐E, CFU‐GM, and CFU‐mix improved upon the addition of IL‐3 and GM‐CSF in HCL patients but not in healthy donors. To test the suppressive role of HCs in our assay system, cultures were performed after removal of autologous HCs. The results showed that in HC‐depleted cultures the numbers of BFU‐E, CFU‐GM, and CFU‐mix were significantly higher. This inhibitory effect of HCs could partially be neutralized by the addition of monoclonal antibodies against TNF‐α. When the assays were performed with the removal of HCs and the addition of CSFs normal progenitor cell counts were detected in most patients. We conclude that HCs mediate the inhibition of colony growth in part by TNF‐α. Monocytopenia is related with a deficiency of CSFs in this disease. The reduced colony growth in HCL, therefore, is due to both the inhibitory effects of HCs and the deficiency of CSFs. We suppose that the CPC‐compartment is actually preserved in this disease.
CORRELATION OF IMMUNOLOGICAL SURFACE ANTIGENS WITH SURVIVAL IN DIFFUSE LARGE CELL LYMPHOMA
Authors: Pilkington G. , Juneja S. , Tan L. , Matthews J. , Quirk J. , Lee G. , Ironside P. , Cooper I. , Jose D.
Published: February 2007

The prognostic value of immunophenotyping lymphomas with a panel of monoclonal antibodies (Mab) to various lymphoid antigens was assessed by studying 47 cases of diffuse large cell lymphoma. Cell suspensions were analysed by flow cytometry after labelling by indirect immunofluorescence. Thirty‐eight cases were demonstrated to be of B cell and nine of T cell phenotype. Univariate analysis demonstrated that survival was significantly longer in patients expressing higher levels of HLA‐DR (p=0·01) and normal levels of CD8 (p=0·04) but was not significantly associated with any of the other antigens. Our results support the possible value of HLA‐DR in determining the prognosis of patients with diffuse large cell lymphoma.
The management of chronic lymphocytic leukemia at a single centre over a 24‐year period: prognostic factors for survival
Authors: Karmiris T. , Rohatiner A. Z. S. , Love S. , Carter M. , Ganjoo R. K. , Amess J. , Norton A. J. , Lister T. A.
Published: February 2007

Over a 24‐year period, 137 patients were referred for management of newly diagnosed chronic lymphocytic leukemia. One hundred and nineteen patients have been reviewed in terms of response to therapy and prognostic factors for survival; 18 patients were excluded either because lymph node biopsy was not compatible with the diagnosis of CLL (11 patients), or because the lymphocyte count at presentation was < 5 × 109/1 (seven patients).

Patients were staged retrospectively according to both the Rai and Binet Classifications. Forty‐eight per cent (57/119) were deemed not to be in need of any treatment at presentation, 36 per cent (43/119) have never received any specific therapy. The majority of patients received chlorambucil alone, at a dose of 10 mg daily given for 6 weeks, followed by a 2‐week interval, followed by three, 2‐week cycles. The overall response rate (complete + partial remission) was 38 per cent.

In terms of survival, there was a trend in favour of patients who responded to treatment in comparison with those who did not but this did not reach statistical significance (P=0.07). Correlation with stage were highly significant, the median survivals for patients with stage A, B and C disease (Binet) were 12.5, 8 and 3.5 years respectively. On univariate analysis, the absolute lymphocyte count at presentation was the most significant prognostic factor for survival, patients presenting with an absolute lymphocyte count above 50 × 109/1 having a less favourable prognosis (P=0.002). However, on multivariate analysis, older age, a low hemoglobin, low platelet count, and the presence of lymphadenopathy and fever at presentation correlated adversely with survival.

Overall, 40 patients died as a consequence of CLL or from disease‐related causes, 34/40 dying of infection. Twenty‐one patients developed second cancers.

With a median follow‐up of 13 years, these results confirm that the two staging systems can separate patients into prognostic groups, however in practice, there is heterogeneity of outcome within stage. New approaches are urgently needed.
Interleukin‐4 inhibits proliferation of human leukemic megakaryoblast cell line mhh 225
Authors: Hassan H. T. , Grell S. , Borrmann‐Danso U. , Freund M.
Published: February 2007

The effects of six recombinant human cytokines: erythropoietin, GM‐CSF, G‐CSF, interleukin‐3, ‐4 and ‐6 on the proliferation and differentiation of a human multilineage myeloid leukemia cell line MHH 225, established from the bone marrow of an AML(M7) patient in our laboratory determined by changes in antigen expressions using monoclonal antibodies in APAAP technique were examined in liquid suspension culture. The MHH 225 cells have been growing exponentially without cytokines or conditioned media. About 90 per cent of MHH 225 cells are CD33+CD34+CD3–CD7–CD19–CD20–TdT– with 57.6 per cent, 28.3 per cent and 7.8 per cent of them being CD41+, glycophorin A+ and CD15+, respectively. After five days of treatment with erythropoietin, GM‐CSF, G‐CSF or IL‐6 no change was observed in MHH 225 cell antigens expression. IL‐3 (100 U/ml) induced a moderate increase in only CD13 and alpha naphthyl esterase positive cells from 6.5 ± 1.9 per cent and 5.7 ± 2.4 per cent in control cultures to 21.6 ± 3.0 per cent and 19.1 ± 2.8 per cent, respectively. On the other hand, 100 U/ml IL‐4 significantly increased the number of CD13, CD15 and alpha naphthyl esterase positive cells to 48.9 ± 5.0 per cent, 47.2 ± 3.6 per cent and 46.1 ± 3.0 per cent, p < 0.001, respectively. Also, 100 U/ml IL‐4 decreased the number of CD41 positive cells from 57.6 ± 2.8 per cent to only 25.9 ± 3.6 per cent and did not change the number of CD33 or glycophorin A positive cells. The present results showed that out of the six myelopoietic growth factors tested, IL‐4 was the only one to inhibit selectively the proliferation of CD33+CD41+ leukemic megakaryoblast cells suggesting that IL‐4 may have a lineage regulatory effect in favour of a myeloblastic CD33+CD13+CD15+ at the expense of a megakaryoblastic CD33+CD41+ amplification in human leukemia cells and with apparently no effect on leukemic erythroblast cells. The MHH 225 cell line provides a useful tool and freely available model to scientists for studying signal transduction via IL‐4 and for studies of‘lineage switch’.
Autologous bone marrow transplantation in adults with non‐Hodgkin's lymphoma: A southwest oncology group study
Authors: Saez Ruben , Dahlberg Steve , Appelbaum Frederick R. , Hartsock Robert J. , Lemaistre Frederick , Coltman Charles A. , Fisher Richard I.
Published: February 2007

Patients with non‐Hodgkin's lymphoma (NHL) who fail conventional chemotherapy have a dismal outcome. Reports from single institutions utilizing high‐dose chemoradiotherapy plus Autologous Bone Marrow Transplantation (ABMT) in this setting suggest three‐year disease‐free survival between 15–60 per cent. From 1985 to 1989 the Southwest Oncology Group performed a prospective multi‐institutional study involving ABMT in relapsed/refractory NHL.

Forty‐five patients, ages 6–60 (median 38), with relapsed NHL were treated with high‐dose cyclophosphamide (60 mg/kg/d × 2), total body irradiation (200 cGy/d × 6), and autologous unpurged bone marrow. Histologic subtypes included high grade lymphoma (10), intermediate grade lymphoma (33), and low grade lymphoma (2). Disease status pre‐ABMT was sensitive relapse (16), resistant relapse (13), and untreated relapse (16).

The actuarial three‐year event‐free survival and overall survival for all patients were 27 per cent and 38 per cent respectively. Causes of failure included regimen‐related deaths (4), lack of response (10), or tumour progression (20) which occurred at a median of 5 months (1–22) post‐ABMT and usually at previous sites of involvement. Response to salvage therapy pre‐ABMT, a reflection of a tumour's biological behaviour, was the most important predictor of good outcome post‐ABMT.

This study confirms that a significant number of patients with recurrent NHL can achieve prolonged disease‐free survival after ABMT.
Induction of eosinophilic granules, nonspecific esterase activity and CD14 expression in the human eosinophilic leukemia cell line, EoL‐1
Authors: Shintaku Noriaki , Ohshima Yusei , Jung Eun‐Young , Kanazashi Shu‐Ichi , Sumimoto Shin‐Ichi , Ohmori Katsuyuki , Heike Toshio , Katamura Kenji , Mayumi Mitsufumi
Published: February 2007

We examined the expression of eosinophilic granules, esterase activity and CD14 in a human eosinophilic cell line, EoL‐1. Unstimulated EoL‐1 cells were weakly positive for nonspecific esterase, but negative for surface CD14, and contained a few eosinophilic granule‐positive cells. A combination of G‐CSF and TNF‐α increased the eosinophilic granule‐containing cells, but failed to increase esterase activity or CD14 expression. IFN‐γ alone or in combination with TNF‐α enhanced nonspecific esterase activity but failed to induce CD14 expression or increase eosinophilic granule‐containing cells. dbcAMP increased eosinophilic granule‐containing cells, nonspecific esterase activity and CD14 expression. Specific esterase activity was not detected in any circumstances. EoL‐1 cells fractionated by density gradients or CD14 expression showed nonspecific esterase activity and CD14 expression in both the eosinophilic granule‐positive and negative cell populations. Forskolin and butyrate had a synergistic effect on CD14 induction and protein kinase A was suggested to play a role in dbcAMP‐induced CD14 expression. A protein kinase C activator, phorbol 12‐myristate 13‐acetate, did not increase eosinophilic granules, nonspecific esterase activity or CD14 experession in EoL‐1 cells. The results show that EoL‐1 cells can express nonspecific esterase and CD14, but the expression is not necessarily restricted to cells which have differentiated into the monocyte/macrophage lineage.
Differential platelet‐associated factor gene expression by a panel of human cell lines with megakaryoblastic properties after treatment with phorbol myristate acetate
Authors: Micallef Mark , Matsuo Yoshinobu , Takayama Kazue , Ariyasu Toshio , Otani Takeshi , Minowada Jun
Published: February 2007

Four human megakaryocytoid cell lines, namely MOLM‐1, MOLM‐7, MEG‐01 and HEL, were treated with phorbol 12‐myristate 13‐acetate (PMA) and expression of the platelet‐derived growth factor (PDGF) A chain, von Willebrand factor (vWF) and endothelial cell growth factor (ECGF) genes was examined by the reverse transcriptase‐polymerase chain reaction (RT‐PCR) using specific primers. The gene for PDGF A chain is constitutively weakly expressed by MEG‐01 cells and strong expression is induced in MEG‐01, MOLM‐1 and MOLM‐7 but not in HEL cells after treatment with PMA for three days. All four cell lines express the vWF gene both constitutively and after exposure to PMA. None of the cell lines constitutively express the gene for ECGF but MEG‐01 cells can be induced to do so after treatment with the phorbol diester. Immunohistochemical staining after exposure to PMA showed that the expression of the platelet‐associated markers CD41 and CD61 was enhanced in all cell lines indicating possible differentiation along the megakaryocyte lineage. Our results illustrate differential platelet‐associated factor gene expression in different megakaryoblastic cell populations in response to treatment with PMA, and suggest that expressions of the PDGF A chain gene and the ECGF gene may be good markers for megakaryocyte maturation.