Search

Background: Bleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding., Objective: To investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding., Methods: We included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of > 100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin-activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available., Results: Fibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0 μg L(-1) vs. 24.5 μg L(-1) )., Conclusion: Systemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding., (© 2014 International Society on Thrombosis and Haemostasis.)

Study Question: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors?, Summary Answer: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood., What Is Known Already: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before., Study Design, Size, Duration: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors., Participants/materials, Setting, Methods: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36)., Main Results and the Role of Chance: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen., Limitations, Reasons for Caution: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed., Study Funding/competing Interests: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

To complement the existing treatment guidelines for all tumour types, ESMO organizes consensus conferences to focus on specific issues in each type of tumour. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, next to the 11th International Conference on Malignant Lymphoma. The conference convened ∼30 experts from all around Europe, and selected six lymphoma entities to be addressed; for each of them, three to five open questions were to be addressed by the experts. For each question, a recommendation should be given by the panel, referring to the strength of the recommendation based on the level of evidence. This consensus report focuses on the three less common lymphoproliferative malignancies: marginal zone lymphoma, mantle cell lymphoma, and peripheral T-cell lymphomas. A first report had focused on diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukaemia.

Background/objectives: The traditional view that patients with hemophilia are protected against cardiovascular disease is under debate. The aim of the present study was to evaluate the presence and extent of atherosclerosis by coronary artery calcification score (CACS) and carotid intima media thickness (IMT) in patients with hemophilia, and to evaluate their cardiovascular risk profile., Methods: Sixty-nine patients (51 with hemophilia A; 18 with hemophilia B) were studied [median age: 52 years (interquartile range [IQR] 43–64)]. Cardiovascular risk factors and prior major adverse cardiovascular events (MACEs) were recorded. CACS was derived from electron-beam or dual-source computed tomography, and carotid IMT was assessed by ultrasound measurements and compared with age-specific reference values., Results: The median CACS in all patients was 35 (IQR 0–110) and the geometric mean IMT was 0.80 mm (95% confidence interval [CI] 0.76–0.84); neither was different from the reference values. Patients with a previous MACE (n = 9) had significantly higher CACS and IMT than patients without a previous MACE:CACS median 1013 (IQR 530–1306) vs. 0 (IQR 0–67), and IMT geometric mean 1.09 mm (95% CI 0.95–1.26) vs. 0.76 mm (95% CI 0.73–0.79), both P < 0.001. A higher calculated 10-year cardiovascular risk was related to higher IMT and CACS., Conclusion: Patients with hemophilia are not protected against the development of atherosclerosis as measured by CACS and IMT. The extent of atherosclerosis is related to the traditional cardiovascular risk factors. This suggests that traditional cardiovascular risk factors should be monitored and treated in patients with hemophilia.

Background: Lack of survival improvement in adolescents and young adults (AYA) with cancer has led to increased awareness of this young population., Design: We carried out a population-based study of incidence and survival of primary tumours and second primary tumours in patients aged 12-24 in north Netherlands. Age-specific incidence rates per 100,000 and 3-year moving means were calculated. Factors associated with incidence and survival were assessed using a Poisson model, log-rank test and multivariate Cox proportional hazards analysis., Results: From 1989 to 2003 a total of 1118 patients were diagnosed. The total age-specific incidence rates per 100,000 were as follows: males: 13.4 (12-15 years), 26.9 (16-19 years) and 27.5 (20-24 years) and females: 13.9, 20.7 and 20.7. Male : female ratio was 1.32. The overall estimated annual percentage change (EAPC) in incidence was 2.15% (P < 0.01). Five-year survival was 80.8% and did not improve during the study period. With median follow-up of 5.5 years (range 0.0-16.0) in our cohort the standardized incidence ratio (SIR) of second primary tumours was 30.55 (95% confidence interval = 19.96-44.76, P < 0.05)., Conclusions: The total incidence of cancer in AYA increased (EAPC = 2.15%). Survival was unchanged. The SIR of a second primary tumour in this young cohort increased 31-fold. Further research is needed to study this increasing incidence and optimise treatment outcome in these young patients.

Background: It has been suggested that normal concentrations of biogenic amines and 'histamine-releasing foods' may exacerbate symptoms in mastocytosis. The purpose of this study was to look for scientific evidence in the literature on diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastocytosis., Methods: Medline (1966 to 2004), Cinahl (1982 to 2004) and the Cochraine Library were searched for double-blind placebo-controlled food challenge (DBPCFC) studies with biogenic amines and/or histamine-releasing foods in mastocytosis., Results: No studies employing DBPCFC with dietary biogenic amines or histamine-releasing foods in mastocytosis were found. Only a few in vitro studies in other diseases, animal studies and studies in humans in which histamine-releasing agents were incubated directly with duodenal tissues were found. One case was reported of severe adverse reactions to alcohol in mastocytosis, objectified by an open challenge., Conclusion: Despite the widespread belief that biogenic amines and histamine-releasing foods may cause allergy-like, non-IgE-mediated symptoms in certain patients, the role of diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastosytosis remains hypothetical but worthy of further investigation. There is some evidence for adverse reactions to alcohol in mastocytosis.

Hairy cell leukemia (HCL) is a chronic mature B-cell leukemia characterized by malignant B cells that have typical hairy protrusions. To characterize possible HCL-associated tumor antigens, we generated an HCL-specific and HLA class II (DPw4)-restricted proliferative CD4+ T-cell clone. To identify the target antigen of these T cells, we constructed a synthetic peptide library dedicated to bind HLA DPw4, and identified a mimicry epitope recognized by the T-cell clone. With this epitope, the recognition motif of the T-cell clone was deduced and a peptide of human synaptojanin 2 (Syn 2) was identified that stimulated the HCL-reactive T-cell clone. Both Northern and Western blot analyses showed that Syn 2 expression was increased in HCL samples compared to other B cells. Besides, the Syn 2-expressing cell line AML193, with the introduced restrictive HLA-DPw4 molecules, was recognized by the HCL-specific T-cell clone. These results indicate that Syn 2 is a target of autoreactive HCL-specific T cells. Since Syn 2 is a phosphatidylinositol 4,5-biphosphatase involved in cell growth and rearrangement of actin filaments, the increased Syn 2 expression may correlate with the disease etiology or the characteristic morphologic alterations caused by the disease.

Background: The definition of primary extranodal non-Hodgkin's lymphoma (NHL) is a controversial issue, especially in patients where both nodal and extranodal sites are involved., Patients and Methods: The impact of different definitions of primary extranodal NHL on incidence and prognosis is explored using data from a population-based NHL registry., Results: Using liberal criteria, 389 (34%) cases were classified as primary extranodal NHL. Overall survival (OS) rates of nodal and extranodal NHL patients defined this way were comparable; however, extranodal NHL patients had a better disease-free survival (DFS). When strict criteria were applied, 231 cases (20%) were classified as primary extranodal NHL. OS and DFS rates of extranodal NHL patients defined this way were superior to nodal NHL patients; however, the difference in OS was reversed after correction for differences in International Prognostic Index and malignancy grade., Conclusion: This study illustrates the selection bias that is introduced when a strict definition of primary extranodal NHL, that excludes cases with disseminated disease, is used. Patients with primary extranodal NHL were found to have a superior DFS, irrespective of which definition of primary extranodal NHL was used.

Background: The EORTC clinical trial 20901, activated in 1990, was designed to treat non-Hodgkin's lymphomas (NHL) of intermediate/high-grade malignancy according to the Working Formulation. Established in 1994, the R.E.A.L. Classification on NHL has now replaced all former classifications., Patients and Methods: We reanalysed all cases (n = 273) documented by material available for review according to the R.E.A.L. Classification. In addition, we subdivided cases recognised as diffuse large B-cell lymphoma (DLBCL) into three morphologically distinct categories, namely, large cleaved DLBCL (LC-DLBCL), T-cell-rich/histiocyte-rich B-cell lymphoma (T-cell-rich/histiocyte-rich BCL) and CD30+ DLBCL with anaplastic cell features (CD30+ DLBCL). Finally, T/NULL anaplastic large-cell lymphoma (ALCL) cases were subdivided into ALK+ and ALK- lymphomas. Review was performed independently by two pathologists from two different centres., Results: DLBCL (61%), T/NULL ALCL (15%) and mantle-cell lymphoma (MCL, 50%) were the main NHL categories represented in the study. Fifty-seven of one hundred sixty DLBCL cases were further subclassified as LC-DLBCL (33 cases), T-cell-rich/histiocyte-rich BCL (13 cases) or CD30+ DLBCL (11 cases). The remaining cases were indicated as unspecified DLBCL. A clinico-pathological correlation confirmed the findings of previous studies suggesting that MCL, DLBCL and ALCL represent distinct entities with MCL being characterised by a short survival, in contrast with the longer survival and less frequent progression typical of ALK+ compared to ALK- ALCL. Within DLBCL, T-cell-rich/histiocyte-rich BCL showed distinctive features at presentation whereas CD30+ DLBCL showed a trend towards a more favourable prognosis, that might be comparable to that of ALK+ ALCL., Conclusions: Our data further support the usefulness of the R.E.A.L. Classification and illustrate the feasibility of DLBCL subtyping. Moreover, our results demonstrate the distinct clinical characteristics of T-cell-rich/histiocyte-rich BCL and CD30+ DLBCL with anaplastic cell features suggesting that they may represent clinico-pathologic entities.

Background: To compare characteristics, treatment and outcome of patients > or = 70 years with patients < 70 years in a population-based non-Hodgkin's lymphoma (NHL) registry., Patients and Methods: All new patients with NHL (n = 1168) in a geographically defined region in the western part of The Netherlands were registered during a nearly 10-year period. Patient, tumour and treatment characteristics, response to therapy and survival were analysed for both age groups. An age-adjusted prognostic index was determined for elderly patients with aggressive lymphoma., Results: The elderly comprised 41% of the registered patients. There were significantly more females, a preponderance of intermediate-grade histology (diffuse large B-cell lymphoma) and a lower performance status. Incomplete staging in the elderly was mostly due to the omission of a bone marrow biopsy. With respect to WF grading the complete remission rate (except for patients with low-grade/stage I NHL, patients with extranodal NHL and for patients with intermediate grade/extensive NHL) and overall survival at five years (except for patients with low-grade/stage I NHL and for patients with intermediate-grade/extensive NHL) were significantly inferior in the elderly. With respect to the R.E.A.L. Classification the exceptions were in patients with high grade MALT lymphomas (elderly good) and patients with mantle-cell and peripheral T-cell lymphomas (younger group bad too). However, once complete remission was reached, the disease-free survival did not differ significantly between the two age groups, emphasising the importance of achieving complete remission. Although 65% of the classified elderly patients presented with intermediate-grade NHL, only 26% of the elderly patients treated with chemotherapy received anthracycline-based chemotherapy. In the elderly, lymphoma (treatment-related toxicity included) contributed to death in 70% and concomitant disease (other malignancy included) in 30%, versus 78% and 22%, respectively, for the younger group (P = 0.04). The age-adjusted prognostic index, made up of the factors serum LDH, stage and Karnofsky index, showed a clear distinction between the four risk categories low, low/intermediate, intermediate/high and high, with a median survival time of 43, 20, seven and four months, respectively. For the younger group the respective numbers were 144, 45, 19 and 11 months., Conclusions: In a population-based NHL registry the elderly, predominately female patients, formed a larger proportion of the patient group than the one usually reported in the literature. In this population-based cohort inferior remission and overall survival rates were seen in the elderly. However, obtaining complete remission was beneficial for the prognosis of this disease in the elderly. By the application of the R.E.A.L. Classification important subgroups emerge.

Background: Interferon alfa is a conservative and widely used alternative to bone marrow transplantation in treatment of patients with early chronic myeloid leukemia (CML). A meta-analysis was conducted to develop a reliable prognostic scoring system for estimation of survival of patients with CML treated with interferon alfa., Methods: Patients treated in prospective studies, including major randomized trials, were separated into learning and validation samples. Cox regression analysis and the minimum P-value approach were used to identify prognostic factors for patient survival and to discover groups in the learning sample with the greatest differences in survival. These findings were then validated by applying the new scoring system to patients in the validation sample., Results: We collected data on 1573 patients who were participants in 14 studies involving 12 institutions; 1303 patients (learning sample, n = 981; validation sample, n = 322) were eligible for inclusion in this analysis, and their median survival time was 69 months (range, 1-117 months). Because two previously described prognostic scoring systems failed to discriminate risk groups satisfactorily, we developed a new scoring system that utilizes the following covariates: age, spleen size, blast count, platelet count, eosinophil count, and basophil count. Among 908 patients with complete data in the learning sample, three distinct risk groups were identified (median survival times of 98 months [n = 369; 40.6%], 65 months [n = 406; 44.7%], or 42 months [n = 133;14.6%]; two-sided logrank test, P< or =.0001). The ability of the new scoring system to discriminate these risk groups was confirmed by analysis of 285 patients with complete data in the validation sample (two-sided logrank test, P = .0002)., Conclusions: A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.

Although the results of treatment of Hodgkin's disease (HD) have improved considerably in the last decades, the disease remains fatal in a minority of patients. We have recently shown that numbers of activated cytotoxic T cells (CTLs), present in tumor biopsy specimens, differ considerably among individual HD patients. Because CTLs are the major effector cells in elimination of neoplastic cells, we investigated whether the number of activated CTLs is related to the clinical outcome of the individual patient with HD. Activated CTLs present in tumor biopsy specimens of patients with nodular sclerosis or mixed cellularity HD were identified by immunohistochemistry using an antibody directed against granzyme B (GrB), a major constituent of the cytotoxic granules of activated CTLs and natural killer cells, and an antibody directed against CD8. The presence of a high percentage of GrB+ lymphocytes was found to be an unfavorable prognostic marker. The large majority of GrB+ cells were also CD8+, indicating that these cells are activated CTLs. Prognosis was found to decrease with increasing percentages of GrB+ lymphocytes. Optimal discrimination between patients with good and poor prognosis was obtained when the threshold was set at 15% GrB+ cells; 6 of 10 patients with > or = 15% GrB+ lymphocytes died as a result of the disease, as compared with 6 of 70 patients with less than 15% GrB+ lymphocytes (P < .0001). In stage-2 patients, the percentage of GrB+ lymphocytes retained its predictive value in a multivariate analysis including histology, sex, age, erythrocyte sedimentation rate, and the presence of B symptoms as covariables. In addition, patients with > or = 15% GrB+ lymphocytes had a shortened progression-free survival time (P = .002). We conclude that a high percentage of activated CTLs present in biopsy material of HD patients is a strong indicator for an unfavorable clinical outcome.

CHOP has been and still is regarded by many as the 'standard' treatment of advanced non-Hodgkin's lymphoma. In 1980 the EORTC Lymphoma Cooperative Group started a study to evaluate the addition of vincristine and bleomycin to its standard four-drug combination chemotherapy, CHVmP (cyclophosphamide, hydroxorubicin, Vm-26, prednisone). Eligible patients were stage III or IV, intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation E-I). One-hundred-eighty-nine patients were entered, of whom 140 were eligible and evaluable. A previous report showed an improved response rate and failure-free survival (FFS) and overall survival for the combination CHVmP-VB. At ten years, the outcome still favors the addition of vincristine and bleomycin. The FFS was 34% vs. 23% and the overall survival 34% vs 22%. This difference was mainly due to a difference in CR rate (74% vs. 49%), Relapse-free survival for patients reaching a CR was the same in both arms. When the patients were grouped according to the International Prognostic Factor Index, no statistically significant difference could be observed in favor of one treatment within either group. This trial clearly demonstrates the benefit gained by the addition of vincristine and bleomycin to 'standard' chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma.

Background: Previous results suggested increased mRNA expression of CCND1 in hairy cell leukemia (HCL). The CCND1 gene is involved in the t(11;14)(q13;q32) chromosomal rearrangement, a characteristic abnormality in mantle cell lymphoma (MCL). We and others reported that, in contrast to other B-cell lymphomas, almost all MCL have over-expression of the CCND1 gene with a good correlation between RNA and protein analysis. Recent studies showed that overexpression of the cyclin D1 protein can be easily detected by immunohistochemistry (IHC) on formalin-fixed, paraffin embedded tissues., Patients and Methods: To investigate whether the CCND1 gene is involved in HCL, we performed IHC on a series of 22 cases using formalin-fixed paraffin embedded splenectomy specimens. For IHC the sections were boiled in citrate buffer. The presence of rearrangements within the BCL-1 locus and the CCND1 gene was analyzed in 13 of 22 cases by Southern blot analysis using all available break-point probes. Expression of CCND1 was analyzed at the mRNA level (Northern blot) and protein level (IHC)., Results: Overexpression of the cyclin D1 protein using IHC was observed in all cases, with strong expression in 5 cases. Pre-existing B- and T-cell areas of the spleen did not express significant levels of the cyclin D1 protein. Seven of 9 cases analyzed by both IHC and Northern blotting showed overexpression of the CCND1 gene with both methods. No genomic abnormalities were observed in any of the 13 cases studied by Southern blot analysis. Additionally, no 11q13 abnormalities were detected by banding analysis of 19 of 22 cases., Conclusions: The elevated levels of CCND1 mRNA and protein in conjunction with the absence of overt rearrangements within the BCL-1 locus distinguish HCL from MCL and other B-cell malignancies. This suggests that activation of the CCND1 gene in HCL is due to mechanisms other than chromosomal rearrangement.

Reed-Sternberg (RS) and Hodgkin's (H) cells are considered to be the neoplastic cells in Hodgkin's disease. Although most data suggest a lymphoid origin, the nature of these cells still remains the subject of considerable controversy. Recently, monoclonal antibodies became available, directed against granzyme B, a serine protease specifically expressed by activated cytotoxic T cells (CTLs) and natural killer (NK) cells. Using two granzyme B-specific antibodies directed against different epitopes, we studied the expression of granzyme B in a well characterized group of Epstein-Barr virus (EBV)-positive and EBV-negative cases of Hodgkin's disease. Granzyme B expression was found in part of the H-RS cells in 11 out of 61 tested cases (18%, 9 of 46 cases of nodular sclerosing and 1 of 12 mixed cellularity Hodgkin's disease). In none of these cases did H-RS cells express B-cell markers, whereas in four cases, expression of either the T-cell marker CD3 or CD8 was found in a small minority of H-RS cells. The percentage of granzyme B-positive H-RS cells ranged from < 10% to > 50%. Granzyme B-positive H-RS cells were present in 6 of 26 EBV-positive cases and in 5 of 35 EBV-negative cases, indicating no relationship with the presence of EBV. Moreover, no significant differences were found regarding either stage at presentation or clinical outcome. We conclude that in a restricted number of cases of Hodgkin's disease, the H-RS cells express granzyme B, and therefore might be considered the neoplastic equivalent of either activated CTLs or NK cells.

A 19 year old man with a history of Crohn's disease treated with azathioprine and prednisone, died after a primary infection with Epstein-Barr virus. He had the characteristics of the virus associated haemophagocytic syndrome, a rare complication of viral infections, which consists of fever, constitutional symptoms, hepatosplenomegaly, liver function and coagulation abnormalities, and hypertriglyceridaemia. Additionally, there was pain, cytopenia, and histiocytic hyperplasia in the bone marrow, spleen, or lymph nodes. This severe complication has been reported previously in renal transplant patients, but not in those with inflammatory bowel disease taking azathioprine. The immunosuppressive therapy may have contributed to this fatal complication of infectious mononucleosis, and this complication should be considered when treating a patient with inflammatory bowel disease with azathioprine.

We report the cases of two patients who had infections due to Yersinia enterocolitica. The first patient exhibited chronic recurrent fever, hepatic and splenic granulomas, and bone marrow abnormalities, and the second patient presented with enterocolitis with leukocytoclastic vasculitis of the skin. Cultures and agglutination titers were negative. Indirect immunofluorescence techniques with use of serotype-specific antisera and antisera to Yersinia outer-membrane proteins (Yops) were applied to biopsy specimens, and immunoblotting techniques for determining class-specific circulating antibodies to Yops were used for demonstrating these unusual manifestations of Y. enterocolitica infections.

Since monocytes and macrophages that arise during the culture of bone marrow progenitor cells are potential sources of interleukin 6 (IL-6), we investigated whether auto- or paracrine production of this factor is involved in colony formation by normal hematopoietic progenitor cells. We added a polyclonal anti-IL-6 antiserum and a monoclonal anti-IL-6 antibody to cultures of monocyte- and T cell-depleted bone marrow cells. Colony formation was stimulated with granulocyte/monocyte-colony-stimulating factor (GM-CSF), monocyte-CSF, or IL-3. Addition of anti-IL-6 antibody resulted in decreased numbers of monocytic colonies to 40-50% of control values, whereas the numbers of granulocytic colonies were not altered. The inhibitory effect was preserved in cultures of CD34(+)-enriched bone marrow cells. As a second approach, we added a monoclonal antibody directed against the IL-6 receptor to cultures of monocyte- and T cell-depleted bone marrow cells. This antibody almost completely inhibited the growth of monocytic colonies, again without decreasing the number of granulocytic colonies. Finally, the importance of IL-6 in monocytopoiesis was demonstrated in serum-deprived bone marrow cultures: addition of exogenous IL-6 to cultures stimulated with GM-CSF resulted in increased numbers of monocytic colonies. Our results indicate that the permissive presence of IL-6 is required for optimal monocytic colony formation by bone marrow progenitor cells.

A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma who had relapsed following a complete remission (CR) induced by a doxorubicin-containing chemotherapy regimen participated in the PARMA pilot study. The patients ranged in age from 16 to 60 years (median age, 42). All patients received DHAP (dexamethasone/high-dose cytarabine/cisplatin) for two courses at 3- to 4-week intervals. Patients achieving a partial response (PR) or CR were scheduled to receive involved-field radiotherapy and high-dose BEAC (carmustine/etoposide/cytarabine/cyclophosphamide) followed by autologous bone marrow transplantation (ABMT). Of 48 evaluable DHAP-treated patients (one patient was lost to follow-up and one had no measurable disease), seven achieved CR, 21 PR, and 20 patients had no response or progressive disease. One responder died from treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and received ABMT. In all, 22 patients underwent ABMT (20 with BEAC and two with cyclophosphamide plus total body irradiation); two patients (9%) died from toxicity and ten (45%) relapsed. One patient in continuous CR committed suicide 28 months post-ABMT, and nine are alive and disease-free 24 to 32 months (median, 30) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documented the ability of DHAP followed by ABMT to produce durable CR in a significant proportion of patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). Forty-four percent of all study patients with relapsed lymphoma actually underwent ABMT, and 20% of the total group are projected to be long-term disease-free survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Two sisters and a brother from one family are described whose sera were deficient in haemolytic complement function. This defect was restored by addition of purified C1q. In their sera, C1q like material was found, whereas C1r and C1s were normal or increased in concentration, as were the other complement components tested. All three had suffered from glomerulonephritis during childhood. A renal biopsy in the brother recently disclosed a membranous glomerulopathy stage 1; otherwise, he is apparently healthy. In both sisters, a systemic lupus erythematosus like disease became manifest at the age of 20 and 23, respectively, resulting in the death of one of them. In the serum of these three family members, the C1q like material was antigenically deficient compared with normal C1q and had, on sucrose gradient analysis, a molecular weight of approximately 65,000 daltons. It did not bind to C1r and C1s. Binding of the dysfunctional C1q to aggregated human gammaglobulin could be demonstrated. On double immunodiffusion analysis, the abnormal C1q was identical with reduced and alkylated C1q. The possible structure of the abnormal C1q molecule is discussed.

Although follicle center cell (FCC) lymphomas represent mature B cells, a considerable percentage do not have detectable Ig production. We have used Southern blotting and the polymerase chain reaction (PCR) to study the involvement of translocations t(14;18) and t(8;14) in causing defective Ig production in 16 Ig- FCC-derived lymphomas and three Ig- B cell acute lymphoblastic leukemias. In 6 of 19 cases, a t(14;18) was present with the other allele either deleted or in germline. In two cases a t(14;18) and a t(8;14) affected both Ig alleles, as confirmed by karyotyping. In two other cases, rearrangement of both bcl-2 on chromosome 18 and c-myc on chromosome 8 were found as well. Although cytogenetic proof was not available, the latter was probably involved in t(8;14). Restriction map analysis of one more case showed rearrangement on the pseudo-JH3 gene on one allele and t(14;18) on the other. Thus, in 11 of 19 cases, defective Ig H chain production could be explained by the inactivation of both Ig H chain genes due to translocation of one allele, in combination with deletions or defective rearrangements of the other allele. In contrast, in 28 of 30 Ig+ lymphomas, one functional Ig H chain allele was found, either in, or not in, combination with t(14;18). In two cases a single rearranged Ig H chain allele was found in combination with rearrangement of bcl-2. No comigration of the single Ig rearrangement with bcl-2, however, was found both by Southern blotting and PCR, suggesting a variant bcl-2 translocation, which leaves the Ig H chain allele functionally intact.