Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis.

BACKGROUND: Presently, no validated data exist on symptom severity and disease-specific quality-of-life (QoL) for patients with mastocytosis. Simultaneously, clinical trials and drug application processes increasingly mandate reporting patients' perspectives on symptoms and QoL. We report on the development and validation of the mastocytosis quality-of-life questionnaire (MQLQ) and the mastocytosis symptom assessment form (MSAF). METHODS: Both outcome measures were developed in a standardized stepwise method, starting with the identification of items in focus groups (n = 12), item reduction and subsequent cross-sectional validation in a 63% female cohort of 164 adult patients with indolent systemic mastocytosis. RESULTS: The MSAF reveals that fatigue is the severest mastocytosis symptom while the MQLQ indicates that fear of anaphylaxis mostly impacts QoL. Cross-sectional validity was assessed by correlating both individual domains and the total scores of the MQLQ and MSAF with independent measures of mastocytosis. The total scores of both the MQLQ (P < 0.001; Spearman's r: 0.568) and the MSAF (P < 0.001; Spearman's r: 0.559) correlated significantly with the consensus on physician-scored mediator symptoms. The MQLQ domains displayed a high internal consistency (Cronbach's alpha: 0.841-0.958) and the domains 'bones', 'skin symptoms' and 'anaphylaxis' differed significantly between patients with and without osteoporosis, urticaria pigmentosa or anaphylaxis, respectively (P < 0.001). CONCLUSIONS: The MQLQ is the first disease-specific QoL questionnaire for mastocytosis and is complemented by the MSAF, a short and convenient symptom scoring form. Both patient-reported outcome measures are valid, reliable and discriminate between patients with different disease characteristics, making them useful instruments for clinical research.

Cryopreservation, semen use and the likelihood of fatherhood in male Hodgkin lymphoma survivors: an EORTC-GELA Lymphoma Group cohort study.

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.

ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.

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.

Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions.

BACKGROUND: Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM. METHODS: Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM, was carried out. RESULTS: In total, 142 patients were included. SM was absent in all 44 patients with tryptase <10 µg/l, in 45 of 98 (46%) patients with tryptase ≥10 µg/l and in 18 of 52 patients (35%) with tryptase >20 µg/l. Above 43 µg/l, all patients had ISM (n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA, and MH were independent ISM predictors. If tryptase was ≥10 µg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92). CONCLUSIONS: In suspected patients without UP, the ISM risk is very low (if present at all) if tryptase is <10 µg/l. If tryptase is ≥10 µg/l, this risk depends on MIMA and MH, being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is <10 µg/l. Our results question the reliability of the minor diagnostic World Health Organization criterion of tryptase >20 µg/l.

Reproductive choices and obstetrical experience in Dutch carriers of haemophilia A and B.

Reproductive choices, pregnancy and childbirth are influenced by culture and traditions. This probably also plays a role in carriers of haemophilia. The aim of the study is to evaluate the reproductive choices and obstetrical experiences in the current generation of carriers of haemophilia in our Haemophilia Centre in the north of the Netherlands, a largely secular country with liberal abortion laws and a unique tradition of home births. Retrospective survey among haemophilia carriers. We sent a questionnaire to 74 carriers, 65 were available, 75% responded. Median age was 41 (range 20-83) years. Of the 49 women, 46 had 120 pregnancies: 25 resulted in foetal loss, two in pregnancy termination (one for haemophilia) and 93 in live births. No woman had chosen not to start a family. Mean number of children was 2.0, 2.4 vs. 1.8 in women with and without sons with haemophilia (P = 0.008), respectively. Twenty women (20 of 46) were unaware of their carriership during 1st pregnancy; they were younger at 1st pregnancy than known carriers (25 vs. 29 years, P = 0.03). Twenty-three percentage reported bleeding complications during the first delivery. Overall, 10% vs. 3% of deliveries was complicated by a primary and secondary postpartum haemorrhage (PPH), respectively. In our Haemophilia Centre, carrier state has not influenced reproductive choices in the past, other than older age at first pregnancy. Carriers of haemophilia have an increased risk of primary PPH.

Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells.

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.

Translocation t(14;18) in B cell lymphomas as a cause for defective immunoglobulin production.

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.

Cancer in adolescents and young adults in north Netherlands (1989-2003): increased incidence, stable survival and high incidence of second primary tumours.

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.

[Lymphoma in patients who have undergone organ transplantation: severe and variable clinical presentation]. / Lymfoom bij patiënten na een orgaantransplantatie: ernstig en variabel ziektebeeld.

Two patients presented with post-transplant lymphoproliferative disorder (PTLD). PTLD encompasses a broad range ofoften malignant proliferations of lymphoid tissue arising in the immunocompromised host after transplantation. The first patient, a 62-year-old woman, received a bilateral lung transplant due to end-stage emphysema and was diagnosed with PTLD 27 days after transplantation. Treatment consisted of reduction in immunosuppression and administration of rituximab. The PTLD regressed. The second patient, a 57-year-old woman, presented with a massively disseminated PTLD 12 years after kidney transplantation. Immunosuppression was reduced and rituximab was administered, but no response was observed. Despite salvage chemotherapy, the patient died due to progressive disease. These two cases illustrate the heterogeneous presentation of PTLD. The condition is caused by the proliferation of B lymphocytes infected with Epstein-Barr virus (EBV) that are no longer controlled by EBV-specific cytotoxic T lymphocytes, due to the immunosuppressive medication given to prevent transplant rejection. Regression of the lymphoma may be achieved by reducing the immunosuppression or treating with rituximab, which attacks B lymphocytes.

A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

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.

Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group.

PURPOSE: Before recognizing mantle-cell lymphoma (MCL) as a distinct entity, these patients were grouped into low-grade (LG) or intermediate-/high-grade categories (IGHG) according to the Working Formulation and received various therapies. This was a unique opportunity to evaluate characteristics, behavior, response to treatment, and outcome of patients with MCL from two phase III trials conducted by the European Organization for the Research and Treatment of Cancer (EORTC): EORTC 20855 IGHG and EORTC 20856 LG. PATIENTS AND METHODS: After histologic review, 64 diagnosed MCL patients (29 IGHG and 35 LG) were compared with other patients in their respective trials. In the IGHG group, patients received cyclophosphamide, doxorubicin, teniposide (VM26), prednisone, vincristine, and bleomycin (CHVmP-VB) or modified doxorubicin, cyclophosphamide, etoposide (VP 16), mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE-MOPP). In the LG group, after receiving cyclophosphamide, vincristine, and prednisone (CVP) induction, patients were randomized between maintenance treatment with interferon alfa-2a (IFN) or no further treatment. RESULTS: MCL patients compared with IGHG subtypes showed a similar overall survival and response rate, but shorter duration of response and progression-free survival. Comparing with LG patients, their response rate, duration of response, and progression-free survival showed no difference, while their overall survival was nearly twice shorter. MCL patients treated with CHVmP-VB had the longest survival. No treatment showed any significant improvement in terms of progression-free survival. CONCLUSION: These data confirm that MCL represents a clinicopathologic entity. In terms of survival, it behaves like IGHG subtypes, while in terms of progression-free survival, it behaves like LG lymphoma. It is still not clear which first-line treatment offers patients with MCL the best chance to obtain both a complete response (CR) and a long-term survival.

Treatment of T-cell prolymphocytic leukemia with human CD52 antibody.

PURPOSE: T-prolymphocytic leukemia (T-PLL) is an aggressive malignancy of mature T cells refractory to conventional chemotherapy, with a median survival duration of 7.5 months. We report here promising results with the use of a genetically reshaped human CD52 antibody, CAMPATH-1H. PATIENTS AND METHODS: Fifteen patients with T-PLL, most of whom had received the purine analog deoxycoformycin (DCF), were treated with CAMPATH-1H. Results were compared with those of 25 patients treated with DCF. RESULTS: Major responses occurred in 11 patients (73%) treated with CAMPATH-1H compared with 40% with DCF. Complete remissions (CRs) were documented in nine (60%) of the CAMPATH-1H cases and only three (12%) were obtained with DCF. CRs with CAMPATH-1H were durable, and re-treatment with the antibody resulted in second CRs in three relapsed patients. Two of them were successfully autografted with peripheral-blood and bone marrow stem cells collected during the first CR. Apart from first-dose reactions, infusions of CAMPATH-1H were well tolerated. However, two responding patients developed severe bone marrow aplasia that was fatal in one; the second remained moderately pancytopenic 21 weeks after stopping CAMPATH-1H therapy. The cause of this adverse effect is unknown. CONCLUSION: CAMPATH-1H is an effective agent in T-PLL and represents a significant improvement over other types of therapy. However, CAMPATH-1H alone is not sufficient for long-term remissions, and the role of autologous stem-cell transplantation needs further investigation.

CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group.

PURPOSE: We report the results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group, which compared a chemotherapy regimen specifically devised for elderly patients, ie, etoposide, mitoxantrone, and prednimustine (VMP), versus the standard regimen of cyclophosphamide, doxorobucin, vincristine, and prednisone (CHOP) in patients older than 70 years of age with intermediate- and high-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients older than 70 years of age with stage II, III, or IV intermediate- and high-grade NHL, with an Eastern Cooperative Oncology Group (ECOG) performance status less than 4 and acceptable cardiac, renal, and liver function were randomized to receive six courses of VMP or six courses of CHOP. Between February 1989 and June 1994, 130 patients aged 70 to 93 years (median, 75) were enrolled and 120 were assessable for response, 60 patients in each arm. RESULTS: Overall objective response rates were 50% and 77% in VMP- and CHOP-treated patients, respectively (P = .01), while complete response (CR) rates were borderline significant (27% v 45%; P = .06). At 2 years, the progression-free survival (PFS) rate was 25% with VMP versus 55% with CHOP (P = .002) and the overall survival (OS) rate was 30% with VMP versus 65% with CHOP (P = .004). Statistically significant more alopecia and neurologic and gastrointestinal toxicities were reported with CHOP. CONCLUSION: CHOP is the standard regimen for patients > or = 70 years of age with stage II to IV intermediate- and high-grade NHL.

Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.

PURPOSE: We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS: Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS: Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION: bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

Mantle-cell lymphoma: a population-based clinical study.

PURPOSE: From a population-based non-Hodgkin's lymphoma (NHL) registry, 41 patients with mantle cell lymphoma (MCL) -- a recently defined distinct B-cell NHL -- were selected and compared with patients with low- or intermediate-grade NHL from the same registry. PATIENTS AND METHODS: The incidence and behavior of MCL in the area of the Comprehensive Cancer Center West (CCCW) from 1981 to 1989 were analyzed. Age, performance, tumor bulk, extranodal localization, stage, response to therapy, and survival were registered. Expression of cyclin D1 protein and Ki-67 were measured in 29 patients. RESULTS: MCL made up 3.7% of NHLs. The median age was 68 years, and the male-to-female ratio was 1.6:1. Seventy-eight percent presented with stage IV, with the majority having bone marrow involvement. The complete response (CR) rate was 32% (13 of 41), with a median duration of 25 months. The median overall survival time was 31.5 months. The International Prognostic Index identified five patients with a low-risk score and a median survival time of 93+ months. In 23 of 29 patients, cyclin D1 overexpression was present, without any relation to overall or disease-free survival. In contrast, a proliferative index less than 10% was significantly related to a better overall survival time (50 v 24 months). CONCLUSION: MCL is a disease of the elderly, who present with widespread disease and with a poor response to therapy. Although it harbors features of an indolent NHL, it behaves clinically as an aggressive NHL with a short overall survival time.

Mantle cell lymphoma proliferates upon IL-10 in the CD40 system.

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma, characterized by a poor response to therapy and short survival. To assess the proliferative capacity, we cultured MCL cells, using irradiated 3T6 mouse fibroblasts transfected with human CD40L ('CD40 system') in the presence of different cytokines. Proliferation was measured by 3H-thymidine incorporation and by CFSE fluorescence. Thirteen out of 16 MCL cases proliferated well in the CD40 system. In 10 cases a strong response upon further addition of IL-10 was seen, whereas IL-4 had an additional effect in only four cases. CFSE staining of cells before and after culture showed an increased number of cell divisions in the IL-10/CD40L stimulated cells. The MCL cells remained CD5+CD19+. Neither plasma cell differentiation nor isotype switching was seen. The light chain expression was strictly monoclonal. IL-1beta, IL-2, IL-6, G-CSF and GM-CSF did not stimulate MCL proliferation. IL-10 receptor expression correlated with the response to IL-10 in the culture system and the effect of added IL-10 could be blocked by antibodies directed against IL-10 and the IL-10 receptor. Autocrine IL-10 production by the MCL cells was detected in eight of 10 cases tested. IL-10 receptor blocking decreased proliferation when no exogenous IL-10 was used in four of seven cases tested. EBV assessed by EBER in situ hybridization was not detected in six cases tested. In conclusion, MCL can successfully be cultured upon CD40 stimulation if 3T6 CD40L+ cells are used. In this context IL-10 is a costimulatory factor. IL-10 receptor expression seems to correlate with response to CD40 crosslinking and IL-10. Autocrine IL-10 production might play a role in the proliferation of this lymphoma. This culture system may be useful to test new treatment strategies for this, thus far, therapy-resistant lymphoma.

Lactic acidosis in a patient with B-cell non-Hodgkin's lymphoma.

A patient with an intermediate grade B-cell non-Hodgkin's lymphoma who presented with severe dyspnea caused by lymphoma-related lactic acidosis is described. The serum lactate and pyruvate levels paralleled the disease activity. Although oncologists are familiar with the relationship between bulky solid tumors and lactic acidosis, well-documented lymphoma cases are extremely rare.

Inhibitory effect of interleukin-4 on the proliferation of acute myeloid leukemia cells with myelo-monocytic differentiation (AML-M4/M5); the role of interleukin-6.

Since interleukin-4 (IL-4) specifically inhibits monocytic colony formation in human bone marrow cultures, we investigated whether a similar inhibition could be observed in cultures of optimally stimulated acute myeloid leukemia cells with myelomonocytic differentiation (AML-M4/M5). Sensitivity to IL-4 was tested in 19 cases of AML-M4/M5, using both a 3H-thymidine incorporation assay and a clonogenic assay. Proliferation was stimulated with a combination of IL-3, granulocyte-monocyte colony-stimulating factor (GM-CSF), and conditioned medium from phytohemagglutinin-stimulated leukocytes (PHA-CM). In 13 out of 14 evaluable cases, IL-4 inhibited 3H-thymidine incorporation; stimulation was seen in one case. Using a clonogenic assay, IL-4 inhibited colony formation in all evaluable cases (n = 7). Addition of IL-6 did not alter the observed inhibition by IL-4 in 9 out of 10 cases tested. We conclude that IL-4 inhibits the proliferation of optimally stimulated AML-M4/M5 cells in most cases tested, and that this effect is not generally caused by inhibition of autocrine IL-6 production.