Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: an analysis based on data from the European Blood and Marrow Transplantation Registry.

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma.

BACKGROUND: The prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab-chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON). PATIENTS AND METHODS: Patients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight. RESULTS: Twenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19-41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment. CONCLUSIONS: Although intensified alemtuzumab-CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.

[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.

Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma.

BACKGROUND: Associations of Hodgkin's lymphoma with HLA have been reported for many years. In 20-40% of patients with this disorder, Epstein-Barr virus (EBV) is present in the neoplastic cells. Because presentation of EBV antigenic peptides can elicit vigorous immune responses, we investigated associations of the HLA region with EBV-positive and EBV-negative Hodgkin's lymphoma. METHODS: In a retrospective, population-based study, patients with Hodgkin's lymphoma were reclassified according to the WHO classification, and EBV status was assessed by in-situ hybridisation of EBV-encoded small RNAs. Germline DNA was isolated from 200 patients diagnosed between 1987 and 2000 and from their first-degree relatives. Genotyping was done with 33 microsatellite markers spanning the entire HLA region and two single-nucleotide polymorphisms in the genes for tumour necrosis factor alpha and beta. Classic association analysis and the haplotype sharing statistic were used to compare patients with controls. FINDINGS: Classic association analysis (but not the haplotype sharing statistic) showed an association of consecutive markers D6S265 and D6S510 (p=0.0002 and 0.0003), located in the HLA class I region, with EBV-positive lymphomas. The haplotype sharing statistic (but not classic association analysis) showed a significant difference in mean haplotype sharing between patients and controls surrounding marker D6S273 (p=0.00003), located in HLA class III. INTERPRETATION: Areas within the HLA class I and class III regions are associated with susceptibility to Hodgkin's lymphoma, the association with class I being specific for EBV-positive disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV-involved Hodgkin's lymphoma. RELEVANCE TO PRACTICE: Polymorphisms in the HLA region could explain ethnic variation in the incidence of Hodgkin's lymphoma. The association of EBV-positive Hodgkin's lymphoma with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

LAMA tumor in the rat as an experimental model for pre-B-cell leukemia.

A late pre-B-cell leukemia model in the rat, the LAMA tumor, is described. A mouse monoclonal antibody (HIS30) was developed against LAMA cells. HIS30 reacts with a membrane antigen in tumor tissue, whereas its reactivity with normal tissues is limited to the zona glomerulosa of the adrenal cortex and to the adrenal medulla. HIS30 was used for both the immunohistological detection of tumor cells in tissue sections and the immunolocalization of tumor cells in vivo. To enable in vitro studies with the LAMA model, an in vitro growing cell line (LAMA-K1) was established from the LAMA tumor. LAMA-K1 is immunophenotypically similar to the original tumor. Two tumor transplantation models were characterized. In the first model LAMA was implanted s.c., and local tumor growth occurred at the injection site, which was then followed by lymphatogenic and subsequently hematogenic tumor spread. In the second model i.v. transplantation caused direct hematogenic tumor dissemination. In both models early dissemination was especially prominent to the bone marrow, spleen, and liver. Later in the disease most visceral organs became involved, and partial paralysis of the animal was observed in the end stage of the disease. In combination with HIS30, the LAMA pre-B-cell tumor offers a model for both the investigation of in vivo transplanted tumor cells and for the in vivo detection of tumor cells by HIS30 in LAMA tumor-bearing rats.

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Successful treatment of veno-occlusive disease of the liver with urokinase in a patient with non-Hodgkin's lymphoma.

A 38-year-old man with a non-Hodgkin's lymphoma of intermediate grade malignancy attained partial remission after three courses of CHOP (cyclophosphamide+hydroxydaunorubicin+vincristine+prednisolone). He was assigned to undergo autologous bone marrow transplantation (ABMT). The conditioning regimen consisted of cyclophosphamide and whole body irradiation. Two weeks later he developed veno-occlusive disease (VOD) of the liver. Doppler sonography confirmed the diagnosis showing a reversal of the blood flow in the portal vein. In addition a large thrombus was present in the inferior caval vein. Protein C level was strongly reduced (28%). Because of clinical deterioration intravenous urokinase was started. The transaminases normalised rapidly and the patient showed a dramatic clinical improvement. There were no major bleeding complications. Repeat Doppler sonography showed a normal antegrade flow in the portal vein. This case suggests that a coagulopathy in the hepatic vascular bed might contribute to the development of VOD and that patients with VOD are at risk for other thrombotic complications. Furthermore it shows that urokinase with platelet support can be given safely and effectively to a patient with VOD and severe thrombocytopenia.

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells.

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

Gender and age-related differences in Burkitt lymphoma--epidemiological and clinical data from The Netherlands.

Although Burkitt's lymphoma (BL) is classified as one entity in the World Health Organisation (WHO) classification, we wondered whether BL should not be considered as a different disease in children compared with adults. Netherlands Cancer Registry (NCR) data were obtained from 1994 to 1998 (n=203). Detailed clinical data from two treatment protocols were compared: one for adults up to the age of 65 years (n=27) and one for children (n=80). All slides of the two clinical studies were centrally reviewed which included immunophenotyping and when necessary breakpoint analysis of MYC/8q24. Only cases with an unambiguous diagnosis of BL (classical and atypical BL) were accepted. The age distribution of BL-patients showed a bimodal distribution with a peak at the paediatric age and a steady increase after approximately 60 years of age. Most of the patients were males (89% for children and 78% for adults) and only male patients showed this bimodality. Children more often had extranodal disease (81% vs. 59%), whereas adults more often had nodal disease (89% vs. 53%). Based on epidemiology and clinical presentation, the concept that BL is one disease should be re-challenged.

Feasibility of tumor imaging using L-3-[iodine-123]-iodo-alpha-methyl-tyrosine in extracranial tumors.

UNLABELLED: L-3-[123I]-Iodo-alpha-methyl-tyrosine (IMT) is a modified amino acid. It is reported to be avidly taken up in brain tumors, reflecting amino acid transport and is suitable for SPECT. METHODS: To determine whether tumors outside the brain can also accumulate this tracer, we injected 300-450 MBq IMT into 20 patients with different tumors [5 breast cancers, 4 lung tumors (1 benign), 2 carcinoid liver metastases, 4 soft-tissue tumors (1 benign), 3 malignant lymphomas and 2 primary brain tumors]. Tumor size ranged from 1-12 cm. Imaging was repeated after radiotherapy in two patients with breast cancer. Histology was available in all cases. Dynamic scans, whole-body imaging and SPECT were performed during the first hour and 3 hr after injection. Plasma samples were analyzed for IMT, free 1231 and other metabolites. RESULTS: All primary tumors were visualized. Tumor-to-background ratios ranged from 1.1 to 3.8 on planar and from 1.3 to 6.2 on SPECT images. Tumor uptake peaked in the first hour. Two carcinoid lesions in the liver tumors exhibited no IMT uptake above liver background. Tumor-to-background ratios in a benign bone inflammatory process and a focal pulmonary vasculitis were less than 1.2 (planar) and 1.9 (SPECT) and could be differentiated from uptake in all malignant nonbrain tumors. IMT was rapidly cleared from the plasma [3.6% +/- 0.6% (mean +/- s.d.) injected dose/liter at 10 min postinjection]. Minor in vivo deiodination was present (<1% of injected dose 1 hr postinjection). No other metabolites were found. Normal distribution consists of some uptake in the brain, liver, spleen, muscles, pancreatic region and intestinal structures and massive uptake and excretion in the kidneys and bladder. CONCLUSION: IMT has potential as a metabolic tracer in tumors outside the brain.

Heparin small pool high yield purified factor VIII: in vivo recovery and half-life of routinely produced freeze-dried concentrate.

New approaches and techniques for improving source material collection and Factor VIII production at Blood Bank level have been reported recently. Heparin has been shown to be of importance in increasing yields and stability of FVIII in the purification and concentration process. Work has been done to develop on a routine scale the heparin double cold precipitation technique for the production of a freeze-dried high yield purified FVIII concentrate. The product has been tested clinically in 4 severe hemophilia A patients for recovery, half-life and acute side-effects, using two dosages over 8 infusions. There was no significant difference between the two dosages. Mean recovery 99.1% and mean half-life 8 hr, ranging from 6.5 to 10.3 hr. No side-effects justify further exploration of the potential of heparin for high yield purified FVIII production.

Reduced platelet activation and improved hemostasis after controlled cardiotomy suction during clinical membrane oxygenator perfusions.

Platelet damage and postoperative blood loss are less severe after cardiopulmonary bypass performed with a membrane oxygenator than with a bubble oxygenator. However, this advantage of the membrane oxygenator can be partly negated by the platelet damage caused by cardiotomy suction, which implies the aspiration of air along with suction of blood. In order to reduce platelet damage by cardiotomy suction, we developed an automatic controlled cardiotomy suction system by which the aspiration of air was prevented. We evaluated platelet damage in a group of 28 patients (uncontrolled suction, n = 13; controlled suction, n = 15), and we studied the relationship between increasing volumes of cardiotomy suction and postoperative blood loss in a second group of 80 patients (uncontrolled suction, n = 47; controlled suction, n = 33). All patients underwent a coronary artery bypass operation with a membrane oxygenator. We measured significantly lower beta thromboglobulin concentrations during perfusions of approximately 2 hours and we observed a tendency toward shorter postoperative bleeding times if controlled cardiotomy suction was used. There were no significant differences between uncontrolled and controlled cardiotomy suction in platelet number and adenosine diphosphate-induced platelet aggregation. However, blood loss 18 hours postoperatively was significantly less in the controlled than in the uncontrolled suction group when the total volume of cardiotomy suction exceeded 65 L., which corresponded to perfusion times of over 3 hours. In conclusion, prevention of the aspiration of air along with suction of blood significantly reduced platelet activation and postoperative blood loss, particularly when large volumes of blood were aspirated.

Costs of introducing autologous BMT in the treatment of lymphoma and acute leukaemia in The Netherlands.

In a retrospective study we calculated the costs of introducing autologous BMT in the treatment of patients with malignant lymphoma and acute leukaemia in The Netherlands. The cost analysis has been performed in five university hospitals and one cancer centre, in a series of patients with intermediate and high grade non-Hodgkin's lymphoma (NHL) and patients with AML. Conventional treatment consisted of chemotherapy. The average costs of the conventional NHL treatment varied from US$3120 to U$12,900. The costs of autologous BMT amounted to US$40,220. In the AML group the costs of conventional treatment amounted to about US$11,040, as only 50% of the patients were treated further. The costs of autologous BMT including a follow-up period of 2 years, amounted to US$55,440. In The Netherlands the total number of autologous BMTs per year in these patient groups was estimated at 230; 180 in the NHL group and 50 in the AML group. The costs of introducing autologous BMT to the NHL group will vary between 4.93 and 6.68 million dollars and for the AML group these costs were estimated at 2.22 million dollars. As a result, the total extra costs of introducing autologous BMTs are expected to be between 7.15 and 8.9 million dollars.

Urinary polyamines and their metabolites during new combination chemotherapeutic treatments of high grade non-Hodgkin lymphoma.

Nineteen patients with non-Hodgkin lymphoma of unfavourable histology (15 high grade and 4 intermediate grade) were treated with two new combination chemotherapeutic schemes. Except for one all were partial (8) or complete (10) responders to treatment. Polyamines were measured in every spontaneously voided urine sample. Pretherapeutically all (11) stage III and IV patients had borderline or increased urinary putrescine (Pu) and sum of isoputreanine, spermidine and spermine (sigma Isoputr,Sd,Sp), except for the non-responder. Except for one, all (8) stage I and II patients had normal urinary Pu and sigma Isoputr,Sd,Sp. Posttherapeutically patients with pretherapeutically increased sigma Isoputr,Sd,Sp returned to normal (5), borderline (2), or slightly increased (3) levels. The post-therapeutic achievement of normal or borderline sigma Isoputr,Sd,Sp was not necessarily connected with accomplishment of complete remission. From the start of therapy until clinical restaging, partially or completely responding stage III and IV patients excreted 5-234 mmol sigma Isoputr,Sd,Sp per mol of creatinine above the mean normal value plus 2 SD. For stage I and II patients and the clinical non-responder this parameter amounted to 0-5 mmol/mol of creatinine. Peaks in urinary Pu and sigma Isoputr,Sd,Sp follow-up curves were related in time to the administration of chemotherapeutics. For responding stage III and IV patients the rate of the decrease of sigma Isoputr,Sd,Sp levels paralleled the clinically observed rate of tumour load reduction. This study suggests that notably for non-Hodgkin lymphoma patients with high tumour loads the constant monitoring of polyamines can provide information on pretherapeutic spontaneous tumour cell loss, the efficacy of chemotherapeutic combinations, the kinetics-, and (within certain limitations) the extent of therapeutically induced tumour cell death.

Nephrotic syndrome preceding Hodgkin's disease by 42 months.

A 52-year-old man developed minimal change nephrotic syndrome which responded only partially to prednisolone. The addition of cyclophosphamide resulted in a complete remission. During a second episode of nephrotic syndrome prednisolone and cyclophosphamide only gave a partial remission. During a third episode, 42 months after the initial presentation, Hodgkin's disease clinical stage IA was diagnosed. Mantle field radiation therapy was given after which proteinuria gradually decreased to zero in the course of 17 months. The patient has remained free of disease until now (15 months).

Bone marrow separation, purification and cryopreservation: application for autologous bone marrow transplant (ABMT).

Autologous bone marrow transplantation is used in the treatment of patients suffering from malignant diseases. The intention of this study was to develop a technique for cryopreservation of bone marrow stem cells. A technique of purification described elsewhere (2), gave recoveries of 80% of nucleated blood cells and 87% of mononucleated blood cells after apheresis and centrifugation of buffy-coat, but when applied to bone marrow only 59% of NBC and 32% of CFUc have been harvested. We therefore modified the apheresis technique and replaced the centrifugation step by sedimentation with hydroxy-ethyl-starch. This change resulted in a small but significant increase in the yield of bone marrow cells and improved the asepsis of the procedure. From a second group of bone marrow handled with this modified protocol, final yields of 46% of NBC and 62% of MNC were obtained. After cryopreservation 87% of NBC were recovered as assessed by counting.

[Bilateral swelling of the parotid glands as part of a systemic disease]. / Bilaterale zwelling van de glandulae parotideae als onderdeel van een systeemziekte.

In four patients, a man aged 34 years and three women aged 35, 32 and 55 years respectively bilateral swelling of the parotid glands was caused by systemic disease i.e. HIV-salivary gland disease, mucosa-associated lymphoid-tissue (MALT) lymphoma, sarcoidosis with coexisting Sjögren's syndrome, and sialosis and hypothyroidism, respectively. The HIV patient was treated with antiretroviral therapy, the first two women were treated expectantly and the third woman was given a thyroid hormone supplement which resulted in regression of the bilateral parotid enlargement. Bilateral enlargement of the parotid glands is not necessarily caused by infection, it can also be of systemic origin. Minimal invasive investigations of the salivary glands, such as sialography, measurement of salivary secretion rate (sialometry) and analysis of salivary composition (sialochemistry) can offer valuable information about the origin of the parotid gland swelling. Histopathological investigation of an incision biopsy of the parotid gland is an easy way to confirm the diagnosis. The morbidity associated with parotid biopsy is negligible.

Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.

On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.