Infantile fibrosarcoma with an EGFR kinase domain duplication: Underlining a close relationship with congenital mesoblastic nephroma and highlighting a similar morphological spectrum.

Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS. We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients. This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors.

Defibrillation testing during implantation of the subcutaneous implantable cardioverter-defibrillator: a necessary standard or becoming redundant?

Since the publication of the SIMPLE and NORDIC trials, defibrillation testing (DFT) is rarely performed during routine implantation of transvenous implantable cardioverter-defibrillators (ICD). However, the results of these trials cannot be extrapolated to the later introduced subcutaneous ICD (S-ICD) and a class I recommendation to perform DFT during the implantation of these devices remains in the current guidelines. Due to the high conversion success rate of DFT on one hand, and the risk of complications on the other, a significant number of physicians omit DFT in S­ICD recipients. Several retrospective analyses have assessed the safety of the omission of DFT and report contradicting results and recommendations. It is known that implant position, as well as device factors and patient characteristics, influence defibrillation success. A better comprehension of these factors and their relationship could lead to more reliable and safer alternatives to DFT. An ongoing randomised clinical trial, which is expected to end in 2023, is the first study to implement a method that assesses implant position to identify patients who are likely to fail their DFT.

A comprehensive scoping review on transvenous temporary pacing therapy.

Transvenous temporary cardiac pacing therapy (TV-TP) is widely used to treat life-threatening arrhythmias. Yet aggregated evidence on TV-TP is limited. We conducted a systematic scoping review to evaluate indications, access routes and complications of TV-TP, as well as permanent pacemaker therapy (PPM) following TV-TP. Clinical studies concerning TV-TP were identified in Ovid MEDLINE. Case studies and studies lacking complication rates were excluded. To assess complication incidence over time, differences in mean complication rates between 10-year intervals since the introduction of TV-TP were evaluated. We identified 1398 studies, of which 32 were included, effectively including 4546 patients. Indications varied considerably; however TV-TP was most commonly performed in atrioventricular block (62.7%). The preferred site of access was the femoral vein (47.2%). The mean complication rate was 36.7%, of which 10.2% were considered serious. The incidence of complications decreased significantly between 10-year interval groups, but remained high in the most recent time period (22.9%) (analysis of variance; p < 0.001). PPM was required in 64.2% of cases following TV-TP. Atrioventricular block was the primary indication for TV-TP; however indications varied widely. The femoral vein was the most frequent approach. Complications are common in patients undergoing TV-TP. Although a decrease has been observed since its introduction, the clinical burden remains significant. The majority of patients who underwent TV-TP required PPM therapy.

An Overview of Clinical Outcomes in Transvenous and Subcutaneous ICD Patients.

PURPOSE OF REVIEW: Clear guidelines on when to select a subcutaneous ICD (S-ICD) over a transvenous ICD (TV-ICD) are lacking. This review will provide an overview of the most recent clinical data on S-ICD and TV-ICD therapy by pooling comparison studies in order to aid clinical decision making. RECENT FINDINGS: Pooling of observational-matched studies demonstrated an incidence rate ratio (IRR) for device-related complication of 0.90 (95% CI 0.58-1.42) and IRR for lead-related complications of 0.15 (95% CI 0.06-0.39) in favor of S-ICD. The IRR for device infections was 2.00 (95% CI 0.95-4.22) in favor of TV-ICD. Both appropriate shocks (IRR 0.67 (95% CI 0.42-1.06)) and inappropriate shocks (IRR 1.17 (95% CI 0.77-1.79)) did not differ significantly between both groups. With randomized data underway, the observational data demonstrate that the S-ICD is associated with reduced lead complications, but this has not yet resulted in a significant reduction in total number of complications compared to TV-ICDs. New technologies are expected to make the S-ICD a more attractive alternative.

Comparison of complications and shocks in paediatric and young transvenous and subcutaneous implantable cardioverter-defibrillator patients.

BACKGROUND: Young implantable cardioverter-defibrillator (ICD) patients are prone to complications and inappropriate shocks (IAS). The subcutaneous ICD (S-ICD) may avoid lead-related complications. This study aims to describe the incidence and nature of device-related complications in young transvenous ICD (TV-ICD) and S­ICD patients. METHODS: Single-chamber TV-ICD and S­ICD patients up to and including the age of 25 years implanted between 2002 and 2015 were retrospectively analysed. Complications were defined as device-related complications requiring surgical intervention. IAS were defined as shocks for anything other than ventricular tachycardia or ventricular fibrillation. Follow-up data were collected 5 years post-implantation. Kaplan-Meier estimates for complications at 5­year follow-up were calculated with a corresponding 95% confidence interval. RESULTS: Eighty-one patients (46 TV-ICD, 35 S-ICD) were included (median age 19.0 (IQR 16.0-23.0) and 16.5 (IQR 13.0-20.2) years respectively). Median follow-up was 60 and 40 months respectively. All-cause complication rate was 34% in the TV-ICD group and 25% in the S­ICD group (p = 0.64). TV-ICD patients had more lead complications: 23% (10-36%) versus 0% (p = 0.02). The rate of infections did not differ between TV-ICD and S­ICD: 2% (0-6%) versus 10% (0-21%) (p = 0.15). No systemic infections occurred in the S­ICD patients. The rates of IAS were similar, TV-ICD 22% (9-35%) versus S­ICD 14% (0-30%) (p = 0.40), as were those for appropriate shocks: 25% (11-39%) versus 27% (6-48%) (p = 0.92). CONCLUSION: The rates of all-cause complications in this cohort were equal, though the nature of the complications differed. S­ICD patients did not suffer lead failures or systemic infections. An era effect is present between the two groups.

Outpatient treatment with the wearable cardioverter defibrillator: clinical experience in two Dutch centres.

INTRODUCTION: The latest European Society of Cardiology Guidelines recommend consideration of a wearable cardioverter-defibrillator (WCD) for patients with a poor left ventricular ejection fraction (LVEF) who are at risk of sudden arrhythmic death but are not eligible for an implantable defibrillator. For these patients a WCD can be an alternative to long-term hospitalisation. PURPOSE: To evaluate the use of WCD therapy in these patient groups in two Dutch centres. METHODS: All consecutive patients treated with the WCD between 2009 and 2016 were included from two centres in the Netherlands. Data on events and compliance were collected retrospectively through home monitoring systems and adjudicated by the investigators. RESULTS: A total of 79 patients were treated with a WCD. Common indications were newly diagnosed cardiomyopathy without optimal medical treatment in 46 patients (58.2%) and bridge to implantable cardioverter-defibrillator (ICD) implant in 33 patients (41.8%). Bridge to implant indications consisted of contraindications for immediate implantation such as infections (e. g. previous device-related infections) and radiotherapy. Compliance was over 97% per day (median 23.3 h, 22.6-23.7), during a median of 79 days (50.0-109.8.0). Two patients (2.6%) received an appropriate shock (annual rate 13.6%), there was 1 (1.3%) inappropriate shock (annual rate 6.7%). In 24 patients (52.2%) without optimal medical treatment, the LVEF was sufficiently improved and ICD implant was avoided. Eight (10.1%) patients did not receive an ICD. In 45 patients an ICD was implanted (57.0%). CONCLUSION: WCD therapy provides a safe and effective treatment in outpatient setting for patients at high risk for sudden cardiac death and reduces the number of ICDs implanted.

Combined leadless pacemaker and subcutaneous implantable defibrillator therapy: feasibility, safety, and performance.

AIMS: The subcutaneous implantable cardioverter-defibrillator (S-ICD) and leadless pacemaker (LP) are evolving technologies that do not require intracardiac leads. However, interactions between these two devices are unexplored. We investigated the feasibility, safety, and performance of combined LP and S-ICD therapy, considering (i) simultaneous device-programmer communication, (ii) S-ICD rhythm discrimination during LP communication and pacing, and (iii) post-shock LP performance. METHODS AND RESULTS: The study consists of two parts. Animal experiments: Two sheep were implanted with both an S-ICD and LP (Nanostim, SJM), and the objectives above were tested. Human experience: Follow-up of one S-ICD patient with bilateral subclavian occlusion who received an LP and two LP (all Nanostim, SJM) patients (without S-ICD) who received electrical cardioversion (ECV) are presented. Animal experiments : Simultaneous device-programmer communication was successful, but LP-programmer communication telemetry was temporarily lost (2 ± 2 s) during ventricular fibrillation (VF) induction and 4/54 shocks. Leadless pacemaker communication and pacing did not interfere with S-ICD rhythm discrimination. Additionally, all VF episodes (n = 12/12), including during simultaneous LP pacing, were detected and treated by the S-ICD. Post-shock LP performance was unaltered, and no post-shock device resets or dislodgements were observed (24 S-ICD and 30 external shocks). Human experience : The S-ICD/LP patient showed adequate S-ICD sensing during intrinsic rhythm, nominal, and high-output LP pacing. Two LP patients (without S-ICD) received ECV during follow-up. No impact on performance or LP dislodgements were observed. CONCLUSION: Combined LP and S-ICD therapy appears feasible in all animal experiments (n = 2) and in one human subject. No interference in sensing and pacing during intrinsic and paced rhythm was noted in both animal and human subjects. However, induced arrhythmia testing was not performed in the patient. Defibrillation therapy did not seem to affect LP function. More data on safety and performance are needed.

Defibrillation threshold in elective subcutaneous implantable defibrillator generator replacements: Time to reduce the size of the pulse generator?

INTRODUCTION: The first step-down defibrillation studies in the subcutaneous implantable cardioverter-defibrillator (S-ICD) described a defibrillation threshold (DFT) of 32.5 ± 17.0 J and 36.6 ± 19.8 J. Therefore, the default shock output of the S-ICD was set at 80 J. In de novo implants, the DFT is lower in optimally positioned S-ICDs. However, a retrospective analysis raised concerns about a high DFT in S-ICD replacements, possibly related to fibrosis. OBJECTIVE: We aimed to find the DFT in patients undergoing S-ICD generator replacement. METHODS: This prospective study enrolled patients who underwent S-ICD generator replacement with subsequent defibrillation testing. A pre-specified defibrillation testing protocol was used to determine the DFT, defined as the lowest shock output that effectively terminated the induced ventricular arrhythmia. RESULTS: A total of 45 patients were enrolled, 6.0 ± 2.1 years after initial implant. Mean DFT during replacement in the total cohort was 27.4 ± 14.3 J. In patients with a body mass index (BMI) 18.5-25 kg/m2 (N = 22, BMI 22.5 ± 1.6), median DFT was 20 J (IQR 17.5-30). In 18/22 patients, the DFT was ≤30 J and 5/22 patients were successfully defibrillated at 10 J. One patient with hypertrophic cardiomyopathy had a DFT of 65 J. In patients with a BMI >25 kg/m2 (N = 23, BMI 29.5 ± 4.2), median DFT was 30 J (IQR 20-40). In 15/23 patients, the DFT was ≤30 J and 4/23 patients had a successful defibrillation test at 10 J. CONCLUSIONS: This study eases concerns about a high DFT after S-ICD generator replacement. The majority of patients had a DFT ≤30 J, regardless of BMI, suggesting that the shock output of the S-ICD could be safely reduced.

The volume effect in paediatric oncology: a systematic review.

BACKGROUND: For several adult cancer types, there is evidence that treatment in high volume hospitals, high case volume providers, or in specialised hospitals leads to a better outcome. The aim of this study is to give an overview of the existing evidence regarding the volume effect in paediatric oncology related to the quality of care or survival. MATERIALS AND METHODS: An extensive search was carried out for studies on the effect of provider case volume on the quality of care or survival in childhood cancer. Information about study characteristics, comparisons, results, and quality assessment were abstracted. RESULTS: In total, 14 studies were included in this systematic review. Studies with a low risk of bias provide evidence that treatment of children with brain tumours, acute lymphoblastic leukaemia, osteosarcoma, Ewing's sarcoma, or children receiving treatment with allogenic bone marrow transplantation in higher volume hospitals, specialised hospitals, or by high case volume providers, is related with a better outcome. CONCLUSIONS: This systematic review provides support for the statement that higher volume hospitals, higher case volume providers, and specialised hospitals are related to the better outcome in paediatric oncology. No studies reported a negative effect of a higher volume.

Behavioural digital biomarkers enable real-time monitoring of patient-reported outcomes: a substudy of the multicenter, prospective observational SafeHeart study.

INTRODUCTION: Patient-reported outcome measures (PROMs) serve multiple purposes, including shared decision-making and patient communication, treatment monitoring and health-technology assessment. Patient monitoring using PROMs is constrained by recall and non-response bias, respondent burden and missing data. We evaluated the potential of behavioural digital biomarkers obtained from a wearable accelerometer to achieve personalised predictions of PROMs. METHODS: Data from the multicenter, prospective SafeHeart study conducted at Amsterdam University Medical Center in the Netherlands and Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark, was used. The study enrolled patients with an implantable cardioverter defibrillator (ICD) between May 2021 and September 2022 who then wore wearable devices with raw acceleration output to capture digital biomarkers reflecting physical behaviour. To collect PROMs, patients received the KCCQ and EQ5D-5 L questionnaire at two instances; baseline and after 6 months. Multivariable Tobit regression models were used to explore associations between digital biomarkers and PROMs, specifically whether digital biomarkers could enable PROM prediction. RESULTS: The study population consisted of 303 patients (mean age 62.9 ± 10.9 years, 81.2% male). Digital biomarkers showed significant correlations to patient-reported physical and social limitations, severity and frequency of symptoms and quality of life. Prospective validation of the Tobit models indicated moderate correlations between the observed and predicted scores for KCCQ (concordance correlation coefficient (CCC) = 0.49, mean difference: 1.07 points) and EQ5D-5 L (CCC = 0.38, mean difference 0.02 points). CONCLUSION: Wearable digital biomarkers correlate with PROMs, and may be leveraged for real-time prediction. These findings hold promise for monitoring of PROMs through wearable accelerometers.

Worsening tricuspid regurgitation after ICD implantation is rather due to transvenous lead than natural progression.

BACKGROUND: Transvenous implantable cardioverter-defibrillators (TV-ICDs) are associated with greater tricuspid regurgitation (TR) severity, which leads to increased mortality. The pathophysiology is assumed to be lead-related, hence, treatment includes lead extraction. However, TR may also naturally occur in the high-risk ICD population, or may be caused by right ventricular pacing. We sought to evaluate the effect of ICD type (with or without lead) and pacing percentage on post-implantation TR severity. METHODS: In this retrospective cohort study, consecutive patients were included with a primary S-ICD or TV-ICD implantation between 2009 and 2019 and echocardiography studies ≤3 months before and ≤ 3 years post-implantation. The effect of ICD type on TR severity at follow-up was estimated adjusting for ventricular pacing percentage and potential confounders. The effect of ventricular pacing percentage on TR severity at follow-up was adjusted for potential confounders. RESULTS: 118 patients were included (mean age 52 ± 21): 31 (26%) with an S-ICD and 87 (74%) with a TV-ICD. Median 20 months post-implantation, worsening TR was found in 11/31 (34%) S-ICD patients and 45/87 (52%) TV-ICD patients (p = 0.15). Adjusted for age, atrial fibrillation, baseline TR and mitral regurgitation, ventricular pacing percentage, ICD dwelling time, BMI, hypertension and left ventricular ejection fraction, TV-ICDs were significantly associated with greater TR severity (OR 9.90, p = 0.002). Ventricular pacing percentage was very low, and not significantly associated with greater TR severity (OR 0.95, p = 0.066). CONCLUSIONS: Our results suggest that greater TR severity in ICD patients is mainly caused by the transvenous lead, rather than natural progression in the ICD population.

High-quality care for all children with cancer.

BACKGROUND: Providing high-quality care for children with cancer could improve treatment outcomes, survival and quality of life of the children and parents. The aim of this study is to select high-quality care recommendations for all children with cancer based on literature and consensus for future development of quality indicators. MATERIALS AND METHODS: We performed an extensive search in databases for scientific literature and in websites of international health care and guideline development organizations to create an inventory of recommendations for the care for all children with cancer. The RAND modified Delphi method was used to grade and select recommendations for high-quality care. RESULTS: Our search resulted in a list of 131 recommendations on care for all children with cancer. The expert panel graded, discussed and prioritized these recommendations. Analysis of these ratings resulted ultimately in a list of 109 high-quality care recommendations for all children with cancer, including 31 prioritized recommendations. CONCLUSIONS: This study defines a set of high-quality care recommendations based on literature and consensus. These recommendations provide a basis for the development of a comprehensive set of quality indicators to evaluate care in paediatric oncology.

Long-term follow-up of persisting mixed chimerism after partially T cell-depleted allogeneic stem cell transplantation.

Using red cell phenotyping (RCP) and/or cytogenetics (CYT) we identified 19 patients with persisting mixed chimerism (MC) among 231 patients transplanted with partially T cell-depleted stem cell grafts from HLA-identical siblings. Persisting MC is defined as MC for more than 2 years in patients without any evidence of relapse. Median leukemia-free survival in these patients was 150 (range, 50-218) months. Diagnoses were ALL (n= 10); AML (n = 2); CML (n = 2); NHL (n = 2); MDS (n= 1); MM (n = 1) and SAA (n = 1). Purpose of this study was the long-term follow-up of MC and definition of patterns of chimerism in the various subsets of PBMCs and granulocytes. Using a PCR-STR technique CD3(+)/CD4(+) (T4 lymphocytes), CD3(+)/CD8(+) (T8 lymphocytes), CD45(+)/CD19(+) (B lymphocytes), CD45(+)/CD14(+) (monocytes), CD45(+)/CD15(+) (granulocytes) and CD3(-)/CD56(+) (NK-cells) were analyzed. The majority of patients with persisting MC were conditioned with a less intensive conditioning regimen and had little GVHD. Sequential monitoring of the chimerism resulted in a group of patients (n = 7) with very slow transient mixed chimerism that resulted in complete DC after median 7 years. Another nine patients had a relatively high percentage of persisting autologous cells for a median of 12 years and in three patients we observed a stable low percentage of autologous cells. Only two out of 19 patients (AML-CR1, CML-CP1) relapsed during follow-up. Both patients had a relatively high percentage of autologous cells. Chimerism in granulocytes and PBMC subsets was analyzed at a median of 8 years after SCT in nine patients. In five patients mixed chimerism simultaneously detected by RCP and CYT was associated with MC in all subsets. Within each individual patient the percentages of donor and recipient cells were very different between the different subsets. Two CML-CP1 patients were mixed chimera in only two subsets and in one patient these subsets represented pending relapse. In another two patients mixed chimerism with a very low number of autologous red cells was not found in the PBMCs because of the different sensitivity level of the RCP and the PCR-STR technique. We conclude that in patients with persisting mixed chimerism after partially T cell-depleted SCT a remarkable number of patients had lymphoid malignancies, the majority of the patients were conditioned with less intensive conditioning regimens and the mixed chimerism was not correlated with relapse. Chimerism in granulocytes and PBMC subsets did show great intra-individual differences in the subsets and these data correlated well with RCP and CYT data with the exception of the NK cells.

Immunotherapy with monoclonal anti-idiotypic antibodies: tumour reduction and lymphokine production.

A patient with a B-cell chronic lymphocytic leukaemia was treated with a murine IgG1 monoclonal anti-idiotypic antibody (MoAb anti-id). After a total of 773.2 mg MoAb anti-id had been administered with a maximum daily dose of 83.2 mg, 90% tumour reduction was established within 2 weeks. Although in vitro the tumour cells were stimulated by MoAb anti-id no signs of tumour cell activation were observed in vivo during therapy with MoAb anti-id. The rapid tumour reduction suggests that the proliferation-enhancing property of anti-id is not a contra-indication for immunotherapy. The FcR II receptors on the patients monocytes could interact with the IgG1 monoclonal used. MoAb anti-id administration induced strongly decreased platelet counts, dependent on the amount of serum idiotype that had to be cleared. Antibody administration activated the macrophage/monocyte system, reflected in the neopterin profile, resulting in TNF alpha production and simultaneously strong reductions of circulating tumour cells. The partial remission lasted 3 months, then the tumour reappeared. These data show that a straightforward therapy with MoAb anti-id, in itself, has a strong potential, but is not sufficient to eradicate the tumour permanently. Further study will be needed to improve the clinical results with this kind of therapy.

Long-term experience (6 years) with simvastatin in patients with heterozygous familial hypercholesterolaemia.

OBJECTIVE: To study the long-term efficacy and safety of the cholesterol synthesis inhibitor, simvastatin, in the treatment of familial hypercholesterolaemia. METHODS: This is an open long-term follow-up of patients treated for 5 years or more in the Nijmegen University lipid clinic. Forty-four patients with heterozygous familial hypercholesterolaemia (mean baseline serum cholesterol level 11.5 mmol/l) were treated with simvastatin alone (monotherapy group) in doses ranging from 20 to 80 mg/day, or in combination with other lipid-lowering agents (combination-therapy group). RESULTS: Over the intervention period of 6 years the mean overall reduction of the serum cholesterol level was 37.8% for the total group, 37.7% for the monotherapy group and 42.6% for the combination-therapy group. The reduction of the low-density lipoprotein (LDL)-cholesterol in the three groups was 45.0, 44.6 and 50.3%, respectively. The serum triglyceride concentration was reduced by 14.0, 20.5 and 12.5%, respectively. The increase in the high-density lipoprotein (HDL)-cholesterol level was 14.4, 16.2 and 14.0%, respectively. One patient died from a myocardial infarction and 2 patients had a non-fatal cardiac event. Two patients stopped taking medication due to side-effects (dizziness and insomnia). Biochemical adverse effects were confined to elevations of the alanine aminotransferase level and the creatine phosphokinase level and did not lead to discontinuation of therapy. CONCLUSIONS: Simvastatin proves to be a safe and effective lipid-lowering drug during long-term treatment.

First experience with the wearable cardioverter defibrillator in the Netherlands.

The implantable cardioverter defibrillator (ICD) has significantly improved survival in patients with an increased risk of sudden cardiac death (SCD). The wearable cardioverter defibrillator (WCD) is an alternative to the ICD in patients with a transient ICD indication or those in whom an ICD temporarily cannot be implanted. We describe here the technical details of the WCD and report three patients who were treated with a WCD in an outpatient setting. The WCD allowed the cardiac condition of two patients to improve to such an extent that permanent ICD implantation was deemed unnecessary. This new form of therapy may result in significant cost reduction, avoidance of unnecessary ICD implantation, and increased patient satisfaction.

Phenotypic and functional changes of tumour cells from patients treated with monoclonal anti-idiotypic antibodies.

In this paper data are presented indicating that immunotherapy with monoclonal anti-idiotypic antibodies (MoAb anti-id) can provoke different responses in the B-cell tumour concerned. With respect to the course of disease during and after immunotherapy, the in vitro findings may very well explain the in vivo observations in the two patients (D.E.F., B.O.R.) with B-cell chronic lymphocytic leukaemia (B-CLL) who were treated with MoAb anti-id. After initial tumour reduction, there was a recurrence of tumour cells with altered functional and phenotypic properties. In both cases the recurring tumour cells still expressed the same idiotype. In one patient (D.E.F.) the phenotypic changes (a surface Ig change from IgM, IgG, IgA, and IgD to weakly positive IgM and IgD) and functional changes (a 10-fold increase in [3H]thymidine uptake and a decreased idiotype secretion in vitro), together with the in vivo findings with respect to the course of disease--at relapse an impressive tumour regrowth rate with constant serum idiotype level--suggest that immunoselection might have taken place favouring the survival and relapse of a less mature, more aggressive tumour cell population with a lower idiotype expression. In the second patient (B.O.R.), the phenotypic changes (an isotype change from IgM and IgD to IgM with the loss of IgD, and a gradual decrease in expression of CD19 and CD24) and functional changes (a 10-fold increase of idiotype secretion in vitro), together with the in vivo finding that the serum idiotype level had increased 25-fold compared with the preimmunotherapy serum level with comparable tumour load, strongly suggest an immunotherapy-induced differentiation of the malignant B cell. We also describe an increased expression of CD74, detected by MoAb BoM22, on the recurring tumour cells of patient B.O.R., whereas the expression of HLA-DP, -DQ and -DR did not change. The significance of this finding is unclear.