[Febrile neutropenia in pediatric and adolescent cancer patients]. / Fieber während der Granulozytopenie bei krebskranken Kindern und Jugendlichen.

Febrile neutropenia is the most common potential emergency situation in children and adolescents with cancer. The host response of these patients is severely compromised by treatment-induced immunosuppression resulting in a lack of important defence mechanisms, so that bacterial infections and in certain risk groups also fungal infections can be life threatening. As the clinical course of these infectious complications may be rapid and fatal, early antibiotic treatment can save lives. This article aims to raise awareness to this emergency situation and gives an overview of the management of pediatric cancer patients with febrile neutropenia.

Bloodstream infection in paediatric cancer centres--leukaemia and relapsed malignancies are independent risk factors.

UNLABELLED: In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. CONCLUSION: This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. WHAT IS KNOWN: • Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). • In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy-induced alterations of host defence mechanisms (e.g. mucositis). What is New: • This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. • It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions.

Aspergillus PCR-based investigation of fresh tissue and effusion samples in patients with suspected invasive Aspergillosis enhances diagnostic capabilities.

Although it is a severe complication in immunocompromised patients, diagnosing invasive fungal disease (IFD), especially invasive aspergillosis (IA), remains difficult. In certain clinical scenarios, examining tissue samples for identification of the infectious organism becomes important. As culture-based methods rarely yield results, the performance of an Aspergillus-specific nested PCR in fresh tissue or pleural effusion samples was evaluated. Fresh tissue (n = 59) and effusion (n = 47) specimens from 79 immunocompromised patients were subjected to an Aspergillus-specific PCR assay. Twenty-six patients had proven (n = 20) or probable (n = 6) IFD, according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria, while the remaining patients were classified as having either possible IFD (n = 30) or no IFD (n = 23). IA was identified as the underlying IFD in 21/26 proven/probable cases. PCR positivity was observed for 18/21 proven/probable and 6 possible IA cases; cases classified as no IA did not show positive signals. Patients with proven IFD (n = 5) with cultures positive for non-Aspergillus molds also had negative Aspergillus PCR results. Aspergillus PCR performance analysis yielded sensitivity and specificity values of 86% (95% confidence interval [CI], 65% to 95%) and 100% (95% CI, 86% to 100%), respectively, thus leading to a diagnostic odds ratio of >200. In this analysis, good diagnostic performance of the PCR assay for detection of IA was observed for tissue samples, while effusion samples showed lower sensitivity rates. PCR testing represents a complementary tool; a positive PCR result strengthens the likelihood of IA, whereas IA seems unlikely in cases with negative results but findings could indicate non-Aspergillus IFD. Thus, PCR testing of these specimens enhances the diagnostic capabilities.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato-oncology and hematopoietic stem cell transplantation patients.

BACKGROUND: For children with hemato-oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown. METHODS: A retrospective chart study was performed of pH1N1 cases diagnosed between October 2009 to January 2010 in the hemato-oncologic unit of the University Children's Hospital of Düsseldorf, Germany. FINDINGS: In total, 21 children were diagnosed with laboratory-confirmed pH1N1; in 16 patients with malignancies (acute leukemia 7, lymphoma 4, solid tumors 2, others 3) and in 5 with benign hematologic disorders. Five patients had undergone prior HSCT, although 1 patient was diagnosed during conditioning therapy with high-dose chemotherapy in preparation for haploidentical HSCT. Most frequent symptoms were fever (>38.5°C) and cough (in 100%), and rhinorrhea (57%). The 2 patients acquiring pH1N1 infection under high-dose or intensive chemotherapy did not require intensive care or mechanical ventilation, and both recovered under antiviral therapy. Oseltamivir was administered to 11 patients; in 1 patient, therapy was switched, on a compassionate-use basis, to intravenous zanamivir because of lack of clinical improvement after oseltamivir therapy. Complications were hospitalization (19%), demand of oxygen supplementation, delay/interruption of antineoplastic therapy, and prolonged administration of antibiotics and antipyretics. CONCLUSION: In the investigated patient population, pH1N1 was mild in most cases, but was associated with substantial morbidity in a proportion of patients and led to interruption and delay in anticancer treatment.

Human leukocyte antigen distribution in German Caucasians with advanced Ewing's sarcoma.

BACKGROUND: Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls. PATIENTS: HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients. RESULTS: After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05). CONCLUSION: We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.

Invasive aspergillosis in pediatric oncology patients: a rare event with poor prognosis--case analysis to plan better targeted prophylactic or therapeutic measurement.

Despite the implementation of new antifungal drugs, invasive aspergillosis (IA) still remains a considerable challenge in pediatric oncology with a severe mortality. Prophylactic and therapeutic measurement have to be evaluated in these rare but poor prognostic patients. Therefore the entire group of patients at risk of developing IA has to be defined before cooperative prospective trials. In a retrospective analysis including all our patients with malignancies we looked for patients with proven/probable IA. Cases of the period from 2003 to 2008 were analyzed in detail.In the period between 2003 to 2008 24 of 755 patients were affected by proven/ probable IA. Compared to former studies incidence increased from 1.3%in 1980 to 3.4% in 2008. AML patients with or without allogeneic/haploidentical stem cell transplantation were at highest risk (24% and 25% respectively, in comparison to 1% in ALL-patients). Survival after 2 years was 50% for patients with AML and IA. In patients with high risk to develop IA the effect of intensified, intravenous antimycotic prophylaxis has to be proven prospectively in a cooperative and randomized setting.

[Guideline for antiretroviral therapy of HIV-infected children and adolescents]. / Leitlinie der Pädiatrische Arbeitsgemeinschaft AIDS (PAAD) e.V. zur antiretroviralen Therapie bei HIV-infizierten Kindern und Jugendlichen (2011).

The HIV-infection in adults or children and adolescent differs substantially. Differences include the mode of infection, viral dynamics facing a developing immune system and the clinical course of the infection. In addition to the virological, immunological and epidemiological aspects the psychosocial situation is also very different. The above aspects and the decreased number of antiretroviral substances underline the need for specific guidelines for HIV-therapy in children and adolescents. The German Pediatric Working group AIDS (PAAD) has formulated this guideline in 2011 based on new study results, changes in international recommendations and newly available drugs.

Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

Array-based sequence capture and next-generation sequencing for the identification of primary immunodeficiencies.

Primary immunodeficiencies are genetic disorders in which components of immunological pathways are either missing or dysregulated. With the advent of next-generation sequencing, testing for genes in conditions with a heterogeneous genetic background seems more promising. We designed a custom microarray with 385K probe capacity to capture exons of 395 human genes, known or predicted to be associated with primary immunodeficiency and immune regulation. Enriched target DNA was sequenced using a GS FLX Titanium 454 platform. The patients selected were likely to have an underlying immunodeficiency. In one patient with hepatosplenomegaly, recurrent infections and an elevated IgM level, sequence analysis of the patient and his two unaffected parents identified ATM (ataxia telangiectasia mutated) as the underlying defect. In a second child with a clinical SCID phenotype, we detected a mutation in the ARTEMIS gene after focusing on SCID-associated genes. 454 sequencing yielded 152,000-397,000 high-quality reads per patient. 78-99% of the targeted nucleotides were covered at least one time, 76-82% at least five times. Array-based sequence capture expands our capacities to sequence large targeted DNA regions in a less laborious and time-consuming approach. Our array was capable to find the underlying genetic defect in two patients with suspected primary immunodeficiency. Upcoming whole-exome sequencing definitely will add more valuable data, but bioinformatical analysis and validation of variants already pose major challenges.

Induction maintenance concept for HAART as initial treatment in HIV infected infants.

BACKGROUND: Early initiated antiretroviral therapy (ART) in HIV infected infants leads to improved long-term viral suppression and survival. Guidelines recommend initiating therapy with a triple ART consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either one additional non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Compared to older children and adults, viral relapse is seen more frequently in infants receiving triple ART. We now address the possibility of a more potent ART with a quadruple induction and triple maintenance therapy. METHODS: We examine the longitudinal course in four HIV infected infants, who were referred from other centers and could not be recruited to multicentre trials. We introduced ART initially consisting of two NRTIs, one NNRTI and one PI and later discontinued the PI at the age of 12 months maintaining a triple regime consisting of two NRTIs and one NNRTI. RESULTS: Provided that therapy adherence was maintained we observed an effective sustained decline of viral load and significant CD4 cell reconstitution even after switching to a triple regime. No drug associated toxicity was seen. CONCLUSION: We suggest that a four drug therapy might be a possible initial therapy option in HIV infected infants, at least in those with a high viral load, followed by a maintenance triple regime after 12 months of therapy.

iNKT cell frequency in peripheral blood of Caucasian children and adolescent: the absolute iNKT cell count is stable from birth to adulthood.

Human invariant natural killer T cells (iNKT cells) are a unique population of T cells that express a semi-invariantly rearranged T cell receptor (TCR) and are involved in a variety of immunoregulatory processes. We assessed the frequency of peripheral blood iNKT cells in 64 healthy Caucasian children from 7 months to 18 years of age and five cord blood samples by flow cytometry. iNKT cells were measured as CD3(+) cells co-expressing TCRVα24 and TCRVß11 and using the monoclonal antibody 6B11, which recognizes specifically their invariant TCR rearrangement. The absolute number of iNKT cells ranged from 86 to 10,499 (CD3(+) /TCRVα24(+) / TCRVß11(+)) and 233 to 11,167 (CD3(+) /6B11(+)) iNKT cells per millilitre of blood. This range is stable from birth to adulthood. The relative iNKT cell count was found to be 0.003-0.71% (CD3(+) /TCRVα24/TCRVß11) and 0.019-0.776% (CD3/6B11) of peripheral blood T cells and shows only a slight increase with age.

Physiotherapy home exercise program for haemophiliacs.

BACKGROUND: Regular physiotherapy can improve the stability and flexibility of joints and decrease the bleeding risk in patients with haemophilia. To reduce the appointments for the patients and to make exercising a part of daily live, an individualized home exercise program (HEP) was designed. Retrospectively the number of bleedings during the HEP was compared to number of bleedings before. METHOD: 8 patients aged between 4 and 16 years with haemophilia A were evaluated. At start and after 13 month patients had a motion analysis via topographic ultrasound. According to the results and clinical findings an individualized HEP was created. Standardised scores for clinical evaluation and the patient based evaluation of exercises were designed. At every appointment exercises were individually adjusted. RESULTS: Patients exercised in median 1.7 times a week. No training related bleeds occurred. 7 of 8 patients showed reduced joint and/or muscle bleeds (p<0.02). Clinical scores raised slightly in every patient. However the second motion analysis of squat and gait showed a worsening in 7 of 8 patients (p>0.05). CONCLUSION: A HEP can help to advance in physical fitness and coordination and may reduce bleeding tendency, but needs to be accomplished regularly. Patients are interested but the motivation to exercise at home is low. Disorders measured by motion analysis seem not to be sufficiently influenced by our surrogate training program.

No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

MHC class II deficiency cured by unrelated mismatched umbilical cord blood transplantation: case report and review of 68 cases in the literature.

MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor.

Magnetization transfer imaging provides no evidence of demyelination in methotrexate-induced encephalopathy.

Subacute MTX-induced encephalopathy is characterized by an abrupt onset of focal neurologic deficits within days after intrathecal or systemic therapy. Demyelination is one proposed mechanism. We describe the neuroimaging features of 2 patients with clinical symptoms of subacute encephalopathy after intrathecal and systemic MTX therapy. DWI showed restricted diffusion, indicating cytotoxic edema. MTI yielded no evidence of demyelination in either patient because there was no loss of MTR in areas of restricted diffusion.

Prospective, comprehensive, and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation.

Major advances in the monitoring and treatment of viral infections after hematopoietic stem cell transplantation (HSCT) have been achieved over the last decade. The appropriate extent of viral monitoring and antiviral therapy remains controversial, and reports in pediatric patients receiving allogeneic unmanipulated hematopoietic stem cells (HSCs) are sparse. A total of 40 pediatric patients who underwent HSCT with either peripheral blood stem cells (PBSCs, n = 30) or bone marrow (BM; n = 10) were prospectively monitored every week for viral DNAemia (VDNA) by simultaneous detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), human adenovirus (ADV), and polyoma BK virus (BKV) using real-time TaqMan polymerase chain reaction (PCR). All patients received prophylactic acyclovir and preemptive ganciclovir (GCV) when 500 copies/microg DNA (EBV/HHV6) or >1 copy/microg DNA (CMV) were detected on 2 consecutive measurements. VDNA occurred in 25 of 40 recipients (CMV, 11/40 patients [28%]; EBV, 19/40 [48%]; HHV6, 2/40 [5%]; ADV/BKV, 1/40) and was found exclusively after neutrophil engraftment and in most cases up to day +100. Recurrent VDNA (P = .028) and (readily treatable) viral disease (P = .003) were observed predominantly in patients suffering from nonmalignant diseases, a cohort characterized by delayed lymphocyte engraftment. VDNA occurred more frequently in HLA-mismatched HSCT and in the 24 of 40 patients receiving antithymocyte globulin (ATG). The incidence of EBV, but not that of CMV, was increased in the ATG group. Yet, in these patients, viral loads of both EBV and CMV were higher, but with prompt initiation of preemptive GCV, no posttransplantation lymphoproliferative disorder or other life-threatening morbidities occurred. HHV6 was typically detected at low viral loads (<10(2) copies/microg DNA), with only 5% of HSC recipients fulfilling our HHV6 criteria for triggering GCV treatment. In multivariate analysis, ATG treatment, HLA mismatch, recipient CMV seropositivity, and stem cell source, but not severe acute graft-versus-host disease were identified as independent risk factors for VDNA. This comprehensive viral monitoring program with defined thresholds for initiation of preemptive GCV effectively prevents the development of critical viral disease, even in high-risk patients receiving ATG.

[Updated statement by the German Society for Pediatric and Adolescent Rheumatology (GKJR) on the FDA's report regarding malignancies in anti-TNF-treated patients from Aug. 4, 2009]. / Aktualisierte Stellungnahme der GKJR zur Meldung der FDA über Fälle von Malignomen bei Anti-TNF-behandelten Patienten vom 04.08.2009.

TNF inhibitors and other biologicals have greatly expanded the therapeutic options for juvenile idiopathic arthritis (JIA). While the efficacy of etanercept and adalimumab has been proven in randomized controlled clinical trials, their long-term safety remains the subject of ongoing investigations. Reports of leukaemia and tumours in children and adolescents treated with etanercept, infliximab and adalimumab have raised questions about an increased risk for malignancies, with lymphoma accounting for the largest group at 50% of all 48 malignancies reported by the FDA.Consequently, TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pre-treatment with carcinogenic substances such as cyclophosphamide. This is particularly true for non-approved substances, and non-approved indications, and for combination therapy of TNF inhibitors with immunosuppressive drugs. On the other hand, however, treatment should not be stopped or started in any patient in whom treatment is necessary due to the current knowledge. Adequate patient information, surveillance and documentation of treatment in the registry of the GKJR is strongly recommended.

Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases.

We examined the role of total body magnetic resonance imaging (TB-MRI)-governed involved compartment irradiation (ICI) and high-dose chemotherapy (HDC), followed by stem cell rescue (SCR) in patients with high-risk Ewing tumors (ETs) with multiple primary bone metastases (high-risk ET-MBM). Eleven patients with high-risk ET-MBM receiving initial assessment of involved bones by TB-MRI were registered from 1995 to 2000 (group A). In all, 6 patients out of 11 had additional lung disease at initial diagnosis; all had multifocal bone disease with more than three bones involved. After systemic induction with etoposide, vincristine, adriamycin (doxorubicin), ifosfamide, and actinomycin D (EVAIA) or VAIA chemotherapy, ICI of all sites positive by TB-MRI was administered, followed by HDC and SCR. A second group matched for observation period and consisting of 26 patients with more than three involved bones at diagnosis was treated with the European Intergroup Cooperative Ewing Sarcoma Study-92 (EICESS-92) protocol (group B). These patients did not receive TB-MRI and consequently did not receive TB-MRI-governed ICI, or HDC and SCR. Survival in group A vs group B was 45 vs 8% at 5 years and 27 vs 8% at 10 years after diagnosis (log rank and Breslow: P<0.005). We conclude that TB-MRI-governed ICI followed by HDC and SCR in ET-MBM is feasible and warrants further evaluation in prospective studies.