[show abstract][hide abstract] ABSTRACT: Human cytomegalovirus infections are still significant causes of morbidity and mortality in transplant recipients. The use of antiviral agents is limited by toxicity and evolving resistance in immunocompromised patients with ongoing viral replication during therapy. Here, we present the first documented case of genotypic resistance against maribavir in a bone marrow transplant (BMT) recipient.
The female 13-year-old patient was suffering from a refractory cytopenia. Ganciclovir, foscarnet, cidofovir, leflunomide and maribavir, an inhibitor of the cytomegalovirus UL97 protein, were administered to treat a therapy-resistant cytomegalovirus infection. Viral mutations conferring resistance against nucleotide and pyrophosphate analogs as well as maribavir (MBV) have evolved sequentially. Particularly, impressive was the fast emergence of multiple mutations T409M, H411Y and H411N conferring maribavir resistance after less than 6 weeks.
We describe the fast emergence of cytomegalovirus variants with different maribavir resistance associated mutations in a bone marrow transplant recipient treated with MBV 400 mg p.o. twice per day. The results suggest that a high virus load permitted a selection of several but distinct therapy-resistant HCMV mutants. Since a phase II study with MBV is intended for the treatment of resistant or refractory HCMV infections in transplant recipients this has to be kept in mind in patients with high viral loads during therapy (NCT01611974).
[show abstract][hide abstract] ABSTRACT: Respiratory viruses are an important yet underestimated cause of infectious morbidity and mortality in immunocompromised children and adolescents. Here, we report the occurrence of fatal lower respiratory tract disease associated with human metapneumovirus (HMPV) infection in a 10-year-old girl with chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HSCT) for secondary chronic myeloid leukemia. Symptoms occurred 8 months after HSCT while on immunosuppression with 0.2 mg/kg/day of prednisone, and presented as dry cough, bilateral pneumonitis, and progressive respiratory distress. Non-invasive and invasive microbiological investigations revealed HMPV type B as the sole pathogen. Histopathological findings showed interstitial and intra-alveolar pneumonitis with profound alveolar cell damage. The patient was treated with intravenous and oral ribavirin and polyvalent immunoglobulins, but ultimately died from respiratory failure. The case reflects the potentially fatal impact of infections by respiratory viruses in immunocompromised patients and the need for effective approaches to their prevention and treatment.
[show abstract][hide abstract] ABSTRACT: Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions.Bone Marrow Transplantation advance online publication, 29 October 2012; doi:10.1038/bmt.2012.204.
Bone marrow transplantation 10/2012; · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report the long-term follow-up of children transplanted with Treosulfan (TREO)-based conditioning in Germany and Austria. Nine centres reported a total of 109 transplantations. Patients were stratified according to the paediatric TRM risk score derived from the paediatric BMT registry (PRST) and compared with the historical transplant population of this registry. Underlying diseases were malignancies, immunodeficiencies, and haematologic and metabolic disorders. TREO total dose ranged from 21-42 g/m(2). Additional conditioning drugs included fludarabine, thiotepa, melphalan, CY and/or TBI. EFS at 3 years for non-malignant and malignant diseases was 88% and 49%, respectively. Leukaemia patients in remission had a survival of 51% at 3 years; nonremission patients relapsed and died within 18 months. TRM and OS in the low-risk groups 0 and 1 were similar to PRST controls. TRM in the high-risk groups 2 and 3 was markedly lower (9% vs 28% and 13% vs 53%, respectively) than in the PRST group, but OS was similar. In conclusion, TREO-based conditioning regimens in children resulted in excellent engraftment and long-term survival in nonmalignant disease. In high-risk malignancy, low acute toxicity was followed by low TRM but it did not translate into increased survival.Bone Marrow Transplantation advance online publication, 22 October 2012; doi:10.1038/bmt.2012.188.
Bone marrow transplantation 10/2012; · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ehlert K, Groll AH, Rossig C, Fruehwald MC, Juergens H. Late graft failure in FA - case report and review of the literature. Abstract: Hematological disorders in patients with FA can only be cured by allogeneic HSCT. Severe infections in primary and early secondary graft failures pose a particular risk. Whereas most graft failures occur within 100 days, those observed after day +100 are infrequent. Here, we present our analysis of a secondary graft failure more than five yr after a first allogeneic HSCT. In this patient, isolated thrombocytopenia over a period of 12 months resulted in a chimerism subset analysis revealing a considerable decrease in the CD34-positive donor cell fraction. After a second fludarabine-based preparative regimen, the patient received PBSC from the same donor. Chimerism returned to full donor in all subsets. This clinical course demonstrates that isolated thrombocytopenia can precede complete graft failure for several months. Our review of the literature on late graft failures in patients with FA after day +100 reveals the absence of fludarabine in the preparative regimen as a potential risk factor. Further clinical research is necessary to identify more suitable approaches for ensuring safe and stable engraftment.
[show abstract][hide abstract] ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.
[show abstract][hide abstract] ABSTRACT: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.
In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948.
Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.
Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.
Gentium SpA, European Group for Blood and Marrow Transplantation.
The Lancet 02/2012; 379(9823):1301-9. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective: Busulfan (BU), in combination with melphalan (MEL),
highdose chemotherapy (HDC) with autologous stem cell transplantation
is widely used in consolidation treatment of poor-prognosis Ewing sarcoma
patients. Treosulfan (TREO) has been newly introduced recently
into the treatment protocols. We analyzed treatment-related toxicities
and outcome in patients treated with BU-MEL or TREO-MEL HDC according
to the EURO-E.W.I.N.G.99 (EE99) protocol of the German Society
of Pediatric Hematology and Oncology (GPOH) from 1998–2009.
Methods: 157 patients were identified with full records of BU-based
HDC, administrated PO in 113 patients and IV in 44 patients, and 44 patients
with IV TREO-based HDC. BU-MEL was given in 31.8% (n=50)
according to high-risk localized disease mainly for poor response to
initial chemotherapy (R2loc), in 25.5% (n=40) for pulmonary metastases
(R2pulm), and in 42.7% (n=67) for primary mainly skeletal dissemination
(R3). TREO-MEL patients had a more progressed risk profile
(R2loc: 6; 13.6%; R2pulm: 5; 11.4%; R3: 33; 75%; p=0.001). HDC toxicity
was analyzed by descriptive statistics according to modified CTC toxicity
grade scales of the EE99 protocol. Outcome was analyzed descriptively
by event-free survival (EFS) and overall survival (OS) controlled
for risk factors by multivariate regression analysis.
Results: Grade 3 and 4 ratings occurred in 654 of 2500 toxic episodes
(26.2%) in BU-MEL HDC (PO: 27.3%; IV: 23.5%), and in 163 of 842 toxic
episodes (19.4%) in TREO-MEL HDC (vs. BU-MEL PO+IV: p<0.0001;
IV only: p=0.046). Clinical relevant reductions of severe toxicities
>10% in total in single scales were observed in TREO-MEL compared
to PO+IV BU-MEL and compared to IV BU-MEL: WBC (vs. BU-MEL
PO+IV: p=.001; IV only: p=.016); granulocytes (p=.016; p=.120); platelets
(p=.016; p=.114); infection (p=0.020; p=0.075); stomatitis (p<0.001;
p=0.044). 3y-EFS (OS) was 0.51 (0.67; SE=0.08) in IV BU-MEL, 0.45 (0.61;
SE=0.05) in PO BU-MEL, and 0.24 (0.47; SE=0.07–0.08) in TREO-MEL.
Adjusted for risk group (R2loc; R2pulm; R3), primary tumor volume
(cut-off 200 ml) and age (cut-off 15 years), the risk ratio regarding EFS
for TREO-MEL vs. IV BU-MEL was 1.86 (95% CI 1.02–3.39; p=0.044),
and the risk ratio regarding OS was 1.75 (95% CI 0.88–3.47; p=0.110).
Conclusions: Results from this large cohort of high-risk Ewing sarcoma
patients indicate a reduction in toxicity with Treosulfan-based HDC.
The outcome regarding EFS and OS must be carefully monitored.
*supported by Deutsche Krebshilfe.
Journal of Cancer Research and Clinical Oncology 02/2012; 138(Suppl.1):9. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children.
[show abstract][hide abstract] ABSTRACT: Currently, a routine bone marrow biopsy (BMB) is performed to detect bone marrow (BM) involvement in pediatric Hodgkin's lymphoma (HL) stage greater than IIA. [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used for the initial staging of HL. The value of using FDG-PET to detect BM involvement has not been sufficiently defined. We compared the results of BMBs and FDG-PET for the diagnosis of BM involvement in a large pediatric group with HL.
The initial staging of 175 pediatric patients with newly diagnosed classical HL stage greater than IIA was determined by using BMB, FDG-PET, chest computed tomography (CT), and magnetic resonance imaging (MRI) or CT of the neck, abdomen, and pelvis. Staging images were prospectively evaluated by a central review board. Skeletal regions that were suggestive of BM involvement by either method were re-evaluated by using different imaging modalities. In suspicious cases, bone scintigraphy was performed. If follow-up FDG-PET scans were available, the remission of skeletal lesions during treatment was evaluated.
BMB results were positive in seven of 175 patients and were identified by FDG-PET. FDG-PET scans showed BM involvement in 45 patients. In addition, the lesions of 32 of these 45 patients had a typical multifocal pattern. In 38 of 39 follow-up positron emission tomography scans, most of the skeletal lesions disappeared after chemotherapy. There was no patient with skeletal findings suggestive of BM involvement by MRI or CT with a negative FDG-PET.
FDG-PET is a sensitive and specific method for the detection of BM involvement in pediatric HL. The sensitivity of a BMB appears compromised by the focal pattern of BM involvement. Thus, FDG-PET may safely be substituted for a BMB in routine staging procedures.
Journal of Clinical Oncology 08/2011; 29(26):3523-8. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Infertility is a major late effect in patients receiving haematopoietic stem cell transplantation (HSCT). The aim of this study was to determine the proportion of patients having fertility impairment after allogeneic HSCT in childhood/adolescence and to identify the potential risk factors. Treatment and fertility data of paediatric patients with malignant and non-malignant diseases treated with allogeneic HSCT between 2000 and 2005 were collected from seven European centres. Data were obtained for 138 female and 206 male patients after a median follow-up of 6 years (range 3-12). The patients' median age was 13 years (range 4-28) at the time of HSCT and 19 (range 12-35) years at the time of the enquiry. Seven children were born to the overall group, all at term and healthy. Fertility impairment was suspected in 69% males and 83% females. Start of treatment at age 13 years was a risk factor in females (odds ratio (OR) 4.7; 95% confidence interval (CI), 1.5 to 14.9), whereas pre-pubertal therapy was a risk factor in males (OR 0.4; 95% CI, 0.2 to 0.8). The major treatment-related risk factors were BU in females (OR 47.4; 95% CI, 5.4 to 418.1) and TBI in males (OR 7.7; 95% CI, 2.3 to 25.4). In light of the significant proportion of HSCT patients reviewed with impaired fertility, fertility conservation procedures should be considered for all patients undergoing HSCT, particularly those receiving TBI or BU-based preparative regimens.
Bone marrow transplantation 04/2011; 47(2):271-6. · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Invasive aspergillosis (IA) at the insertion site of central venous catheters is a rare event. Here we report the occurrence of chest wall aspergillosis at the insertion site of a Broviac catheter in a 5-year-old child undergoing allogeneic hematopoietic stem cell transplantation. The infection arose during profound granulocytopenia under conditions of reverse isolation with laminar air flow and high efficiency particulate air filtration and was successfully managed with repeat surgical debridement, voriconazole/caspofungin combination therapy guided by therapeutic drug monitoring, and adjunctive use of granulocyte colony-stimulating factor. The case reflects the occurrence of IA despite reverse isolation and air decontamination, the principles of treatment of Aspergillus soft tissue infections in granulocytopenic patients, and the need for therapeutic drug monitoring of voriconazole particularly in young children.
[show abstract][hide abstract] ABSTRACT: Objectives: Busulfan (BU), in combination with melphalan (MEL), high-dose chemotherapy (HDC) with autologous stem cell transplantation is widely used in consolidation treatment of poor-prognosis Ewing sarcoma patients. Intravenous (IV) BU was approved for application during the EURO-E.W.I.N.G.99 (EE99) trial. We analyzed treatment-related toxicities and outcome of BU administered orally (PO) or IV in patients treated from 1999-2009 according to the EE99 protocol.
Methods: Administration method and doses of busulfan given to 157 patients (pts) treated with BU-based HDC (BU-MEL) were extracted from patient records and the EE99 trial database of the German Society of Pediatric Hematology and Oncology (GPOH). 113 pts had received PO BU; 32 pts had high-risk localized disease mainly for poor response to initial chemotherapy (R2loc; 28.3%), 31 pts pulmonary metastases (R2pulm; 27.4%), and 50 pts had primary mainly skeletal dissemination (R3; 44.2%). 44 pts had received IV BU (R2loc: 18; 40.9%; R2pulm: 9; 20.5%; R3: 17; 38.6%). HDC toxicity was analyzed by descriptive statistics according to modified CTC toxicity grade scales of the EE99 protocol. Outcome was analyzed descriptively by event-free-survival (EFS) and overall-survival (OS) controlled for risk factors by multivariate regression analysis.
Results: Grade 3 & 4 toxicity ratings occurred in 480 of 1759 cases (27.3%) in the PO group, and in 174 of 741 cases (23.5%; p=.048) in the IV group. Most of these serious toxicities were hematological with no difference in both groups (431 cases; >85% of patients per group; p=.59). Major differences with a clinical relevant reduction of more than 10% in single scales were observed in the IV group regarding: general condition (IV: 18.2% vs. PO: 33.3%; p=.028; non-dichotomous), stomatitis (51.2% vs. 63.2%; p=.032; non-dichotomous); diarrhoea (0% vs. 12.5%; p=.033) and elevated bilirubin (2.8% vs. 13.3%; p=.104). 5y-EFS (OS) was 0.47 (0.57; SE=.08) for IV BU vs. 0.42 (0.49; SE=.05) in PO BU. Adjusted for risk group (R2loc; R2pulm; R3) and age (cut-off 15years), the EFS risk ratio for PO vs. IV BU was 1.35 (95%CI 0.82-2.22), and the OS risk ratio was 1.49 (95%CI 0.85-2.61).
Conclusion: Results from this retrospective analysis of a large cohort of high-risk Ewing sarcoma patients indicate a reduction in toxicity with IV BU-based HDC.
Bone Marrow Transplantation 04/2011; 46(1):S381-S381. · 3.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report a 6-year-old female with congenital bone marrow failure, who was referred for allogeneic stem cell transplantation. An initial work-up in infancy had not revealed any consistent symptoms associated with an inherited syndrome. Computed tomography of her abdomen for gastrointestinal bleeding after transplantation incidentally revealed a fat-replaced pancreas and led to the molecular diagnosis of Shwachman-Diamond syndrome (SDS) in the absence of clinical exocrine pancreatic insufficiency. We conclude that SDS may escape the clinical consensus criteria for the disease. Increased awareness of unusual presentations may allow confirming the suspected diagnosis by molecular analysis and ensure optimal management.
Pediatric Blood & Cancer 07/2010; 55(1):177-9. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although the standard of care in febrile neutropenic patients includes the initiation of empirical antibacterial and antifungal therapy, many patients do not respond and need further diagnostic work up and treatment. Here, we report on an immunosuppressed neutropenic patient with a prolonged episode of fever unresponsive to empirical antibacterial therapy. Herpes polymerase chain reaction revealed systemic reactivation of herpes simplex virus type 1 (HSV-1) infection and treatment with acyclovir was associated with the prompt resolution of signs and symptoms of infection. Screening for HSV in persistently febrile neutropenic patients may discover HSV reactivation that can be treated successfully by acyclovir administration.
Journal of Pediatric Hematology/Oncology 12/2009; 32(1):e19-21. · 0.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Treatment with rituximab is highly effective for EBV-associated post transplant lymphoproliferative disease. However, little is known about its immunological sequelae in pediatric allogeneic hematopoietic SCT (HSCT). Time to normal CD19+ B-lymphocyte values in blood and intravenous immunoglobulin (IVIG) substitution needed to maintain an IgG>400 mg per 100 ml in six consecutive pediatric allogeneic HSCT patients treated with rituximab for symptomatic EBV reactivation were compared with a matched cohort of non-rituximab-treated patients. Follow-up of the six patients ranged from 149 to 1546 days; all but one survived. The mean (+/-s.d.) time to recovery of CD19+ B-lymphocytes was 353+/-142 days as compared with 139+/-42 in the controls (P<0.01). Similarly, substitution of IVIG as a measure of functional B-cell recovery was extended from a mean of 122+/-45 to a mean of 647+/-320 days, and the cumulative dose of IVIG increased from a mean of 1.86+/-0.51 to 4.4+/-0.97 g/kg, respectively (P<0.05). One patient had functional B-lymphocyte deficiency for >3 years and ultimately required two stem cell boosts. Rituximab is a live-saving treatment for pediatric HSCT patients but may lead to prolonged and even persistent B-cell deficiency.
Bone marrow transplantation 12/2008; 43(9):679-84. · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Presumed or proven invasive pulmonary aspergillosis (IPA) is an important cause of infectious morbidity in patients with acute leukaemia. Although prior IPA is not a contraindication for subsequent allogeneic haematopoietic stem cell transplantation (HSCT), its management during granulocytopenia and immunosuppression remains challenging.
In the absence of an evidence-based approach, 11 adolescents (11-18 years) with acute leukaemia and a history of antecedent possible (4) or probable (7) IPA received liposomal amphotericin B (LAMB; 1 mg/kg once a day) from the start of the conditioning regimen until engraftment and ability to take oral medication, followed by oral voriconazole (200 mg twice a day) until the end of the at-risk period. Nine patients had a good partial response (>50% reduction in pulmonary infiltrates) and two had a complete response prior to HSCT.
The median duration of intravenous treatment with LAMB was 30 days (range, 19-36), followed by a median of 152 days (range, 19-210) of oral voriconazole. LAMB was discontinued early in one patient and voriconazole was transiently or permanently discontinued due to adverse events/new contraindications in two and two patients, respectively. At +180 days post-transplant, eight patients were alive, six with complete, and one each with near complete and ongoing resolution of pulmonary infiltrates; all but one were in continuing haematological remission. Three patients had succumbed either to recurrent leukaemia (two) or refractory graft failure (one); whereas one of these patients had maintained a complete response, two died with secondary possible (one) or probable (one) IPA. Both patients had discontinued voriconazole early and developed IPA in lung areas involved during the primary episode.
This prospective paediatric series supports the notion that secondary antifungal prophylaxis for possible or probable IPA can be safely achieved in allogeneic HSCT. In the absence of chronic graft-versus-host disease, breakthrough infection appeared to be associated with recurrent leukaemia/graft failure and shorter duration of post-engraftment prophylaxis.
Journal of Antimicrobial Chemotherapy 04/2008; 61(3):734-42. · 5.34 Impact Factor