Lorenz Grigull

Role of diagnostic and ablative minimally invasive surgery for pediatric malignancies

The use of minimally invasive surgery (MIS) in pediatric cancer is a matter of debate. The diagnostic and ablative roles of MIS were evaluated in a consecutive series of children with malignancies.

Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies

Fungal infections represent a life-threatening complication for patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Historically, antifungal monotherapy is associated with a poor outcome. We treated three children with hematological malignancies and proven fungal infections (one cerebral mold infection, one disseminated Candida infection, one naso-pharyngeal mucor infection) with combination antifungal therapy plus granulocyte-colony-stimulation-factor-mobilized granulocyte transfusions as secondary prophylaxis during subsequent neutropenic episodes. With this approach, the fungal infection was effectively treated, and the anticancer therapy was completed without major delay. All children survived the fungal infection and the underlying malignancy. These experiences illustrate the feasibility of this approach using more than one antifungal agent together with immune-therapy in high-risk patients.

Intravenous and oral sequential itraconazole antifungal prophylaxis in paediatric stem cell transplantation recipients: A pilot study for evaluation of safety and efficacy

Abstract:  This single‐centre, retrospective, observational pilot study was performed to evaluate the safety and efficacy of intravenous and oral itraconazole prophylaxis in paediatric haematopoietic stem cell transplantation (HCT). Study end‐points were proven invasive fungal infection (IFI), survival, adverse reactions and graft‐vs.‐host disease (GVHD); 53 children and one young adult (median age 8.6 yr; range 0.4–18.3) transplanted between November 2001 and August 2004 were included in this study. Itraconazole was given intravenously from day +3 after HCT until oral medication became possible and continued until day +100 after HCT. Two proven new IFI in the itraconazole group (candidiasis, n = 1; aspergillosis, n = 1) were observed. After a median follow‐up of 1.6 yr (0.3–6.1), six deaths (8%) were seen; 24 patients (45%) developed GVHD degree I–II, three children (6%) had GVHD degree III–IV. In 11 of 53 patients (21%), itraconazole prophylaxis was discontinued prematurely, mostly because of fever of unknown origin (n = 7). In total, 21 of 53 (40%) of the children had abnormal results of laboratory investigations during the prophylaxis. The results of this pilot study indicate that itraconazole prophylaxis during HCT in children is feasible and safe, despite abnormal laboratory results. The efficacy in terms of prevention of IFI, however, has to be addressed in a prospective large‐scale study.

Developmental Outcome in Five Children with Hurler Syndrome after Stem Cell Transplantation: A Pilot Study.

Hurler syndrome (mucopolysaccharidosis type 1H; MPS1H) is a lysosomal storage disease caused by a deficiency of α‐L‐iduronidase activity. The natural course of this neurodegenerative disease inevitably leads to premature death within the first 10 years of life. Enzyme replacement therapy is effective in correcting the enzymatic deficiency of organs other than the central nervous system. Hematopoietic stem cell transplantation (SCT) is the only treatment known to prevent psychomotor deterioration. However, the classical transplantation protocols resulted in a high incidence of graft failure and regimen‐related toxicity. Recently, we published a well‐tolerated, fludarabine‐based, radiation‐free conditioning regimen for SCT in patients with Hurler syndrome. Here we report the developmental outcome (assessed by the Denver Developmental Screening Test before and yearly after SCT) of four females and one male with MPS1H (mean age at last follow‐up 71mo, range 42‐87mo) treated in accordance with this strategy. Mean age at SCT was 25 months (range 10‐36mo). All children were engrafted and in ambulatory care. They all showed psychomotor development without neurodegeneration. In all patients, after SCT a regression of intracranial lesions could be seen that paralleled the psychomotor improvements. SCT led to a relative reduction of head circumference in all cases.

Efficacy and Safety of G-CSF Mobilized Granulocyte Transfusions in Four Neutropenic Children with Sepsis and Invasive Fungal Infection

Abstract.Background: Bacterial and fungal infections are serious complications of cancer therapy. Especially during longstanding neutropenia, patients are at risk for life-threatening infections. The aim of this study was to assess the effect and safety of G-CSF mobilized granulocyte transfusions (GTX) in four neutropenic pediatric patients with sepsis. Patients and Methods: The patients were between 4.6–17.5 years old and their diagnoses included very severe aplastic anemia, non-Hodgkins lymphoma (NHL) and acute myeloid leukemia. Before GTX, all patients had fever despite antibiotic and antimycotic therapy, neutropenia (absolute neutrophil count ANC < 500/μl), increasing C-reactive protein (CRP) values, hypotension requiring dopamine infusion and three patients needed supplemental oxygen. The granulocyte donors received G-CSF (Neupogen™, 5 μg/kg body weight) 12 h prior to granulocyte apheresis. Results: In total, 40 GTX were performed (range 2–28 per patient). The mean increase of the granulocyte count 1 h after GTX was 1,310/μl (range 200–2,950/μl). Within the period of GTX the CRP values decreased in all patients. During or 24 h after the last GTX, the hypotension resolved and supplemental oxygen was stopped. One GTX was discontinued because of oxygen desaturation. Conclusion: GTX were a safe therapeutic measure with beneficial effects on serious infections in neutropenic children.

Pharmacokinetic monitoring of intravenous cyclosporine A in pediatric stem‐cell transplant recipients. The trough level is not enough

Abstract:  In order to monitor CsA serum levels after SCT, trough levels (C0) are widely used. The aim of this study was to estimate the population and individual PK parameters for patients receiving intravenous CsA after SCT. In 27 pediatric patients after SCT receiving CsA (3 mg/kg/day) every 12 h, a total of 289 CsA concentrations was obtained. To describe the PK parameters of CsA, a two‐compartment model with first order elimination was used. Covariate analysis identified body weight, age, and the co‐administration with itraconazole and tobramycine as factors influencing the Cl. The statistical comparison of AUC, trough level, and C2 indicates a correlation between AUC and C2, but no correlation between the AUC and C0, r = 0.24 (p = 0.146) vs. r = 0.526 (p = 0.000692), respectively. Our results underscore the fact that CsA trough levels do not reflect the drug exposure in patients receiving intravenous CsA after SCT. By contrast, CsA blood levels measured 2–6 h after CsA infusion showed a better correlation with the AUC. Our data provide new information to optimize the balancing act between GvHD‐prophylaxis, graft vs. leukemia effect, and CsA side‐effects after SCT.

A dose‐response analysis of lenograstim plus dexamethasone for neutrophil mobilization and collection

BACKGROUND: The objective was to evaluate the dose‐response relationship of lenograstim plus dexamethasone for neutrophil mobilization and collection.

Supporting diagnostic decisions using hybrid and complementary data mining applications: a pilot study in the pediatric emergency department

Introduction:This article demonstrates the capacity of a combination of different data mining (DM) methods to support diagnosis in pediatric emergency patients. By using a novel combination of these DM procedures, a computer-based diagnosis was created.Methods:A support vector machine (SVM), artificial neural networks (ANNs), fuzzy logics, and a voting algorithm were simultaneously used to allocate a patient to one of 18 diagnoses (e.g., pneumonia, appendicitis). Anonymized data sets of patients who presented in the emergency department (ED) of a pediatric care clinic were chosen. For each patient, 26 identical clinical and laboratory parameters were used (e.g., blood count, C-reactive protein) to finally develop the program.Results:The combination of four DM operations arrived at a correct diagnosis in 98% of the cases, retrospectively. A subgroup analysis showed that the highest diagnostic accuracy was for appendicitis (97% correct diagnoses) and idiopathic thrombocytopenic purpura or erythroblastopenia (100% correct diagnoses). During the prospective testing, 81% of the patients were correctly diagnosed by the system.Discussion:The combination of these DM methods was suitable for proposing a diagnosis using both laboratory and clinical parameters. We conclude that an optimized combination of different but complementary DM methods might serve to assist medical decisions in the ED.

Oxaliplatin, irinotecan, and gemcitabine: a novel combination in the therapy of progressed, relapsed, or refractory tumors in children.

Therapeutic options for unresectable neuroendocrine carcinomas and relapsed or refractory solid tumors are still limited in pediatric patients. We present a retrospective review of 12 children (3 to 16 y) in a case series treated with a novel combination of oxaliplatin, irinotecan, and gemcitabine (triple therapy). We defined its feasibility in a mainly outpatient setting and assessed its toxicity and effectiveness. Three patients with unresectable neuroendocrine carcinomas received triple therapy as first-line treatment; 9 children with relapsed or refractory solid tumors of different entities were assigned after failure of standard treatment protocols. The treatment schedule comprised oxaliplatin (85 mg/m2), irinotecan (175 mg/m2), and gemcitabine (1,000 mg/m2), the latter to be repeated on day 8. A median of 7 cycles was applied. Nine of 12 patients showed hematotoxicity 0-III degrees. Gastrointestinal toxicity I-II degrees were handled satisfactorily by supportive drugs. Tumor response was defined as partial response in 1 of 12 children, stable disease in 8 of 12 children, and progressive disease in 3 of 12 children with a median time of disease control of 7 months. We regard triple therapy as a well-tolerated outpatient treatment option offering children a high quality of life and showing considerable effectiveness in delaying tumor progress.

The Role of Laparoscopic Techniques in Children with Suspected Post-Transplantation Lymphoproliferative Disorders

AIM To assess the role of minimally invasive surgery (MIS) to diagnose post-transplantation lymphoproliferative disorder (PTLD) in pediatric patients. METHODS Thirty-four patients (20 male, 14 female) underwent organ transplantation (14 liver, 14 kidney, 3 heart, 2 lung, 1 heart-lung) from May 1992 to November 2008 (mean age at transplantation, 66 months; range, 5-277), in whom a biopsy was performed for suspected PTLD from May 1993 to September 2009. The time point of onset, type of PTLD, rate of intraabdominal manifestations with need of MIS, and its accuracy were assessed. RESULTS Twenty-four of 34 patients (70%) had biopsies of superficial lymph nodes (9), oropharyngeal biopsy (5), gastrointestinal endoscopy or bronchoscopy (5), ultrasound-guided biopsies (3), biopsy of the bone marrow (1), or of the orbita (1). Data of the technique used were unavailable in 3 (9%). Due to lack of superficially located lesions, 6 of 34 patients (18%) had laparoscopic biopsy, of which 4 had abdominal organ graft. Laparoscopic biopsy was successful in 5 of 6 cases (83%). Abscess formation at area of transplanted kidney led to conversion in 1. Tumor extension to the abdominal wall led to a primary biopsy via a mini-laparotomy in another case. One patient with abdominal Burkitts lymphoma developed a trocar metastasis, successfully treated by systemic chemotherapy. No other complications were observed after MIS. Accuracy of MIS biopsies was 100%. The onset of PTLD was significantly later diagnosed in cases of explicit intraabdominal PTLD (81 ± 6.3 versus 28 ± 5.3 months; P < .001). Morbidity and mortality were not influenced by biopsy technique or time point of PTLD onset. CONCLUSIONS In 20% of pediatric PTLD cases an intraabdominal biopsy is required due to explicit intraabdominal manifestation. As laparoscopic surgery was even feasible in patients after prior abdominal organ transplantation, we suggest laparoscopic biopsy as a safe tool for diagnosing PTLD.