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Papers by Andreas Klein-Franke

Journal of Pediatric Gastroenterology and Nutrition, 2010

Journal of Cancer Research and Clinical Oncology, Jul 1, 1994

Rhamnogalacturonan-mediated enhancement of MHC-unrestricted cytotoxicity was studied with freshly... more Rhamnogalacturonan-mediated enhancement of MHC-unrestricted cytotoxicity was studied with freshly isolated CD56+CD3-natural killer (NK) cells, interleukin-2 (IL-2)-activated CD56 + lymphokine-activated killer (LAK) cells und IL-2/anti-CD3-activated T cells as effector cells using NK-sensitive and NK-insensitive tumor cells as targets. The rhamnogalacturonan fractions IM, IR and IQ were prepared from commercially available extracts of Viscum album. The dose/response relation of IM, IR and IQ demonstrated the presence of various concentrations of cytotoxicity-enhancing compounds in all three fractions that were identified as rhamnogalacturonans by degradation studies with poly-c~-Dgalacturonidase (EC 3.2.1.15) and c~-1,6-rhamnosidase (EC 3.2.1.40). Specific cytotoxicity of all three effector cell populations as well as the respective rhamnogalacturonan-mediated cytotoxicity enhancement was readily inhibited in a dose-dependent manner by 60%-deacetylated mannose pentaacetate. Rhamnogalacturonan-mediated enhancement of cytotoxicity of fresh CD56 § NK cells was also observed with four of five NK-insensitive tumor cells as targets, indicating that the effector-cell/tumor-cell bridging activity of rhamnogalacturonans renders NK-insensitive targets susceptible to NK-mediated lysis. Moreover, the rhamnogalacturonan-mediated cytotoxicity enhancement became even more prominent when lymphokine-activated CD56 § LAK and CD3 + T cells were assayed with the NK-insensitive tumor cell targets.

Pediatric Blood & Cancer, 2006

BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) ... more BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age‐ and sex‐specific reference data from the UK General Practice Research Database (GPRD).ProcedureMedical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis.ResultsSkeletal complications occurred at a 5‐year incidence of 32.7%. The 5‐year incidence of fractures, ON, and isolated bone pain was 13.5%, 12.1%, and 12.3%, respectively. The relative rate of fractures adjusted for age and sex was 2.03 (95% confidence interval 1.15–3.57) compared to the GPRD, with greatest rates in children <5 years. Thirty ON occurred in 10 patients with a 15 times greater incidence in children >10 years than in those <5 years. Nearly all skeletal complications occurred during maintenance therapy at a median of 14.92 months (range 0.0–53.8) after diagnosis and in weight‐bearing bones.ConclusionsThe doubled fracture rate and the high incidence of skeletal complications during the first years after diagnosis suggest the developing skeleton is very vulnerable in this period. Adolescents develop more ON whereas younger children may be more prone to fractures. Serious “immediate effects” of chemotherapy on bone appear of great concern and should entail preventative studies in this group of patients. Pediatr Blood Cancer 2007;48:21–27. © 2005 Wiley‐Liss, Inc.

Pediatric Blood & Cancer, Feb 1, 2008

BackgroundChildren with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboemb... more BackgroundChildren with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboembolism (TE) that is related to L‐asparaginase‐induced antithrombin (AT) deficiency and placement of central venous lines. Recent in vitro studies showed that the anticoagulant effects of low‐molecular‐weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy.MethodsA total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocols were enrolled in this trial. This prospective cohort study was carried out to determine the influence of combined low molecular weight heparin‐prophylaxis (enoxaparin 1 mg/kg/ per day) and AT supplementation versus AT alone (noncontemporaneous control group) on the incidence of symptomatic TE during a follow‐up of 240 days.ResultsTo maintain AT plasma levels above 50%, nearly 60% of all children needed at least one, most children two or three AT supplementations during induction therapy. 12.7% of the children that did receive only AT‐prophylaxis (n = 71) (95% CI = 6.0–22.7) developed objectively confirmed symptomatic TE, as compared with no TE in children after combined prophylaxis (n = 41) (95% CI = 0.0–8.6, P < 0.05). Thromboses were located in the sinovenous system in the brain (n = 3), the lower deep veins (n = 3), the upper deep veins (n = 2) and in an upper deep vein combined with pulmonary embolism (n = 1).ConclusionProphylaxis with enoxaparin was safe and effective in preventing TE. Although our data are encouraging, the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospective randomized clinical trial. Pediatr Blood Cancer 2008;50:298–303. © 2007 Wiley‐Liss, Inc.

Neuropediatrics, Sep 11, 2014

Immunology Letters, Oct 1, 1993

Spontaneous cytotoxicity of human monocytes (purity: 92-95%) against K562 tumor cells was only ob... more Spontaneous cytotoxicity of human monocytes (purity: 92-95%) against K562 tumor cells was only observed in 31% healthy donors but, in the presence of rhamnogalacturonan (500 ng/ml), enhanced cytotoxicity was recorded for 79% (n = 14) of the donors. Monocytes activated by culturing with interleukin-2 and/or IFN gamma showed increased antitumor cytotoxicity against K562 tumor cells in 86% (n = 21) of the donors exhibiting additional increases in specific cytotoxicity when the cytotoxicity assays were carried out in the presence of rhamnogalacturonan. Increases of monocyte cytotoxicity achieved by activation with cytokines coincided with increased formation of monocyte/tumor cell conjugates. Similarly, increased monocyte cytotoxicity mediated by rhamnogalacturonan also correlated with increased monocyte/tumor cell conjugate formation most likely due to effector cell/target cell bridging as was originally described for rhamnogalacturonan interacting with CD56+ natural killer or lymphokine-activated killer cells and tumor cells. The chemospecificity of the monocyte-based receptors responsible for cytotoxicity and for monocyte/tumor cell conjugate formation, as well as for their rhamnogalacturonan-mediated enhancements, appears to be identical since all these effects could be inhibited in a dose-dependent manner by partially deacetylated (60%) mannose pentaacetate.

Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed i... more Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0 % of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of...

Journal of dentistry for children, 2020

Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathet... more Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathetic nervous system. Curative therapy is challenging, especially because early-stage diagnosis in toddlers is difficult. Successful treatment of high-risk neuroblastoma is only achieved in approximately half of the cases and requires an immediate interdisciplinary approach. We present a 34-month-old toddler with swelling of the left side of the face of three days duration and a mandibular mass of unknown duration, which was diagnosed as a metastasis of a neuroblastoma. He also had metastases in the kidney, long bones and skull. Despite the poor prognosis in cases of disseminated skeletal involvement and N-myc amplification, the young patient remained free of recurrence during a follow-up period of 36 months after multidisciplinary treatment. The purpose of this case report is to increase awareness of the clinical features of neuroblastoma among pediatric dentists to support early-stage dia...

Journal of Allergy and Clinical Immunology, 2021

Background: The recognition of viral nucleic acids is one of the primary triggers for a type I in... more Background: The recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections, as a result of dysbalanced interferon production. NFX1-type zinc-finger-containing 1 (ZNFX1) is an interferon-stimulated double-strand RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1's role in the human immune response is not known. Objective: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocyticlymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease. Methods: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, post-transcriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. Results: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of ISGs mRNA and was associated with poorer clearance of virus infections by monocytes. Conclusion: ZNFX1 is an important regulator of the response to doublestranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Child's Nervous System, 2020

Background Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor, which usually occur... more Background Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor, which usually occurs in infants under the age of one. Early diagnosis and radical surgery seem to be critical for long-term cure. Case presentation We describe a case of a 4-month-old boy with a MNTI to the skull. The mass was first noticed at 4 month of age and grew very rapidly over a time of 2 weeks. Initially, a fine needle biopsy ruled out a sarcoma and led to the diagnosis. The tumor originated from the sphenoid wing and infiltrated the frontotemporal bone, the lateral wall of the right orbit, and the underlying dura mater. A total excision of the tumor, including the adjacent bone and dura, was achieved. Reconstruction of the bone was performed using absorbable plates and Tutobone. Histology confirmed the initial diagnosis, while molecular diagnosis showed high conformity of the MNTI with medulloblastoma group 3. The patient recovered well, while the reconstruction led to a good cosmetic result. A local recurrence occurred leading to a single-dose chemotherapy with Vincristine and a second surgery after 15 weeks. Thereafter, the patient developed recurrent large pseudomeningocele, which was treated by multiple shunt procedures and finally reconstruction of the bone using Palacos. Radiological follow-up 3 months after the second resection showed no tumor recurrence. Conclusion Radical surgery for MNTI is to date the gold standard since it seems to minimize recurrence rates. Because of the rapid and destructive growth within the bone, reconstruction is necessary, which can be very challenging in infants.

Pediatric Blood & Cancer, 2004

Teratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and c... more Teratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and carcinosarcoma components. The authors report on a case of TCS in the oral cavity of a child. Rapid growth and extensive local destruction were prominent features prior to treatment. Histologic examination revealed various tissue elements, such as epithelial, mesenchymal, and neuroectodermal components. Chemotherapy was effective in reducing tumor mass, followed by partial anterior mandibulectomy and reconstruction with composite microvascular tissue transfer. The approach allowed radical resection of the tumor and functional reconstruction with excellent aesthetic results.

Pediatric Blood & Cancer, 2006

BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) ... more BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age‐ and sex‐specific reference data from the UK General Practice Research Database (GPRD).ProcedureMedical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis.ResultsSkeletal complications occurred at a 5‐year incidence of 32.7%. The 5‐year incidence of ...

Orphanet Journal of Rare Diseases, 2012

New England Journal of Medicine, 2002

Background The group of susceptibility genes for pheochromocytoma that included the proto-oncogen... more Background The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. Methods Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. Results Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. Conclusions Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

Klinische Pädiatrie, 2013

Anemia in toddlers may result from many disorders including excessive feeding with cow&am... more Anemia in toddlers may result from many disorders including excessive feeding with cow's milk. Another sequel of age-inadequate cow's milk nutrition may be gastric lactobezoar (GLB), a dense lump of coagulated milk and mucus in the stomach. 3 toddlers presented with a history of excessive intake of full cream cow's milk, abdominal distension, vomiting, dehydration, fatigue, marked pallor and tachycardia. Diagnostic imaging revea-led large GLBs as the likely origin of the abdominal symptoms. Laboratory evaluation showed severe anemia with depleted iron stores and signs of protein catabolism. Non-cow's milk-induced causes of anemia including defects of erythropoiesis, hemoglobin structure, RBC-enzymes and blood coagulation, hemolysis, immune disorders, infection, inflammation, extraintestinal hemorrhage, nephropathy were - according to the available data - unlikely to cause the anemia in our patients. Thus their anemia is thought to be due to age-inadequate cow's milk nutrition leading to 1) low intake, decreased absorption/bioavailability and increased intestinal loss of iron, and 2) GLB which induced blood loss following mechanical irritation of the gastric mucosa and vomiting causing high gastric pH and decrease in duodenal iron absorption. The anemia in our patients is due to both exaggerated feeding with cow's milk and adverse effects of GLBs. This hypothesis is supported by the finding that, after erythrocyte transfusion, iron substitution, age-adapted nutrition and GLB-dissolution, the anemia did not recur. We propose to include GLB in the differential diagnosis of anemia in cow's milk fed small children.

Journal of Pediatric Gastroenterology & Nutrition, 2010

Journal of Pediatric Gastroenterology and Nutrition, 2010

Journal of Cancer Research and Clinical Oncology, Jul 1, 1994

Rhamnogalacturonan-mediated enhancement of MHC-unrestricted cytotoxicity was studied with freshly... more Rhamnogalacturonan-mediated enhancement of MHC-unrestricted cytotoxicity was studied with freshly isolated CD56+CD3-natural killer (NK) cells, interleukin-2 (IL-2)-activated CD56 + lymphokine-activated killer (LAK) cells und IL-2/anti-CD3-activated T cells as effector cells using NK-sensitive and NK-insensitive tumor cells as targets. The rhamnogalacturonan fractions IM, IR and IQ were prepared from commercially available extracts of Viscum album. The dose/response relation of IM, IR and IQ demonstrated the presence of various concentrations of cytotoxicity-enhancing compounds in all three fractions that were identified as rhamnogalacturonans by degradation studies with poly-c~-Dgalacturonidase (EC 3.2.1.15) and c~-1,6-rhamnosidase (EC 3.2.1.40). Specific cytotoxicity of all three effector cell populations as well as the respective rhamnogalacturonan-mediated cytotoxicity enhancement was readily inhibited in a dose-dependent manner by 60%-deacetylated mannose pentaacetate. Rhamnogalacturonan-mediated enhancement of cytotoxicity of fresh CD56 § NK cells was also observed with four of five NK-insensitive tumor cells as targets, indicating that the effector-cell/tumor-cell bridging activity of rhamnogalacturonans renders NK-insensitive targets susceptible to NK-mediated lysis. Moreover, the rhamnogalacturonan-mediated cytotoxicity enhancement became even more prominent when lymphokine-activated CD56 § LAK and CD3 + T cells were assayed with the NK-insensitive tumor cell targets.

Pediatric Blood & Cancer, 2006

BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) ... more BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age‐ and sex‐specific reference data from the UK General Practice Research Database (GPRD).ProcedureMedical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis.ResultsSkeletal complications occurred at a 5‐year incidence of 32.7%. The 5‐year incidence of fractures, ON, and isolated bone pain was 13.5%, 12.1%, and 12.3%, respectively. The relative rate of fractures adjusted for age and sex was 2.03 (95% confidence interval 1.15–3.57) compared to the GPRD, with greatest rates in children <5 years. Thirty ON occurred in 10 patients with a 15 times greater incidence in children >10 years than in those <5 years. Nearly all skeletal complications occurred during maintenance therapy at a median of 14.92 months (range 0.0–53.8) after diagnosis and in weight‐bearing bones.ConclusionsThe doubled fracture rate and the high incidence of skeletal complications during the first years after diagnosis suggest the developing skeleton is very vulnerable in this period. Adolescents develop more ON whereas younger children may be more prone to fractures. Serious “immediate effects” of chemotherapy on bone appear of great concern and should entail preventative studies in this group of patients. Pediatr Blood Cancer 2007;48:21–27. © 2005 Wiley‐Liss, Inc.

Pediatric Blood & Cancer, Feb 1, 2008

BackgroundChildren with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboemb... more BackgroundChildren with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboembolism (TE) that is related to L‐asparaginase‐induced antithrombin (AT) deficiency and placement of central venous lines. Recent in vitro studies showed that the anticoagulant effects of low‐molecular‐weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy.MethodsA total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocols were enrolled in this trial. This prospective cohort study was carried out to determine the influence of combined low molecular weight heparin‐prophylaxis (enoxaparin 1 mg/kg/ per day) and AT supplementation versus AT alone (noncontemporaneous control group) on the incidence of symptomatic TE during a follow‐up of 240 days.ResultsTo maintain AT plasma levels above 50%, nearly 60% of all children needed at least one, most children two or three AT supplementations during induction therapy. 12.7% of the children that did receive only AT‐prophylaxis (n = 71) (95% CI = 6.0–22.7) developed objectively confirmed symptomatic TE, as compared with no TE in children after combined prophylaxis (n = 41) (95% CI = 0.0–8.6, P < 0.05). Thromboses were located in the sinovenous system in the brain (n = 3), the lower deep veins (n = 3), the upper deep veins (n = 2) and in an upper deep vein combined with pulmonary embolism (n = 1).ConclusionProphylaxis with enoxaparin was safe and effective in preventing TE. Although our data are encouraging, the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospective randomized clinical trial. Pediatr Blood Cancer 2008;50:298–303. © 2007 Wiley‐Liss, Inc.

Neuropediatrics, Sep 11, 2014

Immunology Letters, Oct 1, 1993

Spontaneous cytotoxicity of human monocytes (purity: 92-95%) against K562 tumor cells was only ob... more Spontaneous cytotoxicity of human monocytes (purity: 92-95%) against K562 tumor cells was only observed in 31% healthy donors but, in the presence of rhamnogalacturonan (500 ng/ml), enhanced cytotoxicity was recorded for 79% (n = 14) of the donors. Monocytes activated by culturing with interleukin-2 and/or IFN gamma showed increased antitumor cytotoxicity against K562 tumor cells in 86% (n = 21) of the donors exhibiting additional increases in specific cytotoxicity when the cytotoxicity assays were carried out in the presence of rhamnogalacturonan. Increases of monocyte cytotoxicity achieved by activation with cytokines coincided with increased formation of monocyte/tumor cell conjugates. Similarly, increased monocyte cytotoxicity mediated by rhamnogalacturonan also correlated with increased monocyte/tumor cell conjugate formation most likely due to effector cell/target cell bridging as was originally described for rhamnogalacturonan interacting with CD56+ natural killer or lymphokine-activated killer cells and tumor cells. The chemospecificity of the monocyte-based receptors responsible for cytotoxicity and for monocyte/tumor cell conjugate formation, as well as for their rhamnogalacturonan-mediated enhancements, appears to be identical since all these effects could be inhibited in a dose-dependent manner by partially deacetylated (60%) mannose pentaacetate.

Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed i... more Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0 % of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of...

Journal of dentistry for children, 2020

Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathet... more Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathetic nervous system. Curative therapy is challenging, especially because early-stage diagnosis in toddlers is difficult. Successful treatment of high-risk neuroblastoma is only achieved in approximately half of the cases and requires an immediate interdisciplinary approach. We present a 34-month-old toddler with swelling of the left side of the face of three days duration and a mandibular mass of unknown duration, which was diagnosed as a metastasis of a neuroblastoma. He also had metastases in the kidney, long bones and skull. Despite the poor prognosis in cases of disseminated skeletal involvement and N-myc amplification, the young patient remained free of recurrence during a follow-up period of 36 months after multidisciplinary treatment. The purpose of this case report is to increase awareness of the clinical features of neuroblastoma among pediatric dentists to support early-stage dia...

Journal of Allergy and Clinical Immunology, 2021

Background: The recognition of viral nucleic acids is one of the primary triggers for a type I in... more Background: The recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections, as a result of dysbalanced interferon production. NFX1-type zinc-finger-containing 1 (ZNFX1) is an interferon-stimulated double-strand RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1's role in the human immune response is not known. Objective: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocyticlymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease. Methods: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, post-transcriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. Results: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of ISGs mRNA and was associated with poorer clearance of virus infections by monocytes. Conclusion: ZNFX1 is an important regulator of the response to doublestranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Child's Nervous System, 2020

Background Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor, which usually occur... more Background Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor, which usually occurs in infants under the age of one. Early diagnosis and radical surgery seem to be critical for long-term cure. Case presentation We describe a case of a 4-month-old boy with a MNTI to the skull. The mass was first noticed at 4 month of age and grew very rapidly over a time of 2 weeks. Initially, a fine needle biopsy ruled out a sarcoma and led to the diagnosis. The tumor originated from the sphenoid wing and infiltrated the frontotemporal bone, the lateral wall of the right orbit, and the underlying dura mater. A total excision of the tumor, including the adjacent bone and dura, was achieved. Reconstruction of the bone was performed using absorbable plates and Tutobone. Histology confirmed the initial diagnosis, while molecular diagnosis showed high conformity of the MNTI with medulloblastoma group 3. The patient recovered well, while the reconstruction led to a good cosmetic result. A local recurrence occurred leading to a single-dose chemotherapy with Vincristine and a second surgery after 15 weeks. Thereafter, the patient developed recurrent large pseudomeningocele, which was treated by multiple shunt procedures and finally reconstruction of the bone using Palacos. Radiological follow-up 3 months after the second resection showed no tumor recurrence. Conclusion Radical surgery for MNTI is to date the gold standard since it seems to minimize recurrence rates. Because of the rapid and destructive growth within the bone, reconstruction is necessary, which can be very challenging in infants.

Pediatric Blood & Cancer, 2004

Teratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and c... more Teratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and carcinosarcoma components. The authors report on a case of TCS in the oral cavity of a child. Rapid growth and extensive local destruction were prominent features prior to treatment. Histologic examination revealed various tissue elements, such as epithelial, mesenchymal, and neuroectodermal components. Chemotherapy was effective in reducing tumor mass, followed by partial anterior mandibulectomy and reconstruction with composite microvascular tissue transfer. The approach allowed radical resection of the tumor and functional reconstruction with excellent aesthetic results.

Pediatric Blood & Cancer, 2006

BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) ... more BackgroundSkeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age‐ and sex‐specific reference data from the UK General Practice Research Database (GPRD).ProcedureMedical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis.ResultsSkeletal complications occurred at a 5‐year incidence of 32.7%. The 5‐year incidence of ...

Orphanet Journal of Rare Diseases, 2012

New England Journal of Medicine, 2002

Background The group of susceptibility genes for pheochromocytoma that included the proto-oncogen... more Background The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. Methods Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. Results Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. Conclusions Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

Klinische Pädiatrie, 2013

Anemia in toddlers may result from many disorders including excessive feeding with cow&am... more Anemia in toddlers may result from many disorders including excessive feeding with cow's milk. Another sequel of age-inadequate cow's milk nutrition may be gastric lactobezoar (GLB), a dense lump of coagulated milk and mucus in the stomach. 3 toddlers presented with a history of excessive intake of full cream cow's milk, abdominal distension, vomiting, dehydration, fatigue, marked pallor and tachycardia. Diagnostic imaging revea-led large GLBs as the likely origin of the abdominal symptoms. Laboratory evaluation showed severe anemia with depleted iron stores and signs of protein catabolism. Non-cow's milk-induced causes of anemia including defects of erythropoiesis, hemoglobin structure, RBC-enzymes and blood coagulation, hemolysis, immune disorders, infection, inflammation, extraintestinal hemorrhage, nephropathy were - according to the available data - unlikely to cause the anemia in our patients. Thus their anemia is thought to be due to age-inadequate cow's milk nutrition leading to 1) low intake, decreased absorption/bioavailability and increased intestinal loss of iron, and 2) GLB which induced blood loss following mechanical irritation of the gastric mucosa and vomiting causing high gastric pH and decrease in duodenal iron absorption. The anemia in our patients is due to both exaggerated feeding with cow's milk and adverse effects of GLBs. This hypothesis is supported by the finding that, after erythrocyte transfusion, iron substitution, age-adapted nutrition and GLB-dissolution, the anemia did not recur. We propose to include GLB in the differential diagnosis of anemia in cow's milk fed small children.

Journal of Pediatric Gastroenterology & Nutrition, 2010