Publications by authors named "Winfried Barthlen"

27 Publications

  • Page 1 of 1

Possible New Strategies for the Treatment of Congenital Hyperinsulinism.

Front Endocrinol (Lausanne) 2020 27;11:545638. Epub 2020 Oct 27.

Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany.

Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.

Research Design And Methods: In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K (K) channels. Additionally, K channel-independent targets as Ca-activated K channels of intermediate conductance (K3.1) and L-type Ca channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1) mice. The cytosolic Ca concentration ([Ca]) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.

Results: The selective K channel opener NN414 (5 µM) diminished [Ca] in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional K channels (SUR1) the drug was without effect. VU0071063 (30 µM), another K channel opener considered to be selective, lowered [Ca] in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1 mice, showing that [Ca] is influenced by additional effects besides K channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of K3.1 channels, DCEBIO (100 µM), significantly decreased [Ca] in SUR1 and human CHI islet cell clusters. To target L-type Ca channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca] in stimulated human CHI islet cell clusters as well as in stimulated SUR1 islet cell clusters. Similar effects on [Ca] were observed in experiments with simvastatin (7.2 µM).

Conclusions: NN414 seems to provide a good alternative to the currently used K channel opener diazoxide. Targeting K3.1 channels by channel openers or L-type Ca channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of K channels not sensitive to K channel openers.
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http://dx.doi.org/10.3389/fendo.2020.545638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653201PMC
October 2020

Management of tumor rupture and abdominal compartment syndrome in an infant with bilateral high risk stage 4 neuroblastoma: A case report.

Medicine (Baltimore) 2019 Aug;98(34):e16752

Clinic of Pediatric Surgery, Ferdinand-Sauerbruch-Strasse 1Greifswald, Germany.

Rationale: Tumor rupture and bleeding at initial presentation of infants with neuroblastoma (NBL) is a rare, but life threatening condition and challenge in pediatric oncology. Here, we report successful multidisciplinary management of an abdominal compartment syndrome as a result of tumor rupture and bleeding in an infant with bilateral high risk stage 4 NBL.

Patient Concerns: The patient was admitted to a cooperating hospital with vomiting, failure to thrive and a large mass in the abdomen and was then referred to our center.

Diagnoses: Stage 4 NBL with MYC-N amplification and 1p36 deletion was diagnosed in an 11 months old girl. Due to rapid and massive tumor growth she developed abdominal compression with renal failure, severe bleeding, and tumor lysis syndrome (TLS).

Interventions: Surgical decompression by enterostomy, local, and systemic bleeding control with platelets and coagulation factors, antiinfective and TLS therapy were effective in stabilizing the patient's condition. This allowed initiation of the multimodal antineoplastic treatment according to protocol NB 2004.

Outcomes: Mechanical ventilation was stopped after 11 days, the abdominal wall was closed 3 months after the start of therapy, and treatment according to the protocol be started and successfully completed.

Lessons: Only the immediate, coordinated multidisciplinary intervention managed to overcome the life-threatening abdominal compartment syndrome and its associated problems, eventually enabling successful curative treatment.
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http://dx.doi.org/10.1097/MD.0000000000016752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716702PMC
August 2019

Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD antibody ch14.18/CHO.

MAbs 2018 01 5;10(1):55-61. Epub 2017 Dec 5.

a Department of Pediatric Oncology , University Medicine Greifswald , Greifswald , Germany.

Immunotherapy with short term infusion (STI) of monoclonal anti-GD antibody (mAb) ch14.18 (4 × 25 mg/m/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m ch14.18/CHO (d8-17) as LTI combined with 6 × 10 IU/m s.c. IL-2 (d1-5; 8-12) and 160 mg/m oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.
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http://dx.doi.org/10.1080/19420862.2017.1402997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800385PMC
January 2018

Clowns in Paediatric Surgery: Less Anxiety and More Oxytocin? A Pilot Study.

Klin Padiatr 2017 Sep 14;229(5):274-280. Epub 2017 Aug 14.

Pediatric Surgery, Universitaetsmedizin Greifswald, Greifswald, Germany.

Hospital stays and medical interventions are accompanied by worries and anxiety in children and parents. Recent studies show that hospital clowns may reduce anxiety and enhance well-being. However, so far studies are based solely on subjective measures and clowns are usually not integrated in medical routine. With this pilot study, we aim to provide both psychological and physiological evidence of positive effects of clowns' interventions in hospitalized children. In a consecutive randomized intervention-control group design with 31 children aged 4 to 13 years, 17 patients were accompanied by a clown prior to surgery or during ward round (intervention group) and 14 were not (control group). Saliva samples for oxytocin measurement were taken from all patients before hospitalization (T1) and prior to surgery or after ward round (T2). Self- and parents-reports were obtained at T1, T2 as well as at time of discharge from hospital (T3) regarding children's anxiety (STAI), worries and well-being. Clowns evaluated their success in cheering up the child. Health professionals were asked for their acceptance of clowns in hospitals. Children in the intervention group had lower anxiety ratings and a higher oxytocin concentration at T2 as compared with T1; the control group showed no changes. Parents rated the well-being of their children higher if their child had clown's contact and were more willing to recommend the hospital. The staff judged the clowns as helpful for patients. Consistent psychological and physiological results suggest the positive impact of a clown's intervention in hospitalized children.
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http://dx.doi.org/10.1055/s-0043-106854DOI Listing
September 2017

Surgery in Focal Congenital Hyperinsulinism (CHI) - The "Hyperinsulinism Germany International" Experience in 30 Children.

Pediatr Endocrinol Rev 2016 Dec;14(2):129-137

Otto-von-Guericke-University, Pediatrics, Magdeburg, Germany.

Objectives: Results of surgery for focal CHI in 30 children PATIENTS AND METHODS: All showed an ABCC8 or KCNJ11 mutation. After PET/CT in 29 children and PET/MRT in 1 case, frozen-section guided resection was performed, in left-sided cases by laparoscopy. Mean age at surgery was 11.7 months (2-49).

Results: In 28/30 children, the PET/CT or MRT correlated with histopathology. In two cases, a focal lesion was undectable; one of these was cured, one not. In total, 24 children showed lesions with sizes of 5-12 mm. All were cured instantly. In four children with huge lesions in the pancreatic head, pathological cells remained at the resection margins. One child was cured instantly, two children after a 2nd surgery, and one child was not cured, even after three surgeries. The overall cure rate was 93%.

Conclusions: Imaging, surgical findings, histopathology and clinical outcome in surgery for focal CHI match in most, but not all cases.
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http://dx.doi.org/10.17458/PER.2016.BVE.SurgeryinfocalDOI Listing
December 2016

The LXR Ligand T0901317 Acutely Inhibits Insulin Secretion by Affecting Mitochondrial Metabolism.

Endocrinology 2017 07;158(7):2145-2154

Institute of Pharmacy, Department of Pharmacology, University of Tübingen, 72076 Tübingen, Germany.

The role of liver X receptor (LXR) in pancreatic β-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in β-cells induces lipotoxicity, a key step in the development of β-cell dysfunction, which accompanies type 2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the micromolar range to study the significance of LXR activation. In the current study, we have evaluated acute effects of T0901317 on stimulus-secretion coupling of β-cells. We found that 10 µM T0901317 completely suppressed oscillations of the cytosolic Ca2+ concentration induced by 15 mM glucose. Obviously, this effect was due to inhibition of mitochondrial metabolism. T0901317 markedly depolarized the mitochondrial membrane potential, thus inhibiting adenosine triphosphate (ATP) production and reducing the cytosolic ATP concentration. This led in turn to a huge increase in KATP current and hyperpolarization of the cell membrane potential. Eventually, T0901317 inhibited glucose-induced insulin secretion. These effects were rapid in on-set and not compatible with the activation of a nuclear receptor. In vivo, T0901317 acutely increased the blood glucose concentration after intraperitoneal application. In summary, these data clearly demonstrate that T0901317 exerts acute effects on stimulus-secretion coupling. This observation questions the chronic use of T0901317 and limits the interpretation of results obtained under these experimental conditions.
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http://dx.doi.org/10.1210/en.2016-1941DOI Listing
July 2017

Kidney protein profiling of Wilms' tumor patients by analysis of formalin-fixed paraffin-embedded tissue samples.

Clin Chim Acta 2014 Jun 27;433:235-41. Epub 2014 Mar 27.

Clinic for Pediatric Surgery, University Medicine Greifswald, Sauerbruchstr. 1, D-17475 Greifswald, Germany. Electronic address:

Unlabelled: Wilms' tumor (nephroblastoma, WT) is the most frequent renal cancer in children. However, molecular details leading to WT have not been characterized sufficiently yet. Proteomic studies might provide new insights but are hampered by limited availability of fresh frozen tissue specimen. Therefore, we tested formalin-fixed paraffin-embedded (FFPE) tissue sections routinely collected for pathological inspection for their use in in-depth-proteomic analyses of WT samples in comparison to fresh frozen specimen. The overlap of the proteins identified was over 65%. Thus we used FFPE material from 7 patients for tandem mass spectrometry based comparison of the proteomes of WT and healthy renal tissues. We detected 262 proteins, which were differentially expressed in tumor compared to healthy renal tissue. The majority of these proteins displayed lower levels in the tumor tissue and only 30% higher levels. For selected candidates data were confirmed by immunohistochemical staining. Correlation analysis of blastemal proportions in WT and protein intensities revealed candidates for tumor stratification.

Conclusion: This proof of principle proteomic study of FFPE tissue sections from WT patients demonstrates that these archived tissues constitute a valuable resource for larger in-depth proteomic studies to identify markers to follow chemotherapy efficiency or for stratification of tumor subtypes.
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http://dx.doi.org/10.1016/j.cca.2014.03.020DOI Listing
June 2014

Long-term culture and functionality of pancreatic islets monitored using microelectrode arrays.

Integr Biol (Camb) 2014 May;6(5):540-4

NMI Natural and Medical Sciences Institute at the University of Tübingen, Department of Electrophysiology, Markwiesenstraße 55, D-72770 Reutlingen, Germany.

Extracellular recording of the glucose-induced electrical activity of mouse islets of Langerhans on microelectrode arrays (MEAs) is an innovative and powerful tool to address beta-cell (patho-)physiology. In a dual approach we tested whether this technique can detect concentration-dependent drug effects as well as characterize alterations in beta-cell activity during prolonged culture. First we established conditions that allow long-term investigation of beta-cell function by recording electrical activity. The results provide the first measurements of beta-cell membrane potential oscillations of individual murine islets during long-term culture. Oscillations were recorded for up to 34 days after islet isolation. Importantly, the glucose dependence of electrical activity did not change over a period of one month. Thus we can follow electrophysiological changes of individual islets induced by alterations in the beta-cell environment over weeks. Second, we used the MEA technique to assay beta-cell damage induced by oxidative stress and to evaluate appropriate protection mechanisms. Oxidative stress plays a key role in the development of type 2 diabetes mellitus (T2DM). Examination of the acute effects of H2O2 on electrical activity showed that the oxidant reduced the electrical activity in a concentration-dependent manner. The superoxide dismutase mimetic, tempol, protected against the detrimental effects of H2O2. In conclusion, we demonstrated that MEA recordings can be used to address disease-related mechanisms and protective interventions in beta-cells. In the future, this fundamental work should enable the monitoring of the electrical activity of islets of Langerhans under controlled ex vivo conditions including long-term exposure to oxidative stress, glucolipotoxicity, and other diabetes-inducing agents.
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http://dx.doi.org/10.1039/c3ib40261dDOI Listing
May 2014

Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism.

Horm Res Paediatr 2014 7;81(3):156-68. Epub 2014 Jan 7.

Department of Pediatrics, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease.
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http://dx.doi.org/10.1159/000356905DOI Listing
December 2014

Spontaneous vesicoureteral reflux resolution in children: A ten-year single-centre experience.

Afr J Paediatr Surg 2013 Jan-Apr;10(1):9-12

Department of Pediatric Surgery, University Children's Hospital Greifswald, Germany.

Background/aim: To evaluate the spontaneous resolution rate in infants and young children with vesicoureteral reflux (VUR).

Patients And Methods: Paediatric patients with VUR treated in our hospital from January 2000 to December 2010 were retrospectively analyzed. Only patients with pretreatment and follow-up voiding cystourethrogram were included into the study. Treatment success was defined as complete VUR resolution.

Results: The resolution rate for infants less than 1 year of age was 38.6% (17 of 44 renal units). Renal units with mild-moderate VUR (I-III) had a resolution rate of 40% (12 of 30 renal units) compared to 35.7% (5 of 14 renal units) with severe grade (IV-V) VUR. The resolution rate for children over 1 year of age was 39,1% (9 of 23 renal units). Renal units with mild-moderate VUR (I-III) had a resolution rate of 42.9% (9 of 21 renal units) compared to 0% (0 of 2 renal units) with severe grade (IV-V) VUR.

Conclusion: Infants less than 1 year of age with nonsymptomatic, mild, moderate or severe VUR have a spontaneous resolution rate of more than 35% and therefore should receive a primary conservative therapy. Children over 1 year of age with nonsymptomatic mild-moderate VUR (I-III) have a spontaneous resolution rate of about 40% and should receive primary conservative treatment as well.
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http://dx.doi.org/10.4103/0189-6725.109375DOI Listing
December 2013

Hepatitis in an infant treated with octreotide for congenital hyperinsulinism.

J Pediatr Endocrinol Metab 2013 ;26(1-2):183-5

Armon Child Center, Haifa, Israel.

Congenital hyperinsulinism is characterized by hypoglycemia caused by several genetic disorders of inappropriate insulin secretion. Octreotide, an analogue of somatostatin, plays a major role in the pharmaceutical treatment of this condition. A 9-month-old infant treated with octreotide developed anicteric hepatitis with no other proven cause. After the discontinuation of this drug, the liver enzymes declined rapidly. Liver function tests should be followed in patients receiving octreotide.
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http://dx.doi.org/10.1515/jpem-2012-0372DOI Listing
June 2013

Mucoepidermoid carcinoma of the lung in a 6-year-old boy.

Afr J Paediatr Surg 2012 May-Aug;9(2):159-62

Department of Pediatric Surgery, University Hospital Greifswald, Greifswald, Germany.

Primary malignant lung tumours, especially the mucoepidermoid cancer of the bronchus, are very uncommon in childhood. Obtaining the diagnosis might be difficult due to unspecific initial symptoms but early detection and treatment is crucial for a good long-term survival. Bronchoscopy is considered the "gold standard" for making the diagnosis. The recommended therapy for a mucoepidermoid lung cancer is sleeve lobectomy with favourable overall survival after complete resection. We report the case of a 6-year-old boy with a right-upper-lobe bronchus tumour. The histological examination revealed a low-grade mucoepidermoid carcinoma.
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http://dx.doi.org/10.4103/0189-6725.99406DOI Listing
January 2013

A rare case of an isolated triquetrum body fracture in a 14-year-old boy.

Afr J Paediatr Surg 2012 May-Aug;9(2):157-8

Department of Pediatric Surgery, University Hospital Greifswald, Germany.

Isolated carpal fractures are uncommon injuries usually caused by a fall on the outstretched hand. The patient might present with non-specific clinical signs and X-ray diagnosis might be difficult due to bone overlay. An isolated triquetrum body fracture is an absolute rarity. The treatment is easy and the outcome excellent but if missed, degenerative changes with chronic pain and impaired movement might be the consequence.
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http://dx.doi.org/10.4103/0189-6725.99405DOI Listing
January 2013

Impact of magnetic resonance urography and ultrasonography on diagnosis and management of hydronephrosis and megaureter in paediatric patients.

Afr J Paediatr Surg 2012 May-Aug;9(2):122-7

Department of Pediatric Surgery, University Hospital Greifswald, Germany.

Background: (1) To evaluate the diagnostic value of magnetic resonance urography (MRU) in comparison with ultrasonography (US) to determine the extent of upper urinary tract dilation and (2) to evaluate the impact of MRU on therapy management.

Materials And Methods: From January 2005 to December 2010, paediatric patients with hydronephrosis or megaureter who underwent MRU in addition to standard work-up imaging were included. Data were retrospectively collected and analysed in comparison with the data obtained from results by US.

Results: Forty-five patients with upper urinary tract dilatation were included into the study. Twenty-six patients (58%) had a hydronephrosis and 19 patients (42%) presented with a megaureter. Diagnosis was established in all patients by multimodulary imaging work-up including micturating cysto-urethrography, MAG3 renography, US and MRU and could be confirmed in all patients who underwent surgery (n = 28). Hydronephrosis was detected in 26 of 26 patients by US (100% sensitivity) and in 25 of 26 patients (96%) by MRU (Not significant (n.s.)). Megaureter was detected in 17 of 19 patients (sensitivity 89%) by US and in 18 of 19 patients (sensitivity 95%) by MRU (n.s.). In all 45 patients, MRU had no impact on surgical or conservative management of hydronephrosis or megaureter.

Conclusion: In our experience, MRU was not superior to US in detecting hydronephrosis or megaureter and had no impact on the surgical or conservative management of upper urinary tract dilation.
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http://dx.doi.org/10.4103/0189-6725.99397DOI Listing
January 2013

Self-bougienage of oesophageal stricture by an 8-year-old child.

Afr J Paediatr Surg 2012 Jan-Apr;9(1):77-9

Department of Pediatric Surgery, University Hospital Greifswald, Germany.

Oesophageal corrosive injuries have a high potential to result in stricture formation with the requirement for repeat oesophageal dilation. Especially in children, oesophageal bougienage is performed under general anaesthesia or strong sedation. In developing countries without comprehensive medical care, this service might not be available. We report the case of daily oesophageal self-bougienage performed by an 8-year-old Afghan child as highly effective treatment of recurrent oesophageal stricture formation after caustic substance ingestion.
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http://dx.doi.org/10.4103/0189-6725.93318DOI Listing
June 2012

Gastric teratoma in a 6-month-old boy.

Afr J Paediatr Surg 2012 Jan-Apr;9(1):71-3

Department of Pediatric Surgery, University Hospital Greifswald, Germany.

Gastric teratomas are very rare embryonal neoplasms, accounting for 2.6% of all perinatal diagnosed germ cell tumours. About 85% are well-differentiated mature lesions and about 15% are immature tumours with the potential of malignant transformation. The recommended therapy for gastric teratomas is surgical excision. We present the case of a 6-month-old boy with an incidentally detected epigastric mass. The histological examination revealed a mature gastric teratoma. The diagnostic imaging, therapy and postoperative follow-up are discussed.
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http://dx.doi.org/10.4103/0189-6725.93315DOI Listing
June 2012

Techniques in pediatric surgery: congenital hyperinsulinism.

Horm Res Paediatr 2011 16;75(4):304-10. Epub 2011 Feb 16.

Clinic for Pediatric Surgery, University Greifswald, Greifswald, Germany.

For surgery in congenital hyperinsulinism (CHI), a distinct surgical strategy and technique is required for focal, diffuse and atypical CHI. In focal CHI, a confined, localized and parenchyma-sparing resection which is guided by the PET-CT is always indicated in order to cure the patient. In diffuse CHI, however, the results of surgical therapy are unpredictable and cure is an exception. Therefore, a strong tendency exists nowadays that medical therapy should be preferred in diffuse CHI. In atypical CHI the situation is more complex: if the focal lesion or the segmental mosaic are not too extensive, cure by resection should be possible. But care must be taken in atypical cases not to resect too much of the gland in order not to induce diabetes.
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http://dx.doi.org/10.1159/000323532DOI Listing
July 2011

Surgery in congenital hyperinsulinism-tips and tricks not only for surgeons. A practical guide.

Semin Pediatr Surg 2011 Feb;20(1):56-9

Clinic for Pediatric Surgery, University of Greifwald, Germany.

Each form of congenital hyperinsulinism (CHI)-focal, diffuse, atypical-requires its own surgical strategy and technique. Focal CHI is treated by a positron emission tomography/computed tomography-guided, local resection which is confined only to the lesion. As much healthy pancreatic tissue as possible is preserved. On the contrary, the therapeutic mainstay of diffuse CHI must be conservative nowadays. Only in the exceptional cases in which medical treatment fails surgical therapy is warranted to prevent hypoglycemia. However, the extension of resection that is able to cure hyperinsulinism while avoiding diabetes is not known today. The outcome, therefore, is unpredictable. In the rare atypical cases it is important to stop the resection at the right time in order not to finish unnecessarily with a mutilating operation.
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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.002DOI Listing
February 2011

Visualization of the focus in congenital hyperinsulinism by intraoperative sonography.

Semin Pediatr Surg 2011 Feb;20(1):28-31

Pediatric Radiology, O. v. Guericke University, Magdeburg, Germany.

In surgery for focal congenital hyperinsulinism (CHI), the identification and complete resection of the focus without collateral damage is of utmost importance. In a pilot study we applied intra-abdominal high-frequency sonography during surgery for focal CHI in 2 infants. The focus could be identified, its relation to the pancreatic and common bile duct could be shown, and the typical octopus-like tentacles could be demonstrated. In one case the resection was successful; in the other it was not. These preliminary results suggest that intraoperative sonography could be a valuable tool in the surgical therapy of focal CHI and warrants further evaluation in a clinical study.
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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.011DOI Listing
February 2011

Positron emission tomography/computed tomography diagnostics by means of fluorine-18-L-dihydroxyphenylalanine in congenital hyperinsulinism.

Semin Pediatr Surg 2011 Feb;20(1):23-7

Diagnostisch Therapeutisches Zentrum, Kadinerstrasse, Berlin, Germany.

The unfavorable prognosis of congenital hyperinsulinism (CHI) can be avoided if the patients are treated with high-dose glucose infusions and timely surgical intervention. Circumscribed foci used to be identified by selective percutaneous pancreatic vein catheterization and determination of the insulin level. Fluorine-18-L-dihydroxyphenylalanine-positron emission tomography (PET) was developed as a milder alternative for diagnostic localization of focal disease. The uptake of fluorine-18-L-dihydroxyphenylalanine is considerably increased in foci with high insulin synthesis rates. In Berlin, diagnosis was achieved by high definition PET/computed tomography with multiphase contrast media protocols that provided all necessary data with one investigation. We have investigated 135 patients with congenital hyperinsulinism, including 45 patients with focal disease (33.3%). All the foci were excised on the basis of PET/computed tomography images. The German data demonstrate that 87% to 91% of the operated patients could be completely healed.
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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.007DOI Listing
February 2011

Congenital hyperinsulinism.

Semin Pediatr Surg 2011 Feb;20(1):1-2

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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.001DOI Listing
February 2011

Techniques in pediatric surgery: congenital hyperinsulinism.

Horm Res Paediatr 2010 24;74(6):438-43. Epub 2010 Nov 24.

Clinic for Pediatric Surgery, University Greifswald, Greifswald, Germany. winfried.barthlen @ uni-greifswald.de

For surgery in congenital hyperinsulinism (CHI), a distinct strategy and technique is required for focal, diffuse and atypical types. In focal CHI, a confined, localized and parenchyma-sparing resection which is guided by the PET-CT is always indicated in order to cure the patient. In diffuse CHI, however, the results of surgical therapy are unpredictable and cure is an exception. Therefore, a strong tendency exists nowadays that medical therapy should be preferred in diffuse CHI. In atypical CHI the situation is more complex: if the focal lesion or the segmental mosaic are not too extensive, cure by resection should be possible. But care must be taken in atypical cases not to resect too much of the gland in order not to induce diabetes.
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http://dx.doi.org/10.1159/000321902DOI Listing
April 2011

Proteome analysis reveals new mechanisms of Bcl11b-loss driven apoptosis.

J Proteome Res 2010 Aug;9(8):3799-811

Interfakultäres Institut für Genetik und Funktionelle Genomforschung, Ernst-Moritz-Arndt-Universität Greifswald, Germany.

The Bcl11b protein was shown to be important for a variety of functions such as T cell differentiation, normal development of central nervous system, and DNA damage response. Malignant T cells undergo apoptotic cell death upon BCL11B down-regulation, however, the detailed mechanism of cell death is not fully understood yet. Here we employed two-dimensional difference in-gel electrophoresis (2D-DIGE), mass spectrometry and cell biological experiments to investigate the role of Bcl11b in malignant T cell lines such as Jurkat and huT78. We provide evidence for the involvement of the mitochondrial apoptotic pathway and observed cleavage and fragments of known caspase targets such as myosin, spectrin, and vimentin. Our findings suggest an involvement of ERM proteins, which were up-regulated and phosphorylated upon Bcl11b down-regulation. Moreover, the levels of several proteins implicated in cell cycle entry, including DUT-N, CDK6, MCM4, MCM6, and MAT1 were elevated. Thus, the proteome data presented here confirm previous findings concerning the consequences of BCL11B knock-down and provide new insight into the mechanisms of cell death and cell cycle disturbances induced by Bcl11b depletion.
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http://dx.doi.org/10.1021/pr901096uDOI Listing
August 2010

Serum levels of Midkine in children and adolescents without malignant disease.

Pediatr Int 2010 Feb 18;52(1):75-9. Epub 2009 May 18.

Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: Midkine (MK), a heparin-binding growth factor, is a secreted protein and can be detected in a patient's sera.

Method: MK was studied in the sera of 215 children and adolescents without malignant disease using an enzyme-linked immunosorbent assay in order to determine the distribution of concentrations in a control population for pediatric oncology patients. Tested subjects either underwent surgical procedures or suffered from endocrinological diseases.

Results: Elevated MK levels were found in patients with short stature, diabetes mellitus, obesity, and cleft lip and palate. These patients were subsequently excluded from the "non-cancer" group. MK serum levels did neither correlate with sex, age, weight or height nor showed a normal distribution (n= 152, range: 0.0-5.58 ng/ml, median: 0.0 ng/ml, mean: 0.26 ng/ml, SD: +/-0.61).

Conclusion: MK serum values in children and adolescents are widely spread and not normally distributed. The present results indicate that the MK expression is influenced by many factors apart from cancer, which have not yet been identified.
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http://dx.doi.org/10.1111/j.1442-200X.2009.02885.xDOI Listing
February 2010

Evaluation of [18F]fluoro-L-DOPA positron emission tomography-computed tomography for surgery in focal congenital hyperinsulinism.

J Clin Endocrinol Metab 2008 Mar 11;93(3):869-75. Epub 2007 Dec 11.

Clinic for Pediatric Surgery, Institute for Pathology, Charité University Medicine Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, Mittelallee 8, D-13353 Berlin, Germany.

Context: In congenital hyperinsulinism (CHI), the identification and precise localization of a focal lesion is essential for successful surgery.

Objective: Our objective was to evaluate the predictive value and accuracy of integrated [18F]fluoro-L-DOPA ([18F]FDOPA) positron emission tomography (PET)-computed tomography (CT) for the surgical therapy of CHI.

Design: This was an observational study.

Setting: The study was performed in the Department of Pediatric Surgery at a university hospital.

Patients: From February 2005 to September 2007, 10 children with the clinical signs of CHI and an increased radiotracer uptake in a circumscribed area of the pancreas in the [18F]FDOPA PET-CT were evaluated.

Interventions: Guided by the [18F]FDOPA PET-CT report, all children underwent partial pancreatic resection, in two cases twice.

Main Outcome Measures: Correlation of the anatomical findings at surgery with the report of the [18F]FDOPA PET-CT, and the results of surgery and clinical outcome were determined.

Results: In nine children the intraoperative situation corresponded exactly to the description of the [18F]FDOPA PET-CT. A limited resection of the pancreas was curative in eight cases at the first surgery, in one case at the second intervention. We observed no diabetes mellitus or exocrine insufficiency in the follow up so far. In one child, hypoglycemia persisted even after two partial resections of the pancreatic head. Histological analysis finally revealed an atypical intermediate form of CHI.

Conclusions: The integrated [18F]FDOPA PET-CT is accurate to localize the lesion in focal CHI and is a valuable tool to guide the surgeon in limited pancreatic resection.
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http://dx.doi.org/10.1210/jc.2007-2036DOI Listing
March 2008

Extrahepatic biliary atresia and caudal regression syndrome in an infant of a diabetic mother.

J Pediatr Surg 2004 Jan;39(1):E20-2

Department of Neonatology, Charite, Virchow Hospital, Berlin, Germany.

Although most cases of extrahepatic biliary atresia are thought to result from perinatal obliterating inflammation, some are associated with a faulty morphogenesis. The authors report on a baby girl of a mother with ill-managed insulin-dependent diabetes mellitus. The baby presented with sacro-coccygeal agenesis, clubfoot, and ano-urinary incontinence. In addition, there was polysplenia, no inferior vena cava, and the portal vein was grossly distorted. Progressive conjugated hyperbilirubinemia prompted liver biopsy at 4 weeks of age, showing intracanalicular cholestasis without fibrosis. The diagnosis of extrahepatic biliary atresia was confirmed during laparotomy performed for hepatoportojejunostomy. Some cases of extrahepatic biliary atresia might be part of a spectrum of malformations associated with maternal diabetes mellitus.
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http://dx.doi.org/10.1016/j.jpedsurg.2003.09.044DOI Listing
January 2004

Significance of heparin-binding growth factor expression on cells of solid pediatric tumors.

J Pediatr Surg 2003 Sep;38(9):1296-304

Department of Pediatric Surgery, University Tübingen, Tübingen, Germany.

Background: The heparin-binding growth factors pleiotrophin (PTN), midkine (MK), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) stimulate tumor cell proliferation and angiogenesis. In this study the authors wanted to know if these growth factors are expressed by cell lines and tumor tissue of solid pediatric tumors, growth factor expression is influenced by proinflammatory cytokines, and local growth factor concentration has an influence on experimental tumor growth.

Methods: Growth factor mRNA expression was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and protein secretion by enzyme-linked immunosorbent assay (ELISA). Neuroblastoma cells were suspended in solutions containing different growth factor concentrations before injection into the nude mice, which were given pentosan polysulfate (PPS) for antagonism.

Results: The analyzed growth factors were expressed by most cells of solid malignant pediatric tumors. Their expression was not influenced by proinflammatory cytokines. The inhibition of tumor growth by PPS in the nude mouse model was dependent on the local growth factor concentration. High concentration excluded significant tumor suppression.

Conclusions: Because of the redundancy of growth factor expression and the abolishment of PPS efficacy by a high local growth factor concentration, the authors conclude that overall targeting of growth factors is a promising approach to cancer therapy in childhood.
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http://dx.doi.org/10.1016/s0022-3468(03)00385-3DOI Listing
September 2003