Support for the hypoxia theory in the pathogenesis of infantile haemangioma.

BACKGROUND: The pathogenesis of infantile haemangioma (IH) is unknown. Several mechanisms have been proposed, including hypoxia, which triggers upregulation and stabilization of hypoxia-inducible factor (HIF)1α. HIF1α stimulates downstream transcription of target genes that enhance angiogenesis. AIM: To identify possible involvement of hypoxia in the pathogenesis of IH, as hypoxia signalling constitutes a potential therapeutic target. METHODS: IH tissue samples collected during the period 1991-2011 (preserved in paraffin wax) were immunohistochemically analysed for HIF1α and the known HIF1α targets: BCL2/adenovirus E1B kD-interacting protein family member 3 (BNIP3), carbon anhydrase (CA)-IX, glucose transporter (GLUT)-1, phosphorylated protein kinase B (pAKT), phosphorylated S6 protein (pS6) and vascular endothelial growth factor (VEGF). Four observers independently assessed the findings. RESULTS: Of the 10 IH samples, 2 appeared to be in the growth phase. In all samples, GLUT-1, BNIP3, pAKT and VEGF were positive, CA-IX was weakly positive, and HIF1α was negative. pS6 was positive in 9/10 cases and negative in 1/10. CONCLUSIONS: Several factors implicated in hypoxia-induced angiogenesis may be involved in IH development. However, the small sample size and retrospective approach of the study preclude definitive conclusions. Prospective studies are needed to conclusively determine which of the factors involved in the (hypoxia) cascade are required for an IH to grow, and could thus be a possible target of drugs for IH treatment.

Intractable vascular autonomic dysregulation (Harlequin phenomenon) in two brothers: another indication for propranolol?

Vascular autonomic dysregulation, in the most extreme presentation known as Harlequin phenomenon, is a rare condition. It manifests as a sudden and brief paroxystic change in skin color, resulting in two different colors on the body. It is supposed that this condition occurs due to a vasomotor instability. This again is caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn. Typically, there is spontaneous regression. We describe two brothers who both had this condition in their first life years. Clinical symptoms included frequent attacks of discoloration of extremities (up to four times per day) accompanied with terrifying crying fits, interpreted by the parents as pain. These patients were treated with propranolol, a nonselective beta-blocker, resulting in improvement of symptoms: only occasional attacks were seen. Beta-blockers act on ß1 -adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. We hypothesize that propranolol, which is very lipophilic and therefore also acts on ß-receptors of the central nervous system, acts on the sympathetic system.

Treatment of small superficial haemangioma with timolol 0.5% ophthalmic solution: a series of 20 cases.

BACKGROUND: Haemangioma of infancy (HOI) on the face may be disfiguring and alarming for parents. Usually they are not treated when they are small. Treatment of HOI with propranolol is a breakthrough. Timolol (topical treatment) and propranolol are closely related. METHODS: We considered topical treatment with timolol 0.5% ophthalmic solution 3-4 times daily in patients with small HOI. Twenty patients with small mostly superficial HOI were included. RESULTS: A series of 20 patients with HOI treated with timolol 0.5% ophthalmic solution are described. The treatment was effective in all superficial HOIs after 1-4 months. A quick direct inhibitory effect on the growth of the HOI followed by slower regression was observed. The children had to be treated during the whole proliferative phase. Deep HOIs on the nose (2 cases) and lower eyelid (1 case) showed no response. CONCLUSION: Topical timolol 0.5% ophthalmic solution is effective in HOI. Safety and effectiveness of drugs like topical timolol and topical propranolol require further investigation but they seem very safe when used in small HOIs. We recommend that small superficial HOIs should be treated in an early proliferative phase.

Scoring the proliferative activity of haemangioma of infancy: the Haemangioma Activity Score (HAS).

BACKGROUND: Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. A good, reliable and objective scoring system for haemangioma activity is not yet available. AIM: We have developed a simple system called the Haemangioma Activity Score (HAS) for scoring the (disease) proliferative activity of haemangiomas. The current study was undertaken to validate this system. METHODS: We validated the HAS in a comparative study of photographs taken during consultations from 2000 until 2008 (n = 78). Agreement between three observers was assessed at two different time points (t(0) and t(1)) with a minimum interval of 6 months between them, using interclass correlation coefficients (ICC). RESULTS: Agreement between observers was good. The average ICC of the HAS at t(0) and t(1) was 0.72 and 0.76, respectively. The average ICC of the HAS for the changes from baseline (HAS at t(0) minus HAS at t(1) ) was 0.69. CONCLUSIONS: We conclude that the HAS is a good system for scoring the proliferative activity of haemangiomas, and believe it to be useful in future investigations. The number of studies comparing different therapies for treating haemangiomas is steadily increasing, and the HAS (before and after treatment) may provide a valuable scoring system for evaluating such therapies.

Influence of tumor site and histology on long-term survival in 193 children with extracranial germ cell tumors.

AIMS: Although germ cell tumors (GCT) supposedly share the same cell type of origin, their clinical course differs considerably depending on tumor site and histology. The aim of this work was to study long-term survival stratified for tumor site and tumor histology. MATERIALS AND METHODS: The medical records of 193 consecutive infants and children with extracranial GCT were studied. The GCT arose in the following anatomical sites: sacrococcygeal (n = 70), ovary (n = 66), testis (n = 20), retroperitoneum (n = 12), neck (n = 8), mediastinum (n = 7), and miscellaneous (n = 10). Histological analysis revealed 152 teratomas (mature: 115, immature: 37), 27 yolk sac tumors, 8 mixed tumors, 2 dysgerminomas, 2 gonadoblastomas, 1 choriocarcinoma and 1 embryonal carcinoma. RESULTS: Overall survival (OS) for the whole patient group was 0.91 +/- 0.02, and event-free survival (EFS) was 0.88 +/- 0.02 at ten years. Patients with gonadal GCT had a higher probability of OS than those with extragonadal GCT (p = 0.029). Patients with cervical and mediastinal tumors had a lower probability of EFS than those with gonadal, retroperitoneal or sacrococcygeal GCT (p = 0.018). Patients with choriocarcinoma, embryonal carcinoma, immature teratoma, yolk sac tumor and mixed GCT had a lower probability of EFS than patients with mature teratoma or gonadoblastoma (p < 0.001). CONCLUSIONS: Mortality in children with extracranial germ cell tumors is not only dictated by malignant histology, but also, as in the case of mature teratomas, by occurrence at certain sites.

Mediastinal germ cell tumors: clinical aspects and outcomes in 7 children.

BACKGROUND: Mediastinal germ cell tumors presenting during childhood are extremely rare. Publications on this entity are very scarce. This paper reports on the clinical presentations, method(s) of treatment, complications, results and outcomes in a series of children with mediastinal germ cell tumors. METHODS: A retrospective chart review of 7 children treated between 1971 and 2001 for mediastinal germ cell tumor was carried out. Age at diagnosis and symptoms were recorded. Each patient's surgical treatment, peri- and postoperative complications, histological staging and final outcome were analysed. RESULTS: The median age of the 4 boys and 3 girls was 3 years (range 21 months-15 years). The most frequent symptoms were respiratory distress, persistent coughing, thoracic pain and anorexia/weight loss. Four patients had histologically benign tumors (mature teratoma). Their sole treatment consisted of complete surgical excision of the tumor and (part of) the thymus using either median sternotomy or left-sided thoracotomy. Recovery was uneventful. No recurrences have been observed. All four are alive with no evidence of disease, between 2.5 and 29 years after treatment. Malignant tumors were observed in three patients (1 yolk sac tumor, 1 choriocarcinoma and 1 malignant teratoma). Treatment consisted of either biopsy or debulking followed by chemotherapy (and radiotherapy in 1 case). Two of them died from uncontrollable metastatic disease. The patient with yolk sac tumor survived; he is now in remission, 4 years after diagnosis. CONCLUSIONS: Both this study and the literature review testify to the extreme rarity of mediastinal germ cell tumors in childhood. Children with this type of tumor usually are severely symptomatic. Histologically benign tumors carry an excellent prognosis provided surgical excision is complete. Histologically malignant tumors, on the other hand, have a worse prognosis. However, the use of platinum-based combination chemotherapy has considerably increased the survival rates.

Rectoperineal fistula in newborn boys.

Three newborn boys presented with features suggestive of classic low anorectal abnormality. However, during surgery they were found to have an intermediate anorectal abnormality and a rectoperineal fistula rather than an anocutaneous fistula. The surgical treatment of these infants is discussed.

Sequential changes in relative liver function assessed by 99mTc-HIDA scintigraphy after auxiliary heterotopic liver transplantation in dogs.

Auxiliary heterotopic liver transplantation (HLT) was used to achieve functional repair in a dog model with an inborn error of metabolism. For the interpretation of the results, information on separate liver function is essential when a normal host liver is also present. We developed a radionuclear method to quantitate the relative contribution of each liver to the total uptake of intravenously (IV) injected 99mTc-HIDA. The HLT was performed between 20 mismatched pairs of dogs from two different strains. Four surgical procedures were used. After autopsy the outcome of the premortem HIDA-scan was compared with the wet weight of the graft and the host liver. A good linear correlation was noted between the relative contribution of the uptake and weight of the graft to the total HIDA uptake and total liver weight. Therefore, the relative contribution of an auxiliary heterotopic liver graft to the total liver function can be quantitated with a 99mTc-HIDA scan. With this technique, changes in relative function after an HLT under various flow conditions can be sequentially followed.

Evaluation of mortality in surgical neonates over a 10-year period: nonpreventable, permissible, and preventable death.

The mortality pattern and causes of death in surgical neonates were evaluated over the period of 1980 through 1990 in order to assess whether any deaths might have been prevented. In the study period 1,010 neonates were admitted, 104 of whom died (10%). These 104 neonates formed our study population. The Clinical Classification System (CCS) and the Therapeutic Intervention Scoring System (TISS) were used to assess the severity of illness. All 104 nonsurvivors were seriously ill (CCS 3 and 4; TISS greater than 20). The mortality pattern was classified in three groups. Group A (nonpreventable death) included 56 deaths, 48 of which were due to the underlying disease. The other 8 patients died of a nonpreventable complication of treatment. Eleven of the patients in group B (permissible death) had (multiple) congenital anomalies associated with chromosomal anomalies. Three of them were not treated and in the other 8 treatment was initially started but later withdrawn. In most of the other 14 patients further treatment was withdrawn because of serious postoperative complications or inoperable cardiac anomalies. Group C (preventable death) consisted of 23 patients. Six of 10 had irreversible brain damage due to prolonged hypoxemia. In the other 13 patients of group C, death was due to sepsis acquired in the postoperative period and treated inadequately. Staphylococcus epidermidis was the most frequent isolated pathogen (7/13).

Congenital diaphragmatic hernia: impact of preoperative stabilization. A prospective pilot study in 13 patients.

In case of congenital diaphragmatic hernia (CDH), survival generally depends not on prenatal diagnosis, planned delivery, and immediate postnatal operation, but on the gravity of pulmonary hypoplasia and persistent hypertension (PPH). Many vasoactive drugs have become available for lowering PPH, but the mortality rate for CDH still amounts to 40% to 70%. Preoperative stabilization might prevent or at least reduce the risk of PPH. This method was evaluated in a pilot study lasting 15 months and involving 13 patients. All were admitted to the pediatric surgical intensive care unit within six hours of birth, all requiring mechanical ventilation. Continuous suction of the stomach and bowel proved successful in reducing the mediastinal shift. Study parameters were alveolar-arterial oxygenation differences ((A-a)DO2), mean airway pressure (MAP), oxygenation index (OI), and ventilation index (VI), measured on admission and at set times before and after surgery. Eight patients did not survive, but in two cases death was not directly related to CDH. The following conclusions were reached: (1) satisfactory ventilation parameters on admission will remain good during the preoperative stabilization phase and will not be affected by its duration or by subsequent surgery, spelling survival; (2) unsatisfactory ventilation parameters on admission may improve with preoperative stabilization, giving these patients a better chance of survival; and (3) poor ventilation parameters on admission that fail to improve with preoperative stabilization will not improve with surgery or postoperatively, spelling death.

Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog.

BACKGROUND/PURPOSE: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model. METHODS: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver. RESULTS: Metabolic correction increased in all groups after transplantation from 0.19 +/- 0.02 to 0.70 +/- 0.05 (P< .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 +/- 27 and 144 +/- 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 +/- 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 +/- 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect. CONCLUSION: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow.

[Favorable results of percutaneous endoscopic gastrostomy in children in need of long-term tube feeding]. / Gunstige resultaten van percutane endoscopische gastrostomie bij kinderen die langdurig sondevoeding nodig hebben.

OBJECTIVE: Analysis of indications, weight and peroperative and postoperative complications in 32 consecutive children who underwent percutaneous endoscopic gastrostomy (PEG). DESIGN: Retrospective. SETTING: Sophia Children's Hospital, Rotterdam, The Netherlands. METHOD: Survey of medical records. RESULTS: In 26 children the indication for PEG was necessity of prolonged tube feeding on account of severe psychomotor retardation. The 6 others had no such retardation and had various indications. Mean hospital stay was 6.7 days, median 6 days. Three patients had immediate postoperative complications: two had leakage, one infection. In 22 patients there were no late complications. One patients died following status epilepticus. One patient had a late peritonitis, and two others gastroesophageal reflux severe enough to require surgical intervention. Six patients had mild long-term complications, mainly infectious. All children showed improvement of weight for length. CONCLUSION: The PEG procedure is well-tolerated, effective way of tube feeding in children, with a relatively low complication rate.

[Liver rupture in a newborn infant; diagnosis, treatment and prognosis]. / Leverruptuur bij pasgeborenen; diagnostiek, behandeling en prognose.

Between August 1989 and August 1992 four neonates with rupture of the liver were admitted to the Neonatal Intensive Care Unit of the Sophia Children's Hospital in Rotterdam, the Netherlands. Two neonates were born after breech delivery, two after caesarean section because of foetal distress. All four patients had Apgar scores < 5 after 1 minute and of < 8 after 5 minutes and required artificial ventilation for a prolonged period. All infants collapsed within 6 hours after birth. Surgical treatment was not considered because of the poor clinical condition. All patients were treated conservatively. Clinical signs were: rapid onset pallor, hypotension, tachycardia and abdominal distension. Ultrasonography of the abdomen confirmed the clinical diagnosis of rupture of the liver. Despite rapid diagnosis and maximal non-surgical treatment mortality was 75%. Surgical intervention is indicated in neonatal liver rupture with significant intra-abdominal bleeding.

A novel AMH missense mutation in a patient with persistent Müllerian duct syndrome.

Persistent Müllerian duct syndrome (PMDS) is characterized by the presence of a uterus, fallopian tubes, and the upper part of the vagina in phenotypic normal male patients. Here, we report a patient diagnosed with PMDS with a novel homozygous missense mutation in the anti-Müllerian hormone (AMH) gene (single nucleotide insertion (C) at position 208 (c.208dup, p.Leu70fs)) leading to a frameshift and the introduction of a premature stop codon. Biopsy of both gonads revealed that germ cells were present in an irregular distribution. However, the absence of OCT3/4, PLAP and c-KIT expression indicated physiological maturation.

Haemangioma of infancy: two case reports with an overdose of propranolol.

An 8-week-old infant was treated with oral propranolol for a haemangioma of infancy. The standard dose (according to protocol) is 2 mg/kg/day but, because of a mistake by the pharmacist, the child was treated with 8 mg/kg/day without any side effects (pulse, blood pressure and glucose stayed normal).