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.

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.

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.

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).

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.

Testicular germ cell tumors in children: management and outcome in a series of 20 patients.

Testicular germ cell tumors occurring during childhood are extremely rare. This study reports the clinical presentation, pathological diagnosis, treatment methods and outcome in a series of 20 boys, aged between 3.5 months and 16 years (median: 1.5 years; 19 were prepubertal), who were treated between 1963 and 2003. Histologically, mature teratoma was present in seven, immature teratoma in four and yolk sac tumor in nine. Nineteen patients were stage I; only one patient was stage IV. Of the 11 teratomas, 10 were treated by orchiectomy and one by testis-sparing tumor excision only. All 11 patients have survived and show no evidence of disease between 10 and 28 years after surgery. The nine patients with yolk sac tumor were managed by orchiectomy, in two plus retroperitoneal lymphadenectomy, and in eight plus chemotherapy. One patient is in remission for 10 months, seven are alive with no evidence of disease for 5.5-23 years, and one patient died from a T-cell acute lymphoblastic leukemia, 2 years after the end of treatment of the testicular tumor. A gradual switch towards less invasive treatment has been observed over the years. This study confirms the excellent cure rates obtained in children with testicular germ cell tumor, provided diagnosis is prompt and treatment accurate.

Quality of life in patients with anorectal malformation or Hirschsprung's disease: development of a disease-specific questionnaire.

PURPOSE: Hirschsprung's disease and anorectal malformation are congenital diseases of the digestive tract with sequelae into adulthood. The quality of life of patients with these diseases is largely unknown. The aim of the study was 1) to construct a self-report disease-specific instrument to assess the quality of life in these patients and 2) to evaluate its psychometric performance. METHODS: An age-specific (6 and 7 years, 8-11 years, 12-16 years, and >17 years) questionnaire called the Hirschsprung's disease/anorectal malformation quality-of-life instrument was constructed. This questionnaire consists of 39 to 42 items, grouped into 10 to 11 scales that cover physical, emotional, and social functions as well as disease-related symptoms. Generic quality-of-life data were obtained in addition. A national sample of 715 patients aged six years and older completed the questionnaire (response rate, 61.9 percent). RESULTS: Multitrait scaling analyses confirmed the hypothesized scale structure with exception of the scales related to diet for the two youngest groups. Cronbach's alpha ranged (with exception of the diet scales) from 0.62 to 0.91 for children (8-11 years), from 0.69 to 0.82 for adolescents (12-16 years) and from 0.57 to 0.91 for adults. Selective scales were able to discriminate between subgroups of adult patients known to differ in disease and disease severity. Relevant scales of the adult version showed substantial correlations (> 0.40) with comparable scales of the SF-36. In the two youngest age groups the differences between subgroups of patients were less significant, but in the expected direction. CONCLUSIONS: With the exception of the scales related to diet, the Hirschsprung's disease/anorectal malformation quality-of-life instrument is an instrument with promising reliability and validity, to measure the disease-specific quality of life of patients with anorectal malformation or Hirschsprung's disease.

Religious circumcision under local anaesthesia with a new disposable clamp.

OBJECTIVE: To compare the results using a new disposable clamp (the Taraklamp Circumcision Device, TCD, Taramedic Europe BV, Bilthoven, The Netherlands), used since 1998 in one clinic, and the conventional dissection technique (CDT) in another clinic, for religious circumcision in infants. SUBJECTS AND METHODS: The TCD and CDT were compared prospectively; the duration of the procedure, complications and postoperative pain were recorded. The cosmetic result and the degree to which the parents were satisfied were evaluated after 6 weeks. After obtaining informed consent, 275 boys were included in the study (median age 3 years). RESULTS: The median operative duration was 8 min less for the TCD (15 vs 7 min; P < 0.001). There was no difference in complication rate (bleeding in one vs two; infection in two vs three) and postoperative pain was comparable in both groups. The cosmetic results were better for the TCD group (P < 0.001). The parents' satisfaction score for the procedure was equal in the groups, at 8, on a scale of 1 (very bad) to 10 (extremely good). CONCLUSION: A religious circumcision outside the hospital with the TCD is quicker and leads to a better cosmetic result than with the CDT, without increasing morbidity.

Inguinal hernias containing the uterus, fallopian tube, and ovary in premature female infants.

Inguinal hernias were diagnosed at 42 and 38 weeks' postconceptional age in 2 premature girls. The hernial sac contained the uterus, one Fallopian tube, and one ovary. The diagnosis was made by physical and sonographic examination and was confirmed during surgical correction. We suggest sonography in the diagnostic workup in (premature) female infants with an inguinal hernia.

Treatment and pain relief of ulcerative hemangiomas with a polyurethane film.

BACKGROUND: Hemangiomas are the most common tumors occurring in young children. The most common complication in the growing phase of hemangioma is ulceration. AIM AND METHOD: We report healing, pain relief and evolutive effects of a polyurethane film in 8 cases with ulcerative hemangiomas. RESULTS: In all 8 infants, prompt pain relief and healing within 1-2 months were observed. An increased regression was also noted within 2-4 months, when the hemangiomas were in the normal proliferative phase. CONCLUSION: As far as the authors know, there is no explanation for the effectiveness of polyurethane film. Explanations could be the occlusive effects of the film inhibiting proliferation or the decrease in blood flow. As primary initial therapeutic approach in ulcerative hemangiomas, we advocate the application of a polyurethane film. This therapy is painless and suitable for children.

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.