Martine F. Raphael

Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants

BACKGROUND Infantile hemangioma (IH) is a frequently encountered tumor with a potentially complicated course. Recently, propranolol was discovered to be an effective treatment option. OBJECTIVE To describe the effects and side effects of propranolol treatment in 28 children with (complicated) IH. METHODS A protocol for treatment of IH with propranolol was designed and implemented. Propranolol was administered to 28 children (21 girls and 7 boys, mean age at onset of treatment: 8.8 months). RESULTS All 28 patients had a good response. In two patients, systemic corticosteroid therapy was tapered successfully after propranolol was initiated. Propranolol was also an effective treatment for hemangiomas in 4 patients older than 1 year of age. Side effects that needed intervention and/or close monitoring were not dose dependent and included symptomatic hypoglycemia (n = 2; 1 patient also taking prednisone), hypotension (n = 16, of which 1 is symptomatic), and bronchial hyperreactivity (n = 3). Restless sleep (n = 8), constipation (n = 3) and cold extremities (n = 3) were observed. LIMITATIONS Clinical studies are necessary to evaluate the incidence of side effects of propranolol treatment of IH. CONCLUSIONS Propranolol appears to be an effective treatment option for IH even in the nonproliferative phase and after the first year of life. Potentially harmful adverse effects include hypoglycemia, bronchospasm, and hypotension.

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome

Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09–0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome.

Is cardiovascular evaluation necessary prior to and during beta-blocker therapy for infantile hemangiomas?: A cohort study.

BACKGROUND Although consensus guidelines for pretreatment evaluation and monitoring of propranolol therapy in patients with infantile hemangiomas (IH) have been formulated, little is known about the cardiovascular side effects. OBJECTIVES We sought to analyze cardiovascular evaluations in patients with IH at baseline and during treatment with an oral beta-blocker. METHODS Data from 109 patients with IH were retrospectively analyzed. Patient and family history, pretreatment electrocardiogram (ECG), heart rate, and blood pressure were evaluated before initiation of beta-blocker therapy. Blood pressure and standardized questionnaires addressing side effects were evaluated during treatment. RESULTS Questionnaire analyses (n = 83) identified 3 cases with a family history of cardiovascular disease in first-degree relatives. ECG findings were normal in each case and no serious complication of therapy occurred. ECG abnormalities were found in 6.5% of patients but there were no contraindications to beta-blocker therapy and no major complications. Hypotension in 9 patients did not require therapy adjustment. In all, 88 parents (81%) reported side effects during beta-blocker treatment. LIMITATIONS The relatively small patient cohort is a limitation. CONCLUSION Pretreatment ECG is of limited value for patients with an unremarkable cardiovascular history and a normal heart rate and blood pressure. Hypotension may occur during treatment.

Caphosol, a therapeutic option in case of cancer therapy-induced oral mucositis in children? Results from a prospective multicenter double blind randomized controlled trial

In pediatric oncology, chemotherapyor radiotherapy-induced oral mucositis (OM) is accompanied by decreased oral intake, pain, analgesics use, and hospital admission [1, 2]. Moreover, OM is correlated with an increased risk of sepsis [3, 4]. Recently, Caphosol, a supersaturated CaPO4 mouth rinse, became available to prevent or treat mucositis [5]. Papas et al. demonstrated Caphosol to have a beneficial prophylactic effect in adult hematopoietic stem cell transplantation (HSCT) patients, but evidence in pediatric patients is lacking [6]. We studied whether Caphosol can be used to treat OM in a prospective randomized study.

Should anthracyclines and dexrazoxane be used for children with cancer

Anthracyclines are widely used to treat childhood malignancies; however, one in 10 children who are treated with a cumulative anthracycline dose of 300 mg/m2 or more will eventually develop clinical heart failure. The consequences of anthracycline-induced cardiotoxicity are extensive; excess mortality due to cardiac disease is eight-times higher than expected for long-term childhood cancer survivors than for the normal population. The risk of developing anthracycline-induced cardiotoxicity is life-long, which is especially important for children who have a long life expectancy after successful treatment. Despite their widespread use, a systematic review has shown that there is no—or only very sparse— evidence from randomised trials, which underscores the use of anthracyclines for diff erent childhood malignancies. Randomised trials were identifi ed for only fi ve malignancies. For acute lymphoblastic leukaemia (three randomised trials; 912 children; one trial assessed standard risk; stages were not mentioned for the other two trials), no signifi cant diff erence in antitumour effi cacy was identifi ed in the meta-analyses, but in most individual studies there was a suggestion of better effi cacy in patients who were treated with anthracyclines. For rhabdomyosarcoma and undiff erentiated sarcoma (one study; 413 children; clinical group III–IV), and for non-Hodgkin lymphoma (one study; 285 children; stage I–IV), no diff erence in antitumour effi cacy between treatment groups was identifi ed. However, for Wilms’ tumour (one study; 316 children; stage II–IV), and for non-metastatic Ewing’s sarcoma (one study; 94 children), a signifi cant diff erence in survival was identifi ed in favour of anthracycline treatment. The hazard ratios for overall survival and for event-free survival in Wilms’ tumour were 1·85 (95% CI 1·09–3·15; p=0·02) and 2·21 (1·44–3·40; p=0·003). For patients with Ewing’s sarcoma, only descriptive results were available (p=0·02 for overall survival; p=0·01 for event-free survival). Long-term followup of the Wilms’ tumour trial has since become available; with long-term follow-up (16 years in some of the patients), the signifi cant diff erence in overall survival disappears, possibly resulting from mortality caused by diff erent late eff ects. Furthermore, in a randomised trial of anthracyclines for standard-risk hepatoblastoma, there was no diff erence in antitumour effi cacy between treatment groups. If treatment with anthracyclines has no added value regarding antitumour effi cacy compared with treatment without them, they should not be used at all, and anthracycline-related cardiotoxicity will not be an issue. However, if treatment with anthracyclines is necessary, it is extremely important to prevent cardiotoxicity. Dexrazoxane is one of the most important cardio protective interventions. It signifi cantly reduces anthracycline-related cardiotoxicity in adults with diff erent solid tumours and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma. With the exception of Hodgkin’s disease (long-term cardiac data not yet available; no diff erence in antitumour effi cacy), no results relating to dexrazoxane use in other childhood malignancies have yet been published. That dexrazoxane is not routinely used in clinical practice might be explained by the suspicion of interference with antitumour effi cacy and by the occurrence of secondary malignancies. However, meta-analyses of antitumour effi cacy showed no signifi cant diff erence between patients who were treated with or without dexrazoxane. Furthermore, a meta-analysis including three of the four randomised trials available about secondary malignancies after dexrazoxane, did not show a signifi cant diff erence in the occurrence of secondary malignancies between children treated with or without dexrazoxane (relative risk 1·16, 95% CI 0·06–22·17, p=0·92; eight secondary malignancies in the dexrazoxane group and four in the control group). One other trial did not provide enough information to be included in the meta-analysis, but showed no statistically signifi cant diff erence in 5-year and 10-year cumulative incidence of secondary malignancies between treatment groups. In conclusion, only very sparse evidence is available supporting the use of anthracyclines in children. Evidence about dexrazoxane shows a strong cardioprotective eff ect in adults with diff erent solid malignancies and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma, while the risk of interference with antitumour effi cacy and the occurrence of secondary malignancies are not substantiated. More research is needed to establish the exact role of anthracyclines in childhood malignancies. If treatment with anthracyclines is necessary, then treatment with dexrazoxane should be considered.

Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory

TMPRSS6 variants that affect protein function result in impaired matriptase‐2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype–phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono‐allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi‐allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482–E490, 2016.

Does high-resolution CT has diagnostic value in patients presenting with respiratory symptoms after hematopoietic stem cell transplantation?

BACKGROUND Hematopoietic stem cell transplantation (SCT) can be complicated by a variety of live-threatening infectious and non-infectious pulmonary complications. The management of these complications is critically dependent on the most probable diagnosis, which is in part based on imaging work-up. METHODS Systematic review of the literature related to the diagnostic value of high-resolution computed tomography (HRCT) in patients who underwent SCT and developed respiratory symptoms. RESULTS Literature review did not reveal systematic cohort studies that included patients with respiratory symptoms post-SCT who underwent HRCT and had a well-defined outcome. Most studies selected participants based on their final diagnosis instead of the indication for diagnostic testing in practice. Nevertheless, several papers clearly indicated a potential role for HRCT when complications after SCT occur. A variety of articles described the role of certain HRCT findings in the diagnosis of specific infectious complications, but less data were available for non-infectious complications. CONCLUSION We believe more diagnostic studies are needed to determine the value of HRCT for a specific diagnosis in SCT-recipients who present with respiratory symptoms at the transplant clinic. Currently, radiologists should be cautious since HRCT interpretation in these patients is not unambiguous.

Treatment of infantile hemangiomas: therapeutic options in regard to side effects and adverse events – a review of the literature

ABSTRACT Introduction: While options for treatment strategies for infantile hemangiomas (IH) are numerous, evidence-based information about agents, optimal dosage, adverse effects, treatment modality, pretreatment and treatment strategies remain limited. Areas covered: To evaluate side effects and adverse events of medical treatment in children with infantile hemangioma, a comprehensive review of the literature was performed to provide information for daily practice. In total 254 studies were retrieved from medical databases and comprised 10,022 patients divided into 5 different treatment groups. Information about working mechanism, side effects and adverse events of therapies used as a single agent for IH are discussed and evaluated according to information from pharmacotherapeutic databases. Randomized controlled trials have only scarcely been performed for the many therapeutic options reported for IH. Short- and long-term side effects and adverse events, have not been systematically studied. Subsequently information about the medical treatment options and pharmacotheraputic databases for therapy in children with IH are incomplete. Expert opinion: From the many therapeutic options, propranolol is the first-line approach for IH, predominantly based on clinical observation, efficacy and tolerability in the short-term. The unsolved ravels of possible short and long-term adverse events of propranolol used during early developmental stages of children need thorough review.

Response from the authors of ‘Treatment of infantile haemangiomas with atenolol: Comparison with a historical propranolol group’

With great interest we have read the comments of Ashvin Raju and Roba Khundkar. We are pleased that the authors acknowledge atenolol as a possible alternative to propranolol. In respect to age adjustment, we included age as a categorical variable (1e6 months, 6e12 months and >12 months) in our model, so linearity between age and efficacy was not assumed. We agree that propranolol was shown to be the more efficacious option with regard to the percentage of patients with clinical involution, but this was not statistically significant (p Z 0.09). When confronted with two patients on propranolol that developed side effects, we initiated atenolol treatment. We hypothesized that the use of a hydrophilic, selective beta-1-blocker could be effective and prevent side effects of propranolol. Good results made atenolol our primary drug of choice. Patients #4 and #9 were excluded for analysis because of previous unsuccessful propranolol treatment and patient #11 because of its non-cutaneous location of IH and inability to assess quantitative outcome. They all responded well to atenolol. Patient #1 with a periorbital IH revealed minor improvement on atenolol and partial surgical debulking was performed. Patient #2 showed minor improvement on atenolol and because of severe pain due to ulceration, surgical excision was performed. For both patients no propranolol therapy was commenced. Patient #3 did not respond to propranolol after two weeks of atenolol treatment. Subsequently an excision was performed. Ever since, no atenolol failures were seen.

Hemangiomen: wanneer en hoe te behandelen

SamenvattingTotté JEE, Breugem CC, De Graaf M, Toonstra J, Raphaël MF, Breur-Raymakers GJLM, Speleman L, Breur JMPJ, Pasmans SGMA. Hemangiomen: wanneer en hoe te behandelen. Huisarts Wet 2013;56(2):74-8.De meeste hemangiomen op de kinderleeftijd hebben een gunstig beloop. Op basis van zorgvuldige anamnese en lichamelijk onderzoek kan de huisarts niet alleen een hemangioom van een vasculaire malformatie onderscheiden, maar ook een inschatting maken van een eventueel verhoogde kans op een gecompliceerd beloop. Bètablokkers zijn effectief gebleken bij hemangiomen en hebben een gunstig bijwerkingenprofiel. Behandeling in een vroeg stadium kan complicaties en zelfs levensbedreigende situaties voorkomen. Vroege doorverwijzing is daarom belangrijk. Dit artikel presenteert aandachtspunten om risicovolle hemangiomen snel te kunnen herkennen.De goede ervaringen met bètablokkers hebben ertoe geleid dat de behandeling, die tot nog toe was voorbehouden aan expertisecentra, voor een deel kan worden overgedragen aan de tweede, en op termijn ook aan de eerste lijn. Een belangrijke rol daarbij speelt het KinderHuidhuis, een digitaal platform voor specialist, huisarts, verzorger en patiënt dat onder andere voorziet in de coaching van de behandelend arts vanuit het expertisecentrum.Totté JEE, Breugem CC, De Graaf M, Toonstra J, Raphaël MF, Breur-Raymakers GJLM, Speleman L, Breur JMPJ, Pasmans SGMA. When and how should haemangioma be treated? Huisarts Wet 2013;56(2):74-8.Most haemangiomas of infancy have a favourable course. With a careful history and physical examination, the general practitioner not only can distinguish between a haemangioma and vascular malformations, but also assess the potentially increased risk of complications. Haemangiomas can be treated effectively with beta-blockers such as propranolol in specialized centres, and a proactive policy is essential to prevent later damage or even life-threatening situations. Early referral is increasingly important. This articles present guidelines on how to recognize potentially dangerous haemangiomas. The beneficial effect of beta-blockers has resulted in doctors in primary and secondary care being involved in the treatment and follow-up of patients with haemangiomas. ‘KinderHuidhuis’, the Dutch digital platform for specialists, general practitioners, care providers, and patients interested in infant skin problems provides expertise and coaching for doctors involved in the treatment of these patients.