Drug-induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies.

Drug ototoxicity limits the quality of life of patients after treatment, having serious consequences, especially for psychosocial development of children. Although the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed.

Serum asparaginase activities and asparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500 IU/m(2) PEG asparaginase in children with ALL treated according to protocol COALL-06-97.

BACKGROUND AND PROCEDURE: Pharmacological surrogate parameters are considered a useful tool in estimating the treatment intensity of asparaginase (ASNase) preparations. When a pegylated ASNase (single infusion of 2,500 IU/m(2) polyethylene glycol (PEG)-ASNase, Oncaspar) was introduced into the treatment protocols of the German Cooperative Acute Lymphoblastic Leukaemia (COALL) study group, this was accompanied by a drug monitoring programme measuring serum ASNase activity and asparagine (ASN) concentrations in the cerebrospinal fluid (CSF) in 70 children. RESULTS: Four hundred fifty-nine serum samples from 67 evaluable patients showed medians of ASNase activity of 1,189.5, 824.5, 310.5, 41 and 4 U/l on day 7 +/- 1, 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. One hundred eighty-four samples from 59 patients were evaluable for ASN concentrations in the CSF. The medians of ASN concentration were <0.2, 0.2, 0.9 and 3.2 microM on day 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. When relating CSF ASN levels to the serum ASNase activity measured on the same day, a median of 1.2 microM CSF ASN was associated with values of serum ASNase activity between > or =2.5 and <100 U/l. Serum ASNase activity values > or =100 U/l were associated with a median CSF ASN of <0.2 microM, with 13/27 samples being incompletely depleted. CONCLUSIONS: The treatment intensity achieved with PEG ASNase in the present study appears to be acceptable based on the surrogate of serum ASNase activity. However, the pharmacological objective of ASNase treatment, that is, complete CSF ASN depletion with an ASNase activity >100 U/l, was not ensured. Nevertheless, one must also be aware that the minimum ASN concentration required for leukaemic cell growth is yet to be established.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters.

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

Operative treatment of supracondylar fractures of the humerus in children. The consequences of pin placement.

BACKGROUND: The commonly accepted treatment of displaced supracondylar fractures of the humerus in children is fracture reduction and percutaneous pin fixation; however, there is controversy about the optimal placement of the pins. A crossed-pin configuration is believed to be mechanically more stable than lateral pins alone; however, the ulnar nerve can be injured with the use of a medial pin. It has not been proved that the added stability of a medial pin is clinically necessary since, in young children, pin fixation is always augmented with immobilization in a splint or cast. METHODS: We retrospectively reviewed the results of reduction and Kirschner wire fixation of 345 extension-type supracondylar fractures in children. Maintenance of fracture reduction and evidence of ulnar nerve injury were evaluated in relation to pin configuration and fracture pattern. Of 141 children who had a Gartland type-2 fracture (a partially intact posterior cortex), seventy-four were treated with lateral pins only and sixty-seven were treated with crossed pins. Of 204 children who had a Gartland type-3 (unstable) fracture, fifty-one were treated with lateral pins only and 153 were treated with crossed pins. RESULTS: There was no difference with regard to maintenance of fracture reduction, as seen on anteroposterior and lateral radiographs, between the crossed pins and the lateral pins. The configuration of the pins did not affect the maintenance of reduction of either the Gartland type-2 fractures or the Gartland type-3 fractures. Ulnar nerve injury was not seen in the 125 patients in whom only lateral pins were used. The use of a medial pin was associated with ulnar nerve injury in 4% (six) of 149 patients in whom the pin was applied without hyperflexion of the elbow and in 15% (eleven) of seventy-one in whom the medial pin was applied with the elbow hyperflexed. Two years after the pinning, one of the seventeen children with ulnar nerve injury had persistent motor weakness and a sensory deficit. CONCLUSIONS: Fixation with only lateral pins is safe and effective for both Gartland type-2 and Gartland type-3 (unstable) supracondylar fractures of the humerus in children. The use of only lateral pins prevents iatrogenic injury to the ulnar nerve. On the basis of our findings, we do not recommend the routine use of crossed pins in the treatment of supracondylar fractures of the humerus in children. If a medial pin is used, the elbow should not be hyperflexed during its insertion.

Reliability of a modified Gartland classification of supracondylar humerus fractures.

Fracture-classification systems are used to recommend treatment and predict outcomes. In this study, a modified Gartland classification system of supracondylar humerus fractures in children was assessed for intraobserver and interobserver variability. Five observers classified radiographs of 50 consecutive children with extension supracondylar humerus fractures on three separate occasions. After a 2-week interval, 90% of fractures were classified the same on both readings, with and intraobserver kappa value of 0.84. After a 36-week interval, 89% of the fractures were classified the same, with a kappa value of 0.81. Interobserver reliability was evaluated by pairwise comparison among observers, resulting in an overall kappa value of 0.74. The reliability of the Gartland classification for supracondylar humerus fractures in children is better than that published for other fracture-classification systems. However, 10% of the time, a second reading by the same observer is different. This makes treatment recommendations based only on fracture type imprecise.

The radiological approach to precocious puberty.

Precocious puberty is caused by a heterogeneous group of disorders, which range from idiopathic to malignant tumours. The radiologist's role is to help: (1) differentiate precocious puberty from pubertal variants; (2) identify the underlying cause of precocity if present; and (3) assess for effectiveness of treatment. This pictorial review discusses the types of precocious puberty and their underlying aetiologies, differentiates precocious puberty from pubertal variants and illustrates the appropriate imaging evaluation for the patient diagnosed with precocious puberty.

Complications of cancer therapy in children: a radiologist's guide.

As advances in cancer therapy improve the prognosis of patients with childhood malignancies, awareness of the consequences of treatment methods assumes increasing importance. All cancer treatment modalities are associated with toxic effects, and the spectrum of therapy-induced complications involves all organ systems. Radiologists have a pivotal role in detecting these sequelae, which can be categorized by the affected organ system and by whether they occur (a) at diagnosis or during initial therapy or (b) after the completion of treatment. The first group consists of oncologic emergencies, infectious complications, and irritant effects. Oncologic emergencies can be further categorized as space-occupying lesions (e.g., superior vena cava syndrome or spinal cord compression), vascular abnormalities (e.g., hyperleukocytosis, anemia, coagulopathy), and metabolic emergencies (e.g., tumor lysis syndrome). Common complications developing after completion of treatment include leukoencephalopathy and neurocognitive defects; cataract formation; cardiomyopathy and congestive heart failure; hepatic dysfunction, fibrosis, and cirrhosis; radiation enteritis; renal dysfunction or failure; scoliosis and short stature; hypothyroidism; gonadal dysfunction; graft-versus-host disease; and development of secondary malignancies. Physician awareness of these complications will permit more effective patient surveillance, which may afford patients the opportunity for earlier intervention in these situations and improved quality of life.

Variability in measurement of acetabular index in normal and dysplastic hips, before and after reduction.

This study examined the variability in the measurement of the acetabular index (AI) in normal and dysplastic hips, both before and after reduction. This variability for dysplastic hips is greater than that of normal hips. The variability is greater before an open or closed reduction than after reduction, and the variability after an open reduction is nearly 3 times greater than after a closed reduction. The 95% confidence interval of the AI is 10.1 degrees intraobserver and 21.9 degrees interobserver for all hips. The AI is most accurate in the situation in which it is most useful, after a closed reduction of a dysplastic hip. A 95% confidence interval of 5.1 degrees in this selected population supports the use of the AI for monitoring acetabular remodeling after closed reductions in accordance with previous clinical recommendations.

Perlman syndrome: a case report emphasizing its similarity to and distinction from Beckwith-Wiedemann and prune-belly syndromes.

Perlman syndrome is a rare entity characterized by hypotonia, facial dysmorphism, gigantism, and visceromegaly including nephromegaly. The current case illustrates the ultrasonographic and computed tomographic appearances of renal abnormalities in this condition. Findings in Perlman syndrome can overlap with and need to be distinguished from two more common clinical entities: prune-belly and Beckwith-Wiedemann syndromes. Additional cranial findings previously unreported are also described.

Psoas over the brim lengthenings. Anatomic investigation and surgical technique.

Lengthening of the psoas tendon commonly is performed for various conditions of the hip including developmental dysplasia and neuromuscular contractures and instability. Anecdotal reports of injury to surrounding neurovascular structures suggest an investigation of the local anatomy is warranted. Using magnetic resonance images from 54 children younger than 10 years, the authors examined the anatomic relationship between major neurovascular structures (femoral artery and vein, external iliac artery and vein, femoral nerve) and the psoas tendon. The mean distance between the neurovascular structures and the psoas tendon in the over the brim position is 1 cm, although it may be as close as 4 mm in a child. The mean distance is 3.1 cm at the tendon's insertion at the lesser trochanter. Surgeons performing psoas over the brim lengthenings should be aware that major neurovascular structures may be only 4 mm from the psoas tendon. The recommended surgical technique is presented.

[Vater Paccini's neurofibroma. Report of 3 cases]. / Neurofibroma de Vater Paccini. Reporte de tres casos.

The authors study three clinical cases of Pacinian neurofibromas. All of them were located in the fingers. A bibliographic review was performed. The morphologic, clinical and histological features are reviewed and stressed its benign behavior and special localization.

[Eosinophilic migratory nodular panniculitis (human gnathostomiasis)]. / Paniculitis nodular migratoria eosinofílica (gnathostomiasis humana).

The case of a patient with thoracic abdominal and left arm, migratory erythema-edematous plates over a space of three years is described. The histopathologic features reveal a eosinophilic panniculitis due to probable larva migrans (gnathostomiasis). This appears to be the first report on the subject because we have not found any reference to the subject in Argentina bibliographic search.

Current concepts in sonographic diagnosis of fetal renal disease.

The fetal kidneys and bladder are usually visible by 15 weeks' gestation on sonograms. The authors present their experience with the diagnosis of renal abnormalities in the fetus.

[Trichodiscomas associated with fibrofolliculomas and acrochordons]. / Tricodiscomas asociados a fibrofoliculomas y acrocordones.

A case of trichodiscomas associated to fibrofolliculomas and acrochordons is presented. The histological and histogenic characteristics are discussed. Bibliographic revision is made. It is possible to consider the case above mentioned as a Birt-Hogg-Dubé syndrome.

Acerca del empleo de la S-adenosil metionina y bajas dosis de cloroquina en el tratamiento de la porfiria cutánea tardia / Use of S-adenosyl methionine and low-doses of chloroquine in the treatment of porphyria cutanea tarda

Se ha aplicado el tratamiento con S-Adenosil metionina (SAM) y bajas dosis de cloroquina en dos niños y adultos con Porfiria Cutánea Tardía (PCT). La terapia consiste en la administración de SAM (comprimidos 12-15 mg/Kg diarios) durante 3 semanas y cloroquina oral (2 x 100mg/semana), durante 120-150 días o hasta normalización del cuadro clínico y bioquímico. El resultado es el mismo en pacientes con PCT hereditaria o adquirida; exhibiendo inicialmente los típicos signos clínicos y bioquímicos. La excreción de porfirinas urinarias, incrementadas en todos los pacientes, disminuyó a valores fisiológicos entre, 3 y 6 meses después de comenzado el tratamiento. El patrón de porfirinas anormal, típico para la PCT y la relación uro/copro, se normalizaron en los pacientes con PCT adquirida, en tanto que en aquellos con PCT hereditaria, si bien hubo una ligera modificación, aún luego de alcanzadas concentraciones normales de porfirinas, se mantuvo el perfil de la PCT. El índice de porfirinas plasmáticos también disminuyó y se niveló al final de la terapia. Se midieron las actividades enzimáticas de ALA-D, Deaminasa y Urógeno Decarboxilasa (URO-D) en sangre, la última sólo se encontró reducida en la PCT hereditaria. En biopsias de hígado se determinaron URO-D y porfirinas, en todos los pacientes la enzima estaba inhibida y el contenido de pirroles notablemente aumentado, con un perfil típico. Con este tratamiento se logró una total recuperación clínica y bioquímica; no se observaron efectos colaterales indeseados ni reacciones oftalmológicas adversas. Es una terapia segura, efectiva y cómoda y la más indicada para niños, ancianos y pacientes que no toleren las flebotomías