Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.

The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy.

Differential in vitro suppressive effects of steroids on leukocyte phagocytosis in two teleosts, tilapia and common carp.

The objectives of this study were to investigate the potential roles of cortisol and gonadal steroids in the phagocytic activity of peripheral blood leukocytes in two teleosts, tilapia (Oreochromis niloticus x O. aureus) and common carp (Cyprinus carpio). An in vitro microtiter plate assay, measuring incorporation of FITC-latex beads into peripheral blood leukocytes, was developed for the first time in teleosts. Peripheral blood leukocytes were cultured in AL medium with tested compounds in a microfluor black plate at 25 degrees C. FITC-latex beads were further incubated for phagocytosis and engulfed fluorescent intensity in phagocytes was detected fluorometrically. Cortisol suppressed leukocyte phagocytosis in a dose (10(-14) to 10(-4) M)- and time (0.5 to 8 h)-dependent manner in tilapia. The glucocorticoid agonist dexamethasone had a suppressive effect similar to that of cortisol, while cortisone and the mineralocorticoid aldosterone had only a weak effect in tilapia. High doses of estradiol and ethynylestradiol, but not of estrone, suppressed phagocytosis in tilapia. No suppressive effect on phagocytosis was observed with various concentrations of progesterone, testosterone, and 11-ketotestosterone. Triiodothyronine was also inactive on phagocytosis. A combination of estradiol and cortisol potentiatingly suppressed phagocytosis. Actinomycin D and cycloheximide blocked the suppressive effects of cortisol and estradiol. Cortisol had weaker suppressive effects on the phagocytosis of leukocytes in common carp than tilapia. Other steroids had no suppressive action on phagocytosis in common carp. It is concluded that the suppressive effects of cortisol and estradiol on phagocytosis in tilapia are mediated by specific glucocorticoid receptors and estrogen receptors, respectively. Cortisol would play a main and important role on the down-regulation of phagocytic activity. Sexual steroids, such as estradiol, also could interact with cortisol to further suppress immunity in tilapia. Differential responsiveness of the immune system to suppressive effects of steroids, among teleosts species, has been demonstrated.

Congenital hypothyroidism in Wales (1982-1993): demographic features, clinical presentation and effects on early neurodevelopment.

OBJECTIVE: Neonatal screening for congenital hypothyroidism (CH) was introduced in Wales in 1982. The aim of the study was to evaluate the demographic features and characteristics of infants identified during the first 12 years of screening and their neurodevelopmental progress in the first 2 years of life. DESIGN: Prospective collection of biochemical and clinical data (including results of Griffiths Mental Development Scales) obtained from questionnaires sent to paediatricians responsible for the ongoing clinical care of children with CH. PATIENTS: In Wales, between 1982 and 1993, 136 infants with primary congenital hypothyroidism (CH) were identified by the neonatal screening programme. RESULTS: Of all new-borns, 99.8% were screened and the prevalence of CH was 1 in 3279 (1 in 2473 girls and 1 in 4770 boys). The prevalence of CH was increased in North Wales. CH was associated with increased birth weight (48.5% of infants weighed greater than 3.5 kg) and an increased prevalence of non-thyroidal congenital abnormalities (8%) and congenital heart disease (3%). Isotope scanning demonstrated an increased prevalence of normal or enlarged thyroid glands and fewer ectopic glands compared to those reported in other studies. The mean developmental quotients (DQs) for individual subsets of intellectual and behavioural functioning in children with CH aged 1 and 2 years were all above 100 (range: 103.5-111.9). In subjects with absent thyroids, these DQs were correlated with the serum concentrations of free thyroxine before treatment. CONCLUSIONS: The demographic features of infants with congenital hypothyroidism born in Wales are similar to those reported from other European studies although there are marked regional variations in prevalence within Wales for which there is no apparent explanation. The median age of starting therapy was 17 days and compares favourably with other screening programmes. The overall mental development of Welsh children aged 1 and 2 years with congenital hypothyroidism identified by neonatal screening is satisfactory.

Secular changes in standing height, sitting height and sexual maturation of Chinese--the Hong Kong Growth Study, 1993.

In 1993 a territory-wide cross-sectional growth survey on 25,000 Chinese children from birth to 18 years was performed in Hong Kong. Compared to the last growth survey in 1963, definite secular changes were observed. There was an increase of final adult standing height of 3.6 cm in boys and 2.7 cm in girls, in which 1.8 cm and 0.5 cm respectively for boys and girls was accounted for by the sitting height. Thus most of the height increase had occurred in the leg length in girls, but in boys only half of it. The height difference was more marked during the pubertal years because secular change had brought about an earlier sexual maturation, including an advancement of median menarcheal age by 0.5 year, coupled with an earlier growth spurt. This paper also provides the first growth standards for Chinese from birth to 18 years, with percentile charts on both standing height and sexual maturation in boys and girls.

Secular trend in the sexual maturation of southern Chinese boys.

A random sample of 3872 southern Chinese boys ranging from 7 to 21 years of age were selected from primary and secondary schools in Hong Kong for the assessment of sexual maturation. The median ages of onset of puberty and pubic hair development were 11.4 and 12.7 years, respectively. The advancement of sexual maturation coincides with the secular increase in height and weight for Chinese children in Hong Kong.

Oral calcium treatment in vitamin D-dependent rickets type II.

Vitamin D-dependent rickets type II is a rare hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3. There is a great heterogeneity in the clinical presentation of this condition. The affected patients usually present early in childhood with clinical and biochemical evidence of rickets. Physiological replacement dosage of 1,25-dihydroxyvitamin D3 has no therapeutic effect. Responses to pharmacological doses of vitamin D metabolites or long-term calcium infusion have been variable. A case is reported here of an 8 year old girl, of consanguineous parents with vitamin D-dependent rickets, type II, in whom treatment with high dose oral calcium resulted in marked biochemical and radiological improvement. It is concluded that high dose oral calcium treatment is an effective treatment option for patients with vitamin D-dependent rickets type II.