The association between platelet indices and presence and severity of psoriasis: a systematic review and meta-analysis.

The role of platelet function indices-platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), immature platelet fraction (IPF), and platelet mass index (PMI)-in psoriasis is uncertain. This systematic review and meta-analysis aimed to evaluate the association of these platelet biomarkers with both presence and severity of psoriasis. We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library from inception to November 2021. To evaluate the association of platelet function indices and psoriasis, we recorded mean differences (MD) and 95% confidence intervals (CI) as well as correlation coefficients (r) for each included study, and generated summary estimates using random-effects inverse-variance modelling. We screened 1,079 unique studies, and included 33 studies with 6724 patients in the quantitative analyses. Compared with controls, patients with psoriasis had higher PLT (MD 12.86 × 109/L, 95% CI 6.34-19.39, p < 0.001), MPV (MD 0.61fL, 95% CI 0.31-0.92, p < 0.001), and PCT (MD 0.05%, 95% CI 0.01-0.09, p = 0.010), but similar PDW (MD 0.16%, 95% CI -0.46-0.79, p = 0.610). Psoriasis Area and Severity Index (PASI) was weakly correlated with PLT (r 0.17, 95% CI 0.06-0.28, p = 0.003), MPV (r 0.36, 95% CI 0.22-0.49, p < 0.001), and PDW (r 0.17, 95% CI 0.08-0.26, p < 0.001). Study numbers were insufficient to judge the relationship of IPF and PMI with psoriasis presence, or PCT, IPF, and PMI with psoriasis severity. In summary, PLT, MPV, and PCT are significantly elevated in patients with psoriasis, and PLT, MPV, and PDW are weakly correlated with PASI. Future studies are needed to evaluate the independent diagnostic and prognostic potentials of these biomarkers in patients with psoriasis.

The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC.

BACKGROUND: Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. DESIGN: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. RESULTS: We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were $155 605 and $187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was $215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183% and decreased the ICER by up to 65%. Pembrolizumab was studied only in patients whose tumors expressed PD-L1. The QALY gain was 0.346 and the ICER was $98 421. Patient selection also reduced the budget impact of immunotherapy. CONCLUSION: The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved.

Pediatric endocrine screening for von Hippel-Lindau disease: benefits and the challenge of compliance.

Fifteen children and adolescents (4 male) with a median age of 5.4 yr (range 1.2 -13.6 yr) were entered into a screening protocol to identify lesions of von Hippel-Lindau (VHL) disease. Fourteen had an affected first-degree relative and one had a previous VHL lesion. Screening during the period of 2000 to 2008 followed published guidelines and consisted of measurement of urinary catecholamines, adrenal and renal imaging and ophthalmological and central nervous system examinations and imaging. Screening identified 8 VHL lesions in 6 asymptomatic patients with confirmed genetic mutations. Five patients had elevated urinary noradrenaline excretion and in each case the presence of a pheochromocytoma was identified on adrenal magnetic resonance imagin scan. In one patient a left-sided tumor was identified 1 yr after a right-sided tumor had been removed. In a sixth patient a retinal capillary hemangioma and a cerebellar hemangioblastoma were identified. Patient compliance with the screening protocol was variable reflecting its time-intensive nature. A formal screening programme for this at-risk population of pediatric patients, despite being intensive, can identify VHL lesions during a pre-morbid phase and may thus have a beneficial impact on prognosis in this serious disorder.

Clinical and endocrine features and long-term outcome of Graves' disease in early childhood.

Hyperthyroidism is rare in early childhood and most commonly caused by Graves' disease. We report 14 children (4 boys, 10 girls) aged 3.4-7.5 yr. At diagnosis, all patients had weight loss, hyperkinetic activity, tachycardia, difficulty sleeping, and poor concentration and 11 presented with proptosis. Four patients developed long-term neuropsychological problems. There was a family history in 7 cases. All patients had goiters, clinically assessed to be large and diffuse in 21%, medium-sized in 43%, and small in 36%. At diagnosis, height was increased with median (range) height; 1.25 standard deviation score (SDS) (-0.2-5.24) and body mass index (BMI) was decreased; -0.48 SDS (-1.65-1.26). Height and BMI SDS values were statistically different (p<0.032) Bone age was advanced in 4 of 5 children, who had assessments. Total or free T4 levels were elevated and TSH was undetectable. Ninety percent of patients (12/14) had positive thyroid peroxidase autoantibodies, mean level 680 IU/ml (range 50-1347). Initial treatment was with antithyroid medication using carbimazole; median dose 0.75 mg/kg/day (no.=13) or propylthiouracyl 15 mg/kg/day (no.=1). T4 was added in 6 patients. Normalisation of serum T4 occurred at 4 months (1- 9) and TSH at 7 months (3-24) after start of therapy. Treatment was discontinued after a minimum of 2 yr in 11 patients, relapse occurring in 9. Median duration of total therapy was 58 months (18-132). During adolescence, 4 patients had curative therapy by surgery (no.=2) or radioiodine (no.=2). In conclusion, disturbance of growth, behavioral difficulties and infrequent spontaneous remission are key features of Graves' disease in early childhood.

Abnormal puberty in paediatric Cushing's disease: relationship with adrenal androgen, sex hormone binding globulin and gonadotrophin concentrations.

OBJECTIVE: Paediatric Cushing's disease is frequently associated with abnormal puberty. We addressed the hypothesis that prepubertal patients show excessive virilization and pubertal patients show suppression of LH and FSH secretion. DESIGN AND MEASUREMENTS: Serum androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS), testosterone (T), and sex hormone binding globulin (SHBG) were determined at diagnosis and converted to standard deviation scores. LH, FSH concentrations were also determined. Severity of CD was assessed from the sleeping midnight cortisol concentration. Puberty was staged and excessive virilization defined as advance in pubic hair stage for breast stage or testicular volume (TV). PATIENTS: Twenty-seven CD patients (17 male, 10 female), median age 13.4 years (range 5.9-17.8) were studied. RESULTS: In the CD group as a whole, A4, DHEAS, T standard deviation scores (SDS) values were normal. SHBG SDS values (n = 19) were low (median -1.93, -4.32-0.86) correlating with BMI (r = -0.49). A4, DHEAS, T, SHBG, LH and FSH did not correlate with midnight cortisol, but A4 and T SDS correlated with ACTH at 09.00 h (both r = 0.51). Thirteen patients (11 male, 2 female) had excessive virilization with increased A4 (P = 0.033), DHEAS (P = 0.008), testosterone (P = 0.033) and decreased SHBG (P = 0.004) compared with subjects without excessive virilization. Pubertal boys (TV > or = 4 ml) (n = 7) and girls (breasts > or = stage 2) (n = 8) had low median LH and FSH. Boys had an LH concentration of 1.2 mU/l (0.3-3.5), FSH, 0.9 mU/l (0.2-6.4) and median T SDS, -1.95 (-3.8-4.65), while girls had an LH concentration of 1 mU/l (0.3-7.4). CONCLUSIONS: Many patients had abnormal puberty and excessive virilization associated with increased adrenal androgens and decreased SHBG. Pubertal patients had low LH and FSH suggesting impaired pituitary-gonadal axis function.

Long-term anterior pituitary function in patients with paediatric Cushing's disease treated with pituitary radiotherapy.

BACKGROUND/OBJECTIVE: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing's disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT. PATIENTS AND METHODS: Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4-17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13-2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0-17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6-16.5). RESULTS: At a mean of 1.0 year (0.11-2.54) following RT, GH deficiency (peak GH <1-17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6-11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2-50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20-25 ml at the age of 14.5-28.5 years. CONCLUSION: This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

Cosegregation of a novel homozygous CYP11B1 mutation with the phenotype of non-classical congenital adrenal hyperplasia in a consanguineous family.

We report a novel missense mutation of CYP11B1 causing non-classical 11beta-hydroxylase deficiency in 3 members of a consanguineous Turkish family. Two siblings presented with clinical evidence of precocious pseudopubarche. Biochemistry suggested 11beta-hydroxylase deficiency and genetic analysis revealed that they were homozygous for the missense mutation L489S within exon 9 of the CYP11B1 gene. The unaffected parents were heterozygotes for the same mutation. In addition, a paternal aunt of the affected siblings presenting with primary infertility and mild hirsutism was found to have the same homozygous mutation. This is the first report of a homozygous mutation in non-classical congenital adrenal hyperplasia that cosegregates with clinical phenotype. The significance of the missense mutation L489S in CYP11B1 is further supported by the conservation of leucine at position 489 in CYP11 genes in eleven other species. Molecular modelling of the enzyme suggests that the mutation L489S in CYP11B1 may alter the enzyme's substrate-binding affinity. These findings suggest that this homozygous mutation affects 11beta-hydroxylase function, resulting in the clinical features of non-classical adrenal hyperplasia in this family.

In situ photoimmunotherapy: a tumour-directed treatment for melanoma.

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children.

Von Hippel-Lindau (VHL) is a rare autosomal dominant syndrome characterised by the association of retinal and CNS haemangioblastomas, phaeochromocytoma and renal cell carcinoma. If a child of an affected parent has inherited a VHL mutation or the parent's mutation cannot be identified, then clinical screening is recommended. We report the clinical features in three parent-offspring pairs where the parents have presented clinically with renal cell carcinoma, phaeochromocytoma, cerebellar haemangioblastoma and retinal haemangioma, and the children have undergone pre-symptomatic screening. During the first screening a 13-year-old boy was diagnosed with bilateral phaeochromocytoma and later developed an endolymphatic sac tumour at 19 years. A right phaeochromocytoma was found in a 12-year-old girl who was screened from the age of 4 years and in a 13-year-old boy screened from 5 years of age. All children were asymptomatic at the time of diagnosis. These families demonstrate that clinical screening of children at risk of VHL can detect tumours before the first symptoms arise with a consequent reduction in morbidity. These observations strongly support the recommendation to undertake screening of the children of VHL patients.

The discriminatory value of the low-dose dexamethasone suppression test in the investigation of paediatric Cushing's syndrome.

BACKGROUND: Low- and high-dose dexamethasone suppression tests (LDDST, HDDST) are used in the investigation of Cushing's syndrome (CS). In adults with Cushing's disease (CD), cortisol suppression during LDDST predicts suppression during the HDDST. METHODS: We reviewed the results of the LDDST (0.5 mg 6 hourly x 48 h), HDDST (2.0 mg 6 hourly x 48 h) and corticotrophin-releasing hormone (CRH) test in 32 paediatric patients with CS: 24 had CD, 1 ectopic ACTH syndrome, 5 nodular adrenal hyperplasia and 2 adrenocortical tumours. RESULTS: In CD, LDDST suppressed cortisol from 590.7 +/- 168.8 (mean +/- SD) to 333.7 +/- 104.0 nmol/l after 48 h (0 vs. 48 h, p < 0.05; mean suppression, 45.1%; CI (30.8, 59.4%); 16/24 (66%) suppressed >30%; mean suppression 68.1%, CI (58.1, 77.9%)). The HDDST suppressed cortisol from 596.3 +/- 174.5 to 47.1 +/- 94.8 nmol/l after 48 h (0 vs. 48 h, p < 0.05; mean suppression, 93.5%; CI (88.2, 98.8%) with 17/24 (71%) suppressing to <50 nmol/l and 100% to <50% of baseline). In the LDDST, suppression correlated with that during the HDDST (r = +0.45, p < 0.05) with >30% suppression predicting that in the HDDST and hence CD. CRH increased cortisol by +100.3% (CI 62, 138.5%), 22/24 (91.7%) showing a >20% increase. In the other CS pathologies (n = 8) the LDDST induced no significant decrease in cortisol. CONCLUSION: The LDDST was of diagnostic value by discriminating between CD and other CS aetiologies. In our view the HDDST is redundant in the investigation of paediatric CS.

Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing's disease.

BACKGROUND: Paediatric Cushing's disease (CD) is rare, but is associated with considerable morbidity and requires effective treatment. Control of hypercortisolaemia is recommended prior to definitive therapy by transsphenoidal pituitary surgery with selective adenomectomy. We describe a 6.2-year-old male with severe hypercortisolaemia and life-threatening complications of Cushing's disease. Control of cortisol with metyrapone and ketoconazole was ineffective, and due to his deteriorating condition, the decision was taken to proceed to bilateral adrenalectomy. METHODS: Low-dose IV infusion of etomidate, with dose titration according to serum cortisol levels, was administered. RESULTS: Etomidate infusion (3.0 mg/h i.v.) decreased serum cortisol from 1,250 to 250 nmol/l within 24 h. Combined etomidate and hydrocortisone therapy was maintained to provide stable serum cortisol levels within the desired range for 12 days prior to successful bilateral adrenalectomy. CONCLUSION: In our experience, etomidate was effective and safe for short-term control of severe hypercortisolaemia in a severely ill child.

Two brothers with non-classical 21-hydroxylase deficiency: to treat or not to treat?

Variations in phenotype in 21-hydroxylase deficiency (21OHD) have cautioned against initiating treatment in the absence of abnormal clinical features. We report 2 Caucasian brothers with compound heterozygous mutations of the CYP21 gene and mild clinical and biochemical features of late-presenting 21OHD. The index case presented aged 8.5 years with mild genital virilization and bone age advanced by 5 years. Elevated basal and synacthen-stimulated 17-hydroxyprogesterone (17OHP; 22.4 and 246 nmol/l) and androstenedione (10.9 and 19.9 nmol/l) levels confirmed 21OHD. His younger brother was investigated at age 7.3 years, and although examination showed normal pre-pubertal genitalia, basal and synacthen-stimulated 17OHP (32.4 and 281 nmol/l) and androstenedione (6.2 and 9.0 nmol/l) were abnormal, and bone age was advanced by 1.5 years. Because of actual or incipient virilization, both patients were treated with glucocorticoid replacement 8-12 mg/m(2)/day. This decision is discussed in the context of published guidelines for the management of 21OHD.

Pseudo-precocious puberty caused by a juvenile granulosa cell tumour secreting androstenedione, inhibin and insulin-like growth factor-I.

We report a female child who presented at age 3.92 years with a 2-year history of consonant pubertal development caused by a large right-sided ovarian juvenile granulosa cell tumour (JGCT). Although JGCTs causing pseudo-precocious puberty have been previously described, they remain rare and endocrine data are often incomplete. In this case the tumour was associated with raised serum oestradiol, androstenedione, inhibin and IGF-I. Histological changes were consistent with JGCT. Immunohistochemical studies revealed positive reactivity to MIC-2, inhibin, melan A, IGF-I and IGFBP-2.

Neonatal thyrotoxicosis and maternal infertility in thyroid hormone resistance due to a mutation in the TRbeta gene (M313T).

We report two unusual cases of resistance to thyroid hormone (RTH) in one family. The first case, a male infant, had clinical features of thyrotoxicosis in the neonatal period. In the fourth week of life weight gain was poor despite a daily intake of standard infant formula almost double the infant's estimated requirements. At this time serum free T4 (fT4) was 60.7 pmol/l (Normal range [NR] 11-25 pmol/l) and TSH was inappropriately normal at 1.8 mU/l (NR 0.3-4.0 mU/l). The infant responded clinically and biochemically to propylthiouracil (PTU) at a dose of 10 mg/kg/day. Following 27 days of treatment serum fT4 was 22.6 pmol/l and TSH had risen to 24.9 mU/l. As the infant was thriving treatment was discontinued. The infant, now aged 6 months old, remains clinically euthyroid and developmentally normal off treatment. The infant's mother, from whom he had inherited a mutation of the thyroid receptor beta (TRbeta) gene (M313T), presented earlier with secondary infertility and clinical features of thyrotoxicosis. Treatment with PTU restored her fertility and she spontaneously conceived. In the subsequent pregnancy, clinical and biochemical features of RTH improved, and she gave birth to a small but healthy female infant. In the next pregnancy, resulting in the birth of the affected male infant, clinical and biochemical features of RTH worsened, and high doses of PTU were required to maintain a clinically euthyroid state. To our knowledge, these are the first case reports of RTH associated with added features of a hypermetabolic state in infancy and secondary infertility.

Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.

Pegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11beta-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39-72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 +/- 271.1 to 346.9 +/- 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 +/- 0.18 to 0.88 +/- 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 +/- 0.19 to 0.90 +/- 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 +/- 0.21 to 0.98 +/- 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 +/- 0.23 to 1.01 +/- 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11beta-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.

Kinetics and effect of percutaneous administration of dihydrotestosterone in children.

BACKGROUND: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5 alpha-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. METHODS: Six patients (age range 1.9-8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15-0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. RESULTS: Peak DHT concentrations were attained within 2-8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5-2.0 cm, was achieved after 3-4 months of treatment in all patients whose DHT concentrations were maintained within adult range. CONCLUSION: Percutaneous administration of DHT in a dose of 0.2-0.3 mg/kg once daily for a period of 3-4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.