The role of protocol biopsies after pediatric kidney transplantation.

Data on protocol biopsies (PBs) after pediatric kidney transplantation are rare.We evaluated 6-month post-transplantation renal function in 86 children after PB as observational study. Patients were divided into 3 groups:Glomerular filtration rate (GFR) and delta GFR were determined.PBs 6 months post-kidney transplantation did not influence the clinical course in stable pediatric patients and are therefore of questionable value. Decreased kidney function may however be stabilized by therapeutic intervention according to results of PB.

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

[Challenges in Long-Term Follow-Up Care of Patients After Kidney Transplantation in Specialized Transplant Centers]. / Herausforderungen der ambulanten Nachsorge von nierentransplantierten Patienten in spezialisierten Transplantationszentren.

Medical care after kidney transplantation requires a close follow-up in specialized transplant centers to minimize complications. Especially in bigger territorial states, the distance the patients have to cover is an underestimated problem for the patients. We performed a survey of 498 patients who underwent kidney transplantation at the transplant center of Hannover Medical School in Lower Saxony in order to find out the burden imposed by having to travel to one of the outpatient clinics affiliated with it for follow-ups. We found that 72% of the patients had to travel more than 100 km to reach the outpatient clinic and the costs for the trip were € 36.30 (standard deviation € 34.15). A distance between home and transplant center of more than 100 km reduced the motivation to attend the outpatient clinic significantly (p=0.023), whereas reimbursement of travel costs improved the motivation to attend the outpatient clinic only partially (p=0.012). We conclude that novel modern media-based care models like televisits could reduce patient burdens and optimize post-transplant care.

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection.

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.

Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study.

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 µg/L over the year) was lower than aspired (2 µg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.

Correction to: Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.

The article "Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation", written by Yasemen Cihan, Nele Kanzelmeyer, Jens Drube, Martin Kreuzer, Christian Lerch, Imke Hennies, Kerstin Froede, Murielle Verboom.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Graft outcomes following diagnosis of post-transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study.

Data related to graft outcomes following post-transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow-up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED-PTLD-2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet-PHL C1. In four patients, donor-specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody-mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range-based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B-cell-depleting therapy of PTLD with rituximab.

Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.

BACKGROUND: Chronic antibody-mediated rejection (cAMR) is the leading cause of late kidney graft loss, but current therapies are often ineffective. Rabbit anti-human thymocyte immunoglobulin (rATG) may be helpful, but its use is virtually undocumented. METHODS: Data were analyzed retrospectively from nine pediatric kidney transplant patients with cAMR were treated with rATG (1.5 mg/kg × 5 days) at our center after non-response to pulsed prednisolone, intravenous immunoglobulin, rituximab, and increased immunosuppressive intensity (including switching to belatacept in some cases), with or without bortezomib. RESULTS: The median time from diagnosis to cAMR was 179 days. rATG was started 5-741 days after diagnosis. Median estimated glomerular filtration rate (eGFR) increased from 40 mL/min/1.73 m2 when rATG was started to 62 mL/min/1.73 m2 9 months later (p = 0.039). Four patients showed substantially higher eGFR after 9 months and 2 patients showed a small improvement; eGFR continued to decline in 3 patients after starting rATG. No grafts were lost during follow-up. At last follow-up, donor-specific antibodies (DSAs) were no longer detectable in 4 out of 8 patients for whom data were available, median fluorescence intensity had decreased substantially in 1 out of 8 patients; anti-HLA DQ DSAs persisted in 2 out of 8 patients. No adverse events with a suspected relation to rATG, including allergic reactions, leukocytopenia or infections, were observed in any of the patients. CONCLUSIONS: In this small series of patients, rATG appears a promising treatment for unresponsive cAMR. Further evaluation, including earlier introduction of rATG, is warranted.

Belatacept after kidney transplantation in adolescents: a retrospective study.

Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non-nephrotoxic, first-in-class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post-KTx. Six patients (median age 15.5 years) were switched after a median of 7.5 months (range 23 days to 12 years), treatment range 3-28 months (cumulative 83 months): Three patients switched early (<3 months after KTx) had increased estimated glomerular filtration rate (GFR); one patient switched 12 years post-KTx has stable GFR; two patients were switched following rapid decline of and with markedly impaired GFR, changing slope in one patient. One patient had one acute rejection. In addition of two patients who received belatacept for other conditions, the only relevant adverse event was neutropenia (after a cumulative 109 months). Belatacept as primary immunosuppression is an option in Epstein-Barr virus-seropositive nonadherent adolescents if administered sufficiently early before deterioration of graft function.

Switching from immediate- to extended-release cysteamine in nephropathic cystinosis patients: a retrospective real-life single-center study.

BACKGROUND: Nephropathic cystinosis is a rare lysosomal storage disease which is characterized by the accumulation of free cystine in lysosomes and subsequent intracellular crystal formation of cystine throughout the body. If not treated with cysteamine, a cystine-depleting agent, end-stage renal disease will develop early, followed by multiple organ failure as the disease progresses. The established cysteamine formulation requires a strict dosing regimen at 6-h intervals. An extended release (ER) twice-daily formulation has recently been developed. The aim of our study was to evaluate the implementation and outcomes of this option in routine care. METHODS: All pediatric cystinosis patients' records in Hannover Medical School were screened, and data on cysteamine therapy, tolerability, dosing, estimated glomerular filtration rates (eGFR), white blood cell cystine levels, and proton pump inhibitor (PPI) use were extracted for the period January 2014 to January 2016. RESULTS: The median age of the 12 patients enrolled in the study was 12.5 (range 1-18) years. At the end of the study period ten of these patients received ER-cysteamine. There were no additional side effects. Halitosis/bad breath was often subjectively judged as improved or eliminated, and PPI use could be stopped in one of three patients. The main reasons for switching to the ER formulation were difficult night-time administration and uncontrolled disease. Mean eGFR values remained stable with a median of 67 ml/min/1.73 m2 before and after the transition. White blood cell (WBC) cystine values remained low after the switch (1 nmol/mg protein before and after transition; p = 0.64). CONCLUSIONS: In this single-center cohort, the switch from IR- to ER-cysteamine was safe and effective over the short term and provided advantages in terms of frequency of administration and less halitosis/bad breath. The long-term benefit of this option needs to be evaluated in future studies.

Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.

BACKGROUND: Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy. METHODS: This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed. RESULTS: The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy. CONCLUSIONS: Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most-if not all-AS patients with heterozygous mutations in the causal genes.

CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chemokine CXC ligand 13 (CXCL13) has been implicated in perivascular inflammation and pulmonary vascular remodeling in patients with idiopathic pulmonary artery hypertension (IPAH). We wondered whether CXCL13 may also play a role in chronic thromboembolic pulmonary hypertension (CTEPH) and whether serum levels of CXCL13 might serve as biomarkers in these conditions. METHODS: Lung tissue from patients with IPAH or CTEPH was immunostained for CXCL13. Serum samples were obtained from patients with IPAH (n = 42) or CTEPH (n = 50) and from healthy controls (n = 13). Serum CXCL13 concentrations were measured by enzyme-linked immunosorbent assay technology and were evaluated for associations with markers of disease severity and survival. RESULTS: CXCL13 was expressed in pulmonary vascular lesions and lymphocytes of patients with IPAH and inoperable CTEPH, respectively. Serum CXCL13 was elevated in patients compared to healthy controls [median, interquartile range, 83 (55,114) pg/ml versus 40 (28, 48) pg/ml; p < 0.001]. Serum CXCL13 showed only weak and inconsistent correlations with markers of inflammation or disease severity. In both populations, patients with serum CXCL13 above the median of the respective groups did not have a higher risk of death than patients with lower serum CXCL13. CONCLUSIONS: CXCL13 was overexpressed in pulmonary vascular lesions of patients with IPAH and CTEPH, and increased serum concentrations were found in patients with IPAH and CTEPH, suggesting a potential pathogenic role of CXCL13 in both diseases. However, given the weak associations between serum CXCL13 and markers of disease severity and outcome, CXCL13 is unlikely to become a promising biomarker in these patient populations.

Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers.

BACKGROUND: Up to now, only limited data on long-term medical treatment in congenital hyperinsulinism (CHI) is available. Moreover, most of the drugs used in CHI are therefore not approved. We aimed to assemble more objective information on medical treatment in CHI with regard to type and duration, dosage as well as side effects. METHODS: We searched MEDLINE (from 1947) and EMBASE (from 1988) using the OVID interface for relevant data to evaluate medical treatment in a large cohort of patients with CHI from different clinical centers. Randomized, controlled trials were not available. We evaluated case reports and case series. No language restrictions were made. RESULTS: A total number of 619 patients were medically treated and information regarding conservative treatment was available. Drugs used were diazoxide (in 84% of patients), somatostatin analogues (16%), calcium channel antagonists (4%) and glucagon (1%). Mean dose of diazoxide was 12.5 (±4.3) mg/kg ⋅ d (range 2-60 mg/kg ⋅ d), mean duration of diazoxide treatment until remission was 57 months. Side effects of diazoxide were usually not severe. The causal relation between diazoxide and severe side effects, e.g. heart failure (3.7%) remains doubtful. Mean dose of octreotide was 14.9 (±7.5) µg/kg ⋅ d (range 2.3-50 µg/kg ⋅ d), of lanreotide 67.3 (±39.8) mg ⋅ month (range 10-120 mg ⋅ month). Mean duration of treatment with somatostatin analogues until remission was 49 months. Frequent side effects included tachyphylaxis and mild gastrointestinal symptoms. The risk of persistent growth deceleration was low (<5%). CONCLUSIONS: Severe side effects are rare and a causal relation remains disputable. We conclude that long-term conservative treatment of CHI is feasible.

A pocket guide to identify patients at risk for chronic kidney disease after liver transplantation.

Chronic kidney disease (CKD) after liver transplantation (LT) has a strong impact on transplant and patient survival. After LT, a significant proportion of patients develop renal dysfunction with a high risk to progress to end-stage renal disease (ESRD). Because of the multifactorial nature of CKD in the post-transplant period, the ability to accurately identify patients at risk and the development of preventative strategies remain unsolved issues. In some patients, the pretransplant kidney function significantly declines within the first year post-LT. Until now, no user-friendly and reliable prediction scores exist to identify these patients early on. Data from 328 consecutive adult patients receiving their first LT between 2004 and 2008 at Hannover Medical School were analyzed to develop a prediction model using ordinal logistic regression. We developed a concise risk score identifying the five most important predictors and performed a temporal validation using a prospectively monitored patient cohort of 120 patients from our transplant center. Based on those five parameters, we developed a pocket guide card for clinical use that could be a useful tool for instant identification of patients at high risk as well as patients more suitable for combined liver and kidney transplantation (CLKT).

Unrelated and alternative donor allogeneic stem cell transplant in patients with relapsed or refractory Hodgkin lymphoma: a systematic review.

Abstract Allogeneic stem cell transplant (allo-SCT) is considered a clinical option for patients with Hodgkin lymphoma (HL) who have experienced at least two chemosensitive relapses. The aim of this systematic review was to determine the benefits and harms of allo-SCT with an unrelated donor (UD) versus related donor (RD) allo-SCT for adult patients with HL. Alternative donor sources such as haploidentical donor cells (Haplo) and umbilical cord blood (UCB) were also included. The available evidence was limited. Ten studies were included in this assessment. Four studies provided sufficient data to compare UD with RD allo-SCT. None of these studies was a randomized controlled trial. Additionally, three non-comparative studies, such as registry analyses, which considered patients with UD transplants were included. The risk of bias in the studies was high. Results on overall and progression-free survival (PFS) showed no consistent tendency in favor of a donor type. Results on therapy-associated mortality and acute (grade II-IV) and chronic graft-versus-host disease were also inconsistent. The study comparing UCB with RD transplants and two non-comparative studies with UCB transplants showed similar results. One of the studies comparing additionally Haplo with RD transplants indicated a benefit in PFS for the Haplo transplant group. In summary, our findings do not indicate a substantial outcome disadvantage of UD and alternative donor sources versus RD allo-SCT for adult patients with advanced HL.

Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children.

OBJECTIVE: To evaluate acceptability of 2 mm solid dosage forms (mini-tablets) as an alternative administration modality in young children in comparison with syrup. STUDY DESIGN: Three hundred six pediatric in- and outpatients aged 6 months-5 years (51 in each of 6 age groups) were recruited. An open, randomized cross-over study was conducted to compare acceptability and capability to swallow 2 mm uncoated or coated mini-tablets vs 3 mL syrup. RESULTS: In the overall patient population of 306 children, the acceptability of uncoated mini-tablets was superior to syrup (difference in proportions 14.8%, 95% CI 10.2-19.4; P < .0001). In line with this finding, the level of capability to swallow was higher for uncoated mini-tablets compared with syrup as well (difference in proportions 12.3%, 95% CI 5.4-19.3; P = .0008). All 3 pharmaceutical formulations were well tolerated, and none of the 306 children inhaled or coughed because of the syrup or the uncoated mini-tablet; only 2 of the 306 children (both in age group 0.5-1 year) coughed because of the coated mini-tablet, in both cases without clinical relevance. CONCLUSIONS: Mini-tablets are a valuable alternative to syrup for children 6 months-6 years of age and are more acceptable compared with liquid formulation. Regulatory bodies such as Food and Drug Administration and European Medicine Agency are encouraged to take our data into account for guideline updates and future drug approval processes.

Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study.

OBJECTIVE: To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5-6 years and their ability to swallow the mini-tablets. METHODS: 60 children aged 0.5-6 years (10 subjects per year of life) were enrolled in our prospective, open random, two-way cross-over exploratory pilot study. The children were administered either an uncoated drug-free mini-tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15% followed by the other formulation. Deglutition was visually assessed for the two different dosage forms using a predefined criteria list. RESULTS: The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets. Surprisingly, the authors found that the acceptance of the mini-tablets, defined as immediate swallowing or chewing first with subsequent swallowing, was higher or at least equal to that of the syrup. Very young children (6-12 months) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation. Some children aged between 2 and 4 years chewed the tablets before swallowing, but still accepted them quite well. The acceptance rate of the mini-tablets in the different age groups was much higher than expected. CONCLUSIONS: Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated.

Pharmacotherapy options for advanced thyroid cancer: a systematic review.

Poor prognosis of anaplastic thyroid cancer and advanced disease in differentiated and medullary thyroid cancer, together with absence of effective therapeutic measures, has induced recent intensified basic and clinical research in this area. The aim of this article is to assess the effects of new drug treatment for advanced thyroid cancer. We searched MEDLINE and EMBASE until the end of September 2011 for relevant data. Further sources were reference lists of original publications and review articles. We included prospective studies that investigated drug interventions for advanced thyroid cancer published in any language. We did not include trials solely communicated as abstracts. For inclusion, studies had to report overall survival, progression-free survival or similar, or response outcomes. Data were extracted by one author and checked by the other. All tables are part of this publication. Because only non-comparative studies were included, we had to focus on descriptive analysis. Twenty-four studies with 715 patients were included; 18 studies investigated kinase inhibitors, the remainder various drugs. All studies reported response (only one complete response was observed; proportions of partial response were up to 49%). Median progression-free survival was about 12 months, ranging from 3.7 to 27.9 months. Adverse events (at least grade 3) of kinase inhibitors included hypertension, hand foot syndrome and diarrhoea (10%, 16% and 9%, respectively). Due to bias-prone data, any interpretation of newer pharmacotherapy options for advanced thyroid cancer is limited because only non-comparative studies could be included. Therefore, we strongly argue the need for adequate randomized controlled trials that should provide a better basis for therapeutic decision making in thyroid cancer.

A prospective clinical pilot-trial comparing the effect of an optimized mixed diet versus a flexible low-glycemic index diet on nutrient intake and HbA(1c) levels in children with type 1 diabetes.

BACKGROUND: Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD). METHODS: This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record. OBJECTIVES: The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA(1c) levels. RESULTS: In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA(1c) levels between the groups were observed. CONCLUSION: OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet.