Risk of third malignancies and death after a second malignancy in retinoblastoma survivors.

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk.

Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study.

BACKGROUND: In 2003, we reported an increased risk of retinoblastoma in children conceived by IVF between 1995 and 2002. However, population-based studies among children conceived by IVF did not find an elevated risk of retinoblastoma. METHODS: From nationwide estimates of numbers of live births conceived by IVF (n = 40 330), we estimated the expected numbers of patients with retinoblastoma conceived by IVF in the period 1995-2007. The observed number of retinoblastoma diagnoses in children conceived by IVF was obtained by questionnaires sent to the parents of children with retinoblastoma diagnosed between 1995 and 2005. For non-responders and patients diagnosed after 2005, information was available through the medical files, in which information on fertility treatment has been routinely recorded since 2000. The relative risk (RR) of retinoblastoma among children conceived by IVF was calculated for the total study period (1995-2007) and for the expanded study period (2002-2007). RESULTS: Of all eligible patients with retinoblastoma (n = 162) diagnosed in the period 1995-2007, seven were conceived by IVF. In the total study period (1995-2007) the risk was significantly elevated [RR = 2.54, 95% confidence interval (CI) = 1.02-5.23]. In the expanded study period (2002-2007), no significantly elevated risk (RR = 1.29, 95% CI = 0.16-4.66) was found. CONCLUSIONS: We found a significantly increased risk of retinoblastoma in children conceived by IVF in the total study period 1995-2007. However, this increased risk was mostly based on the much stronger risk increase observed previously, for 1995-2002. Caution and awareness on the one hand and avoiding unnecessary worries on the other hand are important at this stage of our knowledge.

Urinary NOx:creatinine ratios during gluten challenge in children with celiac disease.

OBJECTIVES: Celiac disease is a gluten-induced small bowel enteropathy. Inflammation is known to be associated with enhanced nitric oxide (NO) production. An increase in urinary nitrate and nitrite (NOx) reflects increased NO production. The urinary NOx:creatinine ratio can be used as an indicator of the endogenous NO production. The aim of the study was to determine whether the urinary NOx:creatinine ratio of celiac disease patients increases during gluten challenge. METHODS: The authors studied 20 patients with unconfirmed celiac disease who had been following a gluten-free diet for at least 1 year. These patients underwent an 80-day gluten challenge. Urinary samples were obtained before and 10, 20, 40, and 80 days after starting the gluten challenge. The Griess reagent method was used for measuring urinary NOx. RESULTS: Gluten challenge confirmed the diagnosis of celiac disease in 15 of 20 patients. The NOx:creatinine ratios (mmol:mmol) of the biopsy-confirmed celiac disease patients were significantly higher than those of the unconfirmed celiac disease patients (0.67 vs. 0.17 on day 10; 0.78 vs. 0.15 on day 20; 0.85 vs. 0.25 on day 40; and 0.85 vs. 0.17 on day 80). CONCLUSIONS: Gluten challenge resulted in an increased urinary NOx:creatinine ratio in patients with biopsy-confirmed celiac disease. The NOx:creatinine ratio could be useful for the serial evaluation of disease activity.

Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene.

BACKGROUND: Defective male sex differentiation in patients with hypoplasia of Leydig cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. PATIENTS AND METHODS: Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1-10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron-exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45-59 healthy persons using denaturation high-performance liquid chromatography. RESULTS: Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1.7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. CONCLUSIONS: Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.