A 3 year-old boy with chronic renal failure associated with prune belly syndrome who developed central precocious puberty is described. He had been maintained on cyclic peritoneal dialysis from age 13 months with creatinine levels of 400-600 μπιοΐ/ΐ. Increased linear growth rate probably began at 18 months, and by 38 months of age he had testicular enlargement and pubic hair consistent with Tanner stage 2. Elevated levels of serum testosterone (3.6 nmol/1; normal <0.7 nmol/1) and luteinizing hormone (LH) (2.8 IU/1; normal <1.0 IU/1) were demonstrated with a pubertal response to luteinizing hormone-releasing hormone (LHRH) stimulation (peak LH 43.5 IU/1). Other endocrine tests demonstrated hyperprolactinemia (170 μ|>/1; normal 3.4-22 μς/Ι), but normal pituitary-thyroid and pituitary-adrenal functions and normal cranial MR imaging. Despite LHRH-agonist therapy with leuprolide over the next 8 months, he showed an incomplete response with only partial inhibition of basal LH and testosterone levels, and continued significant increments in height standard deviation scores (Ht-SDS) and bone age estimates. However, the sexual precocity appeared fully reversible following a successful living-related renal transplant at age 50 months. Despite discontinuation of leuprolide treatment post-operatively, there was a full reversal of his serum LH and testosterone to a prepubertal profile as well as normalization of the serum prolactin levels. Whereas most boys with chronic renal failure show delayed pubertal development and suppressed linear growth, our patient presents a unique phenomenon of reversible central precocious puberty. The effects of leuprolide therapy in the presence of a uremic milieu and the outcome of successful renal transplantation on sexual precocity are described.
BackgroundCancer-related cognitive impairment (CRCI) has been reported in cancer survivors 20 years or more after cancer treatment, and has been associated with sustained increases in circulating inflammatory biomarkers. One of the major risk factors for CRCI is chemotherapy, and preclinical studies typically examine the impact of chemotherapy in cancer naïve mice to evaluate potential mechanisms However, clinical evaluation of the long-term effects of chemotherapy cannot avoid the potential cumulative impact of preceding factors on the brain including the cancer itself and cancer surgery. MethodsTo evaluate the cumulative impact of cancer-related factors on cognitive impairment and hippocampal cytokine expression, we evaluated the effect of paclitaxel chemotherapy vs. placebo on a background of 67NR mammary carcinoma and surgical resection of the primary tumour in mice. Memory was assessed using the Y maze test and novel object/novel place recognition test. Changes in hippocampal pro-inflammatory and anti-inflammatory cytokines, microglia and neuron markers were assessed using qRT-PCR. Results Cancer and cancer surgery was sufficient to induce long-term memory impairment and sustained increases in hippocampal pro-inflammatory cytokines. Paclitaxel prolonged spatial memory impairment in the Y maze test and exacerbated hippocampal Il6 and Tnfa mRNA expression compared with placebo treatment. ConclusionsThese findings suggest that cancer and cancer surgery can sensitise the brain to an exaggerated neuroinflammatory response to chemotherapy, and may contribute to sustained chemotherapy-induced cognitive impairment observed in cancer survivors.
Geneseeq Prime 425-gene panel, at a mean coverage depth of 4892X (with a deduplicated mean coverage depth of 2108X). Result: Systemic tumour burden correlated with the detection of genomic alterations in cfDNA: Four of four of the patients with low tumour burden, despite minor disease progression, exhibited minimal EGFR and co-mutation allele frequencies (AFs). Conversely, significant increases in systemic (but not central nervous system) tumour burden led to increases in driver and co-mutation AFs (two our of three patients). EGFR C797S mutation and inactivating mutations in RB1 and TP53 were detected in the cfDNA of one patient nearly four months prior to the development of small cell lung cancer (SCLC) transformation confirmed on tissue biopsy with distinct transformed and untransformed areas. Both of the specific RB1 and TP53 mutations found in cfDNA have been previously associated with SCLC. Subsequent combination cisplatin-etoposide chemoradiation resulted in temporary complete remission of the transformed SCLC, corresponding to loss of RB1 mutation detection by cfDNA testing. Conclusion: Profiling of plasma cfDNA using hybrid capture deep sequencing of a large gene panel can detect early subclinical transformation of EGFR-mutated lung cancer into small cell lung cancer (i.e., neuroendocrine transformation), leading to earlier diagnosis and management of the transformed disease. Serial liquid biopsy profiling can also be used to monitor disease progression. However, detection sensitivity of tumour cfDNA largely depends on systemic tumour burden.
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