Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study.

BACKGROUND: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer. METHODS: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-ß-D-glucosaminidase, α1-microglobulin, ß2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment. RESULTS: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline. CONCLUSIONS: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

Long-term outcome in children with opsoclonus-myoclonus and ataxia and coincident neuroblastoma.

We reviewed the neurologic and developmental courses in 10 children with opsoclonus-myoclonus ("dancing eyes syndrome") and neuroblastoma. All patients are alive without evidence of neoplastic disease after 8+ to 111+ months of follow-up. All had localized disease and 50% had extraabdominal tumors. Neuroblastomas of nine children had favorable Shimada histologic characteristics, and all tumors had single copies of the N-myc oncogene. After neuroblastoma resection, all patients had persistent opsoclonus-myoclonus or ataxia that responded to therapy with adrenocorticotropic hormone. Nine children had relapses of neurologic symptoms. Three years after resection, six of seven patients with sufficient follow-up were free of symptoms and had discontinued therapy. However, nine children had chronic neurologic deficits, including cognitive and motor delays, language deficits, and behavioral abnormalities. All six patients in educational programs required special assistance. Five children required physical, occupational, or speech therapy. Long-term developmental and cognitive problems should be anticipated in patients with neuroblastoma who have opsoclonus-myoclonus or ataxia or both, and early intervention should be instituted to try to minimize these deficits.

Urinary dopamine/noradrenaline and dopamine/vanillylmandelic acid ratios as a reflection of different biology of adrenergic clones in children's neuroblastic tumors.

The results of calculations of urinary dopamine/noradrenaline (DA/NAd) and dopamine/vanillylmandelic acid (DA/VMA) ratios in 54 untreated children with neuroblastic tumors are reported. Thirteen patients were in the prognostically favorable group (stages I, II, and IV-S and ganglioneuroma [GN]), and 41 had advanced neuroblastoma (stage III and IV). Among patients with ganglioneuroma and favorable neuroblastoma (n = 13), of whom all were survivors, the urinary DA/NAd and DA/VMA ratios exceeded 1.8 in only 2 cases of stage IV-S and stage I, respectively. In the advanced neuroblastoma group, the DA/NAd and DA/VMA ratios exhibited a wide range of values, but among the stage III and IV survivors (n = 10), DA/NAd ratios greater than 1.8 were noted in only 3 patients. The DA/VMA ratio was not greater than 1.8 in those 3 patients. The mean DA/NAd and DA/VMA proportions in the population comprising all survivors were 1.8 +/- 2.7 (mean +/- SD) and 1.1 +/- 0.4, respectively. The same computations carried out in patients who died showed higher values, ie, the mean DA/NAd and DA/VMA ratios were 5.2 +/- 6.3 and 5.6 +/- 10.5, respectively, showing the difference in DA/NAd and DA/VMA ratios between prognostically favorable and unfavorable groups. Of 23 survivors, only 4 had DA/NAd ratios greater than 1.8 (17%), while 24 of 31 children who died (77%) had DA/NAd ratios was greater than 1.8. The reported results suggest dissimilarity in the catecholamine metabolism of adrenergic clones with respect to the stage of advancement of neoplastic disease.

Thoracic neuroblastoma of the neonate.

Five cases of neonatal thoracic neuroblastoma were either clinically asymptomatic or presented as uncharacteristic respiratory distress. Chest radiography demonstrated a spectrum of abnormalities varying from a lobulated, apical thoracic mass with or without evidence of expansion, to a spindle-shaped paraspinal soft tissue widening, or a homogeneously dense hemithorax. In the newborn a neoplasm in the posterior mediastinum most likely represents a neuroblastoma, either primary or metastatic. In a high percentage of cases the primary tumour as well as possible skeletal metastases have an increased uptake of radiopharmaceuticals. Therefore a bone scan should be the next step for evaluation of the neoplasm. Supplementary sonographic screening of the retroperitoneum and lesser pelvis is easily performed and may contribute significant information. Urography is hardly mandatory any longer. Metrizamide CT myelography, highly recommended in infants and children, may be omitted in the neonate with no neurologic deficit. Urinary excretion of catecholamine metabolites is usually elevated and must always be determined.

Calcification and uptake of Tc-99m diphosphonates in neuroblastomas: concise communication.

Sixty-six percent of 54 patients with neuroblastoma demonstrated uptake of bone-seeking radioagents by the primary tumor. This is a higher incidence than previously reported. Uptake was slightly more common in abdominal than thoracic tumors. There was a significant correlation between the size of the tumor and tracer uptake. Calcification was demonstrated in the primary tumor in almost 90% of the 54 patients. This is a much higher incidence of calcification than previously reported. Microscopy shows that the calcification is not always due to tumor necrosis; it also occurs in areas of viable tumor cells. Tracer uptake is believed to be related to calcium metabolism. The rate of metabolic activity rather than the total amount of calcium present within the tumor may be the most important factor in determining the amount of uptake. No significant relationship was found between tracer uptake and tumor stage or homovanillic acid and vanillylmandelic acid metabolic activity.

Extra-adrenal intrathoracic functioning paraganglioma (pheochromocytoma) in childhood.

Extra-adrenal pheochromocytomas are more common in children (30%) than in adults (10%). Of the extra-adrenal sites, the intrathoracic site is the most rare. A 15-year-old boy had a pheochromocytoma successfully removed from the left paraspinal region of his chest. Four years before removal, he had radiation therapy of 3,500 rads to the tumor because of its apparent nonresectability. After therapy, there was transient clinical and biochemical improvement. Preoperative angiography and computed tomography helped define the anatomy of the tumor vessels and the relationship to the thoracic aorta of the tumor. These studies also aided in discounting any other site for the pheochromocytoma, either adrenal or extramedullary. A slow-growing pulmonary metastatic lesion was subsequently identified and successfully excised.

Case reports and studies of paraneoplastic hypotension: abnormal low pressure baroreceptor responses.

Intrathoracic stretch receptors regulate adjustments of the vasculature to gravitational changes and influence urinary water and solute excretion. Few reports of pathologic states involving interruption of these regulatory mechanisms have appeared. Two patients with orthostatic hypotenstion related to advanced intrathoracic carcinoma were studied, utilizing tilt-table examinations and immersion of the entire body in water to test the function of their intrathoracic baroreceptor reflex arcs. Both patients showed abnormalities of antidiuretic hormone level and sodium excretion as compared with normal controls. This suggests that total immersion is a safe and convenient test of the low-pressure baroreceptor system in patients with suspected dysfunction. Three patients are also reported whose charts were reviewed posthumously. Although they were not tested in the laboratory, their clinical data suggest that they too had been suffering from an interference with the transmission of impulses from the intrathoracic receptors.