Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma?

PURPOSE: Use of retroperitoneal lymph node dissection (RPLND) in paratesticular rhabdomyosarcoma (PTRMS) is controversial and has changed over the past 2 decades. The Intergroup Rhabdomyosarcoma Study Group (IRSG) required ipsilateral RPLND (IRPLND) for all patients with PTRMS treated on IRS-III (1984-91), but changed to clinical evaluation of RPLNs using computerized tomography (CT) in IRS-IV (1991 through 1997). In IRS-IV, only those patients with identified lymph node involvement on CT required surgical evaluation of the RPLNs. Nodal radiation therapy was administered only to patients with RPLNs recognized as positive; such patients received more intensive chemotherapy as well. Thus, they compared the incidence of recognized RPLN involvement using these 2 different approaches. They then analyzed patient outcome to determine whether this change in management affected outcome. METHODS: Eligible patients with group I or II PTRMS who were treated on IRS III (n = 100) or IRS IV (n = 134) were analyzed. Failure-free survival (FFS) and survival (S) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: There was a significant change in the distribution of patients with group I versus II tumors from IRS-III to IRS-IV (group I, 68% in IRS-III versus 82% in IRS-IV). This was the result of decreased node recognition when CT was used to stage RPLNs in IRS-IV and was most notable for adolescents (>10 years of age). Overall, 3-year FFS was 92% for patients treated on IRS-III and 86% for those treated on IRS-IV (P =.10), whereas survival estimates were 96% and 92%, respectively (P =.30). Adolescents were at higher risk of RPLN relapse than were children (<10 years of age) and their FFS and survival were worse, regardless of IRS protocol. Furthermore, adolescents with recognized group II tumors experienced better 3-year FFS than those with group I tumors on IRS-IV (100% versus 68%, P =.06), most likely as a result of receiving radiotherapy and intensified chemotherapy. CONCLUSIONS: Use of only CT scan evaluation of RPLN in IRS-IV led to a decrease in identification of RPLN involvement in boys who present with localized PTRMS, and a higher rate of regional relapse as compared with IRS-III. Adolescents had much higher likelihood of RPLN disease, and they fared significantly worse than did younger children on both studies. Furthermore, adolescent boys with group I tumors experienced worse FFS than those with Group II tumors on IRS-IV, probably because some patients with group II tumors were not identified by CT imaging and thus received less effective therapy. These data suggest that adolescents should have ipsilateral RPLN dissection as part of their routine staging, and those with positive lymph nodes require intensified chemotherapy as well as nodal irradiation.

tert-butyl hydroperoxide/hemoglobin-induced oxidative stress and damage to vascular smooth muscle cells: different effects of nitric oxide and nitrosothiols.

The goal of the present work was to determine whether nitric oxide (NO) released from different donors (NONOates and nitrosothiols) can act as a protective antioxidant against oxidative stress and cytotoxicity induced by extracellular hemoglobin/tert-butyl hydroperoxide (Hb/tert-BuOOH) in vascular smooth muscle cells (VSMCs). No changes in phospholipid composition were found in VSMCs incubated with oxyhemoglobin (oxyHb)/tert-BuOOH. Using our newly developed HPLC-fluorescence technique for measurement of site-specific oxidative stress in membrane phospholipids, we produced VSMCs in which endogenous phospholipids were metabolically labeled with an oxidation-sensitive fluorescent fatty acid, cis-parinaric acid. In these cells, we were able to reliably quantitate oxidative stress in major phospholipid classes-phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol-induced by tert-BuOOH in the presence of oxyHb or methemoglobin (metHb). The oxidative stress was accompanied by cytotoxic effects of oxyHb/tert-BuOOH and metHb/tert-BuOOH on VSMCs. We further found that an NO donor, (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen 1-ium-1,2-diolate (PAPANONO), but not nitrosothiols, protected VSMCs against oxidative stress and cytotoxicity induced by Hb/tert-BuOOH. The protective effect of PAPANONO was most likely due to its ability to form NO-heme Hb (detectable by low temperature EPR spectroscopy and visible spectrophotometry). These findings are important for further understanding the physiological antioxidant role of NO against oxidative stress induced by hemoproteins as well as for pathological hypertensive events induced by extracellular Hb via NO depletion.

Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation.

OBJECTIVE: We tested the hypothesis that the independent risk factor for atherosclerosis of increased plasma homocysteine concentration is associated with the pregnancy syndrome of preeclampsia. We further hypothesized that increased plasma homocysteine concentration during pregnancy may advance endothelial dysfunction in preeclampsia by promoting oxidative stress. STUDY DESIGN: Antepartum blood samples were collected >/=6 hours after the last meal from 33 women with normal, uncomplicated pregnancies and from 21 women with preeclampsia. These plasma samples were analyzed for concentrations of total homocysteine; folate; triglycerides; creatinine; a marker of endothelial activation, cellular fibronectin; and a marker of oxidative stress, malondialdehyde. RESULTS: The mean value of total plasma homocysteine in preeclampsia was significantly higher than that observed in normal pregnancy (P <. 04). Similarly, plasma malondialdehyde (P <.001), triglyceride (P <. 001), and cellular fibronectin (P <.006) concentrations were also greater in women with preeclampsia than in control subjects. However, no differences were observed between women with preeclampsia and control subjects in folate (P =.97) or creatinine (P =.28) concentrations. Homocysteine concentration did not correlate with plasma creatinine (P =.61), malondialdehyde (P =.32), or triglyceride (P =.89) concentrations. However, cellular fibronectin concentration correlated positively with homocysteine concentration in both women with preeclampsia and control subjects (r = 0.87, P <. 0001, and r = 0.50, P <.004, respectively), and folate concentrations were weakly but negatively correlated with homocysteine values (P =.03, r = 0.32). CONCLUSIONS: Total plasma homocysteine concentration is increased in preeclampsia and is significantly correlated with cellular fibronectin concentration, suggesting that homocysteine plays a role in promoting endothelial dysfunction in preeclampsia. Furthermore, despite the use of pregnancy multivitamins and no indications of overt folate deficiency in this subject population, homocysteine concentration weakly and negatively correlates with plasma folate concentration.

Vascular function in the vitamin E-deprived rat: an interaction between nitric oxide and superoxide anions.

We tested the hypothesis that oxidative stress, mediated by dietary vitamin E deprivation, would alter vascular function through the interaction of oxygen-derived free radicals and nitric oxide (NO). This interaction may play an important role in the vascular pathophysiology of many diseases associated with oxidative stress. Mesenteric arteries from control (n = 12) and vitamin E-deprived (n = 12) Sprague-Dawley rats were studied with a myograph. Superoxide dismutase, which scavenges superoxide anions, produced a significantly greater relaxation in the arteries from the vitamin E-deprived rats compared with the controls (P<.05). Superoxide dismutase and catalase produced results similar to superoxide dismutase alone. Pretreatment with an NO synthase inhibitor eliminated the superoxide dismutase-induced relaxation in arteries from both control and vitamin E-deprived rats. L-Arginine induced a greater relaxation in arteries of the vitamin E-deprived group (P<.05). Agonist-induced relaxation with methacholine was not altered by superoxide dismutase for either group of animals, indicating that stimulated release of NO was not influenced by superoxide anions. With the use of Western immunoblot analysis, nitrotyrosine residues were shown to be present in arteries from both the vitamin E-deprived and control rats, but the amount of nitrotyrosine observed was not different between the two groups. In summary, our data indicate that there is a greater inhibition of NO caused by superoxide anions in the vitamin E-deprived group. We speculate that in conditions of oxidative stress (reduced vitamin E levels), altered vascular function may be due to increased destruction of NO by oxygen-derived free radicals.