Edgar T. Ballard

Aerosolization of novel nitric oxide donors selectively reduce pulmonary hypertension

OBJECTIVES Inhaled nitric oxide (NO) reduces pulmonary hypertension in acute respiratory failure. Soluble nitric oxide donors (NO/nucleophile adducts-NONOates) are less cumbersome to deliver and may offer clinical advantage compared with inhaled NO. The objective of this study was to examine the pulmonary and systemic hemodynamic effects of tracheal aerosolization of a new class of NONOates in a porcine model of experimentally induced pulmonary hypertension. DESIGN Prospective, randomized, controlled study. SETTING Research laboratory. SUBJECTS Yorkshire pigs (n = 18), weighing 11.4 to 16.4 kg. INTERVENTIONS In anesthetized, mechanically ventilated, instrumented pigs, steady-state pulmonary hypertension (SSPH) was induced using a thromboxane agonist (U46619). Control animals received tracheal aerosolization of saline (n = 6); EP/NO animals received tracheal aerosolization of ethylputreanine NONOate (EP/ NO, n = 6); and DMAEP/NO animals received aerosolized 2-(dimethylamino) ethylputreanine NONOate (DMAEP/NO, n = 6). MEASUREMENTS AND MAIN RESULTS Mean pulmonary (MPAP) and mean systemic arterial pressures (MAP), atrial pressures, cardiac output, and arterial blood gases were measured following drug instillation. DMAEP/NO animals had significant reductions in pulmonary vascular resistance index (PVRI) and MPAP at all time points compared with SSPH and control animals (p < .05), while systemic vascular resistance index did not change. EP/NO animals had a significant reduction in PVRI and MPAP at some time points compared with SSPH and control animals. For both NONOate-treated animal groups, MAP and cardiac index did not change significantly compared with SSPH and control animals (p < .05). CONCLUSIONS In this porcine model of pulmonary hypertension, intratracheal aerosolization of soluble NO donors results in sustained reduction of pulmonary hypertension without reducing systemic arterial pressure. Intermittent aerosolization of NONOates may be an alternative to continuously inhaled NO in the treatment of acute pulmonary hypertension.

Effect of Superoxide Dismutase on a Rabbit Model of Chronic Allergic Asthma

BACKGROUND In bronchial asthma, inflammatory cells infiltrating the airway mucosa release oxygen radicals that cause tissue damage and amplify the airway inflammation. Antioxidant enzymes may have a protective effect on the airways. OBJECTIVE The purpose of this study was to determine whether treatment of a rabbit model of chronic allergic asthma with the antioxidant enzyme superoxide dismutase conjugated to polyethylene glycol will protect the airways from oxygen radical injury, decrease airway inflammation, and attenuate the asthmatic response. METHODS New Zealand white rabbits were sensitized to ragweed. Baseline histamine PC30, ragweed PD30, and early and late phase asthmatic response to ragweed bronchial challenge were measured. The rabbits were then randomized into two groups that received every 48 hours an intravenous dose of either superoxide dismutase-polyethylene glycol 10,000 U/kg or inactivated superoxide dismutase-polyethylene glycol as control, followed by a 1-hour exposure to aerosolized ragweed extract. After 4 weeks the rabbits had a second bronchial challenge, were sacrificed, and lung histology was studied. RESULTS On the posttreatment challenge, the superoxide dismutase-polyethylene glycol group had a rise in ragweed PD30, while the control group had no change in ragweed PD30, and two of five rabbits in the superoxide dismutase-polyethylene glycol group did not have an early or late phase asthmatic response, while all rabbits in the control group had an asthmatic response. There was no significant difference in lung histology between both groups. CONCLUSION A rabbit model of chronic allergic asthma treated with superoxide dismutase-polyethylene glycol showed a trend of improvement in airway responsiveness but no significant effect on airway inflammation.

Malignant rhabdoid tumor mimicking hepatoblastoma: a case report and literature review.

Hepatoblastoma accounts for the vast majority of malignant primary liver tumors in infancy. In contrast, rhabdoid tumors arising in the liver are extremely rare, but they can share clinical and histologic features with hepatoblastoma and can create diagnostic confusion, especially when one is dealing with small biopsies. In this case report we demonstrate that immunohistochemical and molecular techniques can identify the characteristic loss of INI1 and facilitate making the correct diagnosis of primary hepatic malignant rhabdoid tumor. Important similarities and differences between hepatoblastoma and rhabdoid tumors are reviewed, and suggestions are offered to help distinguish these 2 tumor types.

Biologic characteristics of four Ewing's sarcomas

Four Ewings sarcomas were examined for chromosomal characteristics, growth in cell culture, tumorigenicity in nude mice, and presence of beta-adrenergic receptors. Three tumors were from untreated patients (one obtained directly from the patient and two after growth in nude mice) and one was a metastatic lesion obtained after treatment. All four tumors were diploid or near-diploid, with one or more structural rearrangements. In the metastatic lesion, 21 abnormalities were seen. No specific chromosome aberration was found to be common to all four tumors, although a t(1,16) was observed in two and a t(11;22) in two. Abnormalities involving chromosomes #1, #3, #11, #13, #16, and #22 were each found in two of four tumors. All four tumors were tumorigenic in nude mice; two grew well in cell culture, one of which became an established line, and all four expressed high concentrations of beta-adrenergic receptors.

Characteristics of 85 pediatric tumors heterotransplanted into nude mice.

81 primary pediatric tumors and 4 tumor lines were heterotransplanted into nude mice with an overall success rate of 38.3%. There was variability in success between tumor types. Bone sarcomas were highly successful while brain, lymphoid, and benign tumors in general did poorly. With increasing passage lag times decreased but actual growth rates in general did not change. Results suggested that tumors obtained prior to therapy which grew in nude mice were more likely to recur in the patient. During the observation period 7 spontaneous mouse tumors developed, distinguished from human tumors by histology, cytogenetics, and isoenzyme studies.

Chromosome analyses in a rhabdoid tumor of the brain.

A malignant rhabdoid tumor of the brain from a 19-month-old child was studied. Two related clones, 46,XX,-8,+der(8)t(8;22)(p11;q?12)x2,-22,del(22)(q12q?13) and 46,XX-8,+der(8)t(8;22) (p11;q?12) x2,-22,r(22) were found after chromosome analyses of primary and recurrent tumor, and multiple nude mouse passages of the tumor. Breakpoints were studied using FISH.

Osteogenic sarcoma after orbital radiation rhabdomyosarcoma

PURPOSE We describe the occurrence of maxillary and orbital osteogenic sarcoma in a child after treatment of contralateral orbital rhabdomyosarcoma with external beam radiation and chemotherapy. DESIGN Interventional case report. INTERVENTION Treatment of a maxillary and orbital rhabdomyosarcoma with surgical resection, systemic chemotherapy, and local radiation. MAIN OUTCOME MEASURES Occurrence and histology of secondary malignancy after orbital radiation. RESULTS An eleven year-old male presented for evaluation of left facial swelling, occurring ten years after successful treatment of a right orbital embryonal rhabdomyosarcoma with chemotherapy and 5040 cGY of external beam radiation. Computerized tomography demonstrated a mass involving the left maxillary sinus and orbital floor. Biopsy demonstrated osteogenic sarcoma. Despite attempted total excision with radical maxillectomy, resection margins were found to have microscopic extension of the tumor. Postoperatively he was treated with systemic chemotherapy and local radiation. Eight months postoperatively he remains alive despite local progression. CONCLUSIONS Osteogenic sarcoma can occur as a secondary malignancy years after the successful treatment of orbital rhabdomyosarcoma with external beam radiation and chemotherapy. After orbital radiation, subjects should undergo routine lifelong examinations.