Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Influence of Lung Aeration on Pulmonary Concentrations of Nebulized and Intravenous Amikacin in Ventilated Piglets with Severe Bronchopneumonia

Background: Pulmonary concentrations of aminoglycosides administered intravenously are usually low in the infected lung parenchyma. Nebulization represents an alternative to increase pulmonary concentrations, although the obstruction of bronchioles by purulent plugs may impair lung deposition by decreasing lung aeration.

Methods: An experimental bronchopneumonia was induced in anesthetized piglets by inoculating lower lobes with a suspension of 106 cfu/ml Escherichia coli. After 24 h of mechanical ventilation, 7 animals received two intravenous injections of 15 mg/kg amikacin, and 11 animals received two nebulizations of 40 mg/kg amikacin at 24-h intervals. One hour following the second administration, animals were killed, and multiple lung specimens were sampled for assessing amikacin pulmonary concentrations and quantifying lung aeration on histologic sections.

Results: Thirty-eight percent of the nebulized amikacin (15 mg/kg) reached the tracheobronchial tree. Amikacin pulmonary concentrations were always higher after nebulization than after intravenous administration, decreased with the extension of parenchymal infection, and were significantly influenced by lung aeration: 197 +/- 165 versus 6 +/- 5 [mu]g/g in lung segments with focal bronchopneumonia (P = 0.03), 40 +/- 62 versus 5 +/- 3 [mu]g/g in lung segments with confluent bronchopneumonia (P = 0.001), 18 +/- 7 versus 7 +/- 4 [mu]g/g in lung segments with lung aeration of 30% or less, and 65 +/- 9 versus 2 +/- 3 [mu]g/g in lung segments with lung aeration of 50% or more.     

Highly resolved in vivo 1H NMR spectroscopy of the mouse brain at 9.4 T.

An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models.     

Effectiveness of early orthodontic treatment with the Twin-block appliance: a multicenter, randomized, controlled trial. Part 1: Dental and skeletal effects.

This study evaluated the effectiveness of early orthodontic treatment with the Twin-block appliance for the developing Class II Division 1 malocclusion. This multicenter trial was carried out in the United Kingdom. A total of 174 children, aged 8 to 10 years old, with Class II Division 1 malocclusion were randomly allocated to receive treatment with a Twin-block appliance or to an untreated, control group. Data were collected at the start of the study and 15 months later. Results showed that early treatment with Twin-block appliances resulted in reduction of overjet, correction of molar relationships, and reduction in severity of malocclusion. Most of this correction was due to dentoalveolar change, but some was due to favorable skeletal change. Early treatment with the Twin-block appliance is effective in reducing overjet and severity of malocclusion. The small change in the skeletal relationship might not be considered clinically significant.     

Retroperitoneal leiomyosarcoma mimicking acute appendicitis: laparoscopic management.

BACKGROUND: Retroperitoneal leiomyosarcomas (RLMS) are a challenging clinical entity. The vast majority of patients are operated on when tumors are advanced. We report herein a case of RLMS, mimicking acute appendiceal disease and treated successfully via laparoscopy. METHODS: A 37-year-old woman, para 1, was admitted to our department for right lower quadrant abdominal pain, fever, and leukocytosis. She had no changes in gastrointestinal and urologic function. A physical examination revealed the presence of abdominal guarding, rebound, and a tender mass in the right lower quadrant. The abdominal ultrasound showed an inhomogeneous ovoid mass (6 cm in diameter) located below the cecum, with no definite margins, and consistent with an appendiceal abscess. The patient was referred for laparoscopy. The procedure was performed with the aid of 3 ports: a 12-mm trocar in the umbilicus (open technique), a 10-mm trocar in the left iliac fossa, and a 5-mm one in the supra-pubic space. On inspection of the abdominal cavity, a retroperitoneal 6-cm mass was immediately found below the cecum and the appendix. Neither intraperitoneal seeding nor suspected lymph nodes were present. After dissection of the parietal peritoneum, the mass appeared to be encapsulated and well demarcated from all surrounding structures. It was eventually dissected and removed via a plastic bag. A standard appendectomy was also performed. The postoperative course was uneventful, and the patient was discharged on the 3rd day. The histology analysis of the resected specimen showed a totally excised G2 leiomyosarcoma. The appendix had no signs of inflammation. Postoperatively, the patient underwent a total-body CT-scan, which had no signs of residual or distant disease. No adjuvant therapy was necessary. At an 18-month follow-up, the patient was doing well and was disease free. CONCLUSION: Surgery represents the main therapeutic option for resectable RLMS. Laparoscopy is a useful diagnostic tool that allows safe resection of incidentally discovered, small and well encapsulated RLMS.     

Nonrhinologic headache in a tertiary rhinology practice.

OBJECTIVE: Our goal was to determine the etiology of headache in patients who were referred for sinus evaluation but were found to have no evidence of rhinosinusitis on computed tomography (CT) of the sinuses and on endoscopic examination. METHODS: Data were collected prospectively from 100 patients with headache but with normal sinus CT and endoscopic examination. Headache and 20-Item Sino-Nasal Outcomes Test (SNOT-20) scores of patients with the chief complaint of headache and who requested further neurologic evaluation (group I) were compared with the scores of patients who did not list headache as a significant symptom (group II) and with the scores of patients without headache (group III). RESULTS: The most common neurologic diagnosis for group I patients (n = 36) was migraine headaches (58%). These patients also had higher mean SNOT-20 scores (24 +/- 3.3) compared to group II patients with mild headache (14.6 +/- 2.3) or group III patients without headache (12.4 +/- 2.1). CONCLUSION: Migraine was the most common type of headache in patients with normal sinus CT treated for presumed rhinosinusitis as the cause of the headache. Patients with headache as their chief complaint that required further neurologic evaluation had overall higher SNOT-20 scores than nonheadache patients, indicating greater disability of their overall quality of life index.