Use of pluronic micelles to overcome multidrug-resistance

Pluronic P-85 (poly(55)(oxypropylene)dipoly(s)(oxyethylene)) was used to form daunorubicin containing micelles. This new carrier was tested in vitro on sensitive and resistant ovarian cancer cell lines. Drug incorporation was measured by cytofluorometry and the cytotoxicity was measured by the tetrazolium formazan XTT assay. ID50 of 0.16 and 25 mu g/ml were obtained for conjugated and free daunorubicin respectively. The results obtained suggest that this approach may be used in combination with a chemotherapeutic agent to overcome multidrug resistance.     

The Morquio syndrome: neuropathology and biochemistry.

The activity of N-acetyl galactosamine-6-sulfate sulfatase was studied for the first time in the liver and brain of a patient with a clinically typical case of Morquio syndrome with keratosulfaturia. As has been demonstrated in the fibroblasts of patients with this syndrome, this enzymatic activity was markedly decreased in both organs. Neuropathological examination revealed moderately swollen neurons containing PAS-positive, coarse globular inclusions in the cerebral cortex, Ammon's horn, basal ganglia, and thalamic nuclei. Ultrastructurally, the inclusions consisted of stacked, straight or loose, wavy membranes of various lengths, often associated with pale or moderately electron dense homogeneous "lipid droplets." These ultrastructural features of the inclusions were closely similar to the granulomembranous bodies of Hurler syndrome and the inclusions described in type B of the Sanfilippo syndrome. Unlike those mucopolysaccharidoses, however, no abnormalities were found in the gangliosides in the brain of the patient with Morquio syndrome.     

Suramin potently inhibits the enzymatic activity of PSM

BACKGROUND: The polysulfonated napthlyurea suramin has shown significant antitumor activity in patients with hormone-refractory metastatic prostate cancer. The mechanism by which suramin exerts this effect is unknown. In 1993, prostate-specific membrane antigen (PSM) was identified as a prostate biomarker that is elevated in hormone-refractory and metastatic prostate cancer. PSM is a glutamate exocarboxypeptidase capable of cleaving the terminal alpha-linked glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG) and the gamma-linked glutamates from folate polyglutamate. METHODS: Using a NAAG hydrolytic radioenzymatic assay, we tested whether suramin had any effect on the enzymatic activity of PSM. RESULTS: We demonstrate that suramin potently inhibits the enzymatic activity of PSM with a K(i) = 15 nM and 68 nM for the membrane-associated and soluble forms of PSM, respectively. In addition, we show that suramin inhibition of PSM enzyme activity displays the kinetics of a classic competitive inhibitor. CONCLUSIONS: This is one of the most potent activities described for suramin to date and may represent a portion of its pharmacologic and/or toxicological mechanism of action.     

Serial evaluation of segmental esophageal reconstruction using a polyurethane scaffold in a pig model

BackgroundMany esophageal pathologies are clinically treated by resection and reconstruction of the esophagus. Surgical esophagectomy remains a morbid procedure and despite minimally invasive advances, has changed little in decades. Novel approaches to esophageal segmental resection and reconstruction are an unmet need.MethodsCircumferential thoracic esophageal transection was performed in both male and female pigs and the defects reconstructed using 5 or 10 cm polyurethane (PU) tubular grafts and stented. A subset were treated with stent only. Animals were survived to 14, 30, 60, and 399 days. Tissues were evaluated histologically, and via non-invasive serial endoscopy and contrast swallowing studies in long-term animals.ResultsLuminal patency was achieved in all animals with no clinical evidence of leak. In short-term animals, there was healing noted in all cases with a variably sized region of ulceration remaining at the most central part of the repaired tube (between the proximal and distal anastomosis). In four long-term animals following stent removal, two resumed normal diet and thrived, while two animals were euthanized prior to the proposed endpoint because of stricture formation and inability to tolerate a normal diet. Re-epithelialization was observed in all groups, and more complete over time.ConclusionsThe PU scaffold provides a matrix across which formation of new tissue can occur. The mechanisms through which this happens remain unclear, but likely a combination of fibrosis and tissue contraction, in conjunction with new tissue formation.     

Postprocedural Outcomes of Rural Children Undergoing Correction of Congenital Heart Lesions in Yunnan Province, China

The management of congenital heart disease (CHD) remains a significant challenge in developing regions. Since 2006, China California Heart Watch has provided cardiac services in China’s Yunnan province. Our Grants for Kids program aims to diagnose and fund surgical and nonsurgical treatments for underprivileged children with congenitally malformed hearts. This report analyzes our patient outcomes. From 2007 to 2010, 36 children with CHD underwent either surgical or percutaneous procedures at local Chinese medical centers, and 94% of our patients could be contacted for follow-up assessment. The mortality and complication rates of our patient population compare favorably with international data. Our study provides a model through which networking with local hospitals and regional cardiac centers can be an effective way to assist developing areas in providing cardiac care to rural underserved populations.     

Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum

PURPOSE: To evaluate the feasibility of concurrent weekly Cis-platinum chemoradiation (CRT) in the curative treatment of primary vaginal cancer. METHODS: A retrospective review was performed of all primary vaginal cancer patients treated with curative intent at the Ottawa Hospital Regional Cancer Centre between 1999 and 2004 using concurrent Cis-platinum CRT. RESULTS: Twelve patients were treated with concurrent weekly CRT. The median age at diagnosis was 56 years (range, 34-69 years), and the median follow-up was 50 months (range, 11-75 months). Ten patients (83%) were diagnosed with squamous cell carcinoma and 2 patients (17%) with adenocarcinoma. The distribution according to stage was as follows: 6 (50%) Stage II, 4 (33%) Stage III, and 2 (17%) Stage IVA. All patients received pelvic external beam radiotherapy (EBRT) concurrently with weekly intravenous Cis-platinum chemotherapy (40 mg/m(2)) followed by brachytherapy (BT). The median dose of EBRT was 4500 cGy given in 25 fractions over 5 weeks. Ten patients received interstitial BT, and 2 patients received intracavitary BT, with the median dose being 3000 cGy. The 5-year overall survival, progression-free survival, and locoregional progression-free survival rates were 66%, 75%, and 92%, respectively. Late toxicity requiring surgery occurred in 2 patients (17%). CONCLUSIONS: For the treatment of primary vaginal cancer, it is feasible to deliver concurrent weekly Cis-platinum chemotherapy with high-dose radiation, leading to excellent local control and an acceptable toxicity profile.     

Postoperative femoral motor neuropathy: diagnosis and treatment without neurologic consultation or testing

OBJECTIVE: To review the diagnosis and treatment of postoperative femoral motor neuropathy without neurologic consultation or testing. STUDY DESIGN: A retrospective review of 6 consecutive patients with postoperative femoral motor neuropathy following gynecologic surgery. Diagnosis was made on clinical evaluation: history of falling during postoperative ambulation, quadriceps weakness, straight leg raise weakness, diminished knee jerk response, and no evidence of psoas hematoma or abscess. Neurologic consultation, electromyography, nerve conduction study and radiologic imaging, such as computed tomography, were not obtained. Instead, a physical therapy consultation was obtained for a knee orthotic and rehabilitation. RESULTS: Four postoperative femoral motor neuropathies developed following 3,014 cases of major gynecologic surgery (0.1%). Two additional cases were seen in consultation. The median age was 57 years. All patients fell while attempting ambulation on postoperative day 1. Recovery occurred at a median of 3 months (1-4). At a median follow-up of 4 years, no patient had developed additional neurologic sequelae. A history of prior postoperative femoral motor neuropathy was noted in 2 of 6 patients (33%). CONCLUSION: This was the first study of diagnosis and treatment of postoperative femoral motor neuropathy following gynecologic surgery without neurologic consultation or testing. Because of the significant expense of neurologic consultation and testing, patients with postoperative femoral motor neuropathy can have the condition diagnosed by the gynecologist and be referred directly to physical therapy without adversely affecting outcome. This also was the first study to elicit a prior history offemoral neuropathy in 33% of patients. Thus, a prior history may be a risk factor for recurrence.     

Radiation-associated angiosarcoma of the breast with initial presentation as non-mass enhancement on MRI

Radiation-associated angiosarcoma of the breast (RAASB) is a rare and aggressive malignancy occurring after radiation therapy as part of breast cancer treatment. RAASB usually presents several years after prior radiation and typically involves the skin with or without involvement of the parenchyma. Most RAASB are detected as cutaneous changes on physical exam. Herein, we present a unique case of a clinically occult RAASB diagnosed as non-mass enhancement on annual surveillance breast MRI.