Targeting folate receptors to treat invasive urinary bladder cancer.

Folate receptors (FR) may be of use for targeted delivery of cytotoxic drugs in invasive urothelial carcinoma (iUC), for which improved therapy is needed. FR expression and function in iUC were explored and the antitumor activity and toxicity of a folate-targeted vinblastine conjugate were evaluated in dogs with naturally occurring iUC, an excellent model for human iUC. FR immunohistochemistry was carried out on iUC and normal human and dog bladder tissues together with nuclear scintigraphy in dogs to monitor iUC folate uptake. Dose escalation of a folate-targeted vinblastine compound, EC0905, was conducted in dogs with biopsy-confirmed, FR-positive iUC. FRs were detected by immunohistochemistry (PU17) in most primary iUC and many nodal and lung metastases from dogs, and scintigraphy confirmed folate uptake in both primary and metastatic lesions. The maximum tolerated dose of EC0905 in dogs was 0.25 mg/kg IV weekly, with neutropenia at higher doses. Tumor responses included partial remission (≥ 50% reduction in tumor volume) in five dogs and stable disease (<50% change in tumor volume) in four dogs. Immunoreactivity to PU17 was similar in humans (78% of primary iUC, 80% of nodal metastases). Less immunoreactivity to mab343 (22% of cases) occurred. FR-ß was noted in 21% of human iUC cases. Our findings suggest folate-targeted therapy holds considerable promise for treating iUC, where FR-ß may be important in addition to FR-α.

Imaging sites of infection using a 99mTc-labeled folate conjugate targeted to folate receptor positive macrophages.

EC20, a folate-targeted (99m)Tc based radioimaging agent with a high folate receptor (FR) binding affinity, has been used for both the diagnosis and the staging of FR positive malignancies (currently in phase III trials) and also for the localization of inflamed lesions characterized by the accumulation of FR+ macrophages. Because recent evidence has suggested that FR+ macrophages might accumulate at sites of infectious disease, this study evaluated whether EC20 might prove similarly useful for imaging bacterial infection foci. Using gamma scintigraphic imaging, it was demonstrated that EC20 accumulated at sites of Staphylococcus aureus infection with a significant difference (P < 0.0001, n = 12) in enrichment noted between infected and noninfected limbs. Confirmation that the elevated uptake of EC20 in infected limbs was FR-mediated was supported by suppression of EC20 accumulation in the presence of a 200-fold excess of free folic acid (P < 0.0001, n = 12). This study establishes for the first time the use of EC20 to image and localize sites of infectious disease.

Congenital retrosternal (Morgagni) diaphragmatic hernias in three horses.

CASE DESCRIPTION: 3 Horses were examined and treated because of sudden onset of signs of abdominal pain. CLINICAL FINDINGS: All horses had a retrosternal (Morgagni) hernia involving the right side of the diaphragm. In each horse, the large colon was incarcerated in a right muscular defect in the diaphragm with a large hernial sac. TREATMENT AND OUTCOME: Definitive surgical repair of the hernia was not performed during the initial celiotomy. The hernia was repaired with mesh herniorrhaphy, but without resection of the hernia sac in 2 horses. For 1 horse, conservative management was applied. In the 2 horses treated with surgical correction, no major postoperative complications developed, and all 3 horses have been free of signs of abdominal pain. CLINICAL RELEVANCE: Horses with retrosternal hernias involving the diaphragm can develop clinical signs of intermittent obstruction of the large colon and chronic colic. In horses, retrosternal diaphragmatic hernias appear to develop exclusively in the right ventral aspect of the diaphragm and could represent an embryologic defect of diaphragm formation. Affected horses can be successfully treated with mesh herniorrhaphy or, in some instances, with conservative management.

Evaluation of surgical treatment for signs of acute abdominal pain in draft horses: 72 cases (1983-2002).

OBJECTIVE: To determine whether heavy (> or = 680 kg [> or = 1,500 lb]) draft horses undergoing surgical treatment for acute signs of abdominal pain were at a greater risk for anesthetic and postoperative complications and lower postoperative survival rates than light (< 680 kg) draft horses. DESIGN: Retrospective case series. ANIMALS: 72 draft horses. PROCEDURES: Medical records of draft horses that underwent exploratory celiotomy for signs of acute abdominal pain from October 1983 to December 2002 were reviewed. Medical records of draft horses in which a celiotomy was performed for correction of reproductive abnormalities were not included in the study. RESULTS: When compared with light draft horses, heavy draft horses had longer durations of anesthesia, more postoperative complications, and lower survival rates. Seventy-six percent of horses that recovered from anesthesia had postoperative complications. Postoperative complications associated with low survival rates included myopathy and neuropathy, ileus, diarrhea, and endotoxemia. All horses with postoperative myopathy and neuropathy died or were euthanized. The short-term survival rate for horses that recovered from anesthesia was 60%. Horses undergoing small intestinal surgery had a worse prognosis for short-term survival than those undergoing large intestinal surgery. The survival rate for horses for which long-term (> 1 year) follow-up information was available was 50%. CONCLUSIONS AND CLINICAL RELEVANCE: Draft horses weighing > 680 kg that underwent surgery because of acute signs of abdominal pain had longer durations of anesthesia, more postoperative complications, and higher mortality rates than draft horses weighing < 680 kg.