Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients.

PURPOSE: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. EXPERIMENTAL DESIGN: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. RESULTS: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. CONCLUSIONS: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.

Instrumentation for measuring runoff, sediment, and chemical losses from agricultural fields.

This work describes a simple, passive sampling system for measuring runoff, sediment, and chemical losses from typical agricultural fields. The sampler consists of a 5 to 7 m wide runoff collector connected to a series of multislot divisors. These divisors split the flow into aliquots, providing a continuous sampling during the runoff event. Divisors were located in a wooden box below ground level. With an adequate pump, this system can operate in fields with a slope gradient as low as 2%, and can stay in the field during winter to record first snowmelt-generated runoff. A radio transmitter reports by telemetry the occurrence and magnitude of any runoff event, and indicates when the system should be sampled and emptied. This article includes a description of the equipment, advantages, and disadvantages based on 2 yr of operation, and examples of data collected.

Endophthalmitis caused by Haemophilus influenzae.

OBJECTIVE: To investigate the clinical settings, management strategies, antibiotic sensitivities, and visual acuity outcomes for eyes with endophthalmitis caused by Haemophilus influenzae. DESIGN: Retrospective, noncomparative, consecutive case series. METHODS: The medical records were reviewed of all patients treated for culture-proven H. influenzae endophthalmitis at a single institution between January 1, 1980, and December 31, 2002. MAIN OUTCOME MEASURES: Visual acuity and antibiotic sensitivities. RESULTS: The study included 16 eyes of 16 patients with a median age of 68 years (range, 6 months-83 years) and a median follow-up of 26 months (range, 2 months-15 years). Clinical settings included post-trabeculectomy (n = 7), post-cataract surgery (n = 6), post-pars plana vitrectomy (n = 1), post-secondary intraocular lens insertion (n = 1), and post-suture removal from an extracapsular cataract wound (n = 1). Eleven (69%) cases were of delayed onset (>6 weeks from surgery/event), with a median interval between surgery/event and presentation with endophthalmitis of 18 months (range, 44 days-21 years); 5 (31%) cases were of acute onset (median, 6 days; range, 2-14 days). Presenting visual acuity was hand movements or better in 7 (44%) eyes. A vitreous tap and inject was performed initially in 9 (56%) eyes, and a vitrectomy was performed initially in the remaining 7 (44%) eyes. All eyes received intravitreal antibiotics on the day of presentation, and 11 (69%) received intravitreal dexamethasone. In vitro testing of the H. influenzae isolates revealed that 14 of 16 (88%) were sensitive to vancomycin, ampicillin, and trimethoprim/sulfamethoxazole; 15 of 16 (94%) were sensitive to aminoglycosides (1 isolate was resistant to gentamicin); and all were sensitive to cephalosporins, fluoroquinolones, and carbapenems. The organisms were sensitive to at least 1 of the initial antibiotics administered in all cases. Final visual acuity was 5/200 or better in 6 (38%) eyes, and 6 (38%) eyes had a final visual acuity of no light perception. CONCLUSIONS: Endophthalmitis caused by H. influenzae is generally associated with poor visual outcomes despite prompt treatment with intravitreal antibiotics to which the organisms were sensitive.

Immediate postoperative use of a topical agent to prevent intraocular pressure elevation after pars plana vitrectomy with gas tamponade.

OBJECTIVE: To determine whether a single topical aqueous suppressant applied immediately after pars plana vitrectomy with long-acting gas tamponade prevents intraocular pressure (IOP) elevation. METHODS: Fifty patients who met the inclusion criteria and underwent pars plana vitrectomy with long-acting gas tamponade were randomized to receive a combination of timolol maleate and dorzolamide hydrochloride, long-acting timolol alone, dorzolamide alone, or placebo at the conclusion of surgery. The IOP was checked by a portable, handheld tonometer (Tono-Pen) at the conclusion of surgery and at 5 hours, 1 day, and 1 week after surgery. RESULTS: There were no significant differences in IOP among the groups at the conclusion of surgery. The IOP at 5 hours after surgery (27.0 vs 17.4 mm Hg; P<.001) and 1 day after surgery (26.1 vs 19.9 mm Hg; P =.01) showed a statistically significant difference between the placebo and timolol-dorzolamide groups. The timolol-dorzolamide group showed greater IOP control than either the timolol alone or the dorzolamide alone groups at 5 hours (P =.04 for both). CONCLUSION: The use of a single topical aqueous suppressant (timolol-dorzolamide) given after pars plana vitrectomy with long-acting gas tamponade effectively prevents significant postoperative IOP elevation at 5 hours and 1 day after surgery.

Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.

Tumor growth is associated with the accumulation of immature myeloid cells (ImC), which in mice are characterized by the expression of Gr-1 and CD11b markers. These cells suppress Ag-specific CD8+ T cells via direct cell-cell contact. However, the mechanism of immunosuppressive activity of tumor-derived ImC remains unclear. In this study we analyzed the function of ImC isolated from tumor-free control and tumor-bearing mice. Only ImC isolated from tumor-bearing mice, not those from their control counterparts, were able to inhibit the Ag-specific response of CD8+ T cells. ImC obtained from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC isolated from tumor-free animals. Accumulation of H2O2, but not superoxide or NO, was a major contributor to this increased pool of ROS. It appears that arginase activity played an important role in H2O2 accumulation in these cells. Inhibition of ROS in ImC completely abrogated the inhibitory effect of these cells on T cells, indicating that ImC generated in tumor-bearing hosts suppress the CD8+ T cell response via production of ROS. Interaction of ImC with Ag-specific T cells in the presence of specific Ags resulted in a significant increase in ROS production compared with control Ags. That increase was independent of IFN-gamma production by T cells, but was mediated by integrins CD11b, CD18, and CD29. Blocking of these integrins with specific Abs abrogated ROS production and ImC-mediated suppression of CD8+ T cell responses. This study demonstrates a new mechanism of Ag-specific T cell inhibition mediated by ROS produced by ImCs in cancer.