Targeted actinium-225 in vivo generators for therapy of ovarian cancer

Advanced ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p. radioimmunotherapy in a mouse model of human ovarian cancer. Use of a targeted actinium-225 ((225)Ac) in vivo generator of alpha particles exploits the extreme, selective cytotoxicity of alpha particles, while providing a feasible half-life to enable delivery to tumor. (225)Ac chelated with 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid was conjugated to trastuzumab, an anti-HER-2/neu antibody. The radioimmunoconjugate was tested for immunoreactivity, internalization, and cytotoxicity using a human ovarian carcinoma cell line, SKOV3. (225)Ac-labeled trastuzumab retained immunoreactivity (50-90%), rapidly internalized into cells (50% at 2 h), and had an ED(50) of 1.3 nCi/ml after 4 days of incubation in vitro. i.p. administered (225)Ac- or (111)In-labeled trastuzumab behaved similarly with high tumor uptake [56-60% injected dose per gram (% ID/g) at 4 h, which increased to 65-70% ID/g at 24 h]. Tumor uptake was 3-5-fold higher than liver and spleen, the normal organs with the highest uptake. i.v. administration of (111)In-labeled trastuzumab produced slightly higher normal organ uptake compared with i.p.-administered (111)In-labeled trastuzumab. However, tumor uptake was low, 5%-26% ID/g. Therapy was examined with native trastuzumab and 220, 330, and 450 nCi of (225)Ac-labeled trastuzumab or (225)Ac-labeled control antibody at different dosing schedules. Therapy was initiated 9 days after tumor seeding. Groups of control mice and those administered native trastuzumab had median survivals of 33 and 37 or 44 days, respectively. Median survival was 52-126 days with (225)Ac-labeled trastuzumab at various doses and schedules, and 48-64 days for (225)Ac-labeled control the same schedules. Deaths from toxicity occurred with the highest activity levels. In conclusion, i.p. administration with a (225)Ac-labeled internalizing anti-HER-2/neu antibody can extend survival significantly in a nude mouse model of human ovarian cancer at levels that produce no apparent gross toxicity.     

Aeromonas isolates from human diarrheic stool and groundwater compared by pulsed-field gel electrophoresis

Gastrointestinal infections of Aeromonas species are generally considered waterborne; for this reason, Aeromonas hydrophila has been placed on the United States Environmental Protection Agency Contaminant Candidate List of emerging pathogens in drinking water. In this study, we compared pulsed-field gel electrophoresis patterns of Aeromonas isolates from stool specimens of patients with diarrhea with Aeromonas isolates from patients' drinking water. Among 2,565 diarrheic stool specimens submitted to a Wisconsin clinical reference laboratory, 17 (0.66%) tested positive for Aeromonas. Groundwater isolates of Aeromonas were obtained from private wells throughout Wisconsin and the drinking water of Aeromonas-positive patients. The analysis showed that the stool and drinking water isolates were genetically unrelated, suggesting that in this population Aeromonas gastrointestinal infections were not linked with groundwater exposures.     

Variations in the resting oxygen consumption of small babies

Over 200 measurements of the resting rate of oxygen consumption using an open-circuit method were made on 15 small babies nursed in their usual clinical setting during the first month of life. There were striking and persistent variations between babies that could not be explained by postnatal age, relationship to feed, sleep, or time of day. It was not possible from clinical examination to predict which babies had the higher or lower metabolic rates, except that babies who were light-for-dates generally had higher values. Because of these variations the appropriate thermal temperature for small babies cannot be predicted from average values adjusted for body weight and postnatal age alone.     

Activation of submucosal 5-HT3 receptors elicits a somatostatin-dependent inhibition of ion secretion in rat colon

Background and purpose:

5-Hydroxytryptamine (5-HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5-HT₃ receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect.

Experimental approach:

Mucosa/submucosa or mucosa-only preparations from rat distal colon were mounted in Ussing chambers for measurement of short-circuit current (I_sc) as an indicator of ion secretion. Somatostatin release was determined with radioimmunoassay. Intracellular cAMP content was measured with enzyme-linked immunoadsorbent assay (elisa). Immunohistochemical techniques were used to study the expression of 5-HT₃ receptors, somatostatin and somatostatin receptors in colonic tissue.

Key results:

In rat distal colonic mucosa/submucosa preparations, pretreatment with 5-HT₃ receptor antagonists enhanced 5-HT-induced increases in I_sc. However, in mucosa-only preparations without retained neural elements, pretreatment with 5-HT₃ receptor antagonists inhibited 5-HT-induced ΔI_sc. Pretreatment with a somatostatin-2 (sst₂) receptor antagonist in mucosa/submucosa preparations augmented 5-HT-induced ΔI_sc. Combination of sst₂ and 5-HT₃ receptor antagonists did not cause further enhancement of 5-HT-induced ΔI_sc. Moreover, both sst₂ and 5-HT₃ receptor antagonists enhanced 5-HT-induced increase in intracellular cAMP concentration in the mucosa/submucosa preparations. 5-HT released somatostatin from rat colonic mucosa/submucosa preparations, an effect prevented by pretreatment with 5-HT₃ receptor antagonists. Immunohistochemical staining demonstrated the presence of 5-HT₃ receptors on submucosal somatostatin neurons and of sst₂ receptors on colonic mucosa.

Conclusion and implications:

Activation of neuronal 5-HT₃ receptors in the submucosal plexus of rat colon suppressed 5-HT-induced ion secretion by releasing somatostatin from submucosal neurons.     

Comparison of Phaconit Rollable IOL with Acrylic Foldable IOL

Background

Phaconit or ultra micro incision phacoemulsification cataract surgery involves phacoemulsification through a 0.9 millimetre sleeveless phaco tip and irrigating chopper followed by implantation of a rollable intraocular lens. The procedure leads to negligible astigmatism and faster visual recovery as compared to phacoemulsification with a foldable intraocular lens.

Methods

This prospective study analysed 80 cases of sub millimetre phaconit surgery with implantation of rollable intraocular lenses(IOL) in 40 cases and acrylic foldable IOL in the remaining 40 cases. Evaluation of efficacy and adaptability of procedure, equipment settings, operative constraints, postoperative complications, keratometric and topographic evaluation of induced astigmatism with visual outcome and patient''s rehabilitation were studied.

Results

The intraoperative complications were surge/ chamber collapse in 16 (20%), iris chaffing in one and corneal burns in two cases. All cases had an induced astigmatism of less than or equal to ± 0.25 D in four to six weeks after rollable IOL and ± 0.5 D to ± 0.75 D after acrylic IOL implantation. All patients had best-corrected visual acuity of 6/6 by third post operative day.

Conclusion

Phaconit with rollable IOL is a perfect blend of surgical skill, application of technology and ultra thin IOL.Key Words: Phaconit, Ultra micro phaco, Submillimetre incision, Rollable IOL implantation     

Continuous infusion cisplatin and etoposide chemotherapy for cancer of unknown primary site (CUPS) in Taiwan, a region with a high prevalence of endemic viral infections

BACKGROUND: To evaluate the efficacy and toxicity of cisplatin/etoposide continuous infusion chemotherapy for cancer of unknown primary site in Taiwan, a region with a high prevalence of endemic viral infections. METHOD: Between April 1994 and February 1996, 20 patients with a diagnosis of CUPS were treated, including 15 males and five females, of average age 63.3 years (range 41-83 years). Continuous intravenous infusion of etoposide 80 mg/m2 and cisplatin 25 mg/m2 was given for 3 days every 3 weeks. Pretreatment tumor marker and viral serology studies were performed for baseline evaluation. Nearly two-thirds of the patients had poorly differentiated carcinoma. The average number of metastatic sites was 2.65 (range 1-4), with liver and lymph node involvement predominating. RESULTS: The overall response rate was 25% (95% CI 17.7-32.3%); 30.7% for poorly differentiated cancers and 25% for well differentiated cancers. Median survival was 4 months (range 1-12 months), 4.8 months for patients attaining partial response. Toxicity was moderate, grade 3 and 4 neutropenia occurred in 55% and grade 3 and 4 thrombocytopenia in 40%; other toxicities were mild. CA125 and CA199 were elevated in more than 50% of patients. Viral serology studies were not significantly different from those of the indigenous population. CONCLUSION: Etoposide and cisplatin combination chemotherapy has modest activity in patients with extensive CUPS and, at the schedule and dosage given, it is associated with moderate toxicity.