Differences in the cellular response and signaling pathways of cisplatin and BBR3464 ([[trans-PtCl(NH3)(2)]2mu-(trans-Pt(NH3)(2)(H2N(CH2)(6)-NH2)2)]4+) influenced by copper homeostasis

[[trans-PtCl(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)-NH(2))(2))](4+) (BBR3464) is a cationic trinuclear platinum drug that is being evaluated in phase II clinical trials for treatment of lung and ovarian cancers. The structure and DNA binding profile of BBR3464 is different from drugs commonly used clinically. It is of great interest to evaluate the difference between the mechanisms of uptake employed by BBR3464 and cisplatin (c-DDP), as altered uptake may explain chemoresistance. Using transfected cell lines, we show that both c-DDP and BBR3464 use the copper transporter hCTR1 to enter cells and to a lesser extent, the ATP7B transporter to exit cells. Copper influenced c-DDP and BBR3464 uptake similarly; it increased the c-DDP and BBR3464 uptake in ovarian (A2780) and colorectal (HCT116) carcinoma cell lines as detected by ICP-OES. However, the effects of copper on c-DDP- and BBR3464-mediated cytotoxicity differed. Copper decreased c-DDP-induced apoptosis, caspase-3/7 activation, p53 induction and PARP cleavage in cancer cell lines. In contrast, copper increased BBR3464-induced apoptosis, and had little effect on caspase activation, PARP cleavage, and p53 induction. It was concluded that BBR3464 employs mechanisms of intracellular action distinct from c-DDP. Although these drugs use the same cellular transporters (hCTR1 and ATP7B) for influx and efflux, downstream effects are different for the two drugs. These experiments illustrate fundamental differences in the mechanisms of action between cisplatin and the novel Pt-based drug BBR3464.     

The role of scleral buckle in experimental posterior penetrating eye injury.

PURPOSE: Although episcleral buckles are frequently placed as an additional procedure to vitreoretinal surgery, little is known about their independent effect after ocular trauma. The authors created a posterior penetrating ocular injury model to evaluate the isolated role of primary episcleral buckle placement. METHODS: Twenty eyes underwent surgery. The penetrating injury consisted of two 5-mm circumferential incisions placed five clock hours apart and 8 mm behind the limbus. A segmental episcleral buckle was placed over a randomly chosen injury site after wound closure. The degrees of fibrous proliferation, traction, and the presence of retinal detachment were evaluated on follow-up examinations. After enucleation and initial fixation, tissue sectioning was performed, and the greatest dimension of the fibrous proliferation at both wound sites was measured with a caliper. RESULTS: Two eyes were excluded from the study. Three eyes developed a retinal detachment; the remaining 15 eyes showed varying degrees of proliferation and traction on the retina. The greatest dimension of the fibrous proliferation at the buckle site (1.22 +/- 1 mm) was significantly different from that at the nonbuckle site (2 +/- 1.45 mm, P = 0.01). CONCLUSIONS: Primary episcleral buckle placement at the time of surgical repair reduces vitreous traction from the buckle site and decreases the degree of fibrovascular proliferation.     

Surgical management of cataract and posterior chamber intraocular lens implantation in Fuchs‘ heterochromic iridocyclitis

Background: To determine the inflammatory course and level of visual rehabilitation after cataract extraction and posterior chamber lens implantation in patients withFuchs‘ heterochromic iridocyclitis complicated by cataract. Methods: In a clinical trial, 32 eyes (visual acuity of 20/160 or worse) of 30 patients underwent extracapsular cataract extraction (19 eyes) or lensectomy(13 eyes) accompanied by posterior chamber intraocular lens implantation. Indirect ophthalmoscopy was performed intraoperatively prior to intraocular lens implantation and the extent of vitreous haze was assessed. If vitreous haziness was 3+ or more, core vitrectomy (two eyes) or three-port pars plana deep vitrectomy (four eyes) was performed. Results: After an average follow up of14.4 months (6 to 24 months), there was no statistically significant increase in cell and flare in the anterior chamber and vitreous or in keratic precipitates compared with the preoperative status of the eyes. However, 12%of the eyes developed synechiae (anterior and/or posterior) in comparison to preoperative condition (p< 0.05). Eighty-seven percent of the eyes gained visual acuity of 20/40 or better (P < 0.005). Using the logistic regression model, a higher level of preoperative inflammation was associated with reduced likelihood of gaining visual acuity of 20/25 or more (OR = 0.25, 95%CI 0.049, 1.255). The complications of surgery were synechiae, 12%; opaque posterior capsule, 12%; vitreous loss, 3%; chronic glaucoma, 3%; and retinal detachment,3%. Conclusions: Implantation of a posterior chamber intraocular lens can be well tolerated in patients with Fuchs‘ heterochromic iridocyclitis. Vitrectomy, whenever indicated in addition to cataract extraction, improves visual rehabilitation. This revised version was published online in August 2006 with corrections to the Cover Date.     

Management of retinal detachment associated with choroidal coloboma using perfluoroperhydrophenanthrene (Vitreon).

Vitreous surgery using an internal tamponading agent and chorioretinal adhesion is commonly used to repair retinal detachment associated with choroidal coloboma. The detachment may, however, recur if fluid continues to leak through a retinal defect in the area of the coloboma, despite internal tamponade. We present a case in which a recurrent retinal detachment associated with coloboma following vitreous surgery with SF6 was successfully repaired in outpatient surgery using perfluoroperhydrophenanthrene (Vitreon) and endolaser photocoagulation.     

Surgical management of incarcerated retina in the sclerotomy.

We used perfluoroperhydrophenanthrene (Vitreon) to release an incarcerated retina successfully from the pars plana sclerotomy site.     

Efficacy of liposome-bound amphotericin B for the treatment of experimental fungal endophthalmitis in rabbits

The efficacy of intravitreally administered amphotericin B was evaluated. Experimental fungal infections were produced by inoculation of Candida albicans organisms into the vitreous cavities of 46 rabbit eyes. After 72 hr, eight eyes received intravitreal injections of 10 micrograms of free amphotericin B; and ten eyes each received 10 micrograms, 20 micrograms, and 40 micrograms of liposome-bound amphotericin B. The remaining eight eyes served as controls: four eyes received dextrose solution and four eyes received empty liposomes. Histopathologic examination 8 weeks after inoculation showed clear vitreous without retinal damage in groups treated with either 10 micrograms free amphotericin B or 20 micrograms of liposome-bound drug. All eyes in the control group and six eyes (60%) in the group treated with 10 micrograms of liposome-bound amphotericin B developed vitreous abscesses with evidence of fungal infection. In eyes treated with 40 micrograms of liposome-bound amphotericin B, fungal infection was successfully eradicated, but retinal damage was detected in all eyes by light microscopy. It is proposed that a reduced toxicity of intravitreally injected liposome-bound drugs is accompanied by reduced efficacy. In the treatment of fungal endophthalmitis, an increased dosage of liposome-bound amphotericin B (above that dosage of free drug which would be required) is suggested.     

One-step extracapsular cataract extraction and silicone oil-injection in the management of proliferative vitreoretinopathy.

A combined technique of extracapsular cataract extraction and silicone oil injection is described. The anterior capsule is preserved to prevent movement of the silicone oil from the vitreous cavity to the anterior chamber. An anterior chamber tap ensures that the vitreous cavity is completely filled with silicone oil, while a peripheral iridectomy prevents postoperative pupillary block glaucoma.     

A population-based analysis of chemoradiation versus radiation alone in the definitive treatment of patients with stage I–II squamous cell carcinoma of the anus

BackgroundThe optimal management of patients with stage I–II squamous cell carcinoma (SCC) of the anus is controversial. The current study evaluates the efficacy of combined chemotherapy and radiation therapy (CRT) versus radiation therapy (RT) alone in the treatment of these patients using the Surveillance, Epidemiology, and End Results (SEER) registries.MethodsSEER 18 Custom Data registries were queried for patients with stage I–II SCC of the anus. Univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias.ResultsA total of 4,288 patients with stage I–II disease were identified, of whom 3,982 (93%) underwent CRT and 306 (7%) underwent RT. Median follow-up was 42 months. Approximately 30.8% had T1 disease and 69.2% had T2–T3 disease. The IPTW-adjusted 5-year overall survival (OS) was 76.7%, with no significant differences between the CRT and RT groups (77% vs. 73.5%, P=0.33). On multivariate IPTW-adjusted analysis, the lack of association between CRT use and OS was upheld (HR, 0.84, 95% CI, 0.65–1.08, P=0.2). On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I (T1N0) patients, while 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients. CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04).ConclusionsThe current study suggests that omission of concurrent chemotherapy is not associated with inferior OS in patients with stage I SCC of the anus. However, combined chemoradiation was superior to radiation alone in patients with stage II disease. Prospective evidence is needed to optimize clinical decision-making in this patient population.