Amol D. Kulkarni

Resveratrol Inhibits Tumor Growth of Human Neuroblastoma and Mediates Apoptosis by Directly Targeting Mitochondria

Purpose: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action. Experimental Design: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. Results: Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 μmol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold). Conclusions: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.

Intratarsal epidermal inclusion cyst.

Purpose: To report 3 cases of epidermal inclusion cyst that arose within the tarsus, an unusual site of origin. Methods: A retrospective review of medical records of patients undergoing excision of eyelid epidermal inclusion cysts by one surgeon (MJL) over a decade revealed 3 cases of intratarsal epidermal inclusion cyst. Initially, these lesions resembled chalazia and were first addressed with incision and curettage. There was recurrence of the cyst in all the 3 cases from 1 to 4 months, and subsequent complete excision was necessary. Results: At surgery in each of these cases a cyst arising within the tarsus was encountered. Eventually, the tarsus containing the base of the cyst was excised to ensure complete removal. The cysts were approximately 8 mm to 10 mm in greatest dimension and had yellowish-white gelatinous contents. Histopathologic evaluation revealed keratin-filled cysts arising from tarsus and lined by stratified keratinized epithelium. In one of the cases the tarsal tissue around the cyst wall showed epidermal elements presumably derived from sebaceous gland. There have been no recurrences after complete excision (follow-up range, 9–60 months). Conclusions: Intratarsal epidermal inclusion cysts share some clinical features with chalazia. Lack of inflammation, lack of fluctuation in size, gradual continued slow growth, and delayed onset of recurrence may help to differentiate tarsal cyst from recurrent chalazion. Incision and curettage, however, is not effective long-term treatment for this entity. Total excision of the cyst including full-thickness excision of tarsus at the cyst’s base of origin is suggested for definitive treatment.

A Study of Histopathological Features of Latanoprost-Treated Irides With or Without Darkening Compared With Non–Latanoprost-Treated Irides

OBJECTIVES To study the histopathological features of latanoprost-treated irides with or without darkening, compared with non-latanoprost-treated irides. METHODS Iridectomy specimens and patient history forms were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for premalignant changes and for differences in level of pigmentation and degrees of cellularity, inflammation, and vascular abnormalities. RESULTS The specimens consisted of 22 latanoprost-treated darkened irides, 35 latanoprost-treated irides without darkening, and 35 non-latanoprost-treated irides. There was a statistically significant decrease in the number of nuclear invaginations and prominent nucleoli in latanoprost-treated darkened irides compared with the other 2 groups (P = .004 and P = .005, respectively). The average thickness and pigmentation of the anterior border layer was greater in the latanoprost-treated darkened irides than in the other 2 groups (P = .03 and P = .02, respectively). The latanoprost-treated darkened irides had increased pigmentation of the stroma (P < .001), stromal fibroblasts (P < .001), melanocytes (P = .005), vascular endothelium (P = .02), and adventitia (P < .001) relative to the other 2 groups. CONCLUSIONS There is no histopathological evidence of premalignant changes in latanoprost-treated darkened irides. The latanoprost-induced iris color changes are due to a thickening of the anterior border layer and an increased amount of melanin in the anterior border layer and within the stromal melanocytes.

Use of Combination Therapy with Cisplatin and Calcitriol in the Treatment of Y-79 Human Retinoblastoma Xenograft Model

Background: Retinoblastoma is the most common primary malignant intraocular neoplasm of childhood. The poor outcomes of patients with metastatic retinoblastoma have encouraged the search for new therapies. In the current study, the efficacy of combination therapy with calcitriol and cisplatin in athymic mice with subcutaneous Y-79 human retinoblastoma tumours was assessed. Methods: 60 athymic mice were subcutaneously injected with human Y79 retinoblastoma cells. Animals were randomised into four groups: group 1, 50 μg of cisplatin; group 2, 0.05 μg of calcitriol; group 3, 0.05 μg of calcitriol and 50 μg of cisplatin; group 4, control. The cisplatin was administered once a week, and the calcitriol was given five times a week. Results: There was a significant inhibition of tumour growth in animals treated with the combination therapy of calcitriol and cisplatin as compared with controls and cisplatin alone (p = 0.0001 and p = 0.0041 respectively). In terms of toxicity, serum calcium levels were increased, but there was no mortality and minimal nephrotoxicity in any of the groups. Conclusion: The present study shows that cisplatin given in combination with calcitriol may be a viable multidrug therapy option in the treatment of high-risk retinoblastoma.

Clinicopathologic correlation of explanted AlphaCor artificial cornea after exposure of implant.

Purpose: To describe the clinical presentation and histopathologic findings in a case of explantation of an AlphaCor artificial cornea implant caused by exposure of the skirt. Methods: We describe the case report of a 46-year-old man who suffered trauma to the right eye, resulting in 4 failed penetrating keratoplasties (PKPs). Subsequently, an AlphaCor implantation was performed with some visual improvement. Slightly more than 2 years after the implant, skirt exposure occurred, possibly secondary to infectious keratitis in an area of a ruptured bulla, and explantation was performed. Corneal stability was established with repeat corneal transplantation. Results: Histopathologic evaluation of the surgical specimen revealed chronic nongranulomatous inflammation and fibrosis in the peripheral skirt, indicating that biointegration was maintained. However, peripheral corneal stromal melting led to skirt exposure. Focal calcification, as well as retroprosthetic membrane formation, was also identified. Conclusions: The AlphaCor implant is a viable method of treatment for multiple failed PKPs, but it may be associated with unique complications, including corneal stromal melting, focal calcification, and retroprosthetic membrane formation. Infectious keratitis may be a risk factor for corneal stromal melting and needs to be managed aggressively. Explantation of the implant is essential if the skirt is exposed.

Diabetic Macular Edema: Therapeutic Options

Treatment for diabetic macular edema (DME) is continuously evolving with the advent of pharmacologic therapies. Focal laser photocoagulation remains the historical standard of care; however, a new wave of studies is rapidly emerging that shows the benefit of intravitreal antivascular endothelial growth factor medications and corticosteroids. The goal of this review is to compare the various treatment options for DME, and include data from the most recent clinical trials of therapies for this complex condition.