Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

OBJECTIVES: BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. METHODS: Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. RESULTS: Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. CONCLUSION: Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status.

Micro syndrome in Muslim Pakistan children.

OBJECTIVE: To date, Micro syndrome has been reported in only three children from one family. We describe an additional 14 children from 11 families. DESIGN: Retrospective case series. PARTICIPANTS: Fourteen children from 11 families attending one of five British hospitals. MAIN OUTCOME MEASURES: The following features were documented: pre- and postoperative eye findings, electrophysiologic analysis, systemic abnormalities, development, neuroimaging, genealogy, geographic origin of family. RESULTS: We expand and modify the description of ocular and electrophysiologic findings in Micro syndrome. The eye findings of microphakia, microphthalmos, characteristic lens opacity, and atonic pupils were the presenting feature in all infants and were the most reliable diagnostic signs in the immediate postnatal period. Cortical visual impairment, microcephaly, and developmental delay were not always detectable initially; they developed in all children by 6 months of age. Microgenitalia were a useful diagnostic clue in affected males only. Therefore, eye features were more consistently useful in determining diagnosis than dysmorphology or brain imaging. The families of all the children originate from the Muslim population of Northern Pakistan. Inheritance is likely to be autosomal recessive. CONCLUSIONS: Micro syndrome usually presents to the ophthalmologist, who may be able to make the diagnosis on the basis of characteristic eye findings combined with ethnic origin. Initially, the nature and severity of nonophthalmic features are not apparent. Early diagnosis of the underlying condition is important to guide management of the cataracts, glaucoma, and developmental delay. It is helpful for the family and medical staff to be aware of the low level of vision that develops despite optimal ophthalmic intervention. Genetic counseling extending into the wider family is particularly important in view of the high rate of consanguinity.

Surgical excision of subfoveal neovascular membranes.

BACKGROUND: Subfoveal choroidal neovascular membranes (CNV) are a cause of significant visual impairment. Laser treatment of such lesions results in visual loss. Surgical excision of CNV may allow stabilisation or improvement of vision. A series of results of surgical excision are presented. METHODS: The records for 43 eyes of 40 consecutive patients undergoing surgical excision of CNV not associated with age-related macular degeneration (AMD) were reviewed retrospectively. Statistical analyses of the relationship between pre-operative factors and post-operative visual results were made. Improvement or worsening of visual acuity was defined as a change of more than 2 lines of Snellen acuity. RESULTS: In 79.1% of patients visual acuity was improved or unchanged following surgery, and in 20.9% there was a reduction of Snellen acuity. There was no statistically significant association between visual outcome and age, gender, duration of visual symptoms, cause of CNV, presence of subretinal haemorrhage, elevation of retina by subretinal fluid, prior laser surgery, or the presence of pre-operative or intraoperative subretinal haemorrhage. There was a possible association between the non-use of gas tamponade and an increased chance of reduced vision. Visual loss was more likely in those eyes with good pre-operative visual acuity. Recurrence of CNV was noted in 10 (23%) eyes; repeat surgery was not associated with a worse visual outcome. CONCLUSIONS: Surgical excision of CNV not related to AMD is a promising technique. More meaningful assessment of visual function in these patients will allow refinement of case selection.