In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1–2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench to bed-side evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74 year old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5’RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After 2 cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET /CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain-barrier penetration by vandetanib in combination with everolimus.Further research is required in this setting.

Background: Pimpinella anisum known for its various medicinal properties is also a natural antioxidant and a free radical scavenger with no documented evidence as a nephroprotective agent. Objective: To evaluate the nephroprotective activity of aqueous extract of Pimpinella anisum seeds in a rodent model of gentamicin induced nephrotoxicity. Materials and Methods: Wistar albino rats of either sex, weighing 150-200 g was divided into 5 groups; normal saline, gentamicin 80mg/kg, intraperitoneally for 8 days, aqueous extract of Pimpinella anisum seeds at 1, 2, and 4g/kg, per oral for 8 days, the test extract administered 3 days prior and concurrently with gentamicin for 5 days. Blood urea, serum creatinine, uric acid and blood urea nitrogen analyses and microscopic examination of kidney were performed. Results: Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum urea, serum uric acid, serum creatinine and blood urea nitrogen (107.5±16.92mg/dl, 0.8±0.09 mg/dl, 3.05±0.29 mg/dl, 47.8±9.07 mg/dl) respectively when compared to the saline treated groups. Co-administration of Pimpinella anisum extract with gentamicin decreased the rise in these parameters in a dose dependent manner. Histopathological analysis revealed epithelial loss with intense granular degeneration in gentamicin treated rats, whereas aqueous extract of Pimpinella anisum mitigated the severity of gentamicin-induced renal damage. Conclusion: To conclude, our data suggest that aqueous extract of Pimpinella anisum exhibits renoprotective effect in gentamicin induced renal damage and further studies on its mechanism of action are warranted.

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High quality cataract surgery with a low rate of intra-operative complications and good visual outcome can be attained in camp patients operated in the base hospitals, thus justifying more similar screening camps to clear the vast cataract backlog.

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