UNASSIGNED: Two cases of late presentation (>5 years) of bilateral pseudophakic macula edema related to oral tyrosine kinase inhibitors are described. These cases are the first of their type in the published literature. A review of ocular inflammatory complications of tyrosine kinase inhibitors in the current literature is explored.
UNASSIGNED: Case 1 is an 83-year-old female who has been stable on ibrutinib (Imbruvica®) for chronic lymphocytic leukemia. She presented with bilateral blurred vision from severe cystoid macula edema, 7 years following routine cataract surgery. She was treated with intravitreal steroids with complete resolution without relapse. Case 2 is a 76-year-old female who was on therapy for polycythemia vera with ruxolitinib (Jakafi®). She presented with bilateral blurred vision from mild cystoid macula edema, 6 years following routine cataract surgery. She responded well to topical steroids without relapse. In both cases, oral tyrosine kinase inhibitor agents were presumed to be the underlying cause and were ceased. Over the last 5 years, there have been increasing reports in the literature of the inflammatory effects of tyrosine kinase inhibitors on the retina, uvea, and optic nerve.
UNASSIGNED: Late presentation of pseudophakic macula edema following routine cataract surgery is rare. Such presentations should prompt investigation of chronic use of systemic medications, especially oral kinase inhibitors. Patients who must remain on these agents require ongoing ophthalmologic assessment in view of their long-term inflammatory side effects.

OBJECTIVE: Four cases of ibrutinib-related uveitis are presented, which are to the best of our knowledge the first in the literature. Possible mechanisms of ibrutinib-mediated uveitis are explored.
METHODS: Case 1 is a 60-year-old female who had been stable on 1 year of ibrutinib for chronic lymphocytic leukaemia. She was diagnosed with ibrutinib-related uveitis, which responded well to topical steroids. Case 2 is a 63-year-old male diagnosed with uveitis after 2 years of ibrutinib treatment for chronic lymphocytic leukaemia. He responded well to topical and oral steroids; however, he continued to have uveitis relapses after weaning steroids. Case 3 is a 69-year-old male diagnosed with uveitis after 18 months of ibrutinib treatment. He was trialed on topical and intravenous steroids, and restarted ibrutinib without worsening of symptoms. Case 4 is a 66-year-old female who developed uveitis after being stable on ibrutinib for 3 years. She responded well to topical steroids.
CONCLUSIONS: Inflammatory complications of tyrosine kinase inhibitors are well described. While ibrutinib, and other kinase inhibitors, are generally well-tolerated, there are increasing reports of ocular toxicities, including uveitis. It is recommended to monitor patients for potential ocular adverse effects and facilitate rapid ophthalmologic assessment.

Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. We have developed iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive and a negative structural signature that captures the weakly conserved structural features of drug binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We were able to confirm the interaction of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity and specificity of 52% and 55%, respectively. We have validated 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, or MHC Class I molecules can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein-small molecule interactions, when sufficient drug-target 3D data are available. The code for constructing the structural signature is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.

Newer multi-kinase inhibitors (MKI) like sunitinib have changed the therapy of patients of renal cell carcinoma, hepatocellular carcinoma, and gastrointestinal stromal tumor. The use of sunitinib also led to cutaneous toxicity, known as hand-foot skin reaction (HFSR). We report a case of hand-foot skin reaction (HFSR) in an Indian patient being treated with sunitinib. Respective literature on this disorder is also reviewed.

Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI) library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of \"active\" and \"inactive\" compounds included in the training sets. PASS (Prediction of Activity Spectra for Substances), which is based on a modified Naïve Bayes algorithm, was applied since it had been shown to be robust and to provide good predictions of many biological activities based on just the structural formula of a compound even if the information in the training set is incomplete. We used different subsets of kinase inhibitors for this case study because many data are currently available on this important class of drug-like molecules. Based on the subsets of kinase inhibitors extracted from the ChEMBL 20 database we performed the PASS training, and then applied the model to ChEMBL 23 compounds not yet present in ChEMBL 20 to identify novel kinase inhibitors. As one may expect, the best prediction accuracy was obtained if only the experimentally confirmed active and inactive compounds for distinct kinases in the training procedure were used. However, for some kinases, reasonable results were obtained even if we used merged training sets, in which we designated as inactives the compounds not tested against the particular kinase. Thus, depending on the availability of data for a particular biological activity, one may choose the first or the second approach for creating ligand-based computational tools to achieve the best possible results in virtual screening.

BACKGROUND: Metastatic diseases are seen in approximately 25% of all cases with renal cell carcinoma and sometimes they can appear in unusual sites.
METHODS: We present a 35-year old patient with a painful left axillary mass which causes the functional impairment of the left arm. The axillary mass appeared 2 years after the nephrectomy performed for a left renal cell carcinoma. Numerous metastases have been identified through CT scans during the postoperative evolution of the disease for which the patient underwent adjuvant therapy with tyrosine-kinase inhibitors.
CONCLUSIONS: Particular to our case is not just the rare metastatic site but also the fact that the tumor appeared despite the adjuvant therapy with tyrosine-kinase inhibitors. Unfortunately, the prognosis of metastatic RCC with skin metastasis is in most cases unfavorable.
CONCLUSIONS: We believe that our case could add more information to subsequent measures, complete the frame of rare oncologic cases and consolidate the data published on the topic so far.

Kinase inhibitors have revolutionized cancer therapy by becoming the first-line agents for advanced solid malignancies replacing the traditional chemotherapeutic agents. Cutaneous side-effects with these drugs are common, but owing to their infrequent use in Indian patients, our current knowledge of toxicity is scanty and primarily based on the western literature. Cutaneous reactions can adversely affect patients\' quality of life (QoL) and can lead to dose modifications and treatment interruptions. The report discusses concurrent hand-foot skin reaction (HFSR) and hair depigmentation in an Indian patient being treated with sunitinib for advanced renal cell carcinoma. The pathogenesis and treatment strategies for this characteristic phenomenon and other cutaneous toxicities of kinase inhibitors have also been reviewed.