Selective Targeting of the L858R Mutation (EGFR) in Non-Small Cell Lung Cancer: A Mechanism for Advancing Targeted Chemotherapy.

Lung cancer remains one of today's most deadly and intractable cancers. Non-small cell lung cancer (NSCLC) accounts for roughly 85% of lung cancers, with an extremely poor survival rate. To ensure patient comfort and survival, the development of a selective therapy is imperative. However, lung cancer does not display surface proteins associated uniquely with tumor cells; thus, it is very difficult to develop a tumor-specific drug. Current techniques that target overexpression of proteins or inhibit growth pathways are either non-specific or prone to rapid drug resistance. The goal was to design a drug targeted to structural mutations expressed by tumor-associated general surface proteins, thereby combating the lack of tumor-unique markers in lung cancer. Mutant EGFR was identified as a potential target due to its prominence in tumor cells. Due to their size, it was determined that small molecules would be most effective at targeting isolated changes in protein structure, and thereby differentiating between the tumor-associated mutant EGFR and the healthy wild type. Conformational analysis of a virtual binding study conducted in VINA predicted a set of drug-like small molecules specific for the L858R mutation in EGFR. One molecule (ZN47) was then acquired and conjugated to a carrier protein to form a multifaceted hapten-protein conjugate. Multiple ELISAs were conducted to confirm the specificity of the conjugate to both tumor-associated mutant EGFRs. The results indicate that the identified molecule may be highly selective for tumor-associated L858R-EGFR, but further research, including a complete dosage-binding study, is necessary for full validation.

Catastrophic Intracranial Hemorrhages after IV tPA in a Patient with Insidious Onset of Fever and Back Pain.

Infective endocarditis is associated with unstable infective vegetations, which have a propensity to embolize and cause embolic events, such as stroke. Many cases present with an embolic event as the first sign of infective endocarditis. We present a patient who had a history of recent and persistent fever, an acute ischemic stroke treated with intravenous tissue plasminogen activator (IV tPA), and severe, multifocal intracerebral hemorrhage as a complication of tPA treatment. Suspected infective endocarditis in a stroke patient should most likely be considered a contraindication to IV tPA.

Ischemic and Hemorrhagic Strokes due to Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: We report a case of ischemic and hemorrhagic strokes occurring almost simultaneously in a patient diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) previously known as Churg-Strauss vasculitis. To our knowledge, this is the first known case. METHODS: A 59-year-old man presented with a 2-month history of bilateral leg weakness, difficulty ambulating, and dyesthesias. While in the hospital, he developed acute right hand weakness, and magnetic resonance imaging of the brain revealed multiple, bilateral ischemic infarcts. After a few days, he acutely became unresponsive and was found to have a large left frontal hematoma and underwent emergent hematoma evacuation. His weakness was unexplained by the infarcts based on location and so a peripheral process was suspected. RESULTS: Nerve conduction studies showed severe axonal sensorimotor neuropathy. A sural nerve biopsy showed necrotizing vasculitis, consistent with EGPA. CONCLUSIONS: EGPA is the rarest of the antineutrophilic cytoplasmic antibody vasculitides. The peripheral nervous system is frequently involved, but the central nervous system can also be affected. The vasculitis damages the vessel walls, which leads either to stenosis or to dilatation, resulting in ischemic or bleeding consequences which can occur simultaneously, such as in this case. Caution should be exercised when prescribing antiplatelet therapy to such patients.

Isolated cortical vein thrombosis associated with prothrombin gene mutation.

Isolated cortical vein thrombosis (ICVT) accounts for less than 1% of strokes. We report a 47-year-old female patient who had a frontal hemorrhage with headache associated with contralateral hemiparesis and hemisensory deficit on presentation. This hemorrhagic stroke was localized in a nonarterial territory, and it was caused by ipsilateral and isolated thrombosis of the vein of Labbe found on catheter angiogram that demonstrated a filling defect of the vein of Labbe at its connection with the transverse sinus. There were no filling defects in the superficial middle cerebral veins. Our patient had a family history of cardiovascular disease, stroke, and factor V Leiden mutation and cigarette smoking as stroke risk factors. Complete prothrombotic state laboratory workup revealed a heterozygous prothrombin G20210 A gene mutation. The patient's hospital course was uneventful. Neurologic exam was normal at stroke clinic follow-up 6 weeks later. To our knowledge, this is the first report of an ICVT associated with prothrombin gene mutation.

Influence of induction chemotherapy and class of cytotoxics on pathologic response and survival after preoperative chemoradiation in patients with carcinoma of the esophagus.

BACKGROUND: Patients with localized esophageal cancer (LEC) have diverse outcomes (post-therapy pathologic response, disease-free survival [DFS], and overall survival [OS]) after preoperative chemoradiation (P-CTRT), dictated also by inherent molecular heterogeneity. Whether the type of therapy influences the outcomes remains largely unanswered. It is hypothesized that induction chemotherapy (IC) or the type of cytotoxics used would not influence patient outcomes. METHODS: In this retrospective analysis, consecutive patients with LEC who had P-CTRT were analyzed. Data were collected regarding age, sex, baseline clinical stage, location, type of cytotoxics, post-therapy pathology, DFS, and OS. IC and the type of cytotoxics used were found to be correlated with DFS, OS, and post-therapy pathologic response. RESULTS: A total of 180 patients with LEC (119 had IC before P-CTRT, all had received 5-fluorouracil, 87 had received a taxane, and 57 had received a platinol) were analyzed. The median survival (MS) of all patients was 57.7 months and the 3-year and 5-year OS rates were 65.4% and 46.5%, respectively. The type of therapy appeared to have no influence on the outcome: IC versus no IC (P = .58) or platinol versus taxane versus platinol plus taxane (P = .63). Similarly, the type of pathologic response was not found to be influenced by IC (P = .18) or the type of cytotoxics used (P = .42). The data were similar for DFS. CONCLUSIONS: IC or the type of cytotoxics used with radiation for patients with LEC does not appear to influence OS, DFS, or the type of pathologic response after therapy, suggesting that a plateau has been reached. It remains to be seen whether the use of biochemoradiotherapy can provide an advantage in outcome.