Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.
We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.
These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.
© 2016 American Heart Association, Inc.

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Menopausal symptoms (eg, hot flushes and vaginal symptoms) are common, often bothersome, and can adversely impact women’s sexual functioning, relationships, and quality of life. Estrogen-progestin therapy was previously considered the standard care for hormone therapy (HT) for managing these symptoms in nonhysterectomized women, but has a number of safety and tolerability concerns (eg, breast cancer, stroke, pulmonary embolism, breast pain/tenderness, and vaginal bleeding) and its use has declined dramatically in the past decade since the release of the Women’s Health Initiative trial results. Conjugated estrogens paired with bazedoxifene (CE/BZA) represent a newer progestin-free alternative to traditional HT for nonhysterectomized women. CE/BZA has demonstrated efficacy in reducing the frequency and severity of vasomotor symptoms and preventing loss of bone mineral density in postmenopausal women. CE/BZA provides an acceptable level of protection against endometrial hyperplasia and does not increase mammographic breast density. Compared with traditional estrogen-progestin therapy, it is associated with lower rates of breast pain/tenderness and vaginal bleeding. Patient-reported outcomes indicate that CE/BZA improves menopause-specific quality of life, sleep, some measures of sexual function (especially ease of lubrication), and treatment satisfaction. This review looks at the rationale for selection and combination of CE with BZA at the dose ratio in the approved product and provides a detailed look at the efficacy, safety, tolerability, and patient-reported outcomes from the five Phase III trials. Patient considerations in the choice between CE/BZA and traditional HT (eg, tolerability, individual symptoms, and preferences for route of administration) are also considered.

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Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on 3 well-characterised chordoma cell lines. 154 compounds were selected from the single concentration screen (1 μM) based on their growth inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of 7 chordoma cell lines, 4/7 of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream-pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4- position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in 2 xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplification (EGFR, ERBB2, MET), nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-) EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo.
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PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib.
The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort.
In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population.
Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.
Copyright © 2015. Published by Elsevier Inc.

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Hepatosplenic T-cell lymphoma (HSTCL) is a rare malignancy of unknown incidence that has been associated with immune-mediated disease. This study explored the incidence and patient characteristics of HSTCL in a population of 15.5 million over a 13-year period using a comprehensive national pathology database in The Netherlands (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief) with 100% capture. Twelve cases of HSTCL were identified during this period. The overall incidence of HSTCL in the Dutch population over this period was estimated at 0.06 per million inhabitant-years. All but 2 of the patients were adults at the time of diagnosis (median age, 34.5 years), and most patients died within a year of diagnosis. Three patients had a history of immune-mediated disease, 1 of whom was receiving azathioprine at the time of HSTCL diagnosis. Azathioprine as well as anti-tumor necrosis factor-α agents have been reported as possibly being associated with HSTCL. None of the 12 HSTCL patients had been treated with an anti-tumor necrosis factor-α agent.

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