Effect of Psychiatric Comorbidities on In-Hospital Outcomes and Cost for Cervical Spondylotic Myelopathy.

OBJECTIVE: The present study examined the differences in outcomes of cervical spinal surgery for patients with and without a major psychiatric comorbidity using the Healthcare Cost and Utilization Project National Inpatient Sample database. METHODS: Data were queried from the Healthcare Cost and Utilization Project National Inpatient Sample database from 2013 to 2014 for hospitalizations with a major psychiatric comorbidity and a diagnosis of cervical spondylotic myelopathy treated by an appropriate surgical procedure. The included psychiatric comorbidities were schizophrenia, episodic mood disorders (bipolar I and II disorders), delusional disorders, and psychoses not otherwise specified. Univariate and multivariate regression analyses were performed to determine the differences in outcomes between patients with and without a major psychiatric comorbidity. RESULTS: A total of 18,335 hospitalizations met the inclusion criteria, of which 648 (3.5%) included a major psychiatric comorbidity. Multivariate regression analysis demonstrated that psychiatric comorbidity was an independent predictor of non-home discharge (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.43-2.30; P < 0.0001) and a longer hospital stay (+0.52 day; 95% CI, 0.43-0.61; P < 0.0001) but was not an independent predictor of overall complications (OR, 0.79; 95% CI, 0.58-1.07; P = 0.13) or total hospital charges ($1992; 95% CI, -$917-$4902; P = 0.18). CONCLUSIONS: Psychiatric comorbidity was associated with an increased risk of non-home discharge and a longer length of stay for patients undergoing surgical intervention for cervical myelopathy. However, we did not find an associated increased risk of in-hospital mortality, complications, or total hospital charges. Psychiatric comorbidity should not be weighed against patients who require surgical treatment for cervical spondylotic myelopathy, and special attention should be given to postoperative care and discharge planning for this unique patient population.

Combined Inhibition of Both p110α and p110ß Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer.

Purpose: Determine the roles of the PI3K isoforms p110α and p110ß in PTEN-deficient, estrogen receptor α (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors.Experimental Design: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110α inhibitor BYL719, the p110ß inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured.Results: p110ß primed cells for response to growth factor stimulation. Although p110ß inhibition suppressed cell and tumor growth, dual targeting of p110α/ß enhanced apoptosis and provided sustained tumor response. The growth of anti-estrogen-sensitive cells was inhibited by fulvestrant, but fulvestrant inconsistently provided additional therapeutic effects beyond PI3K inhibition alone. Treatment-induced decreases in phosphorylation of AKT and Rb were predictive of therapeutic response. Short-term drug treatment induced tumor cell apoptosis and proliferative arrest to induce tumor regression, whereas long-term treatment only suppressed proliferation to provide durable regression.Conclusions: p110ß is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110ß inhibition, p110α did not induce significant reactivation of AKT, but combined targeting of p110α/ß most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Because apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110α/ß inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents. Clin Cancer Res; 23(11); 2795-805. ©2016 AACR.

New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase.

A monocyclic compound 3 (3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile) is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than the pentacyclic triterpenoid CDDO in inflammation and carcinogenesis related assays. Recently, reversible covalent drugs, which bind with protein targets but not permanently, have been gaining attention because of their unique features. To explore such reversible covalent drugs, we have synthesized monocyclic, bicyclic, and tricyclic compounds containing 3 as an electrophilic fragment and evaluated them as activators of the Keap1/Nrf2/ARE pathway and inhibitors of iNOS. Notably, these compounds maintain the unique features of the chemical reactivity and biological potency of 3. Among them, a monocyclic compound 5 is the most potent in these assays while a tricyclic compound 14 displays a more robust and specific activation profile compared to 5. In conclusion, we demonstrate that 3 is a useful electrophilic fragment for exploring reversible covalent drugs.