Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Coronary Artery Disease in Patients ≥80 Years of Age

Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients ≥80 years of age. Nonetheless, older patients have typically been under-represented in cardiovascular clinical trials. Understanding the pathophysiology, epidemiology, and optimal means of diagnosis and treatment of CAD in older adults is crucial to improving outcomes in this high-risk population. A patient-centered approach, taking into account health status, functional ability and frailty, cognitive skills, and patient preferences is essential when caring for older adults with CAD. The present systematic review focuses on the current knowledge base, gaps in understanding, and directions for future investigation pertaining to CAD in patients ≥80 years of age.     

Lupus‐like cutaneous reaction following pembrolizumab: An immune‐related adverse event associated with anti‐PD‐1 therapy

PD‐1 (programmed cell death‐1) inhibitors, used to treat metastatic melanoma and other malignancies, are associated with development of immune‐related adverse events in the skin. Such reactions include morbilliform eruptions, vitiligo, alopecia areata and bullous pemphigoid. In this report, we describe a patient who developed a lupus‐like cutaneous reaction in the setting of pembrolizumab therapy for metastatic melanoma, adding to the spectrum of reactions which may be observed in association with PD‐1 inhibitor therapy.     

强化剂量阿托伐他汀对不稳定型心绞痛患者介入治疗术后心肌炎症反应的影响

目的：探究强化剂量阿托伐他汀对不稳定型心绞痛患者介入治疗（PCI）术后心肌炎症反应的影响。方法选取2012年1月-2014年1月焦作煤业（集团）有限责任公司中央医院接收治疗的不稳定型心绞痛患者88例，随机分为治疗组（44例）和对照组（44例）。治疗组患者PCI术前口服阿托伐他汀钙片80 mg/d，术后口服40 mg/d。对照组患者术前口服20 mg/d，术后口服20 mg/d阿托伐他汀钙片。比较两组患者术前、术后SOCS1 mRNA、蛋白表达、血清干扰素-γ（IFN-γ）、超敏C反应蛋白（hs-CRP）、肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）等炎症因子的表达。结果术后治疗组SOCS1 mRNA、蛋白表达均较治疗前显著升高，治疗前后差异有统计学意义（P＜0.05）；且治疗后治疗组这两者的表达均高于对照组，两组比较差异有统计学意义（P＜0.05）。术后两组IFN-γ、hs-CRP、TNF-α、IL-10水平均较术前有所提高，同组治疗前后差异有统计学意义（P＜0.05）；术后，治疗组IFN-γ、hs-CRP、TNF-α显著低于对照组，而IL-10水平高于对照组，两组比较差异有统计学意义（P＜0.05）。结论强化剂量阿托伐他汀可以通过上调SOCS1的表达，并调节炎症因子IFN-γ、hs-CRP、TNF-α、IL-10水平从而减轻不稳定型心绞痛介入治疗术后的心肌炎症反应。     

Natural history of descending thoracic and thoracoabdominal aortic aneurysms

ObjectivesElucidating critical aortic diameters at which natural complications (rupture, dissection, and death) occur is of paramount importance to guide timely surgical intervention. Natural history knowledge for descending thoracic and thoracoabdominal aortic aneurysms is sparse. Our small early studies recommended repairing descending thoracic and thoracoabdominal aortic aneurysms before a critical diameter of 7.0 cm. We focus exclusively on a large number of descending thoracic and thoracoabdominal aortic aneurysms followed over time, enabling a more detailed analysis with greater granularity across aortic sizes.MethodsAortic diameters and long-term complications of 907 patients with descending thoracic and thoracoabdominal aortic aneurysms were reviewed. Growth rates (instrumental variables approach), yearly complication rates, 5-year event-free survival (Kaplan–Meier), and risk of complications as a function of aortic height index (aortic diameter [centimeters]/height [meters]) (competing-risks regression) were calculated.ResultsEstimated mean growth rate of descending thoracic and thoracoabdominal aortic aneurysms was 0.19 cm/year, increasing with increasing aortic size. Median size at acute type B dissection was 4.1 cm. Some 80% of dissections occurred below 5 cm, whereas 93% of ruptures occurred above 5 cm. Descending thoracic and thoracoabdominal aortic aneurysm diameter 6 cm or greater was associated with a 19% yearly rate of rupture, dissection, or death. Five-year complication-free survival progressively decreased with increasing aortic height index. Hazard of complications showed a 6-fold increase at an aortic height index of 4.2 or greater compared with an aortic height index of 3.0 to 3.5 (P < .05). The probability of fatal complications (aortic rupture or death) increased sharply at 2 hinge points: 6.0 and 6.5 cm.ConclusionsAcute type B dissections occur frequently at small aortic sizes; thus, prophylactic size-based surgery may not afford a means for dissection protection. However, fatal complications increase dramatically at 6.0 cm, suggesting that preemptive intervention before that criterion can save lives.     

Flare Up Reaction During Provocation Test to Glatiramer Acetate in a Patient With Allergy to Interferon Beta1a

Glatiramer acetate (GA) is a synthetic amino acid polymer, used for relapsing-remitting multiple sclerosis. The most common adverse effect of GA is a skin reaction at the injection site with a probable IgE-mediated mechanism. We report a case of a 45-year-old woman with multiple sclerosis and urticaria to interferon-β1a, who underwent a challenge test to GA. She presented itching wheals at the intradermal sites. A month later the patient repeated the test and presented the same reactions of the first test. The next day she continued the test with subcutaneous injections. One hour later she presented a flare up of the reactions appeared during the previous 2 tests. No reactions appeared at the subcutaneous injection sites. The patient also presented dyspnea. Flare-up reactions are characterized by the reactivation of previously positive reactions to intradermal or skin tests triggered by patch testing and after systemic provocation with an allergen. The phenomenon is not common to drugs. The mechanisms involved in this reaction seem to be heterogeneous and are not completely understood. To our knowledge this is the first case of allergic reaction to GA manifested as a flare-up reaction during challenge test.     

卡贝缩宫素和缩宫素治疗剖宫产高危产妇的效果比较

目的:比较卡贝缩宫素和缩宫素治疗剖宫产高危产妇的效果。方法:选取122例剖宫产高危产妇为研究对象,按照随机数字表法分为观察组与对照组各61例。两组均行剖宫产手术,胎儿娩出后,对照组给予缩宫素治疗,观察组给予卡贝缩宫素治疗,比较两组术中、产后2、24 h出血量,产后加用前列素氨丁三醇率,凝血功能指标[纤维蛋白原(FIB)、D-二聚体(D-D)、凝血酶原时间(PT)、部分凝血活酶时间(APTT)]水平,心率,血压,血红蛋白水平和不良反应发生率。结果:观察组术中、产后2、24 h出血量均低于对照组,差异有统计学意义(P<0.05);观察组加用卡前列素氨丁三醇率为4.92%(3/61),明显低于对照组的16.39%(10/61),差异有统计学意义(P<0.05);术后,两组FIB、D-D水平均高于术前,且观察组高于对照组,两组PT、APTT均短于术前,且观察组短于对照组,差异有统计学意义(P<0.05);术后,两组血红蛋白水平均低于术前,但观察组高于对照组,差异有统计学意义(P<0.05);手术前后,两组心率、血压和不良反应发生率比较,差异均无统计学意义(P>0.05)。结论:卡贝缩宫素治疗剖宫产高危产妇可减少出血量和加用卡前列素氨丁三醇率,提高其术后血红蛋白水平,以及改善凝血功能指标,效果优于缩宫素。