Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers

The recent resurgence of immunotherapy has transformed the therapeutic field of advanced urologic cancers. In this seminars issue, we evaluate the role of emerging and recently approved immunotherapeutic agents in advanced prostate, urothelial, and renal cell carcinoma. In each of these fields, we discuss recent regulatory approvals as well as promising ongoing clinical trials. Finally, we discuss incidence and management of immune related adverse events specifically associated with PD-1/PD-L1 inhibitors.     

氟比洛芬酯对上腹部手术病人术后镇痛中吗啡用量的节俭作用和安全性

目的 评价氟比洛芬酯对上腹部手术病人术后镇痛中吗啡用量的节俭作用和安全性.方法 采用随机分组、安慰剂对照、双盲和多中心临床研究方法,择期行上腹部手术病人96例,年龄18～64岁,ASA Ⅰ或Ⅱ级,随机分为2组(n=48):氟比洛芬酯组和脂肪乳组.静脉注射异丙酚、芬太尼、维库溴铵或罗库溴铵麻醉诱导,吸入N2O和异氟烷,按需追加芬太尼或肌松药维持麻醉.手术结束时,氟比洛芬酯组经2 min静脉注射氟比洛芬酯50mg,脂肪乳组经2 min静脉注射脂肪乳5 ml,2组同时采用吗啡进行病人静脉自控镇痛(PCIA).首剂药物给予后8 h,经2 min静脉注射第二剂药物(氟比洛芬酯或脂肪乳).于术后2、8和24 h时,采用视觉模拟评分法(VAS)评价静息痛和咳嗽痛的程度.记录因镇痛不足而需使用其他镇痛药作为补救镇痛的情况.记录第1次PCIA的时间、术后24 hPCIA总次数和有效次数;记录术后24 h吗啡用量和给药后不良反应的发生情况.结果 与脂肪乳组比较,氟比洛芬脂组术后各时点静息痛和咳嗽痛VAS评分降低,术后24 h PCIA总次数和有效次数降低,第1次PCIA时间延长,术后24 h吗啡用量减少(P<0.05),其他镇痛药物使用情况差异无统计学意义(P>0.05).2组不良反应仅表现为恶心和呕吐,且2组间差异无统计学意义(P>0.05).结论 静脉注射氟比洛芬酯50 mg可提高病人术后镇痛效果,减少吗啡用量,且不良反应少,有利于病人的术后恢复.     

肝缺血再灌注后肺损伤机制及乌司他丁保护作用的实验研究

目的 研究肝缺血再灌注后肺损伤的机制以及乌司他丁的保护作用.方法 新西兰白兔24只,随机分为3组,每组8只.假手术组：麻醉后分离肝门,游离肝动静脉,关腹,120 min后处死.缺血再灌注组：夹闭左侧叶、左中央叶、右中央叶的血管,缺血60 min后再灌注60 min后立即处死.乌司它丁组同缺血再灌注组制作部分肝缺血再灌注模型,但于阻断前15 min注射乌司它丁2万U/kg.测定阻断前（T0）、阻断50min（T1）、再灌注10min（T2）、再灌注60min（T3）四个时点动脉血压、动脉血血气分析和TNF-α、IL-8水平.肝肺病理切片光镜观察、肺干湿重比、肺灌洗液蛋白含量及磷脂水平、肺组织丙二醛（MDA）含量、超氧化物歧化酶（SOD）活力、髓过氧化物酶（MPO）活力、肺组织SP-A mRNA及SP-A蛋白表达水平.结果 病理结果显示,乌司它丁组缺血再灌注肺损害较轻.缺血再灌注组和乌司它丁组pH阻断后降低,TNF-α和IL-8升高,TNF-α、IL-8水平、干湿重比、MDA、MPO高于假手术组,灌洗液蛋白浓度、PC、PG含量、SOD、SP-A蛋白表达低于假手术组（P＜0.05）,而乌司它丁组各项结果要好于缺血再灌注组（P＜0.05）.结论 肝缺血再灌注会导致肺损伤,缺血前给予乌司它丁可以减轻肺损伤.     

RO20-1724对氯胺酮重复麻醉致未成年大鼠认知功能障碍的影响

目的 评价RO20-1724对氯胺酮重复麻醉致未成年大鼠认知功能障碍的影响.方法 健康SD大鼠48只,21日龄,雌雄不拘,体重45～55 g,采用随机数字表法,将其分为4组(n=12):对照组(C组)、氯胺酮组(K组)、氯胺酮+ RO20-1724组(K+R组)和氯胺酮+无水乙醇组(K+A组).K组腹腔注射氯胺酮70 mg/kg,1次/d,连续7d;K+R组和K+A组腹腔注射氯胺酮70 mg/kg,30 min后分别腹腔注射RO20-1724 0.5 mg/kg或等容量无水乙醇,1次/d,连续7d.C组腹腔注射等容量生理盐水,1次/d,连续7d.采用Morris水迷宫实验测定认知功能,记录逃避潜伏期和穿越原平台次数.Morris水迷宫实验结束当日,每组处死6只大鼠,取海马组织,电镜下观察超微结构.Morris水迷宫实验结束当日,每组处死6只大鼠,取海马组织,测定海马磷酸化环腺苷酸应答元件结合蛋白(p-CREB)表达.结果 与C组比较,K组和K+A组第3天和第4天时逃避潜伏期延长,穿越原平台次数减少,海马组织p-CREB表达下调(P＜0.05),K+R组逃避潜伏期、穿越原平台次数和p-CREB表达差异无统计学意义(P＞0.05);与K组比较,K+R组第3天和第4天时逃避潜伏期缩短,穿越原平台次数增多,海马组织p-CREB表达上调(P＜0.05),病理学损伤减轻,K+A组逃避潜伏期、穿越原平台次数和p-CREB表达差异无统计学意义(P＞0.05).结论 RO20-1724可改善氯胺酮重复麻醉致未成年大鼠认知功能障碍,其机制与上调海马p-CREB的表达.     

Current Issues of Targeted Therapy in Metastatic Triple-Negative Breast Cancer

Patients with triple-negative breast cancer are characterized by a poor prognosis compared with patients with other breast cancer subtypes. The angiogenesis inhibitor bevacizumab is effective in the palliative treatment of patients with triple-negative breast cancer as well as in other breast cancer subtypes. PARP inhibitors represent the first group of targeted agents to be developed under the particular aspect of treating patients with hereditary and triple-negative breast cancer. In addition, an increasing number of studies have demonstrated a significant and clinically relevant change in phenotype between primary tumor and metastasis. Consequently, it should be an essential component of the design of modern clinical trials of targeted agents in metastatic breast cancer to determine the relevant tumor phenotype and, depending on the clinical situation, confirm the presence of the therapeutic target in metastatic lesions.     

Intravenous pantoprazole utilization in a level 1 trauma center

Background In recent years there has been a rapid increase in the use of proton pump inhibitors. Our institution has recently had several shortages of IV pantoprazole, each lasting 7–10 days. The purpose of our study was to evaluate in-patient usage of IV pantoprazole. We hypothesized that hospitalized patients with upper gastrointestinal bleeding (GIB) or risk for stress ulcers inappropriately received IV pantoprazole based on current literature. Methods This was a retrospective study of 165 consecutive in-patients identified as receiving pantoprazole from December 2004 to March 2005. Only patients receiving IV pantoprazole were included (n = 78). Data collected included demographics, indication and dosing of pantoprazole, admitting team (surgery vs. medicine), and risk factors for stress ulcers. Results Our study population had a mean age of 54 ± 17 years and 62% were male. Overall, 45% (35/78) of patients receiving IV pantoprazole had an appropriate indication, and 19% (15/78) received the correct dose. Of the 78 patients, 43 (55%) were treated with pantoprazole for stress ulcer prophylaxis (SUP), and 35 (45%) patients were treated for GIB. We found that none of the 43 patients treated for SUP had an appropriate indication for pantoprazole, but all of the patients with GIB (35) had an appropriate indication. Of the 35 patients treated for GIB with pantoprazole, only 40% (14/35) received the correct dose. In all cases of incorrect dosing, the patients were underdosed. Conclusions Pantoprazole is not being prescribed appropriately for stress ulcer prophylaxis in our patient population. Even in patients appropriately receiving pantoprazole the majority were prescribed an incorrect dose. Appropriate indications and dosing of pantoprazole could eliminate the shortages seen at our institution.     

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

The PI3K/mTOR signaling cascade is fundamental in T‐cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T‐cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T‐cell activities. Substantial adverse effects in long‐term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T‐cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI‐103 and PKI‐587 inhibitors interfered IL‐2‐dependent responses in T‐cells. However, in contrast to the inhibitory effects in non‐Treg T‐cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI‐103, and PKI‐587 targeted different signaling events and induced different metabolic patterns in primary T‐cells. Similar to rapamycin, in vivo administration of PI‐103 and PKI‐587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T‐cells and support their potential as a novel therapeutic option in transplantation.     

乳腺癌内分泌治疗发展与未来

乳腺癌是激素依赖性肿瘤,内分泌药物的选择除了根据患者的年龄、病灶部位、手术到复发的间隔时间以及受体测定等因素外,还要根据不同药物的作用机制以及副反应而定。随着对内分泌治疗药物作用机制的深入研究和大规模临床研究的证实,激素受体阳性乳腺癌的内分泌治疗疗效将不断提高。     

Role of immunotherapy in bacillus Calmette–Guérin-unresponsive non–muscle invasive bladder cancer

Intravesical instillation of live attenuated bacillus Calmette–Guérin (BCG) is the gold standard for patients with intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG-unresponsive disease are underway and expected to provide insight regarding these concepts.     

Role of metalloproteinases in platelet function

Platelets contain and release matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and disintegrin metalloproteinases (ADAMs) including MMP-1, MMP-2, MMP-3, MMP-9, MT1-MMP (MMP-14), ADAM-10, ADAM-17, ADAMTS-13, TIMP-1, TIMP-2 and TIMP-4. These proteins exert several effects regulating platelet functions such as agonist-stimulated platelet adhesion and aggregation, tumour cell-induced platelet aggregation and platelet-leukocyte aggregation. In this review, mechanisms of MMPs, TIMPs and ADAMs on platelets are discussed.