BRAF and MEK inhibition in melanoma

Introduction: Selective inhibition of the MAPK pathway with either BRAF or MEK inhibition has emerged as a key component for the treatment of BRAF-mutant metastatic melanoma. New evidence suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival, while potentially attenuating some of the serious adverse events observed with monotherapy.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF (vemurafenib and dabrafenib) and MEK (trametinib) inhibitors as well as the available data on BRAF inhibitor + MEK inhibitor combination therapy (dabrafenib + trametinib and vemurafenib + cobimetinib). The efficacy, safety and toxicity data are discussed from Phase I, Phase II and Phase III trials of these drugs.

Expert opinion: Combination therapy with the BRAF and MEK inhibitors improves response rates and progression-free survival in patients with BRAF-mutant metastatic melanoma. Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma, are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for patients compared to single agent BRAF inhibitors.     

bcl-2表达和淋巴结转移可作为皮肤鳞癌独立预后指标

目的寻找皮肤鳞癌有效的预后指标。方法选取32例皮肤鳞癌患者的病理检验蜡块,记录肿瘤大小、淋巴结转移情况;运用TUNEL染色和形态学方法结合,统计凋亡指数、bcl-2和p53表达情况, 随访患者1、2、3、5年生存情况,用SPSS11．0统计有效的预后指标。结果肿瘤淋巴转移以及病理分级与 3、5年生存率均相关(P值分别为0．026、0．037),肿瘤大小与其不相关(P>0．05)。p53表达与五年无瘤生存率不相关。结论COX多变量分析显示bcl-2表达和淋巴结转移是独立的预测指标。     

miRNA-154在皮肤鳞状细胞癌中的表达及其临床意义

目的 分析miRNA-154在皮肤鳞状细胞癌（CSCC）中的表达水平以及其在CSCC发展过程中的临床意义。方法 采用RT-PCR法和原位杂交法检测98例CSCC组织和60例正常皮肤组织中miRNA-154的表达水平。研究对入组患者均进行了5年的跟踪随访,对患者的生存情况进行统计和总结,同时对miRNA-154表达水平和CSCC患者预后的关系进行进一步分析。结果 CSCC组织中miRNA-154相对表达量为（0.57±0.09）,明显低于其在正常组织中的表达量（1.56±0.02）,差异有统计学意义（P<0.001）。CSCC组织中miRNA-154表达的平均光密度为（63.26±10.08）,明显低于正常组织的（109.56±30.05）,差异有统计学意义（P<0.001）。CSCC组织中miRNA-154表达水平越低,则临床分期越高、肿瘤分化程度越低,同时越容易发生淋巴结转移,差异均有统计学意义（P<0.05）。miRNA-154高表达组患者的总生存期显著长于miRNA-154低表达组（41.9个月vs. 31.4个月,P<0.001）。Cox回归分析结果显示...     

头颈部鳞状细胞癌靶向治疗的研究进展

靶向治疗是目前治疗头颈部鳞状细胞癌的研究热点。许多新型的药物制剂治疗方案都在进行临床试验的评估。治疗头颈部鳞状细胞癌的靶向治疗制剂主要有涉及EGFR信号通路的单克隆抗体,如西妥昔单抗;EGFR-TKI,VEGF抑制剂、NF-kB信号通路的阻断剂、IGFR抑制剂和p53信号通路的载体。     

威罗菲尼和易普利单抗治疗恶性黑色素瘤中继发耐药机制的研究进展

酪氨酸激酶抑制剂威罗菲尼和抗免疫抑制剂易普利单抗于2011年获美国食品药品管理局批准用于恶性黑色素瘤（MM）的治疗。通过研究靶向药物和免疫药物的耐药机制,发现肿瘤微环境、信号转导通路及细胞因子等在继发耐药中均具有重要作用。本文简要综述上述两药的继发耐药机制和克服耐药策略的研究进展。     

VEGF和CD31在皮肤鳞癌中的表达

目的 观察皮肤鳞癌(SSCC)中血管内皮生长因子(VEGF)和内皮细胞黏附分子(CD31)的表达,研究其与皮肤鳞癌发展的关系.方法 采用免疫组化染色法检测正常皮肤组织及鳞癌组织中VEGF和CD31的表达变化.结果 在正常组织中,VEGF和CD31表达低于鳞癌皮损组织,在Ⅲ~Ⅳ期鳞癌中的表达明显高于Ⅰ～Ⅱ期鳞癌中的表达(P<0.05).结论 VEGF及CD31蛋白的异常表达在皮肤鳞癌的进展过程中发挥重要作用.     

Impact of a prognostic 40-gene expression profiling test on clinical management decisions for high-risk cutaneous squamous cell carcinoma

Abstract

Objective: To determine how results from a prognostic 40-gene expression profiling (40-GEP) test would impact clinician management decisions and how their choices would align with a National Comprehensive Cancer Network (NCCN) compliant, risk-directed management plan for high-risk cutaneous squamous cell carcinoma (cSCC).

Methods: Clinicians attending a national dermatology conference were presented with 40-GEP test validation data. They were asked to rate clinicopathological features and molecular test results to assess their opinion of how concerning each is to cSCC prognosis. When presented with vignettes describing patients with NCCN-defined high-risk features, clinicians were asked to select a treatment plan using pre-test (no 40-GEP results), then, post-test (40-GEP Class 1, 2A, or 2B results) methodology along with corresponding metastasis rates for each test group.

Results: Risk factors deemed of highest concern for metastatic outcomes were a Class 2B 40-GEP result, perineural invasion, immunosuppression, invasion beyond subcutaneous fat, and tumor diameter >1?cm on the scalp. When presented with a 40-GEP result that indicated reduced risk of metastasis (Class 1), clinicians altered their treatment management plan accordingly. Specifically, there was significant reduction in the recommendations for sentinel lymph node biopsy, adjuvant radiation or chemotherapy, follow-up time, and nodal imaging. By comparison, when a 40-GEP result indicated an increased risk of metastasis (Class 2B), significant risk-appropriate increases in management intensity was observed for the aforementioned clinical decisions.

Conclusion: Integration of 40-GEP results impacted management decisions in a significant and risk-appropriate manner for high-risk cSCC patient scenarios, while remaining aligned with national guidelines for patient management.     

Modulating expression of LAMPs and ABH histo-blood group antigens in normal and neoplastic human skin

Although the precise biological role of lysosomal membrane-associated glycoproteins (LAMPs) and ABH histo-blood group antigens (HBGAs) remains somewhat unclear, they are thought to be related to cell differentiation, cellular adhesion, and tumorigenesis. Here, we present the first comparative immunohistochemical study of both LAMPs and HBGAs in normal and neoplastic skin. Their localization is compared to that of high molecular weight cytokeratin and cytokeratin MNF 116. LAMPs and HBGA were differentially expressed in the normal stratified squamous epithelium, suggesting that they are involved in the initial steps of the differentiation process, whereas HBGAs are characteristic of terminal keratinocyte differentiation. No change in the reactivity for HBGA was detected in the stratified epithelium overlying squamous cell or basal cell carcinomas, whereas a considerable loss of LAMPs was detected. LAMPs were overexpressed in tumor cells, whereas HBGAs were lost in tumor zones of basocellular carcinomas. In spinocellular carcinomas, HBGAs were detected in tumor keratinocytes and in keratin pearls. These results provide new evidence for the differential expression of LAMPs and HBGAs in the normal stratified squamous epithelium, as well as the presence of a modulating reactivity in basocellular and spinocellular carcinomas, suggesting that these glycoproteins are involved in differentiation and tumorigenesis of human skin.     

An update on the pharmacodynamics,pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers

Introduction: Nivolumab is a programmed cell death 1 (PD-1) inhibitor that has been approved for treatment of advanced melanoma, non-small cell lung carcinoma, renal cell carcinoma and classical Hodgkin’s lymphoma.

Areas covered: This review summarizes the latest evidence on nivolumab’s pharmacodynamics, pharmacokinetics, safety and clinical efficacy in different solid tumors, based on published studies and abstracts from international conferences.

Expert opinion: Multiple high-level evidence has confirmed the efficacy and safety of nivolumab in solid tumors. Further studies should focus on the identification of potential predictive biomarkers and possibility of combining with other immunotherapeutic or cytotoxic agents. The optimal sequence, treatment duration and possibility of re-challenging patients who had prior nivolumab are yet to be defined.     

Advances in the pharmacotherapeutic management of esophageal squamous cell carcinoma

ABSTRACT

Introduction

Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease.     

免疫检查点抑制剂联合抗血管生成药物治疗晚期非鳞状细胞非小细胞肺癌的研究进展

评价重组人血管内皮抑制素联合阿法替尼及替吉奥二线治疗晚期肺鳞癌患者的有效性和安全性。

共25例驱动基因阴性晚期肺鳞癌患者被纳入这项单臂前瞻性研究,按期二线给予入组患者重组人血管内皮抑制素联合阿法替尼及替吉奥治疗,观察分析患者无进展生存期(progression-free-survival,PFS)、总生存期(overall survival,OS)、疾病控制率(disease control rate,DCR)、客观缓解率(objective response rate,ORR)和不良反应(adverse reaction,AR)。

25例入组患者接受了≥2个周期的二线治疗方案,随访时间截至2023年3月31日,其中4例患者病情部分缓解,17例患者病情稳定,4例患者病情进展。经研究者确认的ORR为16%(95%CI,4.5%~36.1%),DCR为84%(95%CI,63.9%~95.5%),中位PFS为5.3个月(95%CI,3.5~6.9个月),中位OS尚未达到。全组患者治疗耐受良好,治疗相关的Ⅲ级或Ⅳ级AR最常见的是白细胞下降(20%)和皮疹(12%),没有与治疗相关的死亡报告。

重组人血管内皮抑制素联合阿法替尼及替吉奥二线治疗晚期肺鳞癌可延长患者PFS且相对安全,值得进一步探究及推广。

     

Evaluation of Tomudex in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group study

A phase II trial of Tomudex (raltitrexed, ZD 1694), a new thymidylate synthase inhibitor, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. This trial demonstrated that Tomudex was well tolerated in this patient population. Nausea and vomiting were minimal, and hematologic toxicities were relatively infrequent. Only one patient was withdrawn from the study due to toxicity (grade 4 diarrhea). One patient exsanguinated from a rent in the carotid artery in an area of tumor involvement, and was categorized as a grade 5 toxicity. Thus 25/27 patients were able to complete at least 2 cycles of treatment. Tomudex demonstrated a 3.7% response rate (95% CI 0.1–19%), with a median survival of 6 months in this highly resistant disease population. Tomudex is not considered active enough as monotherapy for further evaluation in this disease population.     

Phase II evaluation of menogaril in patients with advanced cervical carcinoma

Fourteen patients with advanced/recurrent squamous cell carcinoma of the uterine cervix received menogaril, 200 mg/m² by one hour intravenous infusion at four-week intervals. No objective regressions were observed. Median time to progression was less than two months and median survival was seven months. All patients experienced neutropenia. Platelet toxicity was negligible. Venous irritation and phlebitis occurred at the infusion site in 43% of patients. Menogaril as administered in this protocol is ineffective in treating previously irradiated advanced/recurrent squamous cell carcinoma of the uterine cervix and warrants no further investigation in this disease at the dosage and administration schedule used in this protocol. Address for offprints: H.J. Long, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA     

Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management

Abstract

Objective: To integrate gene expression profiling into the management of high-risk cutaneous squamous cell carcinoma (cSCC) within the National Comprehensive Cancer Network (NCCN) guidelines to improve risk-aligned management recommendations.

Methods: A cohort of 300 NCCN-defined high-risk cSCC patients, along with the American Joint Committee on Cancer (AJCC) T stage, Brigham and Women’s Hospital (BWH) T stage, and known patient outcomes were analyzed. Risk classifications using a validated 40-gene expression profile (40-GEP) test and T stage were applied to NCCN patient management guidelines. Risk-directed patient management recommendations within the NCCN guidelines framework were aligned based on risk for metastasis.

Results: Of the 300 NCCN high-risk cSCC patients, 159 (53.0%) were 40-GEP Class 1 and AJCC T1-T2, and 173 (57.7%) were Class 1 and BWH T1-2a, indicating low risk for metastasis and, thereby, suggesting low management intensity. The 40-GEP integration suggested high intensity management for only 24 (8.0%) patients (all Class 2B), and moderate intensity management for the remainder of the cohort.

Conclusions: The 40-GEP test can be integrated within existing NCCN guideline recommendations for managing cSCC patients to help refine risk-directed management decisions. Integration of the 40-GEP test would allow >50% of this NCCN-defined high-risk cohort to be managed with the lowest intensity recommendations within the broad NCCN guidelines. High intensity management was deemed risk-appropriate for a small subpopulation (8.0%). This study demonstrates that the 40-GEP test, in combination with T stage, has clinical utility to impact patient management decisions in NCCN high-risk cSCC for improving risk-aligned management within the NCCN guidelines framework.     

皮肤鳞状细胞癌组织微 RNA-103a-2-5p、钙黏附蛋白 11表达及其临床意义

目的分析皮肤鳞状细胞癌组织中微 RNA-103a-2-5p(miR-103a-2-5p)和钙黏附蛋白 11(CDH11)的表达水平,探讨二者在临床研究中的意义。方法选取 2017年 1月至 2019年 6月宝鸡市人民医院诊治的 98例皮肤鳞状细胞癌病人为研究对象,收集病人术中切除的癌组织及癌旁正常组织。采用实时荧光定量 PCR(qRT-PCR)法检测组织中 miR-103a-2-5p的表达水平。采用酶联免疫吸附(ELISA)法检测 CDH11表达水平。 TargetScanHuman网站预测 miR-103a-2-5p与 CDH11的靶向关系; Pearson相关性分析癌组织中 miR-103a-2-5p和 CDH11水平的关系; Kaplan-Meier生存曲线分析 miR-103a-2-5p、CDH11表达与皮肤鳞状细胞癌病人预后的关系;影响皮肤鳞状细胞癌病人预后的因素采用 Cox回归分析;受试者操作特征曲线(ROC曲线)分析 miR-103a-2-5p和 CDH11的表达对皮肤鳞状细胞癌的诊断价值。结果与癌旁正常组织［1.03±0.12,(5.06±1.43)μg/L］相比,皮肤鳞状细胞癌组织 miR-103a-2-5p表达水平(1.46±0.38)显著升高(P<0.05),CDH11表达水平［(2.96±0.62)μg/L］明显降低(P<0.05); TargetScanHuman网址预测 miR-103a-2-5p与 CDH11间存在结合位点;经 Pearson相关性分析, miR-103a-2-5p与 CDH11水平呈负相关( P<0.05);两者均与病人病理分级、 TNM分期、淋巴结转移、侵袭程度相关(P<0.05); miR-103a-2-5p高表达组和 CDH11低表达组复发率显著高于 miR-103a-2-5p低表达组和 CDH11高表达组(P<0.05); TNM分期、淋巴结转移、 miR-103a-2-5p是影响病人预后的危险因素(P<0.05)CDH11是影响病人预后的保护因素(P<0.05); miR-103a-2-5p、CDH11二者联合诊断皮肤鳞状细胞癌的 ROC曲线下面积(AUC)0.836,显著优于其各自单独诊断(P=0.018、0.021)。结论皮肤鳞状细胞癌病人 miR-103a-2-5p表达水平升高, 为,     

Advances and challenges in the treatment of esophageal cancer

Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.     

晚期肺鳞癌血清鳞癌相关抗原检测的临床意义

目的：探讨晚期肺鳞癌血清鳞癌相关抗原(SCC-Ag)检测的临床价值。方法80例肺癌患者为研究对象,其中鳞癌50例,腺癌14例,小细胞肺癌(SCLC)11例,大细胞肺癌(LCLC)5例,另选45例良性病变患者,对所有患者进行SCC-Ag检测。结果肺鳞癌阳性率为68.00%,肺腺癌阳性率14.29%, SCLC阳性率18.18%, LCLC阳性率20.00%,对照组2.22%。经手术前后动态观察显示,根治术后SCC-Ag可在3 d内转阴,与其他术式比较差异有统计学意义(P<0.05)。结论SCC-Ag为肺鳞癌特殊标记物,是对患者手术效果与远期预后进行预测的重要参考指标。     

A drug safety evaluation of valsartan

Introduction: Angiotensin receptor blockers (ARBs) as a class are generally considered safe and better tolerated than other antihypertensive drugs. The purpose of this report is to review the main data on the safety and tolerability of the second generation ARB valsartan after > 10 years since its initial approval.

Areas covered: We searched Medline for clinical studies published between 1997 and 2010 that involve valsartan and focus on its safety and tolerability profile. The main large-scale studies in hypertension, heart failure, post-myocardial infarction (MI) and chronic kidney disease are reviewed.

Expert opinion: Valsartan demonstrates to be safe and well tolerated both in monotherapy and in combination therapy of hypertension in a broad range of patients, including the elderly, children, diabetics, obese patients and patients at high cardiovascular risk. The most frequently reported adverse events (AEs) are malaise/fatigue, dizziness, headache and nausea/vomiting, whose incidence, however, is similar to that observed with placebo. Cough, a common class effect of ACE inhibitors, occurs less frequently with valsartan. When combined with hydrochlorothiazide, valsartan counteracts the adverse metabolic effects of the diuretic, whereas it reduces ankle edema formation when combined with amlodipine. In diabetic hypertensives, valsartan does not adversely affect glucose and lipid metabolism and even improves it. In post-MI patients, the rate of discontinuation due to AE, mainly hypotension, cough and increased serum creatinine, is lower in valsartan than in ACE inhibitor treated patients. Valsartan is also safe and well tolerated in patients with nephropathy although serum potassium levels need to be monitored more closely.