Targeted therapy or immunotherapy? Optimal treatment in hepatocellular carcinoma

INTRODUCTION

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide[1].Sorafenib has been the only food and drug administration(FDA) approved first line treatment in HCC since 2007.Lenvatinib is another promising treatment in first line HCC,demonstrated non-inferiority in median overall survival(mOS) compared to sorafenib[2]. Nivolumab also might have activity in first line HCC. In the second line treatment of HCC, there are 2 FDA approved medications regorafenib and nivolumab. In addition, other targeted therapies such as cabozantinib or pembrolizumab might be beneficial in second line treatment of HCC.

把燕麦粒淘洗两遍，然后加水浸泡，先在冰箱冷藏室里放一夜，等它吸足水分，再带着泡燕麦的水和大米一起煮熟。也可以直接用压力锅煮熟或用豆浆机打成浆。

We will discuss the options of systemic treatment in HCC both for first and second line, the optimal sequencing of treatments, their side effects, and potential biomarkers that may predict benefits of therapy.

FIRST LINE SYSTEMIC TREATMENT IN HCC

Sorafenib is a tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor 1 (VEGFR1),VEGFR2, VEGFR3, platelet-derived growth factor receptorbeta, KIT and RAF/ mitogen-activated protein/MEK. In the phase Ⅲ(SHARP trial) of 602 HCC patients with Child Pugh Class A (preserved liver function), mOS in sorafenib was 10.7 mo[3]. Although it is the first line and only therapy that improves mOS in first line patients, most of patients could not tolerate at the full dose of sorafenib due to the side effects. In the oncology community, most patients are started on lower dose, for example 200 mg PO BID with potential up titration. The most common adverse events(AEs) were diarrhea (39%), fatigue (22%), hand-foot skin reaction (21%), rash (16%), and alopecia (14%)[3].The common grade 3/4 AEs were hypophosphatemia(11%), diarrhea (8%), hand-foot skin reaction (8%),thrombocytopenia (4%), and hypertension (2%)[3].Even though there was no difference in survival benefits whether or not patients are started at a full dose (400 mg BID) or reduced dose (200 mg BID), it improved costeffective in sorafenib treatment[4,5]. Therefore sorafenib is most beneficial for patients with Child Pugh Class A with preserved liver function. In a retrospective subanalyses of phase Ⅲ SHARP study, sorafenib has shown mOS of 14 mo in HCV patients[6]. In the SHARP study, the top 3 risk factors for HCC in the sorafenib group were Hepatitis C (29%), alcohol (26%), and hepatitis B (19%). In the phase Ⅲof Asia Pacific study in 226 HCC patients with Child Pugh Class A, up to 73% patients were HBV positive.This study reported the mOS was 6.5 mo in sorafenib vs 4.2 mo in placebo group[7]. In a retrospective study of 59 unresectable HCC patients who received sorafenib that included Child Pugh Class A (26), B (23), and C (10)[8].The mOS were 8.3, 4.3, and 1.5 mo, respectively[8]. In this study, the top 3 risk factors for HCC were alcohol (38%)and viral hepatitis B/C (26%). This retrospective study suggested that sorafenib may exert the maximum benefit in Child Pugh Class A patient, regardless of etiology for HCC.

Some of the side effects emerged from sorafenib suggested that hypertension (HTN) and diarrhea may be correlated with efficacy. In a retrospective study in 41 HCC patients (Child Pugh Class A/B, 25/16 patients), showed development of HTN led to better response to sorafenib treatment, with mOS of 18.2 mo vs 4.5 mo in patients without HTN[9]. Another retrospective study in 112 patients with advanced HCC showed that diarrhea can also predict the response to sorafenib treatment as well. Patients with diarrhea demonstrated longer mOS of 14.1 mo vs 7.1 mo when compared to patients without diarrhea[10].

POTENTIAL FIRST LINE SYSTEMIC TREATMENT OPTIONS IN HCC

Lenvatinib is a multiple kinase inhibitor that inhibits VEGFR 1-3, fibroblast growth factor receptor 1-4,platelet derived growth factor receptor (PDGFR) alpha,c-Kit and RET proto-oncogene. In the randomized phase Ⅲ (REFLECT) study of lenvatinib vs sorafenib in first line treatment of unresectable HCC in 954 patients (1:1) with Child Pugh Class A, it showed mOS in lenvatinib vs sorafenib was 13.6 mo and 12.3 mo,respectively. It met its primary endpoint of non-inferiority and it achieved the secondary endpoints with the median progression free survival (PFS) of 7.4 mo vs 3.7 mo and the time to progression (TTP) was 8.9 mo vs 3.7 mo[2]. The most common AEs were hypertension (42%),diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%)[2]. The common grade 3/4 AEs were hypertension (23%), decreased weight(8%), decreased platelet count (6%), elevated aspartate aminotransferase (5%), and decreased appetite (5%)[2].The usage dose is oral 8 mg (weight ＜ 60 kg) or 12 mg(weight ≥ 60 kg) once daily. In the phase 2 study of lenvatinib in 46 HCC patients with Child Pugh Class A,the objective response rate (ORR) was 37%[11]. The most common causes of HCC in phase 2 study were Hepatitis C (58.7%), Hepatitis B (32.6%), and Alcohol (4.3%).

20世纪末，学者们开始关注诸多因素共同影响创造力，他们将创造力看成是各种成分的综合体。Amabile(1983)提出创造力由领域相关技能、创造力相关的技能和任务动机组成。斯滕伯格(1988)认为创造力是一种多层面的现象，即创造力的智能层面、智能风格层面和人格层面。斯滕伯格(1993)提出了一个包含六因素在内的创造力模型，智力、知识、认知风格、人格特征、动机和环境。此外，其他研究也揭示了创造力和家庭因素、学校教育、社会文化、生活环境以及期望水平等的关系。将创造力放在一个综合的框架中去理解，这使得创造力的形成过程更接近真实情况。

Merly Contratto, Jennifer Wu, Division of Hematology and Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, United States

SECOND LINE TREATMENT OPTIONS IN HCC

Regorafenib, is an oral multikinase inhibitor specifically inhibits VEGFR-1, 2, 3. It was approved by FDA on April 27, 2017 as a second line treatment in HCC patients who have been previously progressed with sorafenib.In this study, the median treatment time on first line sorafenib was 7.8 mo for both patient groups[13]. This study showed mOS of 10.6 mo in regorafenib groups(379) vs 7.8 mo in placebo groups (194)[13]. The median PFS was 3.1 mo in regorafenib vs 1.5 mo in placebo group[13]. The ORR in regorafenib group was 11%[13]. In the phase Ⅲ(RESORCE) study of regorafenib in 573 HCC patients with Child Pugh Class A, the most common AEs were hand-foot skin reaction (52%), diarrhea (33%),fatigue (29%), anorexia (24%), and hypertension(23%)[13]. The common grade 3/4 AEs were hypertension(13%), hand-foot skin reaction (13%), fatigue (6%),increased blood bilirubin (6%), and increased AST(4%)[13]. The etiologies of HCC in this study were hepatitis B (38%), alcohol use (24%), and hepatitis C(21%)[13]. In this study (RESORCE) showed that 199 patients out of 374 patients who received regorafenib had experience of hand-foot skin reaction during cycle 1,these patients had better mOS of 14.1 mo vs 6.6 mo in patients who did not experience hand-foot skin reaction.It also showed HR of 0.52[14]. It suggests that hand-foot skin reaction should be managed properly to get a better response of regorafenib and mOS benefit.

Nivolumab, is an immunotherapy that inhibits PD-1.It was granted approval by FDA on September 22, 2017 as a second line systemic treatment in HCC patients who have been treated with or intolerant to sorafenib. The phase Ⅰ/Ⅱ study of nivolumab with dose escalation that included 48 patients with Child Pugh Class A and B7, in addition to dose expansion in 214 patients (Child Pugh Class A)[12]. In the dose-escalation phase, ORR was 15%,6 mo and 9 mo OS rates were both 66%, and mOS was 15 mo[12]. In the dose expansion phase, ORR was 20%,6 mo and 9 mo OS rates were 83% and 74%, only the group in sorafenib progressor without viral hepatitis reached mOS of 13.2 mo and the rest of the groups did not reach mOS[12]. In the dose expansion phase, the patients were divided into 113 patients without HBV or HCV (56 untreated/intolerant of sorafenib and 57 progressed post sorafenib)[12]. In addition, this phase also included 51 patients with HBV and 50 patients with HCV[12]. The study demonstrated transient decreased HCV RNA in some HCV infected patients and no reactivation in HBV infected patients. The most common AEs were fatigue (25%), pruritus (20%), diarrhea (18%),rash (11%), and increased AST level (11%)[12]. The grade 3/4 AEs were increased AST (4%), rash (2%),diarrhea (2%), and fatigue (2%)[12]. The dose is 3 mg/kg(240 mg) every 2 wk.

In a retrospective analysis of this study, PD-L1 was showed as biomarker that predicted response to nivolumab in 174 out of 214 patients. The ORR was 26%vs 19% in patients with PD-L1 ≥ 1% compared with PD-L1 ＜ 1%, it suggested that PD-L1 could be a potential biomarker associated with nivolumab treatment[12].

Cabozantinib is an oral tyrosine kinase inhibitor including VEGFR, MET, RET, KIT, and FLT3. In the phaseⅢ (CELESTIAL) study of cabozantinib vs placebo in 707 HCC patients with Child Pugh Class A who previously received sorafenib[15]. The characteristics of the patients were the median age of patients was 64 years, 82%male patients, 38% HBV infected, 25% HCV infected,78% had extrahepatic spread, 30% had macrovascular invasion, and 27% had received two prior systemic therapy[15]. This study has achieved mOS of 10.2 mo in cabozantinib vs 8 mo in placebo group[15]. It also achieved median PFS of 5.2 mo in cabozantinib vs 1.9 mo in placebo group, and ORR of 4% in cabozantinib group vs 0.4% in placebo group[15]. The most common grade 3/4 AEs were hand-foot syndrome (17%), HTN(16%), increased AST (12%), fatigue (10%), and diarrhea (10%)[15]. It suggested that cabozantinib has the potential to be an effective treatment for second line HCC.

Pembrolizumab is an immunotherapy that inhibits PD-1. In the Phase 2 study (KEYNOTE-224) of Pembrolizumab in 104 HCC patients with Child Pugh Class A who progressed on sorafenib treatment. The primary endpoint of this study was achieved with ORR of 16.3% with 1 CR[16]. The median PFS was 4.8 mo and the 6 mo PFS and OS rates were 43.1% and 77.9%,respectively[16]. About 94% of patients who responded,continue to respond at 6 mo[16]. The most common AEs were fatigue (21.2%) and increased AST (12.5%)[16]. The etiologies of HCC were HBV (21.2%) and HCV (26%)[16].The grade 3-5 AE was reported in 25% of patient with 1 death due to ulcerative esophagitis[16]. This study showed that pembrolizumab might have a good response in advanced HCC patients who progressed on sorafenib.

Ramucirumab is a fully monoclonal antibody (IgG1)that inhibits VEGFR2. In the phase Ⅲ study of ramucirumab vs placebo as a second line treatment in 565 HCC patients with Child Pugh Class A (REACH)[17].Eventhough there was no significantly improvement in mOS between patients who received ramucirumab vs placebo (9.2 mo vs 7.6 mo), ORR in ramucirumab group was higher than the placebo group (7% vs ＜ 1%)[17]. The most common AEs were peripheral edema (36%), liver injury (30%), bleeding or haemorrhage (26%), ascites(22%), and fatigue (21%)[17]. The grade 3/4 AEs were liver injury (14%), hypertension (13%), ascites (5%),bleeding or haemorrhage (5%), and asthenia (5%)[17].The etiologies of HCC in this study were Hepatitis B (35%)and Hepatitis C (27%)[17]. In the prespecified subgroup retrospective analysis of 250 patients with α-fetoprotein(AFP) ≥ 400 ng/mL, the mOS was 7.8 mo (ramucirumab group) vs 4.2 mo (placebo group)[17]. It suggested that ramucirumab could be beneficial in HCC patients with AFP ≥ 400 ng/mL. AFP can potentially be used as a biomarker to predict the response of ramucirumab treatment in HCC patients. A phase Ⅲ study looking for HCC patients with AFP ≥ 400 ng/mL not prespecified is ongoing.

SEQUENCING TREATMENTS IN HCC IN THE FUTURE

Sorafenib is the only FDA approved first line treatment in HCC. It is beneficial in HCC patients with Child Pugh Class A and especially in patients with HCV. As demonstrated in a retrospective analysis of HCV patients which comprised 29% of the total patient populations in SHARP study, the mOS was 14 mo, while mOS of the overall population was only 10.9 mo. When patients experience side effects such as HTN or diarrhea, these side effects should be managed aggressively to minimize premature discontinuation of sorafenib. In a two retrospective studies in patients who had HTN or diarrhea were linked to a better mOS compared to patients who did not experience HTN or diarrhea. For instance, the mOS in HTN group was 18.2 mo vs 4.5 mo in group without HTN, the mOS in patients with diarrhea was 14.1 mo vs 7.1 mo in patients without diarrhea (Figure 1).

If patients with Child Pugh Class A tolerate sorafenib well in the first line setting, regorafenib would be a good choice as a second line treatment due to similar toxicities profiles of the two medications. Regorafenib was only studied in patients with Child Pugh Class A.For patients who have difficulty tolerating toxicities of sorafenib, nivolumab could be a good option as a second line treatment, it achieved ORR of 15%-20%. Nivolumab will be beneficial in patients with Child Pugh Class A/B7.Nivolumab achieved higher RR in PD-L1 ≥ 1% (positive)compared to tumors with PD-L1 ＜ 1% (negative), 26%and 19% respectively. However nivolumab does not seem to offer differential outcomes regardless of the length of treatment on first line therapy. Even though cabozantinib or pembrolizumab or ramucirumab have not been FDA approved at this time. Once become FDA approved, then cabozantinib or pembrolizumab could be other second line options. If the phase Ⅲ study in HCC patients with AFP ≥ 400 ng/mL shows improvement mOS with ramucirumab, then the strategy for second line treatment may include testing of AFP. For patients with AFP ≥ 400 ng/mL, ramucirumab could be a second line option.

深圳特区的金融市场已经初具规模，银行业的综合实力不断增强，证券业、保险业持续健康发展，上市公司数量不断增加，在监督管理方面，也建立了相应的行业协会来对彼此进行监督,深圳特区的金融体系功能在全国范围内已经算是较为完备。

Lenvatinib has shown non-inferiority to sorafenib in a phase Ⅲ study, therefore it would be a first line treatment in HCC if granted FDA approval. It could be a good alternate to sorafenib for patients who prefer to have less hand-foot syndrome and/or diarrhea. Once patients progress, the second line treatment options are nivolumab (in patients with Child Pugh Class A or B7 only and PD-L1 +) and regorafenib (in Child Pugh Class A). Other potential second line options are cabozantinib,pembrolizumab, or ramucirumab.

Nivolumab as first line treatment if granted FDA approval, it will be beneficial for patients who have no contraindication to immunotherapy or who have severe HTN at baseline. If patients could not tolerate or progressed while on nivolumab, the second line options could be regorafenib. Other potential second line options are cabozantinib, pembrolizumab, or ramucirumab.

POTENTIAL BIOMARKERS TO MAXIMIZE THE RESPONSE OF TREATMENT IN HCC

AFP

AFP stands for alpha-feto protein, it is used as a diagnostic and prognosis marker in HCC patients. In a singleinstitution prospective study, preoperative value of AFP＞ 400 ng/mL in 108 resectable HCC patients, correlated with higher recurrence rates and lower survival rates at 2 years[18]. In a prespecified group of 250 HCC patients in a phase Ⅲ ramucirumab trial (REACH) with a baseline AFP ≥ 400 ng/mL, mOS of ramucirumab and placebo was 7.8 mo and 4.2 mo, respectively[17]. In the group(310 patients) where baseline AFP ＜ 400 ng/mL, there was no difference in mOS between ramucirumab and placebo. Therefore, AFP could be used as a marker to predict response with ramucirumab treatment. Phase Ⅲ of ramucirumab study is ongoing in HCC patients with AFP ≥400 ng/mL and the mOS benefit needs to be validated in patients with AFP ≥ 400 ng/mL, once the preliminary data is available.

PD-L1

14 Bruix J, Merle P, Granitor A, Huang YH, Bodoky G, Yokosuka O,Rosmorduc O, Breder VV, Gerolami R, Masi G, Ross PJ, Qin S,Song T, Bronowicki JP, Hourmand IO, Kudo M, Xu L, Baumbauer A, Meinhardt G, Han G. Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.J Clin Oncol 2018; 36 [DOI: 10.1200/JCO.2018.36.4_suppl.412]

FUTURE DIRECTION BIOMARKERS

Neoantigen

柳州地处于广西北部，因西江第二大支流—柳江的流经与哺育而得名。江河的贯穿，地形的平坦，都为柳州的文明演化和城市发展奠定了坚实基础。

Tumor mutational burden

1944年8月，国民党六大召开前后，王子壮对于二陈办党，曾有过这样一段评价:“二位陈先生以往十余年之政绩如何，固人所共知，其理论不足以号召党人，其态度则不免于偏狭，其最优之点不过忠实努力，能为蒋先生造成党内之一系干部而已。由今日环境以观，蒋先生既为全国之公认领袖，宜在理论的统率，统一的教导，此正二陈之最不擅长者。”㉘其中特别提出二陈在党的理论宣导上的无能，排除派系批判的色彩，或亦能反映一部分事实。

A tumor-specific mutated peptides on the surface of cancer cells initiate neoantigen production. Each tumor cell causes genetic mutations due to alteration of peptides(amino acid sequencing), it produces neoantigen signature that contains four amino acid strings of peptides[20]. Neoantigen signature is seen in patients with long term clinical benefit of therapy (no evidence of disease for ＞ 6 mo)[20]. Neoantigen was investigated using whole exome sequencing in DNA of tumor cell.Neoantigen can be used as a biomarker to predict the response to immune checkpoint inhibitor treatment.The higher number of neoantigen in a tumor that binds to major histocompatibility complex (MHC) class Ⅰ,it would be recognized easier by T cells to activate T cells. A prospective study of 18 non-small cell lung cancer (NSCLC) samples from patients who received pembrolizumab (anti-PD-1, an immunotherapy),high mutational burden related to high neoantigen(median of 112 candidate neoantigen per tumor) and associated with improvement of PFS for 14.5 mo[21].This study showed high mutational burden at least 200 nonsynonymous mutations (mutations that altered protein in cancer cells) per sample, it related to durable clinical benefit (partial or stable response ＞ 6 mo). High mutational burden by itself was not enough to predict durable clinical benefit, because in a few patients without durable clinical benefit also had high mutational burden.In addition to high mutational burden, high number of neoantigen was a better prediction of treatment response. It showed better PFS in patients with high neoantigen compared to low neoantigen group, with PFS of 14.5 mo vs 3.5 mo, respectively[21]. Another prospective study in 64 stage Ⅳ melanoma patients who received ipilimumab or tremelimumab (anti-CTLA-4)demonstrated long term clinical benefit in 11 out of 25 patients with high number of mutational load, in addition 14 patients with high number of mutational load without long term clinical benefit[20]. In the second set of 39 melanoma patients who received anti-CTLA-4,25 patients with high neoantigen had long term clinical benefit to anti-CTLA-4[20].

Interferon gamma

A cytokine that is produced by several cells including CD4+ T helper cell type 1 (Th1 cells), CD8+ cytotoxic T cell, macrophage, mucosal epithelial cell, natural killer cell(NK), and NK T cell[23-25]. It inhibits cellular proliferation and causes apoptosis[26]. A study in 48 HCC patients who received curative treatment (surgery/RFA), a higher risk of tumor recurrence was observed in patients with lower levels of interferon gamma (IFN-γ)[27]. IFN-γ can therefore be a potential marker to predict HCC recurrence. In two prospective studies from 17 NSCLC and 21 melanoma patients who received pembrolizumab (anti-PD-1),these studies analyzed IFN-γ mRNA to predict response treatment of pembrolizumab. It showed longer PFS and OS in NSCLC patients with high level vs low level of IFN-γ(5.12 vs 2 mo; 10.15 vs 4.86 mo). It also showed longer PFS in melanoma patients with high level vs low level of IFN-γ (4.99 mo vs 1.86 mo)[28].

CONCLUSION

HCC is the second leading cause of cancer mortality worldwide. Sorafenib is the only FDA approved first line treatment in unresectable HCC. Sorafenib has shown median OS response in HCC patients with HCV infection.There are others potential first line treatments in HCC such as lenvatinib and nivolumab, although not FDA approved, hold great promise based on phase Ⅲ studies.The second line treatments of HCC patients who progressed or intolerant to sorafenib, include regorafenib and nivolumab. Regorafenib demonstrated higher median OS in HCC patients who tolerated sorafenib for at least 7 mo. Nivolumab has been reported to be more beneficial in HCC patients with Child Pugh Class A/B7, and achieved higher RR in patients with PD-L1 ≥ 1%. Other potential options for second line treatments are cabozantinib(phase Ⅲ) or pembrolizumab (phase Ⅱ).

There are two current biomarkers that used to predict response of treatment such as PD-L1 and AFP. For instance, PD-L1 indicates higher RR in nivolumab study,and AFP ≥ 400 ng/mL shows a trend for higher median OS in ramucirumab subgroup analysis phase Ⅲ study. In addition, other future biomarkers that might be used to predict response of treatment are neoantigens, tumor mutational burden and IFN-γ. These biomarkers need further validation in large randomized clinical trials.

教学是教师的“教”与学生的“学”相互统一的，即师生应该共同参与，通过有计划、有组织、有目的的教学活动，从而达到预期的教学目标。教学活动的目标是引导学生能够学习体育知识与技能，促进学生身心健康发展，将其培养成为综合素质高，社会所需要的人才。因此，打造初中体育高效课堂，必须以此为目标设计各种教学活动，并结合实际需求对各种教学活动进行优化，确保达到预期效果。

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（1）提高招投标人员业务能力是前提条件，加强法制教育是主要手段。对各方参与招投标工作人员加强法制教育；同时不断加强对招投标工作人员业务能力的培训，使他们熟悉招投标业务和程序，不断提高业务素质和技术水平，达到招标工作的要求。

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Tumor mutational burden (TMB) refers to DNA sample that can be detected in blood, and it is considered one example liquid biopsy. This non-invasive test is helpful and convenience especially if tumor tissue is inadequate. This biomarker might help to predict the response of immune checkpoint inhibitor. In a retrospective analysis of atezolizumab (anti-PD-L1) in NSCLC patients, blood was used to extract TMB to predict benefit in patients who received atezolizumab. It included 211 NSCLC patients in POPLAR and 583 NSCLC patients in OAK trial[22]. The TMB was minimum 10 single nucleotide variants (SNV) from cell free-DNA in plasma. In the POPLAR study, patients with TMB ≥ 10,the atezolizumab group showed better PFS hazard ratio(HR) of 0.68 and OS HR of 0.59 compared to docetaxel group[22]. In the OAK study, PFS and OS were also better in the atezolizumab group compared to docetaxel group with HR of 0.73 and 0.69, respectively[22]. From this data, tumor mutational burden could be beneficial as a biomarker for the efficacy of immune checkpoint inhibitor. Prospective studies using TMB in NSCLC patients are ongoing. It needs further investigation for HCC patients in the future.

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9 Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy.Am J Clin Oncol 2013; 36: 319-324 [PMID: 22547010 DOI:10.1097/COC.0b013e3182468039]

10 Bettinger D, Schultheiss M, Knüppel E, Thimme R, Blum HE,Spangenberg HC. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology 2012; 56: 789-790 [PMID: 22307848 DOI: 10.1002/hep.25637]

网络整体内向接近中心度标准差为7.164，外向接近中心度标准差为6.940，差异较小，且节点间差异没有很大差异，说明三峡地区旅游节点的通畅程度较高，并没有出现明显的阻碍现象。个体节点以白帝城、解放碑、小三峡、三峡大坝、神女峰、重庆红岩的内外向中心度最高，表明这几个节点与三峡地区其他景点通达性较好，受其他节点控制较弱，近20年过去了，游客在三峡旅游的游线组合中仍然包含这几个经典景区。相对这些景区，三峡旅游的经典景区中衰落较快的景区为张飞庙、万州港、大昌古镇、小小三峡、三游洞、葛洲坝、名山、涪陵新城、三峡大瀑布。这些景区节点与其他景区节点依赖性较强，旅游目的地竞争力相对较弱。

11 Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, Tamai T, Suzuki T, Hisai T, Hayato S, Okita K, Kumada H. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017; 52: 512-519 [PMID: 27704266 DOI: 10.1007/s00535-016-1263-4]

12 El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label,non-comparative, phase 1/2 dose escalation and expansion trial.Lancet 2017; 389: 2492-2502 [PMID: 28434648 DOI: 10.1016/S0140-6736(17)31046-2]

圆柱壳轴压屈曲临界载荷试验值与模拟值偏差30.8%，开孔圆柱壳轴压屈曲临界载荷试验值与模拟值偏差33.9%，含补强件圆柱壳轴压屈曲临界载荷试验值与模拟值偏差13.8%。试验结果比模拟结果小，可能的原因有以下几种：(1)由于圆柱壳试验件通过焊接而成，有一条竖向焊缝的影响，采用这类工艺制作完成的圆柱壳主要存在非对称的初始缺陷[1]以及材料本身缺陷；(2)壳体不直度造成荷载偏心。

胺碘酮对心脏瓣膜术后华法林初始抗凝疗效的影响………………………… 成守龙，苗 苗，刘 俊（6·438）

13 Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389: 56-66 [PMID: 27932229 DOI: 10.1016/S0140-6736(16)32453-9]

A programmed death ligand-1 could be a potential biomarker to predict the efficacy of immune checkpoint inhibitors. PD-L1 can be detected using several assays,and the definition of PD-L1 positivity and the methodology of measuring PD-L1 are required to understand about the role of PD-L1 in HCC[19]. In a phase Ⅱ dose expansion cohort study of nivolumab in HCC patients either progressed or intolerant of sorafenib, RR was 26% vs 19% in patients with PD ≥ 1% and PD-L1 ＜1%, respectively[12]. PD-L1 ≥ 1% therefore appears to indicate higher RR in HCC and it also predicts response of nivolumab treatment with mOS benefit.

15 Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L,Ryoo BY, Cicin I, Merle P, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Dadduzio V, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib (C) versus placebo (P) in patients with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from randomized phase III CELESTIAL trial. J Clin Oncol 2018; 36 [DOI: 10.1200/JCO.2018.36.4_suppl.207]

16 Zhu AX, Finn RS, Cattan S, Edeline J, Ogasawara S, Palmer DH, Verslype C, Zagonel V, Rosmorduc O, Vogel A, Sarker D,Verset G, Chan SL, Knox JJ, Daniele B, Ebbinghaus S, Ma J,Siegel AB, Cheng AL, Kudo M. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol 2018; 36 [DOI: 10.1200/JCO.2018.36.4_suppl.209]

17 Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF,Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J,Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M;REACH Trial Investigators. Ramucirumab versus placebo as secondline treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised,double-blind, multicentre, phase 3 trial. Lancet Oncol 2015; 16:859-870 [PMID: 26095784 DOI: 10.1016/S1470-2045(15)00050-9]

18 Ma WJ, Wang HY, Teng LS. Correlation analysis of preoperative serum alpha-fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after hepatectomy. World J Surg Oncol 2013; 11:212 [PMID: 23981851 DOI: 10.1186/1477-7819-11-212]

4 Kaplan DE, Yu S, Taddei TH, Reiss KA, Mehta R, D’Addeo K,Aytaman A, Hunt K, Fox RK, Baytarian M, Valdarrama A. Uptitration of sorafenib for hepatocellular carcinoma: impact on duration of exposure and cost. J Clin Oncol 2017; 35 [DOI: 10.1200/JCO.2017.35.4_suppl.385]

缺乏合适的日常生活能力评价量表可能是日常生活能力改善不明显的另一个原因。目前的评价方法都比较主观，而且不能敏感的反映患者功能的改善，而间接的方法和患者报告的形式又限制了研究者获取患者在生活中实际如何运用功能的能力[14-16]。另外，卒中患者经常使用健侧代偿来完成日常任务，从而不使用患侧。上述原因可能会使研究者错误的解释研究数据因此低估上肢康复机器人康复技术对日常生活能力的改善。

20 Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM,Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371: 2189-2199 [PMID: 25409260 DOI: 10.1056/NEJMoa1406498]

21 Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y,Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN,Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128 [PMID: 25765070 DOI: 10.1126/science.aaa1348]

22 Gandara DR, Kowanetz M, Mok TSK, Rittmeyer A, Fehrenbacher L, Fabrizio D, Otto G, Malboeuf C, Lieber D, Paul SM, Amler L,Riehl T, Schleifman E, Cummings CA, Hegde PS, Zou W, Sandler A, Ballinger M, Shames DS. 12950-Blood-based biomarkers for cancer immunotherapy: tumor mutational burden in blood (bTMB)is associated with improved atezolizumab (atezo) efficacy. 2017 ESMO Congress; 2017 Sep 9-12; Madrid, Spain; Abstract 12950

23 Shin T, Nakayama T, Akutsu Y, Motohashi S, Shibata Y, Harada M, Kamada N, Shimizu C, Shimizu E, Saito T, Ochiai T, Taniguchi M. Inhibition of tumor metastasis by adoptive transfer of IL-12-activated Valpha14 NKT cells. Int J Cancer 2001; 91: 523-528[PMID: 11251976]

24 Gately MK, Warrier RR, Honasoge S, Carvajal DM, Faherty DA,Connaughton SE, Anderson TD, Sarmiento U, Hubbard BR, Murphy M. Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. Int Immunol 1994; 6: 157-167 [PMID: 7908534]

25 Frucht DM, Fukao T, Bogdan C, Schindler H, O'Shea JJ, Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol 2001; 22: 556-560 [PMID: 11574279]

26 Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma:an overview of signals, mechanisms and functions. J Leukoc Biol 2004; 75: 163-189 [PMID: 14525967 DOI: 10.1189/jlb.0603252]

27 Lee IC, Huang YH, Chau GY, Huo TI, Su CW, Wu JC, Lin HC.Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int J Cancer 2013; 133:2895-2902 [PMID: 23749461 DOI: 10.1002/ijc.28311]

28 Karachaliou N, Crespo G, Aldeguer E, Drozdowskyj A, Capitan AG, Teixido C. Interferon-gamma (INFG), an important marker of response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) and melanoma patients. J Clin Oncology 2017; 35 [DOI: 10.1200/JCO.2017.35.15_suppl.11504]