Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. Therefore, we systematically investigated the association between the RTKs and CD8 T-lymphocyte genes (CD8Ts) across cancers. We comprehensively evaluated alterations in RTK genes across cancers and examined the co-expression of RTKs and CD8Ts using a weighted gene co-expression network analysis. We found that RTKs exhibited extensive genetic alterations across cancers and were significantly related to the activity of cancer hallmark-related pathways. We identified co-expression between the RTKs and CD8Ts. The low co-expression score subtype was associated with significant better clinical benefits and was characterized by a hot immune microenvironment, including more infiltrating immune cells, higher chemokine expression, and stronger immunogenicity, such as the tumor mutation burden and neoantigens. Two immunotherapy cohorts confirmed that patients with low co-expression scores had an inflamed TME phenotype and significant therapeutic advantages. Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.

Immune checkpoint inhibitors (ICIs) like programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor have shown considerable efficacy in several important cancers including primary liver cancer (PLC) like hepatocellular carcinoma and cholangiocarcinoma. However, only some patients with PLC will benefit, so combination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important. Herein, we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark (Mk.) 1.0, 2.0, and 3.0. We illustrated the significance of ICI monotherapy (Mk. 1.0), offering combinational approaches with traditional strategies (Mk. 2.0) and additional locoregional therapy (Mk. 3.0) to achieve longer survival and even meet the "No Evidence of Disease" status. We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies. Multidisciplinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.

In recent years, laparoscopic surgery and robotic surgery have been widely used, and various intraoperative image navigation systems have also developed rapidly. However, the liver itself has a complex vessel and duct system, which increase the difficulty of liver surgery. The augmented reality image navigation system combines the three-dimensional reconstructed image of the liver with the real liver anatomy, which presents the specific relationship between the tumor location and the surrounding vessels for the surgeon. Compared with other intraoperative image navigation methods, augmented reality has its unique advantages. This paper provides an overview of current advances in registration technology in augmented reality image navigation system, and focuses on its applications in liver surgery, including laparoscopic surgery and robotic surgery. Finally, the technological problems and difficulties still faced at present are summarized, and future directions worth studying in this field are proposed.

目的:通过四氯化碳(CCl4)和乙醇综合法建立联合门静脉离断与肝脏离断的二步肝切除术(associating liver partition and portal vein ligation for staged hepatectomy,ALPPS)的肝纤维化模型,探讨ALPPS应用于肝纤维化大鼠的安全性及可行性.方法:将40只雄性SD大鼠采用抽签法随机均分为对照组和肝纤维化组,每组各20只.对照组大鼠进行常规饲养,并采用橄榄油注射4周.肝纤维化组大鼠采用40％CCl4的橄榄油溶液背部皮下注射+饮用10％乙醇4周.肝纤维化组和对照组各取5只大鼠,进行天狼猩红染色判断肝纤维化的程度.其余15只大鼠行ALPPS,并于术后即刻、第3天、第6天各取5只大鼠,取再生肝脏称重,检测肝脏增生情况,并进一步通过Ki-67免疫组织化学染色判断肝细胞再生情况.结果:通过CCl4和乙醇综合法建模4周,肝纤维化组大鼠体重缓慢增加,生活基本未受影响,且肝纤维化均匀,有1只大鼠因注射CCl4死亡,建模成功率为95.0％.肝纤维化组和对照组大鼠在ALPPS后均实现了剩余肝脏体积的快速增长,且两组差异无统计学意义(P>0.05).肝纤维化组和对照组大鼠肝组织的Ki-67阳性细胞均在术后第3天明显增多,术后第6天明显减少.结论:采用CCl4背部皮下注射和乙醇综合法可以快速建立肝纤维化大鼠模型,在此基础上进行ALPPS是安全可行的.本研究建立了稳定高效的肝纤维化大鼠ALPPS模型.

Background Ultrasound-guided continuous thoracic paravertebral block can provide pain-relieving and opioid-sparing effects in patients receiving open hepatectomy. We hypothesize that these effects may improve the quality of recovery (QoR) after open hepatectomy. Methods Seventy-six patients undergoing open hepatectomy were randomized to receive a continuous thoracic paravertebral block with ropivacaine (CTPVB group) or normal saline (control group). All patients received patient-controlled intravenous analgesia with morphine postoperatively for 48 hours. The primary outcome was the global Chinese 15-item Quality of Recovery score on postoperative day 7, which was statistically analyzed using Student's t-test. Results Thirty-six patients in the CTPVB group and 37 in the control group completed the study. Compared to the control group, the CTPVB group had significantly increased global Chinese 15-item Quality of Recovery scores (133.14 ± 12.97 vs. 122.62 ± 14.89, P = 0.002) on postoperative day 7. Postoperative pain scores and cumulative morphine consumption were significantly lower for up to 8 and 48 hours (P < 0.05; P = 0.002), respectively, in the CTPVB group. Conclusion Perioperative CTPVB markably promotes patient's QoR after open hepatectomy with a profound analgesic effect in the early postoperative period.

This study investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with PD-1 immunotherapy for advanced biliary tract cancer (BTC) and evaluated the optimal timing of HAIC. A total of 36 unresectable BTC patients treated with HAIC and PD-1 inhibitors between September 2019 and July 2021 were included in this study. Overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) were investigated. Overall, 52.8% patients with advanced BTC were in stage IV, 23 patients who progressed after receiving PD-1 inhibitor had undergone HAIC, and 23 patients have received 2 or more lines of therapy. The median OS was 8.8 months (range: 4.0-24.0 months), and the median PFS was 3.7 months. The objective response rate and disease control rate were 11.5% and 76.9%, respectively. In the subgroup analysis, patients who treated with HAIC early without progression after immunotherapy were associated with a trend toward better OS (median 13.0 vs. 7.6 months; P = 0.004) and PFS (median 7.9 vs. 3.6 months; P = 0.09) compared to with HAIC with progression after PD-1 treatment. No treatment-related deaths occurred. A total of 44.4% of the patients experienced grade 3 or 4 AEs. We conclude that the combination of HAIC and PD-1 inhibitors is safe and effective. Early HAIC combined with immunotherapy can effectively prolong the overall survival of patients with advanced BTC.

Since the publication of the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2019 Edition), many new high-level evidence in line with evidence-based medicine has emerged in the diagnosis and treatment of liver cancer at home and abroad, especially, a number of research results in line with Chinese liver cancer patients have been published. In order to further standardize the diagnosis and treatment of liver cancer in China, the National Health Commission organized multidisciplinary experts in the field of liver cancer to revise and update the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition), aiming to increase the overall cancer 5-year survival rate by 15%, a goal mentioned in the ' Healthy China 2030' Planning Outline. We interpret the main update points of the 2022 version, with the hope of promoting the widespread discussion and dissemination of the new version.

肝脏外科的日常教学目前仍以课堂传统授课模式(lecture-based learning,LBL)的教学模式和观摩为主的手术学习模式为主,但传统的教学方法不易使学生理解肝脏外科复杂的疾病和解剖特点.因此,需要更加有效的教学方法来提高教学质量和学生的学习效率.通过联合多种教学模式,如LBL、基于问题的学习(problem-based learning,PBL)、"基于案例"教学法(case-based learning,CBL)、虚拟现实(virtual reality,VR)技术等,笔者探索出更加有效的综合教学模式,即PBL+CBL+3D打印技术+虚拟现实技术,在肝脏外科教学中具有重要价值.

ObjectiveTo investigate the value of optical trocar insertion technique in establishing pneumoperitoneum in patients undergoing laparoscopic surgery after previous abdominal surgery. MethodsA total of 29 patients, with a history of abdominal surgery, who planned to undergo laparoscopic liver surgery were enrolled and randomly divided into optical trocar insertion group and open approach group. The independent samples t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the Fisher’s exact test was used for comparison of categorical data between groups; the Mann-Whitney U test was used for comparison of ranked data between groups. ResultsThere were no procedure-related complications in either group. Compared with the open approach group, the optical trocar insertion group had a significantly shorter time required to establish pneumoperitoneum ［35.00 (21.00-46.00) seconds vs 180.00 (152.50-252.50) seconds, U=0, P＜0.001］ and a significantly smaller incision length ［1.10(1.00-1.20) cm vs 2.80(2.45-3.00) cm, U=0, P＜0.001］. ConclusionBoth optical trocar insertion and open approach for establishing pneumoperitoneum is relatively safe in patients undergoing laparoscopic liver surgery after previous abdominal surgery, while optical trocar insertion has the advantages of high efficiency and minimal invasiveness in establishing pneumoperitoneum.

Background The study aimed to establish a 68 Ga-FAPI-04 kinetic model in hepatic lesions, to determine the potential role of kinetic parameters in the differentiation of hepatocellular carcinoma (HCC) from non-HCC lesions. Material and methods Time activity curves (TACs) were extracted from seven HCC lesions and five non-HCC lesions obtained from 68 Ga-FAPI-04 dynamic positron emission tomography (PET) scans of eight patients. Three kinetic models were applied to the TACs, using image-derived hepatic artery and/or portal vein as input functions. The maximum standardized uptake value (SUV max ) was taken for the lesions, the hepatic artery, and for the portal veins—the mean SUV for all healthy regions. The optimum model was chosen after applying the Schwartz information criteria to the TACs, differences in model parameters between HCC, non-HCC lesions, and healthy tissue were evaluated with the ANOVA test. Results A reversible two-tissue compartment model using both the arterial as well as venous input function was most preferred and showed significant differences in the kinetic parameters V ND , V T , and BP ND between HCC, non-HCC lesions, and healthy regions ( p < 0.01). Conclusion Several model parameters derived from a two-tissue compartment kinetic model with two image-derived input function from vein and aorta and using SUV max allow a differentiation between HCC and non-HCC lesions, obtained from dynamically performed PET scans using FAPI.

Liver hepatocellular carcinoma (LIHC), an inflammation-associated cancer induced by a variety of etiological factors, is still one of the most prevalent and lethal cancers in human population. In this study, the expression profiles of immune-related genes (IRGs) were integrated with the overall survival (OS) of 378 LIHC patients based on the Cancer Genome Atlas (TCGA) dataset. Moreover, the differentially expressed and survival related IRGs among LIHC patients were predicted through the computational difference algorithm and COX regression analysis. As a result, 7 genes, including HSPA4, S100A10, FABP6, CACYBP, HDAC1, FCGR2B and SHC1, were retrieved to construct a predictive model associated with the overall survival (OS) of LIHC patients. Typically, the as-constructed model performed moderately in predicting prognosis, which was also correlated with tumor grade. Functional enrichment analysis revealed that the genes of high-risk group were actively involved in mRNA binding and the spliceosome pathway. Intriguingly, the prognostic index established based on IRGs reflected infiltration by multiple types of immunocytes. Our findings screen several IRGs with clinical significance, reveal the drivers of immune repertoire, and illustrate the importance of a personalized, IRG-based immune signature in LIHC recognition, surveillance, and prognosis prediction.

Purpose: The immune prognostic index (IPI) has been used as a prognostic biomarker in various cancers. However, the prognostic value of the IPI in gallbladder cancer remains to be determined. Patients and Methods: This study included 139 patients who were diagnosed with gallbladder cancer after surgical resection from 2003 to 2017. We used a Kaplan-Meier curve analysis to evaluate the overall survival (OS). Cox proportional hazards regression methodology was used to identify significant independent prognostic factors. Prognostic nomograms for predicting OS were established to achieve superior discriminatory abilities. The prognostic nomograms were verified according to the concordance index, calibration curves, and decision curve analyses in the training cohort and validation cohort. Results: Of all 139 patients, 87 (62.6%) patients accepted R0 resection, 32% and 68% were stratified into the good and poor IPI group, respectively. The median OS was 55.9 (range, 5.93-182.7) months in the good IPI group and 15.47 (range, 0.29-190.37) months in the poor IPI group (P < 0.001). In the multivariate Cox model, the IPI was an independent predictor of OS along with the CA19-9, curative resection, and postoperative chemoradiotherapy. A nomogram based on these factors was efficient in predicting 1-, 3-, and 5-year survival probabilities. The nomogram showed higher sensitivity and specificity than the current cancer TNM staging system in the training cohort and validation cohort. Conclusion: The IPI is an independent prognostic factor in gallbladder cancer. Our IPI-based nomogram can serve as a useful and convenient prognostic tool for gallbladder cancer.

BACKGROUND:Ectopic pheochromocytomas, the incidence of which is >15%, can occur throughout the entire body but seldom on the diaphragm. Surgery may the first-choice treatment for ectopic pheochromocytomas. PRESENTATION OF CASE:We herein describe a 61-year-old woman with an atopic diaphragmatic pheochromocytoma. She had a 7-year history of paroxysmal headaches, palpitations, and hypertension with no obvious causes; these symptoms were alleviated by nifedipine and metoprolol. Computed tomography (CT) revealed a slightly hypodense lesion on top of the right hepatic lobe. A Metaiodobenzylguanidine (MIBG) scan showed increased radioactive in the lesion. After adequate preoperative preparation, we removed the mass. During the operation, we found that the mass was located on the diaphragm. The pathological examination showed that the main pathologic change was paraganglioma. The patient recovered well after surgery with no recurrence of her hypertension, palpitation, or headache. CONCLUSIONS:Diaphragmatic pheochromocytoma is a rare kind of ectopic pheochromocytomas, which can also affect the patient's quality of life. Combination of qualitative and positioning tests can assist in diagnosis of ectopic pheochromocytoma. Surgical resection is an effective treatment method.

We aimed to investigate whether lncRNA CYTOR could sponge miR-125b-5p to affect hepatocellular carcinoma (HCC) cells through targeting KIAA1522. The expression of CYTOR, miR-125b-5p and KIAA1522 in HCC cells was detected by Real-time quantitative polymerase chain reaction (RT-qPCR) analysis. KIAA1522 expression in HCC tissues was detected by immunohistochemistry. The proliferation, cell cycle and apoptosis of HCC cells after transfection were respectively detected by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, and related protein expression was determined by Western blot analysis. As a result, The Cancer Genome Atlas (TCGA) database indicated that expression of CYTOR and KIAA1522 was increased in HCC tissues and high expression of CYTOR and KIAA1522 was related to worse overall survival. MiR-125b-5p expression was decreased in HCC tissues, which was negatively correlated with the expression of CYTOR and KIAA1522. The proliferation and cell cycle of HCC cells were suppressed by CYTOR interference while promoted by miR-125b-5p interference and KIAA1522 overexpression. The apoptosis of HCC cells was promoted by CYTOR interference while inhibited by miR-125b-5p interference and KIAA1522 overexpression. In conclusion, CYTOR interference suppressed the proliferation and cell cycle, and promoted the apoptosis of HCC cells by regulating the miR-125b-5p/KIAA1522 axis.

Purpose: We aimed to develop a nomogram for predicting the prognosis of patients with distal cholangiocarcinoma (DCC) and to compare its performance with that of the American Joint Committee on Cancer (AJCC) TNM system. Patients and Methods: To develop a nomogram, we collected the clinical data of 147 patients diagnosed with DCC who underwent pancreatoduodenectomy. Predictive accuracy and discriminative ability were determined using a concordance index and a calibration curve. Predictive performance was compared with that of a current staging systems for DCC. Results: Multivariate analysis revealed that jaundice, alcohol consumption, high fibrinogen, poorly differentiated tumor cells, positive lymph nodes, and positive margins were significantly associated with overall survival. These variables were incorporated into the nomogram. The concordance index of the nomogram for predicting overall survival was 0.737 (P<0.001), which is significantly higher than the concordance index values (concordance index = 0.586) acquired using the AJCC TNM system (eighth edition). The calibration curve agreed well with predicted prediction and observed overall survival. Conclusion: We developed a nomogram for predicting the prognoses of patients with distal cholangiocarcinoma, which had superior practical clinical value compared with that of the AJCC TNM system.

目的:报道ALPPS成功治疗尾状叶肝癌1 例,分析ALPPS对于尾状叶肝癌的可行性及安全性.方法:患者,男,58岁,66 kg,因"体检发现肝占位20天"入院,肝脏超声示肝右叶占位性病变,初步诊断:尾状叶肝癌.患者尾状叶肝癌累及门静脉右支、肝中静脉、肝右静脉、下腔静脉肝后段,需行右半肝及尾状叶切除.经术前评估患者剩余肝脏体积不能满足切除要求,遂行ALPPS手术.结果:第一步手术时间210 min,术中出血量200 ml,术中未输血,术后无严重并发症.术后第7 天左半肝体积增长至547 ml,占标准肝脏体积的46.3%,术后第14天行第二步手术.第二步手术时间180 min,术中出血量400 ml,输注红细胞3 U,血浆800 ml.Clavien－Dino并发症分级Ⅱ级,主要并发症为胆漏,予以充分引流后好转.患者术后康复良好,随访13个月,肿瘤无复发.结论:ALPPS为尾状叶肝癌患者提供了新的手术方案参考.

Background: N6-methyladenosine (m6A), the most internal mRNA modification, is involved in various cancers. However, the function of m6A in hepatocellular carcinoma (HCC) is still not well explored. Here, we aimed to develop a prognostic model consist of m6A associated genes in HCC. Methods: The mRNA expression profiles and the corresponding clinical information from the patients with HCC were obtained from The Cancer Genome Atlas (TCGA) database, m6A differentially expressed genes (DEGs) were screened by univariate, Lasso and multivariate Cox regression analyses to develop the prognostic model. The differentially expressed m6A genes in HCC tissues were verified by quantitative reverse transcription PCR (qRT-PCR). Results: The DEGs were obtained between the HCC (n=374) and normal tissues ( n=50). Nine m6A genes were correlated with the prognosis, and five of them (KIAA1429, METTL3, YTHDF1, YTHDF2, ZC3H13) were included in the prognostic model by Lasso regression analyses. Four genes (KIAA1429, METTL3, YTHDF1, YTHDF2) were proved significantly high expression in our ten pairs of matched HCC and normal tissues by PCR. The HCC patients were divided into two groups (high- and low-risk) according to the risk score. The high-risk group associated with a significant poor prognosis (P=1.72x10(-4)). The time-dependent receiver operating characteristic (ROC) curve analysis confirmed the good performance of this prognostic model (AUC =0.617). After univariate [P<0.001, 1.213 (1.136-1.295)] and multivariate Cox regression analyses [P<0.001, 1.198 (1.115-1.288)] by combined with other clinical factors, this prognostic model was identified as an independent prognostic factor of HCC patients. Conclusions: The m6A genes were differentially expressed between HCC and normal tissues, and associated with the prognosis of HCC.

Introduction Cholangiocarcinoma is a common malignant tumor, with an incidence that has continued to rise over the past 40 years. China has a high incidence of cholangiocarcinoma, which is far higher than that in Europe and the United States. Cholangiocarcinoma is divided into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma (ECC). Surgical resection is the first consideration for the treatment of both types of cholangiocarcinoma. The surgical procedure for ECC can be grouped based on the location, as follows: the different conditions of the patients, radiotherapy, chemotherapy, target therapy, and immunotherapy for treatment. Correspondence: Shunda Du Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai-Fu-Yuan, Wang-Fu-Jing, Beijing 100730, People’s Republic of China Tel +86-139 1183 2900 Fax +86-10-69156043 Email dushd@pumch.cn Cancer Management and Research Dovepress

Background It has been widely suggested that the association of hypoxia with the immune status within the microenvironment of hepatocellular carcinoma (HCC) is of great clinical significance. The present work was carried out aiming to establish the hypoxia-related and immune-associated gene signature to stratify the risks in HCC. Patients and Methods The ssGSEA and t-SNE algorithms were utilized to estimate the immune and hypoxia statuses, respectively, using the TCGA database-derived cohort transcriptome profiles. Different immune groups are distinguished according to the ssGSEA scores, while the hypoxia-high and -low groups are inferred based on the distinct overall survival (OS) of the two groups of patients. Moreover, prognostic genes were identified using the Cox regression model in combination with the LASSO approach, which were later used to establish the hypoxia-related and immune-associated gene signature. At the same time, an ICGC cohort was used for external validation. Results A total of 13 genes, namely, HAVCR1, PSRC1, CCNJL, PDSS1, MEX3A, EID3, EPO, PLOD2, KPNA2, CDCA8, ADAMTS5, SLC1A7 and PIGZ, were discovered by the LASSO approach for constructing a gene signature to stratify the risk of HCC. Those low-risk cases showed superior prognosis (OS) to the high-risk counterparts (p<0.05). Moreover, it was suggested by multivariate analysis that our constructed hypoxia-related and immune-associated prognosis signature might be used as the independent factor for prognosis prediction (p<0.001). Patients in high-risk groups had severe hypoxia, higher immune checkpoint expression such as PD-L1, and different immunocyte infiltration states (eg, higher infiltration of regulatory T cells in the high-risk group) compared with those low-risk patients. Conclusion Our as-constructed hypoxia-related and immune-associated prognosis signature can be used as an approach to stratify the risk of HCC.

BACKGROUND:Caudate lobectomy via laparoscopic surgery has rarely been described. This multicenter, propensity score-matched study was performed to assess the safety and efficacy of laparoscopic caudate lobectomy (LCL). METHODS:A multicenter retrospective study was performed including all patients who underwent LCL and open caudate lobectomy (OCL) in four institutions from January 2013 to December 2018. In total, 131 patients were included in this study and divided into LCL (n = 19) and OCL (n = 112) groups. LCLs were matched to OCLs (1:2) using a propensity score matching (PSM) based on nine preoperative variables, including patient demographics and tumor characteristics. The pathological results, perioperative and postoperative parameters, and short-term outcomes were compared between the two groups. RESULTS:After PSM, there were 18 and 36 patients in the LCL and OCL groups, respectively. Baseline characteristics were comparable after matching. LCL was associated with less blood (100 vs. 300 ml, respectively; P < 0.001) and a shorter postoperative stay (6.0 vs 8.0 days, respectively; P = 0.003). Most patients' resection margins were > 10 mm in the LCL group (P = 0.021), and all patients with malignancy in both groups achieved R0 resection. In terms of early postoperative outcomes, the overall morbidity rate was identical in each group (11.1% vs. 11.1%, respectively; P = 1.000). No mortality occurred in either group. CONCLUSIONS:Laparoscopy is a feasible choice for resection of tumors located in the caudate lobe with acceptable perioperative results.