A ten-year experience of inferior vena cava reconstruction for malignancy:The importance of a multidisciplinary approach with hepatobiliary surgery

To the Editor,Tumor invasion of the inferior vena cava(IVC)through direct erosion is a rare and poor prognostic feature of aggressive hepatic or perihepatic malignancies[1,2].Literature shows poor response to chemotherapy,such that resection often is the only option for improved survival[3].Multidisciplinary collaborations can expand technical options;incorporation of transplant techniques has led to successful R0 resection involving difficult vascular reconstruction and extended resection[4,5].This study describes and analyzes the ten-year collaborative experience of hepatobiliary(HPB)surgeons in management of malignancies involving the perihepatic IVC.

Prognosis after splenectomy plus pericardial devascularization vs transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding

BACKGROUND Portal hypertension combined with esophagogastric variceal bleeding(EGVB)is a serious complication in patients with hepatitis B virus(HBV)-related cirrhosis in China.Splenectomy plus pericardial devascularization(SPD)and transjugular intrahepatic portosystemic shunt(TIPS)are effective treatments for EGVB.However,a comparison of the effectiveness and safety of those methods is lacking.AIM To compare the prognosis after SPD vs TIPS for acute EGVB after failure of endoscopic therapy or secondary prophylaxis of variceal rebleeding(VRB)in patients with HBV-related cirrhosis combined with portal hypertension.METHODS This retrospective cohort study included 318 patients with HBV-related cirrhosis and EGVB who underwent SPD or TIPS at West China Hospital of Sichuan University during 2009-2013.Propensity score-matched analysis(PSM),the Kaplan-Meier method,and multivariate Cox regression analysis were used to compare overall survival,VRB rate,liver function abnormality rate,and hepatocellular carcinoma(HCC)incidence between the two patient groups.RESULTS The median age was 45.0 years(n=318;226(71.1%)males).During a median follow-up duration of 43.0 mo,18(11.1%)and 33(21.2%)patients died in the SPD and TIPS groups,respectively.After PSM,SPD was significantly associated with better overall survival(OS)(P=0.01),lower rates of abnormal liver function(P<0.001),and a lower incidence of HCC(P=0.02)than TIPS.The VRB rate did not differ significantly between the two groups(P=0.09).CONCLUSION Compared with TIPS,SPD is associated with higher postoperative OS rates,lower rates of abnormal liver function and HCC,and better quality of survival as acute EGVB treatment after failed endoscopic therapy or as secondary prophylaxis of VRB in patients with HBV-related cirrhosis combined with portal hypertension.There is no significant between-group difference in VRB rates.

Patient-derived xenograft model in colorectal cancer basic and translational research

Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and helpful for improving CRC treat-ment.With huge efforts made in past decades,the systematic treatment regimens have been applied to improve the prognosis of CRC patients.However,the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person,which is an important cause of treatment failure.The emergence of patient-derived xenograft(PDX)models shows great potential to alleviate the straits.PDX models possess similar genetic and pathological characteristics as the features of primary tu-mors.Moreover,PDX has the ability to mimic the tumor microenvironment of the original tumor.Thus,the PDX model is an important tool to screen precise drugs for individualized treatment,seek predictive biomarkers for prognosis supervision,and evaluate the unknown mechanism in basic research.This paper reviews the recent advances in constructed methods and applications of the CRC PDX model,aiming to provide new knowledge for CRC basic research and therapeutics.

Circular RNA hsacirc0000745 may serve as a diagnostic marker for gastric cancer

AIM To determine whether circular RNAs(circ RNAs) are involved in pathological processes of gastric cancer(GC).METHODS Three circ RNAs with differential expression in GC and colorectal cancer were randomly selected for validation by quantitative reverse transcription-polymerase chain reaction(q RT-PCR), using 20 pairs of gastric tissues and normal tissues. Based on the predicted circ RNAmi RNA network, we then focused on hsa_circ_0000745, which was found to be down-regulated in 20 GC tissues compared with normal tissues. The hsa_circ_0000745 levels were further analyzed by q RT-PCR in 60 GC tissues and paired adjacent non-tumor tissues, as well as 60 plasma samples from GC patients and 60 plasma samples from healthy controls. The associations between the levels of hsa_circ_0000745 and the clinicopathological features of GC patients were statistically assessed. A receiver operating characteristic(ROC) curve was used to evaluate the diagnostic value of hsa_circ_0000745 in GC.RESULTS Hsa_circ_0000745 was down-regulated in GC tissues vs non-tumorous tissues(P < 0.001) and in plasma samples from patients with GC vs healthy controls(P < 0.001). The expression level of hsa_circ_0000745 in GC tissues correlated with tumor differentiation, while the expression level in plasma correlated with tumor-nodemetastasis stage. The area under the ROC curve(AUC) of hsa_circ_0000745 in plasma was 0.683, suggesting good diagnostic value. Plasma hsa_circ_0000745 level combined with carcinoembryogenic antigen(CEA) level increased the AUC to 0.775.CONCLUSION Hsa_circ_0000745 plays an important role in GC and its expression level in plasma in combination with CEA level is a promising diagnostic marker for this malignancy.

Role of a liver-first approach for synchronous colorectalliver metastases

AIM: To evaluate the feasibility and survival outcomes of a liver-first approach.METHODS: Between January 2009 and April 2013, 18 synchronous colorectal liver metastases(s CRLMs) patients with a planned liver-first approach in the Hepatopancreatobiliary Surgery Department Ⅰ of the Beijing Cancer Hospital were enrolled in this study. Clinical data, surgical outcomes, morbidity and mortality rates were collected. The feasibility and long-term outcomes of the approach were retrospectively analyzed.RESULTS: Sixteen patients(88.9%) completed the treatment protocol for primary and liver tumors. The main reason for treatment failure was liver disease recurrence. The 1 and 3 year overall survival rates were 94.4% and 44.8%, respectively. The median survival time was 30 mo. The postoperative morbidity and mortality were 22.2% and 0%, respectively, following a hepatic resection, and were 18.8% and 0%, respectively, after a colorectal surgery.CONCLUSION: The liver-first approach appeared to be feasible and safe. It can be performed with a comparable mortality and morbidity to the traditional treatment paradigm. This approach might offer a curative opportunity for s CRLM patients with a high liver disease burden.

Follow-up study on symptom distress in esophageal cancer patients undergoing repeated dilation

BACKGROUND Repeated endoscopic probe dilatation is the most preferred treatment for esophageal stenosis which may cause high levels of symptom distress in the patient’s home rehabilitation stage.AIM To explore the changes in the symptom distress level and its correlation with the dilation effect in patients with esophageal carcinoma undergoing repeated dilations for lumen stenosis.METHODS The difference(R2-R1)between the diameter of the esophageal stenosis opening(R1)of the patients before dilation(R1)and after dilation(R2)was calculated to describe the extent and expansion of the esophageal stenosis before and after dilation.The M.D.Anderson Symptom Inventory was used to describe the symptom distress level of patients with dilation intermittence during their stay at home and to explore the correlation between the dilation effect and symptom distress level.RESULTS The diameter of the esophagus(R1)increased before each dilation in patients undergoing esophageal dilation(P<0.05).The diameter(R2)increased after dilation(P<0.05);the dilation effect(R2-R1)decreased with the number of dilations(P<0.05).The total symptom distress score significantly increased with the number of dilations(P<0.05).The symptom distress scores of the patients were negatively correlated(P<0.05)with the previous dilation effect(R2-R1)and the esophageal diameter(R2)after the previous dilation.After the 1 st to 4 th dilations,the patient’s symptom distress score was negatively correlated with the esophageal diameter(R12)before the next dilation,while there was no significant correlation(P>0.05)with the other dilations.CONCLUSION In patients who have undergone repeated dilations,better effect stands for lower symptom distress level and the increase in symptom distress has a prompt effect on the severity of the next occurrence of restenosis.

Effects of ulinastatin combined with octreotide therapy on systemic inflammatory response and intestinal mucosal function in patients with severe pancreatitis

Objective: To investigate the effects of ulinastatin combined with octreotide therapy on systemic inflammatory response and intestinal mucosal function in patients with severe pancreatitis. Methods: A total of 82 patients with severe pancreatitis who were treated in the First People's Hospital of Liangshan Prefecture between March 2015 and August 2017 were reviewed and divided into control group (n=43) and ulinastatin group (n=39), control group received conventional + octreotide therapy, ulinastatin group received conventional +octreotide + ulinastatin therapy, and both groups were treated for 1 week. The differences in systemic inflammatory response and intestinal mucosal function were compared between the two groups before and after treatment. Results: Before treatment, the differences in serum levels of inflammatory mediators and intestinal mucosal function indexes were not statistically significant between the two groups. After 1 week of treatment, serum levels of inflammatory mediators IL-1β, IL-8, HMGB-1 and MCP-1 as well as intestinal mucosal function indexes ET, DAO and D-lactose of ulinastatin group were lower than those of control group. Conclusion: Ulinastatin combined with octreotide therapy on the basis of conventional treatment can further inhibit the systemic inflammatory response and actively protect the intestinal mucosal function in patients with severe pancreatitis.

Robotic versus laparoscopic liver resection for huge (≥10 cm) liver tumors: an international multicenter propensity-score matched cohort study of 799 cases

Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours≥10 cm.Methods:This was a retrospective review of 971 patients who underwent LLR and RLR for huge(≥10 cm)tumors at 42 international centers between 2002-2020.Results:One hundred RLR and 699 LLR which met study criteria were included.The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching(PSM)(73 vs.219).Before PSM,LLR was associated with significantly increased frequency of previous abdominal surgery,malignant pathology,liver cirrhosis and increased median blood.After PSM,RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time(242 vs.290 min,P=0.286),transfusion rate rate(19.2%vs.16.9%,P=0.652),median blood loss(200 vs.300 mL,P=0.694),open conversion rate(8.2%vs.11.0%,P=0.519),morbidity(28.8%vs.21.9%,P=0.221),major morbidity(4.1%vs.9.6%,P=0.152),mortality and postoperative length of stay(6 vs.6 days,P=0.435).Conclusions:RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes.There was no significant difference in perioperative outcomes after RLR or LLR.

Hsp90-associated DNA replication checkpoint protein and proteasome-subunit components are involved in the age-related macular degeneration

Background:Age-related macular degeneration(AMD)is the leading cause of vision loss worldwide.However,the mechanisms involved in the development and progression of AMD are poorly delineated.We aimed to explore the critical genes involved in the progression of AMD.Methods:The differentially expressed genes(DEGs)in AMD retinal pigment epithelial(RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564,which were downloaded from the gene expression omnibus database.The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The hub genes were identified from these DEGs through protein-protein interaction network analyses.The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866.Following the identification of AMD-related key genes,the potential small molecule compounds targeting the key genes were predicted by PharmacoDB.Finally,a microRNA-gene interaction network was constructed.Results:Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples.These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication,cell cycle,and proteasome-mediated protein polyubiquitination.Among the top ten hub genes,HSP90AA1,CHEK1,PSMA4,PSMD4,and PSMD8 were upregulated in the senescent ARPE-19 cells.Additionally,the drugs targeting HSP90AA1,CHEK1,and PSMA4 were identified.We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.Conclusions:Based on our findings,HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD.Targeting HSP90AA1,CHEK1,PSMA4,PSMD4,and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.

Human U Three Protein 14a Expression is Increased in Hepatocellular Carcinoma and Associated with Poor Prognosis

Background： Human U three protein 14a （hUTP 14a） promotes p53 degradation. Moreover, hUTP 14a expression is upregulated in several types of tumors. However, the expression pattern of hUTP 14a in hepatocellular carcinoma （HCC） remains unknown. The aim of this study was to investigate hUTP 14a expression and its prognostic value in HCC. Methods： The hUTP 14a expression was evaluated using immunohistochemistry （IHC） in HCC tissue specimens. The correlations between hUTP 14a expression and clinicopathological variables were analyzed. The Kaplan-Meier method was used to analyze the association between hUTP14a expression and survival. Independent prognostic factors associated with overall survival （OS） and disease-free survival （DFS） were analyzed using the Cox proportional-hazards regression model. Results： The IHC data revealed that the hUTP 14a positivity rate in HCC tissue specimens was significantly higher than that in nontumorous tissue specimens （89.9% vs. 72.7%, P 〈 0,05）. The hUTP14a expression was detected in both the nucleolus and the cytoplasm. The positivity rate of nucleolar hUTP14a expression in HCC tissue specimens was higher than that in the nontumorous tissue specimens （29.3% vs. 10.1%, P 〈 0.05）. No significant difference was found between HCC and nontumorous tissue specimens of cytoplasmic hUTP 14a expression （60.6% vs. 62.6%, P 〉 0.05）. In addition, no significant correlation was found between nucleolar hUTP 14a expression and other clinicopathological variables. The 5-year OS and DFS rates in patients with positive nucleolar hUTP14a expression were significantly lower than those in patients with negative hUTP 14a expression （P = 0.004 for OS, P = 0.003 for DFS）. Multivariate analysis showed that nucleolar hUTP 14a expression was an independent prognostic factor for OS （P = 0.004） and DFS （P 〈 0.001 ）. Conclusions： The positivity rate of hUTP 14a expression was significantly higher in HCC specimens. Positive expression of nucleolar hUTP 14a might act as a novel prognostic predictor for patients with HCC.

Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer

Metformin is currently a strong candidate anti-tumor agent in multiple cancers.However,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor heterogeneity.It thus remains unclear which hepatocellular carcinoma(HCC)patient subpopulation(s)can benefit from met-formin treatment.Here,through a genome-wide CRISPR-Cas9-based knockout screen,we find that DOCK1 levels determine the anti-tumor effects of met-formin and that DOCK1 is a synthetic lethal target of metformin in HCC.Mechanistically,metformin promotes DOCK1 phosphorylation,which activates RAC1 to facilitate cell survival,leading to metformin resistance.The DOCK1-selective inhibitor,TBOPP,potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids,and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models.Notably,metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression.This study shows that metformin effective-ness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for met-formin-resistant HCC patients.

Quality over quantity:a necessary path for clinical research transformation in China

Since the Chinese economic reform in 1978,its medical field has made remarkable progress in the past 40 years.In most medical fields,China’s diagnosis and treatment methods are comparable to the international high standards.In recent years,with the continuous expansion of the medical research team and the improvement of laboratory research equipment and methods,China has achieved some influential and internationally recognized research outcomes.However,overall,China still lags behind developed countries in terms of high-level original medical research,especially in high evidence-based medical research(1).

International expert consensus on laparoscopic pancreaticoduodenectomy

Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the technical standards for LPD.Objective:The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review:An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy.Statements were produced upon reviewing the literature and assessed by the members of the expert panel.The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019.The Web of Science,Medline,and Cochrane Library and Clinical Trials databases were searched,The search strategy included,but was not limited to,the terms'laparoscopic','pancreaticoduodenectomy,'pancreatoduodenectomy','Whipple's operation',and'minimally invasive surgery'.Reference lists from the included articles were manually checked for any additional studies,which were included when appropriate.Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements.The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan,China.Findings:Twenty-eight international experts from 8 countries constructed the expert panel.Sixteen statements were produced by the members of the expert panel.At least 80%of responders agreed with the majority(80%)of statements.Other than three randomized controlled trials published to date,most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance:The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD.LPD is currently in its development and exploration stages,as defined by the international IDEAL framework for surgical innovation.More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.

Surgical decision-making: can patients benefit?

What is surgery?It is difficult for us to have time to think about this broad question in our busy,day-to-day work.In some“super hospitals”,patient admission and surgical operation have even become an“assembly-line”job.When a patient successfully recovers from an operation without any postoperative complications,we may be silently proud of our surgical skills.

Minimally invasive liver resection for huge(≥10cm)tumors:an international multicenter matched cohort study with regression discontinuity analyses

Background:The application and feasibility of minimally invasive liver resection(MILR)for huge liver tumours(≥10 cm)has not been well documented.Methods:Retrospective analysis of data on 6,617 patients who had MILR for liver tumours were gathered from 21 international centers between 2009-2019.Huge tumors and large tumors were defined as tumors with a size≥10.0 cm and 3.0-9.9 cm based on histology,respectively.1:1 coarsened exact-matching(CEM)and 1:2 Mahalanobis distance-matching(MDM)was performed according to clinically-selected variables.Regression discontinuity analyses were performed as an additional line of sensitivity analysis to estimate local treatment effects at the 10-cm tumor size cutoff.Results:Of 2,890 patients with tumours≥3 cm,there were 205 huge tumors.After 1:1 CEM,174 huge tumors were matched to 174 large tumors;and after 1:2 MDM,190 huge tumours were matched to 380 large tumours.There was significantly and consistently increased intraoperative blood loss,frequency in the application of Pringle maneuver,major morbidity and postoperative stay in the huge tumour group compared to the large tumour group after both 1:1 CEM and 1:2 MDM.These findings were reinforced in RD analyses.Intraoperative blood transfusion rate and open conversion rate were significantly higher in the huge tumor group after only 1:2 MDM but not 1:1 CEM.Conclusions:MILR for huge tumours can be safely performed in expert centers It is an operation with substantial complexity and high technical requirement,with worse perioperative outcomes compared to MILR for large tumors,therefore judicious patient selection is pivotal.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.