Reconsideration of the clinical management of hepatic hemangioma

In this letter,we comment on the article by Zhou et al that was published in the recent issue of the World Journal of Gastrointestinal Surgery.This article proposes a new clinical grading system based on a multidisciplinary team,which prompts us to rethink the clinical management of hepatic hemangioma.Hepatic hemangioma is the most common benign solid liver tumor.In general,follow-up and obser-vation for the vast majority of hepatic hemangioma is reasonable.For those pa-tients with symptoms and severe complications,surgical intervention is ne-cessary.Specific surgical indications,however,are still not clear.An effective grading system is helpful in further guiding the clinical management of hepatic hemangioma.In this article,we review the recent literature,summarize the sur-gical indications and treatment of hepatic hemangioma,and evaluate the potential of this new clinical grading system.

Distal margin distance in radical resection of locally advanced rectal cancer after neoadjuvant therapy

Colorectal cancer has a high incidence and mortality rate in China, with the majority of cases being middle and low rectal cancer. Surgical intervention is currently the main treatment modality for locally advanced rectal cancer, with the common goal of improving oncological outcomes while preserving function. The controversy regarding the circumferential resection margin distance in rectal cancer surgery has been resolved. With the promotion of neoadjuvant therapy concepts and advancements in technology, treatment strategies have become more diverse.Following tumor downstaging, there is an increasing trend towards extending the safe distance of distal rectal margin. This provides more opportunities for patients with low rectal cancer to preserve their anal function.However, there is currently no consensus on the specific distance of distal resection margin.

Consideration on immunotherapy of liver metastases of malignant tumors

In this editorial,we comment on the article“Analysis of the impact of immuno-therapy efficacy and safety in patients with gastric cancer and liver metastasis”by Liu et al that was published in the recent issue of the World Journal of Gastroin-testinal Surgery.It has prompted us to think and summarize some thoughts on immunotherapy for malignant tumor liver metastasis.Immunotherapy plays a crucial role in the treatment of malignant tumors;however,the presence of liver metastases in advanced tumors may impact its efficacy.Although patients with liver metastases can still benefit from immunotherapy,multiple clinical studies have indicated that,compared to other sites of metastasis,liver metastases may diminish the effectiveness of immunotherapy.The efficacy of immune checkpoint inhibitors in patients with liver metastases often fails to reach the ideal level,primarily due to the liver metastases exploiting the host's peripheral immune to-lerance mechanisms to promote systemic CD8(+)T cell exhaustion,resulting in a systemic immune-tolerant environment.This article aims to summarize the reasons for the decreased efficacy of immunotherapy following liver metastasis in various malignant tumors and propose potential clinical strategies for manage-ment.

Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics

Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.

Treatment of osteoarthritis by implantation of Mg- and WE43-cylinders - A preclinical study on bone and cartilage changes and their influence on pain sensation in rabbits

With its main features of cartilage degeneration, subchondral bone sclerosis and osteophyte formation, osteoarthritisrepresents a multifactorial disease with no effective treatment options. As biomechanical shift in thetrabecular network may be a driver for further cartilage degeneration, bone enhancement could possibly delayOA progression. Magnesium is known to be osteoconductive and already showed positive effects in OA models.We aimed to use magnesium cylinders to enhance subchondral bone quality, condition of cartilage and painsensation compared to sole drilling in vivo. After eight weeks of implantation in rabbits, significant increase insubchondral bone volume and trabecular thickness with constant bone mineral density was found indicatingfavored biomechanics. As representative for pain, a higher number of CD271+ vessels were present in controlsamples without magnesium. However, this result could not be confirmed by sensitive, objective lamenessevaluation using a pressure sensing mat and no positive effect could be shown on either cartilage degenerationevaluated by OARSI score nor the presence of regenerative cells in CD271-stained samples. The presented resultsshow a relevant impact of implanted magnesium on key structures in OA pain with missing clinical relevanceregarding pain. Further studies with shifted focus should examine additional structures as joint capsule orosteophytes.

Burden of malignant mesothelioma in China during 1990-2019 and the projections through 2029

Objective:To provide the most up-to-date data on the burden of malignant mesothelioma(MM)and the projections through 2029 in China.Methods:Data on patients diagnosed with MM from China during 1990-2019 were obtained from the Global Burden of Disease(GBD)2019 database,including annual cases and deaths data and age-standardized rates of incidence,mortality,and disability-adjusted life-years(DALYs)associated with MM among different age groups.Temporal trends during 1990-2019 were analyzed by the Joinpoint regression models using 95%confidence interval(CI),while the projections through 2029 were calculated by the Bayesian age-period-cohort model.Data on the production and consumption of asbestos in China were obtained from the United States Geological Survey on Mineral Commodity Summaries during 1996-2023.Results:We observed a significant elevation in incident new cases and deaths over the last 3 decades,increasing from 1193 in 1990 to 2815 in 2019 for incident cases and from 1134 in 1990 to 2773 in 2019 for death cases.We found a roughly 6%increase in the proportion of incident cases for those aged>70 years(30%in 2019 versus 24%in 1990),while for the proportion of deaths similar elevation for those aged>70 years was found.Additionally,men had significantly higher DALYs due to MM across age groups compared with women.Asbestos consumption in China dramatically dropped since 2012 and reached the bottom in 2017 with 230 kilotons.By 2029,the projected age-standardized rate for incidence and mortality is expected to reach 1.2 per million for both.Conclusion:We found,for the first time using GBD data on the Chinese population,that the burden of MM has been significantly increasing in China over the last three decades and will continue to increase in the upcoming decade,suggesting an urgent need for a complete ban on chrysotile asbestos in China.

Biomarkers for immune checkpoint inhibitors in colorectal cancer:recent advances and future perspectives

Colorectal cancer(CRC)has become a major threat to human health.Recent years,improvements have been seen in the treatment of advanced CRC with immune checkpoint inhibitors(ICIs).Nonetheless,sensitivity to ICIs notably varies among patients,thus greatly limiting clinical applications of ICIs in CRC.Hence,the identification of biomarkers that can accurately distinguish between ICI-sensitive and drug-resistant patients is of utmost importance.Such biomarkers are essential for selecting appropriate treatment regimens and achieving precision therapy(Figure 1).The biomarkers discussed below provide insights into the advancements made in this field(Table 1).

Recent developments in application of single-cell RNA sequencing in the tumour immune microenvironment and cancer therapy

The advent of single-cell RNA sequencing(scRNA-seq)has provided insight into the tumour immune microenvironment(TIME).This review focuses on the application of scRNA-seq in investigation of the TIME.Over time,scRNA-seq methods have evolved,and components of the TIME have been deciphered with high resolution.In this review,we first introduced the principle of scRNA-seq and compared different sequencing approaches.Novel cell types in the TIME,a continuous transitional state,and mutual intercommunication among TIME components present potential targets for prognosis prediction and treatment in cancer.Thus,we concluded novel cell clusters of cancerassociated fibroblasts(CAFs),T cells,tumour-associated macrophages(TAMs)and dendritic cells(DCs)discovered after the application of scRNA-seq in TIME.We also proposed the development of TAMs and exhausted T cells,as well as the possible targets to interrupt the process.In addition,the therapeutic interventions based on cellular interactions in TIME were also summarized.For decades,quantification of the TIME components has been adopted in clinical practice to predict patient survival and response to therapy and is expected to play an important role in the precise treatment of cancer.Summarizing the current findings,we believe that advances in technology and wide application of single-cell analysis can lead to the discovery of novel perspectives on cancer therapy,which can subsequently be implemented in the clinic.Finally,we propose some future directions in the field of TIME studies that can be aided by scRNA-seq technology.

DegraPol支架上培养人气管软骨细胞体外合成组织工程软骨

目的探讨以人气管软骨细胞(HTC)为种子细胞在新型生物材料DegraPol泡沫支架上体外合成组织工程气管软骨的可行性。方法从肺移植供体(9例)取人气管软骨片段,胶原酶消化,将所获软骨细胞传代培养,将传代至6～8代的HTC种植到DegraPol支架上体外静态培养。种植前行II型胶原免疫组织化学染色。于体外静态培养第2小时末和第3、7、21、42天取HTC-DegraPol复合物用噻唑蓝(MTT)法测定细胞增殖活性;培养3周后取HTC-DegraPol复合物制备组织学检测标本行阿辛蓝染色观察硫酸软骨素分泌情况,并制备扫描电镜标本观察HTC在DegraPol支架中培养后的超微结构。结果HTC在传代培养中显示稳定的增殖活性并分泌II型胶原。种植到DegraPol支架中后培养2h和3、7、21、42d时MTT法测定的A值分别为0.112±0.004、0.151±0.021、0.170±0.035、0.176±0.023和0.213±0.023(每个时点n=4)。培养21、42d与培养2h比较,活性HTC数量差异均有统计学意义(P<0.05)。阿辛蓝染色显示HTC-DegraPol复合物的基质分泌硫酸软骨素,证实HTC-DegraPol复合物具有软骨样结构。扫描电镜观察显示新生软骨在DegraPol材料表面和中央均有形成,但以表面为主。结论HTC可以在体外良好扩增并以多孔生物材料DegraPol为支架体外合成组织工程气管软骨,但培养条件应进一步优化。

Analysis of variabilities of serum proteomic spectra in patients with gastric cancer before and after operation

AIM： To study the variabilities of serum proteomic spectra in patients with gastric cancer before and after operation in order to detect the specific protein markers that can be used for quick diagnosis of gastric cancer. METHODS： Proteomic spectra of 46 serum samples from patients with gastric cancer before and after operation and 40 from normal individuals were generated by IMAC-Cu protein chip and surface-enhanced laser desorption/ionization time of flight mass spectrometry. RESULTS： Fourteen differentially expressed proteins in serum were screened by analysis of proteomic spectra of preoperative patients and normal individuals. We obtained 4 proteins （heat shock protein 27, glucoseregulated protein, prohibitin, protein disulfide isomerase A3） making up marker pattern which was able to class the patient-team and normal-team. These marker patterns yielded 95.7% sensitivity and 92.5% specificity, respectively. The proteins over-expressed in serum of preoperative patients were obviously down-regulated. CONCLUSION： Specific protein markers of gastric cancer can be used for the quick diagnosis of gastric cancer and judgment of prognosis. SELDI-TOF-MS is a useful tool for the detection and identification of new protein markers in serum.

CacyBP/SIP nuclear translocation induced by gastrin promotes gastric cancer cell proliferation

AIM: To investigate the role of nuclear translocation of calcyclin binding protein, also called Siah-1 interacting protein (CacyBP/SIP), in gastric carcinogenesis.

Total mesopancreas excision for pancreatic head cancer: analysis of 120 cases

Objective： To evaluate the feasibility and safety of total mesopancreas excision （TMpE） in the treatment of pancreatic head cancer. Methods： The clinical and pathological data of 120 patients with pancreatic head cancer who had undergone TMpE in our center from May 2010 to January 2014 were retrospectively analyzed. Results： The mean operative time was （275.0±50.2） min and the average intra-operative blood loss was （390.0±160.5） mL. Post-operative complications were reported in 45 patients, while no peri-operative death was noted. The specimen margins were measured in three dimensions, and 86 patients （71.6%） achieved R0 resection. Conclusions： TMpE is safe and feasible for pancreatic head cancer and is particularly helpful to increase the R0 resection rate.

Prognostic signif icance of HIF-2α/EPAS1 expression in hepatocellular carcinoma

AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.

Overview of studies of the vitamin D/vitamin D receptor system in the development of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the world.NAFLD is known to be associated with obesity,type 2 diabetes,metabolic syndrome and increased cardiovascular events:for these reasons,it is becoming a global public health problem and represents an important challenge in terms of prevention and treatment.The mechanisms behind the pathogenesis of NAFLD are multiple and have not yet been completely unraveled;consequently,at moment there are not effective treatments.In the past few years a large body of evidence has been assembled that attributes an important role in hepatic aberrant fat accumulation,inflammation and fibrosis,to the vitamin D/vitamin D receptor(VD/VDR)axis,showing a strong association between hypovitaminosis D and the diagnosis of NAFLD.However,the data currently available,including clinical trials with VD supplementation,still provides a contrasting picture.The purpose of this editorial is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to VD/VDR.Based on recent data from literature,we focused in particular on the hypothesis that VDR itself,independently from its traditional ligand VD,may have a crucial function in promoting hepatic fat accumulation.This might also offer new possibilities for future innovative therapeutic approaches in the management of NAFLD.

Disrupted NF-κB activation after partial hepatectomy does not impair hepatocyte proliferation in rats

AIM： To analyze the effects of NF-kB inhibition by antioxidant pyrrolidine dithiocarbamate （PDTC） or TNF inhibitor pentoxifylline （PTX） on liver regeneration after partial hepatectomy （PH）. METHODS： Saline, PDTC or PTX were injected 1 h before PH and rats were killed at 0.5 and 24 h after PH. Several control groups were used for comparison （injection control groups）. RESULTS： Compared to saline injected controls, NF-kB activation was absent 0.5 h after PH in rats treated with PDTC or PTX. At 24 h after PH, DNA synthesis and PCNA expression were identical in treated and control rats and thus occurred irrespectively of the status of NF-kB activation at 0.5 h. Signal transducer and activator of transcription 3 （Stat3） acUvatJon was observed already 0.5 h after PH in saline, PDTC or PTX group and was similar to Stat3 activation in response to injection without PH. CONCLUSION： These data strongly suggest that （1） NF-kB p65/p50 DNA binding produced in response to PH is not a signal necessary to initiate the liver regeneration, （2） star3 activation is a stress response unrelated to the activation of NF-kB. In conclusion, NF-kB activation is not critically required for the process of liver regeneration after PH.

m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor(TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors(HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatmentwith the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight(75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin(TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mT OR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells

AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-&#x003b1;)-induced gene expression in human gastric adenocarcinoma cells.

Comparison of Three Experimental Models for Rat Osteoarthritis Induction

Background: Osteoarthritis is a slowly progressive and debilitating disease with high prevalence in adult population. Knee is one of the joints most affected by this disorder. There are several models for animals’ osteoarthritis induction, however it is not identified any paper that compares these techniques. The present study was aimed to define the most appropriate model for rats osteoarthritis induction. Material and Methods: 40 Wistar rats were distributed into 4 groups of 10 animals each: normality group (NG);meniscectomy group (MG);quinolone group (QG) and iodoacetate group (IG). Radiographic images of the rat’s knees were analyzed as well as the amount of chondrocytes in the epiphyseal and articular cartilage. Results: In the radiographic analysis, there was a low correlation between the raters. Regarding the amount of chondrocytes in the epiphyseal cartilage, it was noticed that the IG and QG groups had fewer chondrocytes than NG, in contrast to MG that reported similar results to normality (p > 0.05). There was no significant difference between IG and QG groups (p > 0.05). Regarding the amount of chondrocytes in articular cartilage, it was noticed that the IG group showed fewer chondrocytes than NG (p 0.05). There was no significant difference between QG and MG groups (p > 0.05). Conclusion: Intraarticular injection of iodoacetate in rats is the model with greatest effect on reduction of chondrocytes amount.

旋转生物反应器培养对组织工程气管软骨力学强度的影响

目的研究旋转生物反应器培养对组织工程气管软骨力学强度的影响,探索适宜的组织工程气管软骨培养方法。方法分离2周龄Lewis大鼠剑突软骨细胞传代培养,收集第3代软骨细胞种植到DegraPol管状支架上,静态培养7d,然后将软骨细胞-支架复合物分别置于旋转生物反应器内培养(生物反应器组)或继续静态培养培养3周(静态培养组)。取出软骨细胞-支架复合物,以噻唑蓝(MTT)法测定软骨细胞增殖活性,结果以吸光度(A)值表示(每组n=6);以Zwick1445型材料试验机测定软骨细胞-支架复合物的最大应变值和应力值(每组n=4);并制备扫描电镜标本,观察软骨细胞在DegraPol支架中培养后的超微结构变化。结果不同条件下培养3周,生物反应器组和静态培养组A值分别0.17±0.05、0.12±0.01,最大应力值分别为(0.33±0.04)和(0.26±0.01)MPa,最大应变值分别为(3.53±0.91)和(1.71±0.13)mm/mm,2组间3项指标的差异均有统计学意义(均P<0.05)。扫描电镜观察显示生物反应器组获得更好的软骨样结构和更多的细胞外基质。结论旋转生物反应器能够提供更好的体外培养条件,有利于组织工程气管软骨的形成。

Genetic mutations associated with sensitivity to neoadjuvant chemotherapy in metastatic colon cancer:A case report and review of literature

BACKGROUND Colorectal liver metastases(CLM)occur in 15%-30%of patients with colorectal cancer(CRC).Advancements in next generation sequencing(NGS)can provide more precise prognoses for cancer patients and help guide clinical treatment.However,the genetic variants that predict high sensitivity to neoadjuvant chemotherapy remain unclear,especially in patients with CLM.The aim of this study was to identify the relevant genetic variants in a single CLM patient and to summarize the current evidence on mutations and single nucleotide polymorphisms(SNPs)that objectively predict sensitivity to neoadjuvant chemotherapy.CASE SUMMARY A 76-year-old male patient,who was diagnosed as stage IV colon cancer with liver metastases,was found to have APC/TP53/KRAS mutations.He showed a good therapeutic response to 12 courses of oxaliplatin regimens combined with Bevacizumab.Genetic analysis of the patient identified 5 genes with 7 detected SNPs that may be related to a better response to chemotherapy drugs.In addition,a critical literature review was performed based on a standardized appraisal form after selecting the articles.Ultimately,21 eligible studies were appraised to assess the association between gene mutations and good prognosis.Mutations in KRAS,TP53,SMAD4,and APC were identified as being associated with a poor response to chemotherapy drugs,whereas mutations of CREBBP and POLD1 were associated with longer overall survival.CONCLUSION NGS can identify precise predictors of response to neoadjuvant chemotherapy,leading to improved outcomes for CRC patients.