Laparoscopic gastric surgery for cancer: Where do we stand?

Gastric cancer poses a significant public health problem, especially in the Far East, due to its high incidence in these areas. Surgical treatment and guidelines have been markedly different in the West, but nowadays this debate is apparently coming to an end. Laparoscopic surgery has been employed in the surgical treatment of gastric cancer for two decades now, but with controversies about the extent of resection and lymphadenectomy. Despite these difficulties, the apparent advantages of the laparoscopic approach helped its implementation in early stage and distal gastric cancer, with an increase on the uptake for distal gastrectomy for more advanced disease and total gastrectomy. Nevertheless, there is no conclusive evidence about the laparoscopic approach yet. In this review article we present and analyse the current status of laparoscopic surgery in the treatment of gastric cancer.

Current and future role of three-dimensional modelling technology in rectal cancer surgery:A systematic review

BACKGROUND Three-dimensional(3D)modelling technology translates the patient-specific anatomical information derived from two-dimensional radiological images into virtual or physical 3D models,which more closely resemble the complex environment encountered during surgery.It has been successfully applied to surgical planning and navigation,as well as surgical training and patient education in several surgical specialties,but its uptake lags behind in colorectal surgery.Rectal cancer surgery poses specific challenges due to the complex anatomy of the pelvis,which is difficult to comprehend and visualise.AIM To review the current and emerging applications of the 3D models,both virtual and physical,in rectal cancer surgery。METHODS Medline/PubMed,Embase and Scopus databases were searched using the keywords“rectal surgery”,“colorectal surgery”,“three-dimensional”,“3D”,“modelling”,“3D printing”,“surgical planning”,“surgical navigation”,“surgical education”,“patient education”to identify the eligible full-text studies published in English between 2001 and 2020.Reference list from each article was manually reviewed to identify additional relevant papers.The conference abstracts,animal and cadaveric studies and studies describing 3D pelvimetry or radiotherapy planning were excluded.Data were extracted from the retrieved manuscripts and summarised in a descriptive way.The manuscript was prepared and revised in accordance with PRISMA 2009 checklist.RESULTS Sixteen studies,including 9 feasibility studies,were included in the systematic review.The studies were classified into four categories:feasibility of the use of 3D modelling technology in rectal cancer surgery,preoperative planning and intraoperative navigation,surgical education and surgical device design.Thirteen studies used virtual models,one 3D printed model and 2 both types of models.The construction of virtual and physical models depicting the normal pelvic anatomy and rectal cancer,was shown to be feasible.Within the clinical context,3D models were used to identify vascular anomalies,for surgical planning and navigation in lateral pelvic wall lymph node dissection and in management of recurrent rectal cancer.Both physical and virtual 3D models were found to be valuable in surgical education,with a preference for 3D printed models.The main limitations of the current technology identified in the studies were related to the restrictions of the segmentation process and the lack of 3D printing materials that could mimic the soft and deformable tissues.CONCLUSION 3D modelling technology has potential to be utilised in multiple aspects of rectal cancer surgery,however,it is still at the experimental stage of application in this setting.

Use of artificial intelligence in total mesorectal excision in rectal cancer surgery: State of the art and perspectives

BACKGROUND Colorectal cancer is a major public health problem,with 1.9 million new cases and 953000 deaths worldwide in 2020.Total mesorectal excision(TME)is the standard of care for the treatment of rectal cancer and is crucial to prevent local recurrence,but it is a technically challenging surgery.The use of artificial intelligence(AI)could help improve the performance and safety of TME surgery.AIM To review the literature on the use of AI and machine learning in rectal surgery and potential future developments.METHODS Online scientific databases were searched for articles on the use of AI in rectal cancer surgery between 2020 and 2023.RESULTS The literature search yielded 876 results,and only 13 studies were selected for review.The use of AI in rectal cancer surgery and specifically in TME is a rapidly evolving field.There are a number of different AI algorithms that have been developed for use in TME,including algorithms for instrument detection,anatomical structure identification,and image-guided navigation systems.CONCLUSION AI has the potential to revolutionize TME surgery by providing real-time surgical guidance,preventing complic-ations,and improving training.However,further research is needed to fully understand the benefits and risks of AI in TME surgery.

Lymph node metastasis in early gastric cancer with submucosal invasion:Feasibility of minimally invasive surgery

AIM:To explore the feasibility of pertorming minimally invasive surgery(MIS)on subsets of submucosal gastric cancers that are unlikely to have regional lymph node metastasis. METHODS:A total of 105 patients underwent radical gastrectomy with lymph node dissection for submucosal gastric cancer at our hospital from January 1995 to December 1995.Besides investigating many clinicopathological features such as tumor size,gross appearance,and differentiation, we measured the depth of invasion into submucosa minutely and analyzed the clinicopathologic features of these patients regarding lymph node metastasis. RESULTS:The rate of lymph node metastasis in cases where the depth of invasion was<500 μm,500-2 000 μm,or >2 000 μm was 9%(2/23),19%(7136),and 33%(15/46), respectively(P<0.05).In univariate analysis,no significant correlation was found between lymph node metastasis and clinicopathological characteristics such as age,sex,tumor location,gross appearance,tumor differentiation,Lauren's classification,and lymphatic invasion.In multivariate analysis, tumor size(>4 cm vs≤2 cm,odds ratio=4.80, P=0.04)and depth of invasion(>2 000 μm vs ≤500 μm, odds ratio=6.81,P=0.02)were significantly correlated with lymph node metastasis.Combining the depth and size in cases where the depth of invasion was less than 500 μm, we found that lymph node metastasis occurred where the tumor size was greater than 4 cm.In cases where the tumor size was less than 2 cm,lymph node metastasis was found only where the depth of tumor invasion was more than 2 000 μm. CONCLUSION:MIS can be applied to submucosal gastric cancer that is less than 2 cm in size and 500 μm in depth.

Enhanced recovery after surgery:Current research insights and future direction

Since the concept of enhanced recovery after surgery(ERAS)was introduced in the late 1990 s the idea of implementing specific interventions throughout the perioperative period to improve patient recovery has been proven to be beneficial. Minimally invasive surgery is an integral component to ERAS and has dramatically improved post-operative outcomes. ERAS can be applicable to all surgical specialties with the core generic principles used together with added specialty specific interventions to allow for a comprehensive protocol,leading to improved clinical outcomes. Diffusion of ERAS into mainstream practice has been hindered due to minimal evidence to support individual facets and lack of method for monitoring and encouraging compliance. No single outcome measure fully captures recovery after surgery,rather multiple measures are necessary at each stage. More recently the pre-operative period has been the target of a number of strategies to improve clinical outcomes,described as prehabilitation. Innovation of technology in the surgical setting is also providing opportunities to overcome the challenges within ERAS,e.g.,the use of wearable activity monitors to record information and provide feedback and motivation to patients peri-operatively. Both modernising ERAS and providing evidence for key strategies across specialties will ultimately lead to better,more reliable patient outcomes.

Prognostic implication of isolated tumor cells and micrometastases in regional lymph nodes of gastric cancer

AIM： To determine the prognostic significance of isolated tumor cells （ITCs） and lymph node micrometastases in gastric cancer. METHODS： Hematoxylin and eosin-stained slides of lymph node dissections of 632 consecutive gastric cancers were reviewed. Cytokeratin immunostaining was performed in 280 node-negative cases and 5 cases indefinite for lymph node metastases. Lymph node metastases were divided into ITCs, micrometastases, or macrometastases, according to the sizes of tumor deposits in largest dimension. ITCs were further classified into four groups according to metastasis pattern. RESULTS： Lymph node metastases were identified by immunostaining in 58 of 280 node-negative cases （20.7%） and were not significantly associated with patient survival （P = 0.3460）. After cytokeratin immunostaining, 196 cases were classified as pN1, which consisted of 20 cases with micrometastases detected by immunostaining （pNlmi（i＋））, 34 cases with only micrometastases （pNlmi）, and 142 cases with pN1 with one or more macrometastases （pN1）. Cases with pNlmi and pNlmi（i＋） had a significantly better prognosis than the cases with pN1 （P = 0.0037）. ITCs were found in 38 of these 58 cases, and could be divided into four groups： 12 cases with only a single cell pattern, 7 cases with multiple individual cells, 5 cases with single small cluster, and 14 cases with multiple small clusters. Among these four groups, cases with ITCs of multiple individual cell pattern showed the worst survival （median survival： 28 mo, P〈0.0001）.CONCLUSION： Both size and pattern of lymph node metastases can give prognostic information on the survival of gastric cancer patients.

Detection and management of oligometastatic disease in oesophageal cancer and identification of prognostic factors: A systematic review

BACKGROUND Oesophageal cancer is the eighth most common cancer worldwide.The prognosis of oesophageal cancer patients still remains poor.The 5-year survival rate rarely exceeds 5%in case of metastatic disease.Some patients may however present with oligometastasis which can be treated with loco-regional therapy.AIM To assess the current practice regarding the management of patients with oligometastatic oesophageal cancer and identify prognostic factors affecting survival following treatment for oligometastasis.METHODS A systematic search of the literature was performed in Cochrance Library,MEDLINE and EMBASE databases from September 1950 to January 2019.Relevant electronic databases were searched for studies assessing the clinical outcome of oligometastasis.RESULTS A total of 14 publications were included,of which 12 studies assessing metachronous oligometastasis and 2 on synchronous oligometastasis.All included articles evaluated the specific outcomes of metastasis,management modality and survival outcomes.The majority of the patients presented with oesophageal squamous cell carcinoma.The median disease free interval(time to recurrence)in patients was 19.6 mo and the overall survival reached 30.8 months.Unfavourable prognostic factors were assessed in eight studies and included time to recurrence<12 mo,large diameter pulmonary lesions(>20 mm),disease free interval(DFI)<12 mo,extra-pulmonary metastasis,primary tumour pathological stage III/IV.CONCLUSION Oligometastatic oesophageal cancer in selected patients is amenable to locoregional treatment,and the overall survival of this patient cohort may be improved with patient and tumour-specific treatments.

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases

AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).

Use of three-dimensional printing in preoperative planning in orthopaedic trauma surgery: A systematic review and meta-analysis

BACKGROUND With the increasing complexity of surgical interventions performed in orthopaedic trauma surgery and the improving technologies used in threedimensional(3D)printing,there has been an increased interest in the concept.It has been shown that 3D models allow surgeons to better visualise anatomy,aid in planning and performing complex surgery.It is however not clear how best to utilise the technique and whether this results in better outcomes.AIM To evaluate the effect of 3D printing used in pre-operative planning in orthopaedic trauma surgery on clinical outcomes.METHODS We performed a comprehensive systematic review of the literature and a metaanalysis.Medline,Ovid and Embase were searched from inception to February 8,2018.Randomised controlled trials,case-control studies,cohort studies and case series of five patients or more were included across any area of orthopaedic trauma.The primary outcomes were operation time,intra-operative blood loss and fluoroscopy used.RESULTS Seventeen studies(922 patients)met our inclusion criteria and were reviewed.The use of 3D printing across all specialties in orthopaedic trauma surgery demonstrated an overall reduction in operation time of 19.85%[95%confidence intervals(CI):(-22.99,-16.71)],intra-operative blood loss of 25.73%[95%CI:(-31.07,-20.40)],and number of times fluoroscopy was used by 23.80%[95%CI:(-38.49,-9.10)].CONCLUSION Our results suggest that the use of 3D printing in pre-operative planning in orthopaedic trauma reduces operative time,intraoperative blood loss and the number of times fluoroscopy is used.

Point-of-care testing in the diagnosis of gastrointestinal cancers: Current technology and future directions

Point-of-care(POC) tests enable rapid results and are well established in medical practice.Recent advances in analytical techniques have led to a new generation of POC devices that will alter gastrointestinal diagnostic pathways.This review aims to identify current and newtechnologies for the POC diagnosis of gastrointestinal cancer.A structured search of the Embase and Medline databases was performed.Papers reporting diagnostic tests for gastrointestinal cancer available as a POC device or containing a description of feasibility for POC application were included.Studies recovered were heterogeneous and therefore results are presented as a narrative review.Six diagnostic methods were identified(fecal occult blood, fecal proteins, volatile organic compounds, pyruvate kinase isoenzyme type M2, tumour markers and DNA analysis).Fecal occult blood testing has a reported sensitivity of 66%-85% and specificity greater than 95%.The others are at a range of development and clinical application.POC devices have a proven role in the diagnosis of gastrointestinal cancer.Barriers to their implementation exist and the transition from experimental to clinical medicine is currently slow.New technologies demonstrate potential to provide accurate POC tests and an ability to diagnose gastrointestinal cancer at an early stage with improved clinical outcome and survival.

Coordinated AR and microRNA regulation in prostate cancer

The androgen receptor(AR)remains a key driver of prostate cancer(PCa)progression,even in the advanced castrate-resistant stage,where testicular androgens are absent.It is therefore of critical importance to understand the molecular mechanisms governing its activity and regulation during prostate tumourigenesis.MicroRNAs(miRs)are small w22 nt noncoding RNAs that regulate target gene,often through association with 30 untranslated regions(30UTRs)of transcripts.They display dysregulation during cancer progression,can function as oncogenes or tumour suppressors,and are increasingly recognised as targets or regulators of hormonal action.Thus,understanding factors which modulate miRs synthesis is essential.There is increasing evidence for complex and dynamic bi-directional cross-talk between the multi-step miR biogenesis cascade and the AR signalling axis in PCa.This review summarises the wealth of mechanisms by which miRs are regulated by AR,and conversely,how miRs impact AR’s transcriptional activity,including that of AR splice variants.In addition,we assess the implications of the convergence of these pathways on the clinical employment of miRs as PCa biomarkers and therapeutic targets.

Phytochemically rich dietary components and the risk of colorectal cancer:A systematic review and meta-analysis of observational studies

BACKGROUND Personalized nutrition and protective diets and lifestyles represent a key cancer research priority.The association between consumption of specific dietary components and colorectal cancer(CRC)incidence has been evaluated by a number of population-based studies,which have identified certain food items as having protective potential,though the findings have been inconsistent.Herein we present a systematic review and meta-analysis on the potential protective role of five common phytochemically rich dietary components(nuts,cruciferous vegetables,citrus fruits,garlic and tomatoes)in reducing CRC risk.AIM To investigate the independent impact of increased intake of specific dietary constituents on CRC risk in the general population.METHODS Medline and Embase were systematically searched,from time of database inception to January 31,2020,for observational studies reporting CRC incidence relative to intake of one or more of nuts,cruciferous vegetables,citrus fruits,garlic and/or tomatoes in the general population.Data were extracted by two independent reviewers and analyzed in accordance with the Meta-analysis of Observational Studies in Epidemiology(MOOSE)and Preferred Reporting Items for Systematic Review and Meta-analysis(PRISMA)reporting guidelines and according to predefined inclusion/exclusion criteria.Effect sizes of studies were pooled using a random-effects model.RESULTS Forty-six studies were identified.CRC risk was significantly reduced in patients with higher vs lower consumption of cruciferous vegetables[odds ratio(OR)=0.90;95%confidence interval(CI):0.85-0.95;P<0.005],citrus fruits(OR=0.90;95%CI:0.84-0.96;P<0.005),garlic(OR=0.83;95%CI:0.76-0.91;P<0.005)and tomatoes(OR=0.89;95%CI:0.84-0.95;P<0.005).Subgroup analysis showed that this association sustained when looking at case-control studies alone,for all of these four food items,but no significant difference was found in analysis of cohort studies alone.Nut consumption exhibited a similar trend,but overall results were not significant(OR=0.72;95%CI:0.50-1.03;P<0.07;I2=90.70%).Putative anticarcinogenic mechanisms are proposed using gene-set enrichment analysis of gene/protein perturbations caused by active compounds within each food item.CONCLUSION Increased cruciferous vegetable,garlic,citrus fruit and tomato consumption are all inversely associated with CRC risk.These findings highlight the potential for developing precision nutrition strategies for CRC prevention.

Vaccinia-related kinase 2 variants differentially affect breast cancer growth by regulating kinase activity

Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.

Role and regulation of the forkhead transcription factors FOXO3a and FOXM1 in carcinogenesis and drug resistance

The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.

Sox2, a key factor in the regulation of pluripotency and neural differentiation

Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogram-ming, reversing the epigenetic configuration of differ-entiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mecha-nisms underlying these roles.

Hepatocellular carcinoma: Review of disease and tumor biomarkers

Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.

Laparoscopic vs open approach to resection of hepatocellular carcinoma in patients with known cirrhosis:Systematic review and meta-analysis

AIM: To review the currently available literature comparing laparoscopic to open resection of hepatocellular carcinoma (HCC) in patients with known liver cirrhosis.

Hepatic ischemia-reperfusion injury in liver transplant setting:mechanisms and protective strategies

Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure,and is of increasing significance due to increased use of expanded criteria livers for transplantation.This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation.Pharmacological therapies,the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies.The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury,and is an exciting and active area of research,which needs more study clinically.

Radiofrequency combined with immunomodulation for hepatocellular carcinoma: State of the art and innovations

Hepatocellular carcinoma(HCC)is the most common primary liver tumor and has been considered a very immunogenic tumor.The treatment with radiofrequency ablation(RFA)has been established as the standard ablative therapy for early HCC,and is currently recognized as the main ablative tool for HCC tumors<5 cm in size;however,progression and local recurrence remain the main disadvantages of this approach.To solve this clinical problem,recent efforts were concentrated on multimodal treatment,combining different strategies,including the combination of RFA and immunotherapy.This article reviewed the combination treatment of RFA with immunotherapy and found that this treatment strategy leads to an increased response of anti-tumor T cells,significantly reduces the risk of recurrence and improves survival rates compared to RFA alone.This review highlighted scientific evidence that supports the current recommendations for pre-clinical studies,and discuss the need for further research on this topic.

Liver transplantation and multivisceral transplantation in the management of patients with advanced neuroendocrine tumours

Orthotopic liver transplantation(OLT) represents a generally accepted albeit somewhat controversially discussed therapeutic strategy in highly selected patients with non-resectable hepatic metastases from neuroendocrine tumours(NET). Whilst there are some exclusion criteria, these are not universally followed, and the optimal set of inclusion parameters for deeming patients eligible has not yet been elucidated. This is due to heterogeneity in the study populations, as well differing approaches employed and also divergences in selection criteria between centres. Recent data have suggested that OLT may represent the most efficacious approach in terms of overall and disease-free survival to the management of NET metastatic to the liver when conducted in accordance with the modified Milan criteria. Therefore, a consensus set of selection criteria requires definition to facilitate stringent and fair allocation of deceased-donor organs, as well as consideration for living-donor organs. In the context of classically non-resectable metastatic tumour bulk, multivisceral transplantation with or without the liver may also be indicated, yet experience is very limited. In this review, we discuss the diagnostic work-up of patients in whom the aforementioned transplantation approaches are being considered, critically analyse the published experience and also anticipate future developments in this field, including a discussion of immediate and longer-term research priorities.