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Background Postoperative delirium (POD) is considered as a relatively common and serious problem after major abdominal surgery procedures. It is presumed to be preventable in most of cases. The purpose of this study was to develop and evaluate a POD prediction model for patients undergoing abdominal surgery. Methods From July 2019 to December 2019, patients underwent elective abdominal surgery in our hospital were retrospectively analyzed, and their demographics, pre-operative evaluation, intra-operative and anesthesiologic factors were recorded. Based on the results of the multivariate regression analyzes using P

Long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) plays important roles in the pathogenesis and progression of cancers. However, the role of SNHG12 in the metastasis of gastric cancer (GC) has not yet been thoroughly investigated. In the present study, we demonstrated that SNHG12 was upregulated in GC tissues and cell lines. In addition, the expression level of SNHG12 in GC samples was significantly related to tumor invasion depth, TNM stage and lymph node metastasis and was associated with disease-free survival (DFS) and overall survival (OS) in GC patients. In vivo and in vitro assays indicated that SNHG12 promotes GC metastasis and epithelial-mesenchymal transition (EMT). Bioinformatics and mechanistic analyses revealed that SNHG12 can directly target miR-218-5p to regulate YWHAZ mRNA, forming an SNHG12/miR-218-5p/YWHAZ axis and decreasing the ubiquitination of β-catenin. In addition, SNHG12 stabilizes CTNNB1 mRNA by binding with HuR, thus activating the β-catenin signaling pathway. Further analysis also revealed that the transcription factor YY1 negatively modulates SNHG12 transcription. In conclusion, SNHG12 is a potential prognostic marker and therapeutic target for GC. Negatively modulated by YY1, SNHG12 promotes GC metastasis and EMT by regulating the miR-218-5p/YWHAZ axis and stabilizing CTNNB1 via activation of the β-catenin signaling pathway.

Introduction Gastric cancer (GC) is a common malignant tumor with a high mortality rate. Aim To determine the accuracy of preoperative imaging information obtained from the combined use of general gastroscopy (GS), endoscopic ultrasonography (EUS), and multi-detector computed tomography (MDCT) regarding absolute indication of endoscopic submucosal dissection (ESD) in early gastric cancer (EGC). Material and methods The relationship between clinical features of 794 EGC patients and lymph node metastasis (LNM) was analyzed. Multivariate logistic regression analysis was used to investigate the risk factors for LNM. Additionally, the accuracy of diagnosis of imaging techniques for ESD indications was determined by receiver operating characteristic (ROC) analysis. Results Data showed that tumor size > 2 cm (p = 0.0071), T1b stage (p < 0.0001), undifferentiated histology (p < 0.0001), and vascular invasion (p = 0.0007) were independent risk factors for LNM in patients with EGC. Indications for ESD have a specificity of 100% for the diagnosis of patients with LNM. Additionally, the diagnostic efficacy of the use of GS, EUS, and MDCT in identifying node positive status, T1a disease, tumor size ≤ 2 cm, and ulceration was found to be moderate with area under the curve (AUC) of receiver operating characteristic curve (ROC) of 0.71, 0.64, 0.72, and 0.68, respectively. Furthermore, the use of imaging techniques for overall indication criteria for ESD had a moderate utility value with an AUC of 0.71. Conclusions Our data suggested that, based on the combined use of GS, EUS, and MDCT, a high specificity of patient selection for ESD treatment can be achieved.

The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/mOf 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

Summary: Background: Endoscopic submucosal dissection (ESD) has gained more popularity in the treatment of early gastric cancer (EGC). Although there is a lack of confirmed evidence for the feasibility of ESD for undifferentiated EGC. The aim of the study was to investigate the feasibility of ESD with expanded indications for undifferentiated EGC patients. Methods: Data from patients with undifferentiated EGC (including signet-ring cell carcinoma, mucinous adenocarcinoma, mixed adenocarcinoma, and poorly differentiated adenocarcinoma) who underwent radical surgical resection were retrospectively reviewed. The relationship between the clinical parameters and the incidence of lymph node metastasis (LNM) was investigated. Results: A total of 517 patients were included in this study. The results showed that LNM was significantly associated with ulceration, tumor size, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate stepwise logistic regression analysis revealed that tumor size (OR = 1.61, 95% CI = 1.03–2.52, P = 0.0367), depth of tumor invasion (OR = 2.77, 95% CI = 1.66–4.63, P = 0.0001), and lymphatic invasion (OR = 14.74, 95% CI = 1.58–137.36, P = 0.0182) were independent risk factors for LNM. In the patients who would be included under the new proposed guidelines for ESD, including men with mucosal tumors ≤2 cm and without ulceration or lymphatic or venous infiltration, LNM was present in 11.9% (14/118). Conclusion: Caution to be exercised in expanding application of ESD should be carefully weighed in undifferentiated EGC. Keywords: Early gastric cancer, Endoscopic submucosal dissection, Expanded indication, Lymph node metastasis

Summary: Objective: To explore the quantitative measurements and evaluation of intra-peritoneal fat distribution by MDCT and its significance in predicting intra-operative bleeding volume during D2 lymphadenectomy in gastric cancer (GC) patients. Methods: From June 2016 to September 2017, GC patients scheduled for open gastrectomy with D2 lymph-node dissection were enrolled. According to the BMI, the subjects were then classified as normal BMI(BMI

BackgroundGastric cancer (GC) is a malignancy with high morbidity and mortality rates worldwide. SNHG12 is a long noncoding RNA (lncRNA) commonly involved many types of cancers in the contexts of tumorigenesis, migration and drug resistance. Nevertheless, its role in GC proliferation is poorly understood.MethodsBioinformatics and qRT-PCR assays were used to analyze the expression of SNHG12 in GC tissues and cells. In vitro and in vivo experiments were conducted to detect the role of SNHG12 in GC development. qRT-PCR, PCR, western blotting (WB), RNA binding protein immunoprecipitation (RIP), immunoprecipitation (IP), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) were performed to investigate the underlying mechanisms by which SNHG12 promotes GC proliferation.ResultsSNHG12 was highly expressed in GC cells and tissues, and predicted poor survival. In vitro and in vivo assays showed that SNHG12 knockdown inhibited GC proliferation, while SNHG12 overexpression promoted GC proliferation. Further experiments confirmed that SNHG12 was mainly located in the cytoplasm and bound to HuR. Bioinformatics analysis predicted that YWHAZ was the common target of SNHG12 and HuR, and that the “SNHG12-HuR” complex enhanced the stability of YWHAZ mRNA. Furthermore, YWHAZ, which was highly expressed in GC, predicted poor survival and promoted GC proliferation by phosphorylating AKT. Rescue assays verified that SNHG12 promoted GC proliferation by activating the AKT/GSK-3β pathway.ConclusionsSNHG12 binds to HuR and stabilizes YWHAZ. SNHG12 promotes GC proliferation via modulation of the YWHAZ/AKT/GSK-3β axis in vitro and in vivo. Thus, SNHG12 could become a novel therapeutic target for anti-tumor therapy.

Background: Gastric Cancer (GC) is one of the leading causes of cancer-related deaths and mortality. Long non-coding RNAs (lncRNAs) such as SNHG12 play important roles in the pathogenesis and progression of cancers. However, the role and significanve of SNHG12 in the metastasis of GC has not yet been thoroughly investigated.Methods: The SNHG12 expression pattern was detected in GC tissue samples from our faculty and cell lines using quantitative reverse transcription PCR. In vivo and in vitro gain and loss assays were conducted to observe the effects of SNHG12 regulation on GC cell metastasis potential. The underlying mechanisms of SNHG12 regulation on EMT and metastatic potential of GC cells were further determined by quantitative reverse transcription PCR, western blotting, dual luciferase reporter assays, co-immunoprecipitation, immunoprecipitation, RIP assays, TOPFlash/FOPFlash reporter assays and Ch-IP assays.Results: SNHG12 was upregulated in GC tissues and cell lines. The expression levels of SNHG12 in GC samples was significantly related to tumor invasion depth, TNM staging and lymph node metastasis, and was associated with poorer DFS and OS in the GC patients. SNHG12 was significantly highly expressed in peritoneal metastatic tissues from GC patients and mice subjects, suggesting a possible role of SNHG12 in peritoneal carcinomatosis from GC. Further in vivo and in vitro gain and loss assays indicated that SNHG12 promoted GC metastasis and EMT. Based on hypothetical bioinformatic analysis findings, our mechanistic analyses revealed that miR-218-5p was a direct target of SNHG12 and suggested that both SNHG12 and miR-218-5p could collectively regulate YWHAZ, forming the SNHG12/ miR-218-5p/YWHAZ axis, hereby decreasing the ubiquitination of β-catenin, thus activating the β-catenin signaling pathway and facilitating metastasis and EMT. Further analysis also revealed that the transcription factor YY1 could negatively modulate SNHG12 transcription.Conclusions: Our findings demonstrate that SNHG12 is be a potential prognostic marker and therapeutic target for GC. Negatively modulated by transcription factor YYI, SNHG12 promotes GC metastasis and EMT by regulating the miR-218-5p/YWHAZ axis and hence activating the β-catenin signaling pathway. Furthermore, we discovered high SNHG12 expression could be related to peritoneal carcinomatosis from GC but this requires further validation.

Background Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC). Methods In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate. Discussion This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent. Trial registration World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552, Registered Prospectively on the 16th July, 2019.

Objective: In this study we have retrospectively evaluated the feasibility and safety of a novel therapeutic regimen for the management of Advanced Gastric Cancer (AGC) at risk for peritoneal carcinomatosis (PC) involving neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (NLHIPEC) and neoadjuvant chemotherapy (NAC).Methods: From December 2017 to June 2018, 7 AGC patients undergoing NLHIPEC + NAC + Surgery+ Intraoperative HIPEC + adjuvant chemotherapy (AC) were included in the study and observed for associated complication and morbidity. AGC patients undergoing other neoadjuvant and prophylactic treatment approaches were retrospectively analyzed and case-matched. Intraoperative and post-operative events, clinical recovery and morbidity were closely monitored till 1 month after the last cycle of chemotherapy.Results: Of a total of 328 AGC patients undergoing curative surgery, 7 other patients undergoing NAC + HIPEC, 7 patients undergoing surgery + HIPEC and 17 patients undergoing NAC were retrospectively included. There was no 30-day post-operative mortality recorded in the 4 groups. In total, 14 events were recorded and 5/14 of the complications were rated as Clavien I; 8/14 patients were classified as Clavien II and 1/14 patient was recorded as Clavien grade IIIa. There was no grade IIIb-V event. The results suggest that the proposed treatment regimen is safe and feasible.Conclusions: This combination of NLHIPEC and NAC in the management of AGC at high risk for peritoneal involvement is feasible, safe, well-tolerated and worth exploring.

Background The high incidence of gastric cancer (GC) and paradoxical high prevalence of advanced stage GC, amounting to around 2/3 at time of diagnosis, have urged doctors and researchers around the world not only to ameliorate the detection rate of GC at early stages but also to optimize the clinical management of GC at advanced stages. Content We hereby recommend a more goal-oriented multimodality approach with objectives to increase survival rate and improve survival status. Based on precision and accurate clinical staging at diagnosis, we suggest that advanced stage GC (AGC) patients should be channeled into different treatment plans according to their disease status where they can be subjected to comprehensive measures involving chemo, radio, immunological, or target therapies depending on the pathophysiological behavior of their tumor. Patients assessed as potentially resectable cT4N + M0 can undergo neoadjuvant chemotherapy with intent of tumor downsizing and downgrading followed by surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) to decrease the incidence of peritoneal dissemination due to surgical trauma and adjuvant chemotherapy and radiation in cases of bulky nodal metastasis. In cases with distal metastasis, conversion therapy is recommended with the possibility of surgery of curative intent in case of favorable response. The options of alternate treatment options such as trans-catheter arterial chemoembolization (TACE) for limited liver lesions or neoadjuvant intraperitoneal plus systemic chemotherapy (NIPS) for peritoneal carcinomatosis have to be negotiated. With surgery as the cornerstone for cancer treatment, there is acknowledgment of the significance of perioperative comprehensive approaches but there has not been some consensus guiding clinical application. Henceforth, in this review, based on past literature, current guidelines and ongoing clinical trials, we have shared a proposal of the current treatment modalities in practice for the advanced stages of gastric cancer. Conclusion Even though surgery is the golden standard of radical cancer treatment, clinical reality shows that without proper perioperative management, patients undergoing radical resections manifest high rates of recurrence and metastasis. Hence, in this review, we have outlined a clinical agenda to optimize the management of advanced stage GC with objective to improve survival outcome and quality of life of patients.

Background miR-126 functions as a tumor suppressor in gastric cancer (GC), however, the clinical significance of serum miR-126 in GC remains unclear. Objective To investigate the associations of serum miR-126 level with the clinicopathological characteristics and prognosis of GC patients. Methods Quantitative real-time polymerase chain reaction was performed to examine the expression levels of miR-126 in 338 GC patients' tissues and sera, and 50 healthy controls' sera. The associations of serum miR-126 with clinicopathological characteristics and clinical outcome were evaluated. Results Compared with the matched adjacent non-tumor tissues and normal sera, miR-126 expression was significantly down-regulated in both tumor tissues and sera of GC patients. Importantly, there was a positive correlation between tissue and serum levels of miR-126 in GC patients. A reduced serum miR-126 level statistically correlated with aggressive clinicopathological characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified reduced serum miR-126 level as an independent predictor for the unfavorable prognosis of GC. Conclusions These results indicate for the first time that serum miR-126 may serve as a novel prognostic biomarker in GC.

Background miR-126 functions as a tumor suppressor in gastric cancer (GC) by negatively regulating Crk protein expression post-transcriptionally. Objective The aim of this study was to investigate the associations of miR-126 and Crk protein expression levels, alone or in combination, with the clinicopathological characteristics and prognosis of GC patients. Methods The expression levels of miR-126 and Crk protein in 338 GC patients were analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. The relationship of miR-126 and Crk protein expression with clinicopathologic characteristics and clinical outcome was evaluated. Results Compared with matched adjacent non-tumor tissues, miR-126 was significantly down-regulated while Crk protein was significantly up-regulated in tumor tissues. A reduced miR-126 expression and an elevated Crk protein expression, alone or in combination, statistically correlated with aggressive clinicopathological characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Multivariate analysis showed that combined miR-126-low/Crk protein-high expression was an independent unfavorable prognostic factor of GC. Conclusions These results indicate for the first time that miR-126 down-regulation and Crk protein up-regulation may be synergistically associated with tumor progression in GC and may predict unfavorable prognosis of GC.

Background To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study. Method Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored. Results Faster recovery of bowel function (43 ± 5 h vs 68 ± 7, P P P > 0.05). The 3 year DFS rate analysis showed that the prophylactic HIPEC group had a higher DFS rate (93% vs 65%, P = 0.0054). The peritoneal recurrence rate was lower in the HIPEC group (3% vs 23%, P Conclusion Prophylactic HIPEC with radical D2 Gastrectomy improves survival and peritoneal recurrence rates for AGC with favorable post-operative recovery at low and acceptable morbidity.

BACKGROUND Predicting lymph node metastasis (LNM) accurately is vital to design optimal treatment strategies preoperatively for gastric cancer (GC) patients. However, conventional tumor biomarkers and imaging techniques are not sufficient to predict LNM before surgery. miR-126 has been reported to play important roles in tumor metastasis which may represent a novel tumor biomarker. OBJECTIVE To assess the utility of the combination of serum miR-126 and multi-detector computed tomography (MDCT) in predicting LNM preoperatively in GC. METHODS Quantitative real-time polymerase chain reaction was performed to examine the serum miR-126 expression levels in 338 GC patients. MDCT was also performed. The cut-off value of preoperative serum miR-126 level for LNM was determined by receiver characteristic curve (ROC) analysis. Logistic regression analysis was used to determine independent predictors for LNM. RESULTS The serum miR-126 levels of GC patients with LNM were significantly lower compared with those without LNM (p< 0.05). In addition, the later the N stage was, the lower the serum miR-126 level was in GC patients (p< 0.05). With a cut-off value of 63.4, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of serum miR-126 for predicating LNM were 83.2%, 79.0%, 81.9%, 90.4% and 66.4%, respectively. The combination of serum miR-126 level and MDCT increased the accuracy of MDCT prediction for LNM from 69.2% to 86.7%. Serum miR-126 was an independent predictor for LNM. CONCLUSIONS These results indicate for the first time that the combination of serum miR-126 and MDCT is useful for the prediction of LNM in GC.

Peritoneal carcinomatosis (PC) is manifested in up to 40% of gastric cancer (GC) patients, after which their 5-year survival drops to less than 5%. The currently most acceptable treatment option for advanced GC (AGC) is systemic chemo and radio therapies with however generally very unsatisfying results and this led to a resurgence of interest in regional therapies like cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Small trials have indicated an association with prolonged survival when applying this technique to AGC manifesting with PC. High procedure-related morbidity and mortality associated with the CRS-HIPEC approach have however brought by a polemic on the merits of the latter: with the advent of regulatory approval of more effective as well as novel, more personalized treatment options in AGC, along with advances in tailoring investigational agents specifically for peritoneal delivery, there clearly is a need to outline the appropriate role of CRS-HIPEC in this disease. In a clear objective to improve the therapeutic efficiency of HIPEC, there have been immense developments in the technical aspects of this technology including the use of nanotechnology in more precise drug delivery systems (DDS) or choice of more efficient drugs such as gene-target technology, laparoscopy and so on. Henceforth, in this review, we will be highlighting the past and current status of the CRS + HIPEC procedure, shedding light on the pros and cons in order to boost up the efficiency of this multimodality approach.

In spite of the declining incidence of gastric cancer (GC) in recent years, the mortality rate is still high. The asymptomatic nature and nonspecific clinical manifestations combined with the lack of efficient screening programs delay the diagnosis of GC. Therefore, the prevalence of advanced gastric cancer (AGC) has prompted the need for aggressive and intensive treatment options. Among the various treatment options for AGC, surgery is still the mainstay. However, the efficacy of surgery alone is not established. Results from multiple randomized controlled trials suggest that preoperative chemotherapy is promising intervention for the treatment and management of AGC. The main objective of neoadjuvant chemotherapy is to downstage or control micrometastasis in resectable tumor before surgery. On the other hand, conversion chemotherapy refers to surgical treatment aiming at R0 resection after chemotherapy for originally nonresectable or marginally resectable tumors. Nevertheless, preoperative chemoradiotherapy is considered beneficial for AGC patients. Over the last few decades, the combination of chemotherapy and targeted therapy prior to surgery demonstrated great results for the treatment of AGC. The rapid developments in genomics and proteomics have heralded the era of precision medicine. The combination of preoperative chemotherapy and precision medicine may enhance survival in AGC patients.

Gastric cancer (GC) is still one of the malignant tumors with high morbidity and mortality in the world, with a 5-year survival rate of less than 30%. GC is often either asymptomatic or causes only nonspecific symptoms in its early stages, whereas when the symptoms manifest, the cancer has usually reached an advanced stage, which is one of the main causes of its relatively poor prognosis. Hence, the main focus of GC research has been on discovering new tools and technology to predict, screen and diagnose GC at an early stage which would prompt early treatment. With the tremendous advances in the OMICS technology, serum proteomics has been in the limelight of cancer research over the last few decades and has steered the development of several methods helping to understand the mechanisms underlying gastric carcinogenesis, resulting in the identification of a large number of molecular targets such as circulating tumor cells (CTCs), cell free DNA (cfDNA) and cell tumor DNA (ctDNA) and their sub-molecular components such as miRNA, that show great promise as GC biomarkers. In this review, we are underlying the recent breakthroughs about new blood markers technology for GC while scrutinizing the potential clinical use of CTCs, cfDNA, ctDNA and the role of the methylation of their sub-molecular components in the pathogenesis, diagnosis and management of GC.