The relationship between SPARC expression in primary tumor and metastatic lymph node of resected pancreatic cancer patients and patients' survival

BACKGROUND： Previous researches in pancreatic cancer demonstrated a negative correlation between secreted protein acidic and rich in cysteine （SPARC） expression in primary tumor and survival, but not for SPARC expression in lymph node. In the present study, we aimed to evaluate the SPARC expression in various types of tissues and its impact on patients＇ prognosis. METHODS： The expression of SPARC was examined by immunohistochemistry in resected pancreatic cancer specimens. Kaplan-Meier analyses and Cox proportional hazards regres- sion were applied to assess the mortality risk. RESULTS： A total of 222 tissue samples from 73 patients were collected to evaluate the SPARC expression, which included 73 paired primary tumor and adjacent normal tissues, 38 paired metastatic and normal lymph nodes. The proportion of posi tive SPARC expression in metastatic lymph node was high （32/38）, whereas in normal lymph node it was negative （0/38）. Positive SPARC expression in primary tumor cells was associ- ated with a significantly decreased overall survival （P=0.007） and disease-free survival （P=0.003）, whereas in other types of tissues it did not show a predictive role for prognosis. Univariate and multivariate analyses both confirmed this significance. CONCLUSION： SPARC can serve a dual function role as both predictor for prognosis and potentially biomarker for lymph node metastasis in resected pancreatic cancer patients.

Higher body mass index deteriorates postoperative outcomes of pancreaticoduodenectomy

Background:Previous studies presented controversies in impact of body mass index(BMI)on perioper-ative complications in pancreatectomy,and mainly focused on Western population.This study aimed to explore the impact of BMI on perioperative outcomes in Chinese patients undergoing pancreaticoduo-denectomy.Methods:Seven hundred and seven adult patients undergoing open pancreaticoduodenectomy between January 2005 and December 2016 at Ruijin Hospital were studied retrospectively and categorized as obese(BMI≥25 kg/m^2),overweight(BMI≥23 kg/m^2 and<25 kg/m^2),or normal weight(BMI≥18.5 kg/m^2 and<23 kg/m^2).Associations of these BMI groups with perioperative outcomes were evaluated.Results:The overweight and obese groups experienced higher risk of clinically related postoperative pan-creatic fistula(CR-POPF)(7.6%vs.9.9%vs.17.6%,P=0.002)and re-operation(1.1%vs.2.5%vs.5.1%,P=0.017),and longer systemic inflammation response syndrome(SIRS)duration[2(1–9)d vs.2(1–7)d vs.3(1–10)d,P=0.003]and postoperative hospital stay[19(2–84)d vs.19(7–158)d vs.23(8–121)d,P=0.023]than the normal weight group did.The multiple logistic regression models showed obese as an independent risk factor for CR-POPF(P=0.013).The multiple linear regression analysis confirmed BMI as a predictor for prolonged postoperative hospital stay(P=0.005).Conclusions:Higher BMI results in higher morbidity of Chinese patients undergoing open pancreaticoduo-denectomy.Pancreaticoduodenectomy is still a safe surgery procedure for overweight and obese patients,with intensive perioperative management.

Outcomes of robotic surgery for pancreatic ductal adenocarcinoma

Authors introduction： Qian Zhan, female, who was born in Sept, 1979. She studied in the Shanghai Second Medical University during 1998 to 2005. She majored in Clinical Medicine, and earned her master degree in 2005. In 2005, she went to the Beaujon Hospital of Paris 7th Universit3. in France, as a foreign intern. Later, she came to postgraduate work and residencies in the general surgery department of Shanghai Ruijin Hospital. Her clinical work is focused on multidisciplinary especially postoperative management for the patients with pancreatic cancer. In addition, she is a lead researcher in the pancreatic cancer group for nano based drug delivery, systems. Chenghong Peng, male, who was born in Apr, 1957. He worked in the 2nd Affiliated Hospital of Zhejiang University School of Medicine during 1989 to 2002. In 2002, Chenghong Peng came m Shanghai Ruiiin Hospital and began to take charge of general surgery department. As a pioneer in the hepatobifiopancreatic field, Chenghong Peng devoted himself in the basic and clinical research of pancreatic tmnors. He brings forth new ideas by creating ＂Pancreatic multiple treatment collaborating groups＂, which integrate the advantages of gasn＇oenterology, department, endoscopy department, radiology department, pathology deparnnent and SICU. He constantly strives for excellence in pancreatic surgery. In the previous five years, he performed more than 300 cases of pancreatectomy each year, and has accomplished more than 2,000 cases of pancreatectomy altogether, among which the resectable rate is 74%. Besides, he is also committed to laparoscopic surgery and robotic surgeD,. He has achieved more than 200 laparoscopic hepatectomies, 150 laparoscopic pancreatectomies and 500 robotic hepatobiliopancreatic surgeries （350 robotic pancreatic surgeries included）, which keeps leading position in China. In 2011, Chenghong Peng has won the first prize in 3rd international congress of CRSA, which marked that our achievement in robotic surgery was recognized by oversea peers.Background： To explore the effectiveness, safety, and efficacy of the robot-assisted surgery in the radical resection of pancreatic ductal adenocarcinoma （PDAC）. Methods： The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed. Results： Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3±118.8 min, and the mean intra-operative blood loss was 447.3±269.9 mL. Among 31 patients who underwent the distal pancreatectomy （DP）, the average operative time was 185.5±74.1 min, and the mean intra-operative blood loss was 267.1±305.3 mL. In two patients who received the middle pancreatectomy （NIP）, the average operative time was 225 rain and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2±2.6 lymph nodes were dissected, with an average hospital stay of 22.6±10.7 days. Complications were observed in 18 patients, which included pancreatic fistula （n=11）, bile leak （n=5）, anastomotic bleeding （n：2）, pancreatic fistula complicated with portal vein thrombosis （n=1）, and anastomotic bleeding complicated with acute renal failure （n=l）. Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 （15.6±5.8） months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis. Conclusions- Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post-operative recovery, and therefore can achieve the lymph node dissection scope and tumor resection margin required by the standards of radical resection for pancreatic cancer. Nevertheless, its long-term efficacy requires further validation.

Effects of neoadjuvant chemotherapy vs chemoradiotherapy in the treatment of esophageal adenocarcinoma:A systematic review and meta-analysis

BACKGROUND Neoadjuvant therapy is an essential modality for reducing the clinical stage of esophageal cancer;however,the superiority of neoadjuvant chemotherapy(nCT)or neoadjuvant chemoradiotherapy(nCRT)is unclear.Therefore,a discussion of these two modalities is necessary.AIM To investigate the benefits and complications of neoadjuvant modalities.METHODS To address this concern,predefined criteria were established using the PICO protocol.Two independent authors performed comprehensive searches using predetermined keywords.Statistical analyses were performed to identify significant differences between groups.Potential publication bias was visualized using funnel plots.The quality of the data was evaluated using the Risk of Bias Tool 2(RoB2)and the GRADE approach.RESULTS Ten articles,including 1928 patients,were included for the analysis.Significant difference was detected in pathological complete response(pCR)[P<0.001;odds ratio(OR):0.27;95%CI:0.16-0.46],30-d mortality(P=0.015;OR:0.4;95%CI:0.22-0.71)favoring the nCRT,and renal failure(P=0.039;OR:1.04;95%CI:0.66-1.64)favoring the nCT.No significant differences were observed in terms of survival,local or distal recurrence,or other clinical or surgical complications.The result of RoB2 was moderate,and that of the GRADE approach was low or very low in almost all cases.CONCLUSION Although nCRT may have a higher pCR rate,it does not translate to greater long-term survival.Moreover,nCRT is associated with higher 30-d mortality,although the specific cause for postoperative complications could not be identified.In the case of nCT,toxic side effects are suspected,which can reduce the quality of life.Given the quality of available studies,further randomized trials are required.

SNORA23 inhibits HCC tumorigenesis by impairing the 2'-O-ribose methylation level of 28S rRNA

Objective:The dysregulation of ribosome biogenesis is associated with the progression of numerous tumors,including hepatocellular carcinoma(HCC).Small nucleolar RNAs(sno RNAs)regulate ribosome biogenesis by guiding the modification of ribosomal RNAs(r RNAs).However,the underlying mechanism of this process in HCC remains elusive.Methods:RNA immunoprecipitation and sequencing were used to analyze RNAs targeted by ribosome proteins.The biological functions of SNORA23 were examined in HCC cells and a xenograft mouse model.To elucidate the underlying mechanisms,the 2′-O-ribose methylation level of r RNAs was evaluated by q PCR,and the key proteins in the PI3 K/Akt/m TOR pathway were detected using Western blot.Results:Twelve sno RNAs were found to co-exist in 4 cancer cell lines using RPS6 pull-down assays.SNORA23 was downregulated in HCC and correlated with the poor prognoses of HCC patients.SNORA23 inhibited the proliferation,migration,and invasion of HCC cells both in vitro and in vivo.We also found that SNORA23 regulated ribosome biogenesis by impairing 2′-O-ribose methylation of cytidine4506 of 28 S r RNA.Furthermore,SNORA23,which is regulated by the PI3 K/Akt/m TOR signaling pathway,significantly inhibited the phosphorylation of 4 E binding protein 1.SNORA23 and rapamycin blocked the PI3 K/AKT/m TOR signaling pathway and impaired HCC growth in vivo.Conclusions:SNORA23 exhibited antitumor effects in HCC and together with rapamycin,provided a promising therapeutic strategy for HCC treatment.

Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.

One in four patients with gastrointestinal bleeding develops shock or hemodynamic instability:A systematic review and meta-analysis

BACKGROUND Hemodynamic instability and shock are associated with untoward outcomes in gastrointestinal bleeding.However,there are no studies in the existing literature on the proportion of patients who developed these outcomes after gastrointestinal bleeding.AIM To determine the pooled event rates in the available literature and specify them based on the bleeding source.METHODS The protocol was registered on PROSPERO in advance(CRD42021283258).A systematic search was performed in three databases(PubMed,EMBASE,and CENTRAL)on 14^(th) October 2021.Pooled proportions with 95%CI were calculated with a random-effects model.A subgroup analysis was carried out based on the time of assessment(on admission or during hospital stay).Heterogeneity was assessed by Higgins and Thompson’s I^(2) statistics.The Joanna Briggs Institute Prevalence Critical Appraisal Tool was used for the risk of bias assessment.The Reference Citation Analysis(https://www.referencecitationanalysis.com/)tool was applied to obtain the latest highlight articles.RESULTS We identified 11589 records,of which 220 studies were eligible for data extraction.The overall proportion of shock and hemodynamic instability in general gastrointestinal bleeding patients was 0.25(95%CI:0.17-0.36,I^(2)=100%).In non-variceal bleeding,the proportion was 0.22(95%CI:0.14-0.31,I^(2)=100%),whereas it was 0.25(95%CI:0.19-0.32,I^(2)=100%)in variceal bleeding.The proportion of patients with colonic diverticular bleeding who developed shock or hemodynamic instability was 0.12(95%CI:0.06-0.22,I^(2)=90%).The risk of bias was low,and heterogeneity was high in all analyses.CONCLUSION One in five,one in four,and one in eight patients develops shock or hemodynamic instability on admission or during hospitalization in the case of non-variceal,variceal,and colonic diverticular bleeding,respectively.

A comprehensive review of recent advances in chronic pancreatitis

Chronic pancreatitis(CP)is a multifaceted disorder influenced by environmental and genetic factors,with smoking and alcohol consumption being major contributors.Recent developments encompass the advent of innovative transgenic models and the identification of susceptibility genes,shedding light on the genetic aspect of CP.The pathogenesis of this disease involves a complex interplay of pancreatic acinar cell dysfunction,inflammatory reactions,and fibrosis.Current research delves into understanding these molecular mechanisms.Pain,a pivotal symptom of CP,has been increasingly studied to develop effective therapeutic interventions.Diagnostic advancements,including endoscopic ultrasound,radiomics,and blood-based markers,have shown potential in enhancing early CP detection.Moreover,recent clinical trials have optimized treatment approaches,such as pancreatic stone fragmentation,stent placement,and decision-making between endoscopic and surgical procedures.Emerging therapies,including chemical pancreatectomy and gene therapy,present promising opportunities for improved CP management.

Immune Regulatory Networks and Therapy of yδT Cells in Liver Cancer:Recent Trends and Advancements

The roles of γδ T cells in liver cancer,especially in the poten-tial function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines,have aroused research interest.This re-view briefly describes the basic characteristics of γδ T cells,focusing on their diverse effects on liver cancer.In particular,different subtypes of γδ T cells have diverse or even opposite effects on liver cancer.We provide a detailed description of the immune regulatory network of γδ T cells in liver can-cer from two aspects:immune components and nonimmune components.The interactions between various components in this immune regulatory network are dynamic and pluralis-tic,ultimately determining the biological effects of γδ T cells in liver cancer.We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment,emphasiz-ing the potential of these cells in liver cancer immunotherapy.

Consensus of clinical diagnosis and treatment for non-functional pancreatic neuroendocrine neoplasms with diameter<2 cm

In clinical practice,pancreatic neuroendocrine neoplasms(pNENs)with a diameter smaller than 2 cm are commonly referred to as small pNENs.Due to their generally favorable biological characteristics,the diagnosis and treatment of small pNENs differ from other pNENs and are somewhat controversial.In response to this,the Chinese Pancreatic Surgery Association,Chinese Society of Surgery,Chinese Medical Association have developed a consensus on the diagnosis and treatment of small pNENs,which is based on evidence-based medicine and expert opinions.This consensus covers various topics,including concepts,disease assessment,treatment selection,follow-up,and other relevant aspects.

Acupuncture and moxibustion for malignant tumor patients with psychological symptoms of insomnia,anxiety and depression:a systematic review and Meta-analysis

OBJECTIVE:To evaluate the efficacy and safety of acupuncture and moxibustion therapy(AMT) for cancerrelated psychological symptoms(CRPS) of insomnia,depression and anxiety.METHODS:Seven databases were searched for randomized controlled trials(RCT) comparing AMT to routine care or conventional drug for alleviating CRPS of insomnia,depression,and anxiety before April 2020.Two independent reviewers performed the data extraction and assessed the risk of bias.RESULTS:A total of 30 RCTs involving 2483 cancer patients were enrolled.The pooled analysis indicated that the treatment group was significantly better than the control group in improving the depression effective rate [RR = 1.29,95% CI(1.12,1.49),P = 0.0004],the quality of life(QOL) [MD = 1.11,95% CI(0.80,1.42),P < 0.000 01],and reducing Self-rating Anxiety Scale(SAS) [MD =﹣7.75,95% CI(﹣10.44,﹣5.05),P < 0.000 01].But there was no statistically significant difference between two groups in improving the insomnia effective rate [RR = 1.18,95% CI(0.93,1.51),P = 0.18].The subgroup analysis showed the effectiveness of different intervention on CRPS.Compared with routine care,AMT helps relieve CRPS better evaluated by Pittsburgh Sleep Quality Index(PSQI),Hamilton Depression Scale(HAMD),and Self-rating Depression Scale(SDS),and depression effective rate.Compared with conventional drug,AMT performs better evaluated by SDS,depression effective rate and QOL.Moreover,the conventional drug showed higher treatment efficacy on improving insomnia effective rate compared with AMT.Compared to conventional drug,AMT plus conventional drug resulted in a significant reduction on CRPS such as PSQI,HAMD,SDS,and SAS,and also had a meaningful improvement on insomnia effective rate,depression effective rate and QOL.Fewer published reports were found on the adverse events of AMT than the conventional drug.CONCLUSION:The results suggested that AMT might be effective in improving CPRI;however,a definite conclusion could not be drawn because the quality of trials are low.Further large-scale and high-quality RCTs to verify the efficacy and safety of AMT on CRPS are still warranted.