Personalized pancreatic cancer therapy:from the perspective of mRNA vaccine

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

Analysis of the efficacy of transcatheter arterial infusion chemotherapy in the treatment of pancreatic carcinoma

Objective:To evaluate the clinical efficacy of infusion of gemcitabine(GEM) and fluorouracil(5-FU)through the celiac artery and superior mesenteric artery in the treatment of pancreatic carcinoma(PC).Methods:We analyzed 20 patients diagnosed clinically or pathologically with PC,without metastases,who had an estimated survival duration of>3 months in our department from May 2009 to December 2014.Nine patients were treated directly without surgical resection of the tumor,while the other 11 patients were treated after surgery.In all patients,the femoral artery was punctured using the Seldinger technique,and a catheter was placed in the opening of the celiac artery or the superior mesenteric artery.We administered 500 mg/m2 GEM and 500 mg/m2 5-FU.Observational data included data on clinical efficacy and survival rates during the follow-up period of 3-72 months.Results:Twenty patients were treated 85 times with transcatheter arterial infusion chemotherapy(TAI).The survival rates were 80%,40%,35%,20%,10%,and 5% at 3,6,12,24,and 72 months,respectively.Conclusion: TAI chemotherapy with GEM and 5-FU may be a therapeutic option for the treatment of PC.

Prevalence, diagnosis, and treatment of primary hepatic gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GIST), which is the most common mesenchymal tumor of the digestive tract, account for 1%-3% of gastrointestinal tumors. Primary stromal tumors outside the gastrointestinal tract are collectively referred to as extra GISTs, and stromal tumors in different regions often have different prognoses. A primary hepatic GIST is a rare tumor with an unknown origin, which may be related to interstitial Cajal-like cells. Although primary hepatic GIST has certain characteristics on imaging, it lacks specific symptoms and signs;thus, the final diagnosis depends on pathological and genetic evidence. This review summarizes all cases of primary hepatic GIST described in the literature and comprehensively analyzes the detailed clinical data of all patients. In terms of treatment, local resection alone or with adjuvant therapy was the prioritized choice to obtain better disease-free survival and longer survival time. For advanced unresectable cases, imatinib mesylate was applied as the first-line chemotherapy agent. Moreover, transcatheter arterial chemoembolization,/by-nc/4.0/Manuscript source: Unsolicited manuscript radiofrequency ablation, and microwave ablation were shown to improve overall survival for selected patients. Liver transplantation was a final treatment option after resistance to chemotherapy developed.

Sarcomatoid carcinoma of the pancreas: A case report

BACKGROUND Sarcomatoid carcinoma of the pancreas(SCP) is a rare and aggressive epithelial tumor that has both epithelial and mesenchymal features. It is characterized by sarcomatous elements with evidence of epithelial differentiation. And the term"sarcomatoid carcinoma" is often confused with "carcinosarcoma".CASE SUMMARY We present a case of SCP with lymph node metastasis in a 59-year-old male patient. He had experienced darkening of the urine, scleral icterus, and fatigue for 4 weeks. Computed tomography and magnetic resonance imaging revealed a mass in the pancreatic head, and laboratory tests revealed elevated serum bilirubin levels. The patient underwent pancreaticoduodenectomy after biliary decompression. Histologically, spindle cells with marked nuclear atypia and brisk mitotic activity arranged in a storiform or fascicular pattern were present in the bulk of the tumor. Immunohistochemical analysis found that the spindle cells exhibited strong diffuse positivity for epithelial markers, indicative of epithelial differentiation. Accordingly, the pathologic diagnosis of the pancreatic neoplasm was SCP.CONCLUSION Although sarcomatoid carcinomas and carcinosarcomas have different pathologic features, both have epithelial origin.

Intratumoral heterogeneity of hepatocellular carcinoma: From singlecell to population-based studies

Hepatocellular carcinoma(HCC)is characterized by high heterogeneity in both intratumoral and interpatient manners.While interpatient heterogeneity is related to personalized therapy,intratumoral heterogeneity(ITH)largely influences the efficacy of therapies in individuals.ITH contributes to tumor growth,metastasis,recurrence,and drug resistance and consequently limits the prognosis of patients with HCC.There is an urgent need to understand the causes,characteristics,and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival.Here,we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity.In parallel,evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem.We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions,combined with population-based clinical trials,will help to clarify the clinical implications of ITH,develop novel intervention strategies,and improve patient prognosis.

mRNA vaccine development for cholangiocarcinoma:a precise pipeline

Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade therapy.The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases,however,its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection.A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines.In spite of a promising prospect,further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.

利用深度学习系统筛查新冠病毒肺炎

实时逆转录聚合酶链反应(RT-PCR)检测早期新冠病毒肺炎(COVID-19)患者的痰液或鼻咽拭子中的病毒RNA阳性率较低。同时,COVID-19的计算机断层扫描(CT)影像学的临床表现有其自身的特点,不同于甲型流感病毒性肺炎(IAVP)等其他类型的病毒性肺炎。本研究旨在应用深度学习技术,建立COVID-19、IAVP及健康人群肺部CT的早期筛查模型。本研究共采集618份CT样本,其中219份样本来自110例COVID-19患者(平均年龄50岁,其中男性63例,占57.3%),224份样本来自224例IAVP患者(平均年龄61岁,其中男性156例,占69.6%),175份样本来自健康人群(平均年龄39岁,其中男性97例,占55.4%)。所有CT样本均来自浙江省三家COVID-19定点收治医院。我们首先利用胸部CT图像集的三维(3D)深度学习模型分割出候选感染区域,然后利用位置敏感机制深度学习网络将这些分离的图像归类为COVID-19、IAVP以及与感染无关(ITI)的图像,并且输出相应置信度得分。最后,用Noisy-OR贝叶斯函数计算每份CT病例的感染类型及总置信度。测试数据集的实验结果表明,从整体CT病例来看,本研究利用深度学习系统建立的COVID-19患者的早期筛查模型的总体准确率为86.7%。该模型有望成为一线临床医生诊断COVID-19的一种有效的辅助方法。

Giant nonfunctional ectopic adrenocortical carcinoma on the anterior abdominal wall: A case report

Adrenocortical cancer(ACC)is an infrequent and often aggressive malignancy with a very poor prognosis.It can be classified as functional or nonfunctional.Nonfunctional ACC is hampered by the absence of specific signs or symptoms;only abdominal pain with or without incidental adrenal occupation is typically present.CASE SUMMARY We report a rare case of a patient with a 30 cm×15 cm×8 cm ectopic ACC on the anterior abdominal wall without organ adhesion.A 77-year-old male was admitted to our hospital because of a huge abdominal mass,which,by ultrasonography,had an unclear border with the liver.Computed tomography showed that the mass was not associated with any organ but was adherent to the anterior abdominal wall.The patient underwent tumor resection,and a postoperative pathology examination showed a neuroendocrine tumor,which was diagnosed as ACC.The patient was disease-free at the 9-mo follow up.CONCLUSION The anterior abdominal wall is a rare site of ACC growth.

Model for liver hardness using two-dimensional shear wave elastography,durometer,and preoperative biomarkers

BACKGROUND Post-hepatectomy liver failure(PHLF)increases morbidity and mortality after liver resection for patients with advanced liver fibrosis and cirrhosis.Preoperative liver stiffness using two-dimensional shear wave elastography(2D-SWE)is widely used to evaluate the degree of fibrosis.However,the 2D-SWE results were not accurate.A durometer measures hardness by quantifying the ability of a material to locally resist the intrusion of hard objects into its surface.However,the durometer score can only be obtained during surgery.To measure correlations among 2D-SWE,palpation by surgeons,and durometermeasured objective liver hardness and to construct a liver hardness regression model.METHODS We enrolled 74 hepatectomy patients with liver hardness in a derivation cohort.Tactile-based liver hardness scores(0-100)were determined through palpation of the liver tissue by surgeons.Additionally,liver hardness was measured using a durometer.Correlation coefficients for durometer-measured hardness and preoperative parameters were calculated.Multiple linear regression models were constructed to select the best predictive durometer scale.Receiver operating characteristic(ROC)curves and univariate and multivariate analyses were used to calculate the best model’s prediction of PHLF and risk factors for PHLF,respectively.A separate validation cohort(n=162)was used to evaluate the model.RESULTS The stiffness measured using 2D-SWE and palpation scale had good linear correlation with durometer-measured hardness(Pearson rank correlation coefficient 0.704 and 0.729,respectively,P<0.001).The best model for the durometer scale(hardness scale model)was based on stiffness,hepatitis B virus surface antigen,and albumin level and had an R2 value of 0.580.The area under the ROC for the durometer and hardness scale for PHLF prediction were 0.807(P=0.002)and 0.785(P=0.005),respectively.The optimal cutoff value of the durometer and hardness scale was 27.38(sensitivity=0.900,specificity=0.660)and 27.87(sensitivity=0.700,specificity=0.787),respectively.Patients with a hardness scale score of>27.87 were at a significantly higher risk of PHLF with hazard ratios of 7.835(P=0.015).The model’s PHLF predictive ability was confirmed in the validation cohort.CONCLUSION Liver stiffness assessed by 2D-SWE and palpation correlated well with durometer hardness values.The multiple linear regression model predicted durometer hardness values and PHLF.

mRNA vaccines in disease prevention and treatment

mRNA vaccines have emerged as highly effective strategies in the prophylaxis and treatment of diseases,thanks largely although not totally to their extraordinary performance in recent years against the worldwide plague COVID-19.

Tolerance and acceptance of hepatic venous pressure gradient measurement in cirrhosis(CHESS1904):An international multicenter study

Aim:To determine the tolerance and acceptance of hepatic venous pressure gradient(HVPG)measurements in patients with liver cirrhosis.Methods:This prospective international multicenter study included 271 patients with cirrhosis who were scheduled to undergo HVPG measurement between October 2019 and June 2020.Data related to the tolerance and acceptance of HVPG measurements were collected using descriptive questionnaires.Results:HVPG measurements were technically successful in all 271 patients,with 141(52.0%)undergoing HVPG measurement alone.The complication rate was 0.4%.Postoperative pain was significantly lower than preoperative expected pain(p<0.001)and intraoperative pain(p<0.001),and intraoperative pain was also significantly lower than preoperative expected pain(p=0.036).No,mild,moderate,severe,and intolerable discomfort scores were reported by 36.9%,44.6%,11.1%,6.3%,and 0.4%of these patients,respectively,during HVPG measurement and by 54.6%32.5%,11.4%,1.5%,and 0%,respectively,after HVPG measurement.Of these patients,39.5%had little understanding and 10%had no understanding of the value of HVPG measurement,with 35.1%and 4.1%regarding HVPG measurements as being of little or no help,respectively.Most patients reported that they would definitely(15.5%),probably(46.9%),or possibly(29.9%)choose to undergo additional HVPG measurements again,and 62.7%regarded the cost of the procedure as acceptable.Conclusion:HVPG measurement was safe and well‐tolerated in patients with cirrhosis,but patient education and communication are warranted to improve the acceptance of this procedure.

Huge portal venous aneurysm incidentaloma caused by intrahepatic arterioportal fistula accompany with hepatobiliary stones and cholangitis

A 64-year-old female was admitted to our department because of abdominal discomfort and recurrent fever for 1 month,she had attended her local hospital 10 days earlier,where the sign of fever was regarded as being due to the pulmonary infection,however,moxifloxacin and peramivir had no therapeutic effect.On admission,the physical examinations were showed an upper abdominal thrill and auscultation heard a blood vessel murmur at the same location,lab tests were not showed any remarkable results,the tumor marker levels were within normal range.The portal color contrast ultrasonography was showed a 5.4 cm×3.3 cm bright spot in the left intrahepatic bile duct,and a 0.9 cm distal bright spot in,and 0.7 cm expansion of the right intrahepatic bile duct(Figure 1A).Contrast-enhanced computed tomography(CT)were showed intrahepatic cholangiectasis,tumor-like dilatation of the left portal ramus,and left liver atrophy and cirrhosis(Figure 1B).

An alpha-fetoprotein-negative hepatoid adenocarcinoma of the gallbladder with squamous differentiation

During a routine health examination, a 61-year-old male was incidentally found to have a neoplasm spreading beyond the gallbladder and into the liver on abdominal ultrasound. The ultrasound demonstrated a mixed-echo mass, measuring 7.6 cm × 4.8 cm in diameter, within the capsuled wall of the gallbladder and adhering to the liver. The patient was subsequently admitted to our hospital. His medical, family, and personal history were unremarkable, and serology tests for hepatitis B and C were both negative. Laboratory tumor marker investigations revealed increases in carcinoembryonic antigen (104.7 ng/mL;normal: 0-5 ng/mL), carbohydrate antigen (CA) 125 (421.3 U/mL;normal:0-37 U/mL), CA 242 (220.4 U/mL;normal: 0-20 U/mL), and CA19-9 (2,118.4 U/mL;normal: 0-27 U/mL) levels. Plasma alpha-fetoprotein (AFP) was within the normal range. An enhanced computed tomography (CT) scan revealed a mass in the gallbladder bed with enlarged hilar lymph nodes (Figure 1A,B,C). A cholecystectomy was subsequently performed, along with a liver and lymph node dissection. Histological findings revealed poorly differentiated cells with abundant eosinophilic cytoplasm ( Figure 1D,E ), and positive staining for cytokeratin-7 (CK7) and hepatocyte specific protein (HepPar-1) by immunohistochemistry (Figure 1F,G), suggesting that these cells were hepatoid adenocarcinoma (HAC).

Metastatic solitary fibrous tumor of the pancreas in a patient with Doege-Potter syndrome

A 46-year-old man was admitted to our hospital with a 6-month history of recurrent hypoglycemia with an unknown cause. Four months back, he was diagnosed with a complex ulcer in the stomach and duodenum in a local hospital. Physical examination revealed that the liver was swollen with a hard texture and located 5 cm below the costal margin of the abdomen. On admission, his random blood glucose level was 1.6 mmol/L, and routine laboratory tests, including those for liver enzymes, showed normal findings. The levels of tumor markers, including carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 19-9, and neuron-specific enolase, were normal. Magnetic resonance imaging (MRI) of the brain and pituitary gland showed no abnormalities. However, abdominal MRI revealed solid components in the pancreas and multiple masses on the liver (Figure 1A,B,C). We first considered functional neuroendocrine cancer of the pancreas with multiple liver metastases. For blood glucose control, the patient first received multiple transarterial chemoembolization (TACE) sessions to reduce the tumor burden. This resulted in amelioration of the symptoms of hypoglycemia, although they occasionally manifested. Whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) revealed a slightly hypodense lesion measuring 7.0×6.1 cm2 in diameter in the body of the pancreas. The lesion exhibited significantly different degrees of FDG uptake [ Figure 1D;maximum standardized uptake (SUVmax): 4.74].

Cavernous Transformation of the Portal Vein Secondary to Cholecystolithiasis

To the Editor： A 58-year-old man with tip to a 5-year history of cholecystolithiasis presented with a 1-day history of mild abdominal pain with tenderness in the right upper quadrant before this hospital admission. He complained of similar sylnptoms about 5 years ago and recovered after 11 days of conservative therapy in the same hospital. The temperature was normal, and no special findings were noted on laboratory testing. Ultrasonography revealed multiple small gallstones in the lumen of the gallbladder. Unexpectedly.

Neoadjuvant therapy for resectable pancreatic cancer:a narrative review

The use of neoadjuvant therapy(NAT)for pancreatic ductal adenocarcinoma remains controversial and limited.Therefore,this literature review aimed to assess the feasibility,safety,and efficacy of this treatment.A database search of peer-reviewed articles published in English between January 1990 and June 2021 in PubMed,MEDLINE,and the Web of Science was performed.Original articles,review articles,and meta-analyses relevant to the topic were selected.We found 2 to 4 cycles with FOLFIRINOX,gemcitabine plus nab-paclitaxel,gemcitabine plus S-1,or gemcitabine alone were the most acceptable treatments.Considering the risk of adverse events and cancer progression,NAT is considered safe and tolerable,with a comparable resection rate.Although NAT can result in moderate tumor responses and some extent of local control(improvement of complete resection rate and negative lymph node metastases),no obvious survival benefit is observed.To date,the survival benefits of NAT for resectable pancreatic ductal adenocarcinoma have been very limited.It is too early to say that NAT is the best treatment option for resectable pancreatic cancer.

Synchronous occurrence of hepatocellular carcinoma and multiple biliary hamartomas mimicking hepatocellular carcinoma with multiple intra-hepatic metastases

A 67-year-old man was admitted to our hospital for a space-occupying lesion in his liver found 1 week earlier.There were no obvious complaints in this patient and no obvious abnormalities were founded during the physical examination.He presented with a habit of heavy drinking(500 mL/day)for more than 40 years.There was no history of other neoplasms,no other history of past illness or any family illness in this patient.

5′-tiRNA-Gln inhibits hepatocellular carcinoma progression by repressing translation through the interaction with eukaryotic initiation factor 4A-I

tRNA-derived small RNAs(tsRNAs)are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases.However,their exact presence and function in hepatocellular carcinoma(HCC)remain unclear.Here,differentially expressed tsRNAs in HCC were profiled.A novel tsRNA,tRNAGln-TTG derived 5′-tiRNA-Gln,is significantly downregulated,and its expression level is correlated with progression in patients.In HCC cells,5′-tiRNA-Gln overexpression impaired the proliferation,migration,and invasion in vitro and in vivo,while 5′-tiRNA-Gln knockdown yielded opposite results.5′-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I(EIF4A1),which unwinds complex RNA secondary structures during translation initiation,causing the partial inhibition of translation.The suppressed downregulated proteins include ARAF,MEK1/2 and STAT3,causing the impaired signaling pathway related to HCC progression.Furthermore,based on the construction of a mutant 5′-tiRNA-Gln,the sequence of forming intramolecular G-quadruplex structure is crucial for 5′-tiRNA-Gln to strongly bind EIF4A1 and repress translation.Clinically,5′-tiRNA-Gln expression level is negatively correlated with ARAF,MEK1/2,and STAT3 in HCC tissues.Collectively,these findings reveal that 5′-tiRNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular Gquadruplex structure,and this process partially inhibits translation and HCC progression.

Oncolytic virotherapy:basic principles,recent advances and future directions

Oncolytic viruses(OVs)have attracted growing awareness in the twenty-first century,as they are generally considered to have direct oncolysis and cancer immune effects.With the progress in genetic engineering technology,OVs have been adopted as versatile platforms for developing novel antitumor strategies,used alone or in combination with other therapies.Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future.In this review,we summarized the basic principles of OVs in terms of their classifications,as well as the recent advances in OV-modification strategies based on their characteristics,biofunctions,and cancer hallmarks.Candidate OVs are expected to be designed as“qualified soldiers”first by improving target fidelity and safety,and then equipped with“cold weapons”for a proper cytocidal effect,“hot weapons”capable of activating cancer immunotherapy,or“auxiliary weapons”by harnessing tactics such as anti-angiogenesis,reversed metabolic reprogramming and decomposing extracellular matrix around tumors.Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects.Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.

A 7-year-old girl with giant congenital biliary dilatation

A 7-year-old girl presented to our out-patient clinic with complaints of abdominal mass and pain with yellowish skin for over 3 months.The patient was also accompanied by clinical manifestations such as nausea and vomiting,skin itching and clay-colored stools.She denied any past history of gastrointestinal bleeding or trauma.Examination revealed a non-tender swelling as it moved with breathing(Panel A).