Early diagnosis of pancreatic cancer: Shedding light on an unresolved challenge

Diagnosing early-stage pancreatic cancer(PC)remains a clinical challenge.Hence,studying novel imaging aspects that could enhance the diagnostic accuracy of malignant pancreatic precursor lesions is imperative.This article aims to un-derscore the promising role of emerging imaging aspects that may facilitate the earlier diagnosis of PC,thereby improving its management and prognosis.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Targeting KRAS in pancreatic cancer

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

Treatment patterns and survival outcomes in patients with nonmetastatic early-onset pancreatic cancer

BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.

Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts

BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment

BACKGROUND Pancreatic cancer is one of the most lethal malignancies,characterized by poor prognosis and low survival rates.Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy,often failing to capture the complexity of the disease.The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment.This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer.AIM To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules.METHODS This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2,PLAU,and CCNA2.The results were validated in an independent dataset.This study also examined the correlations between the model risk score and various clinical features,components of the immune microenvironment,chemotherapeutic drug sensitivity,and metabolism-related pathways.Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines.RESULTS The prognostic model demonstrated significant predictive value,with the risk score showing a strong correlation with clinical features:It was significantly associated with tumor grade(G)(bP<0.01),moderately associated with tumor stage(T)(aP<0.05),and significantly correlated with residual tumor(R)status(bP<0.01).There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs.Furthermore,the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer.CONCLUSION The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Verteporfin fluorescence in antineoplastic-treated pancreatic cancer cells found concentrated in mitochondria

BACKGROUND Traditional treatments for pancreatic cancer(PC)are inadequate.Photodynamic therapy(PDT)is non-invasive,and proven safe to kill cancer cells,including PC.However,the mitochondrial concentration of the photosensitizer,such as verteporfin,is key.AIM To investigate the distribution of fluorescence of verteporfin in PC cells treated with antitumor drugs,post-PDT.METHODS Workable survival rates of PC cells(AsPC-1,BxPC-3)were determined with chemotherapy[doxorubicin(DOX)and gemcitabine(GEM)]and non-chemotherapy[sirolimus(SRL)and cetuximab(CTX)]drugs in vitro,with or without verteporfin,as measured via MTT,flow cytometry,and laser confocal microscopy.Reduced cell proliferation was associated with GEM that was more enduring compared with DOX.Confocal laser microscopy allowed observation of GEM-and verteporfin-treated PC cells co-stained with 4’,6-diamidino-2-phenylindole and MitoTracker Green to differentiate living and dead cells and subcellular localization of verteporfin,respectively.RESULTS Cell survival significantly dropped upon exposure to either chemotherapy drug,but not to SRL or CTX.Both cell lines responded similarly to GEM.The intensity of fluorescence was associated with the concentration of verteporfin.Additional experiments using GEM showed that survival rates of the PC cells treated with 10μmol/L verteporfin(but not less)were significantly lower relative to nil verte-porfin.Living and dead stained cells treated with GEM were distinguishable.After GEM treatment,verteporfin was observed primarily in the mitochondria.CONCLUSION Verteporfin was observed in living cells.In GEM-treated human PC cells,verteporfin was particularly prevalent in the mitochondria.This study supports further study of PDT for the treatment of PC after neoadjuvant chemotherapy.

Early detection of pancreatic cancer

The diagnosis of pancreatic cancer associates an appalling significance.Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease.Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development.Pancreatic intraepithelial neoplasms(PanIN)are the most frequent precursors of pancreatic adenocarcinoma(PDAC),and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC.Unfortunately,PanINs are not detectable on radiologic exams.Nevertheless,they can associate indirect imaging signs which would rise the diagnostic suspicion.When this suspicion is established,the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging,which will cost in the best-case scenario a burden of healthcare systems,and potential mortality in the worst-case scenario when the patient underwent resection surgery,worthless when there is no moderate or high grade dysplasia in the final histopathology.This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions,such is the cytology of pancreatic juice obtained by nasopancreatic intubation.Herein,we review the possibility of detection of early malignant lesions before they become invasive PADC.

N-glycan biosignatures as a potential diagnostic biomarker for earlystage pancreatic cancer

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)has a poor prognosis,with a 5-year survival rate of less than 10%,owing to its late-stage diagnosis.Early detection of pancreatic cancer(PC)can significantly increase survival rates.AIM To identify the serum biomarker signatures associated with early-stage PDAC by serum N-glycan analysis.METHODS An extensive patient cohort was used to determine a biomarker signature,in-cluding patients with PDAC that was well-defined at an early stage(stages I and II).The biomarker signature was derived from a case-control study using a case-cohort design consisting of 29 patients with stage I,22 with stage II,4 with stage III,16 with stage IV PDAC,and 88 controls.We used multiparametric analysis to identify early-stage PDAC N-glycan signatures and developed an N-glycan sig-nature-based diagnosis model called the“Glyco-model”.RESULTS The biomarker signature was created to discriminate samples derived from patients with PC from those of controls,with a receiver operating characteristic area under the curve of 0.86.In addition,the biomarker signature combined with cancer antigen 19-9 could discriminate patients with PDAC from controls,with a receiver operating characteristic area under the curve of 0.919.Glyco-model demonstrated favorable diagnostic performance in all stages of PC.The diagnostic sensitivity for stage I PDAC was 89.66%.Core Tip:This study employed a patient cohort to investigate the N-glycan signature of early-stage pancreatic cancer(PC).Serum N-glycans analysis was conducted to identify the serum biomarker signature associated with early-stage pancreatic ductal adenocarcinoma(PDAC),resulting in the identification of nine early-stage PDAC N-glycan signatures.Subsequently,utilizing these biosignatures,a diagnostic model named the“Glyco-model”was developed,demonstrating promising diagnostic performance across all stages of PC.The study revealed that the diagnostic sensitivity for stage I PDAC was determined to be 89.66%.Consequently,this diagnostic model exhibits potential as a prospective strategy for the early detection of PDAC.

B7 homolog 3 in pancreatic cancer

Despite advances in cancer treatment,pancreatic cancer(PC)remains a disease with high mortality rates and poor survival outcomes.The B7 homolog 3(B7-H3)checkpoint molecule is overexpressed among many malignant tumors,including PC,with low or absent expression in healthy tissues.By modulating various immunological and nonimmunological molecular mechanisms,B7-H3 may influence the progression of PC.However,the impact of B7-H3 on the survival of patients with PC remains a subject of debate.Still,most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC.Furthermore,it has been demonstrated that B7-H3 stimulates the migration,invasion,and metastasis of PC cells,and enhances resistance to chemotherapy.In preclinical models of PC,B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibodydependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site.Finally,PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies.This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.

Systemic Inflammation Response Index and weight loss as prognostic factors in metastatic pancreatic cancer: A concept study from the PANTHEIA-SEOM trial

BACKGROUND The prognostic value of the Systemic Inflammation Response Index(SIRI)in advanced pancreatic cancer is recognized,but its correlation with patients´nutritional status and outcomes remains unexplored.AIM To study the prognostic significance of SIRI and weight loss in metastatic pancreatic cancer.METHODS The PANTHEIA-Spanish Society of Medical Oncology(SEOM)study is a multicentric(16 Spanish hospitals),observational,longitudinal,non-interventional initiative,promoted by the SEOM Real World-Evidence work group.This pilot study sought to analyze the association between weight loss and inflammatory status as defined by SIRI.The cohort stems from a proof-of-concept pilot study conducted at one of the coordinating centers.Patients with pathologically confirmed metastatic pancreatic adenocarcinoma,treated from January 2020 to January 2023,were included.The index was calculated using the product of neutrophil and monocyte counts,divided by lymphocyte counts,obtained within 15 days before initiation chemotherapy.This study evaluated associations between overall survival(OS),SIRI and weight loss.RESULTS A total of 50 patients were included.66%of these patients were male and the median age was 66 years.Metastasis sites:36%liver,12%peritoneal carcinomatosis,10%lung,and 42%multiple locations.Regarding the first line palliative chemotherapy treatments:50%received gemcitabine plus nab-paclitaxel;28%,modified fluorouracil,leucovorin,irinotecan and oxaliplatin,and 16%were administered gemcitabine.42%had a weight loss>5%in the three months(mo)preceding diagnosis.21 patients with a SIRI≥2.3×10^(3)/L exhibited a trend towards a lower median OS compared to those with a SIRI<2.3×10^(3)/L(4 vs 18 mo;P<0.000).Among 21 patients with>5%weight loss before diagnosis,the median OS was 6 mo,in contrast to 19 mo for those who did not experience such weight loss(P=0.003).Patients with a weight loss>5%showed higher SIRI levels.This difference was statistically significant(P<0.000).For patients with a SIRI<2.3×10^(3)/L,those who did not lose>5%of their weight had an OS of 20 mo,compared to 11 mo for those who did(P<0.001).No association was found between carbohydrate antigen 19-9 levels≥1000 U/mL and weight loss.CONCLUSION A higher SIRI was correlated with decreased survival rates in patients with metastatic pancreatic cancer and associated with weight loss.An elevated SIRI is suggested as a predictor of survival,emphasizing the need for prospective validation in the upcoming PANTHEIA-SEOM study.

New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy for cancer patients and,consequently,a reduction in the lethality of this aggressive cancer.

Identifying the risk factors for pancreatic fistula after laparoscopic pancreaticoduodenectomy in patients with pancreatic cancer

BACKGROUND Laparoscopic pancreaticoduodenectomy(LPD)is a surgical procedure for treating pancreatic cancer;however,the risk of complications remains high owing to the wide range of organs involved during the surgery and the difficulty of anastomosis.Pancreatic fistula(PF)is a major complication that not only increases the risk of postoperative infection and abdominal hemorrhage but may also cause multi-organ failure,which is a serious threat to the patient’s life.This study hypothesized the risk factors for PF after LPD.AIM To identify the risk factors for PF after laparoscopic pancreatoduodenectomy in patients with pancreatic cancer.METHODS We retrospectively analyzed the data of 201 patients admitted to the Fudan University Shanghai Cancer Center between August 2022 and August 2023 who underwent LPD for pancreatic cancer.On the basis of the PF’s incidence(grades B and C),patients were categorized into the PF(n=15)and non-PF groups(n=186).Differences in general data,preoperative laboratory indicators,and surgery-related factors between the two groups were compared and analyzed using multifactorial logistic regression and receiver-operating characteristic(ROC)curve analyses.RESULTS The proportions of males,combined hypertension,soft pancreatic texture,and pancreatic duct diameter≤3 mm;surgery time;body mass index(BMI);and amylase(Am)level in the drainage fluid on the first postoperative day(Am>1069 U/L)were greater in the PF group than in the non-PF group(P<0.05),whereas the preoperative monocyte count in the PF group was lower than that in the non-PF group(all P<0.05).The logistic regression analysis revealed that BMI>24.91 kg/m²[odds ratio(OR)=13.978,95%confidence interval(CI):1.886-103.581],hypertension(OR=8.484,95%CI:1.22-58.994),soft pancreatic texture(OR=42.015,95%CI:5.698-309.782),and operation time>414 min(OR=15.41,95%CI:1.63-145.674)were risk factors for the development of PF after LPD for pancreatic cancer(all P<0.05).The areas under the ROC curve for BMI,hypertension,soft pancreatic texture,and time prediction of PF surgery were 0.655,0.661,0.873,and 0.758,respectively.CONCLUSION BMI(>24.91 kg/m²),hypertension,soft pancreatic texture,and operation time(>414 min)are considered to be the risk factors for postoperative PF.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis

BACKGROUND Pancreatic cancer remains one of the most lethal malignancies,and has limited effective treatment.Gemcitabine(GEM),a chemotherapeutic agent,is commonly used for clinical treatment of pancreatic cancer,but it has characteristics of low drug delivery efficiency and significant side effects.The study tested the hypothesis that human bone marrow mesenchymal stem cell(MSC)-derived exosomes loaded with GEM(Exo-GEM)would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis.AIM To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro.METHODS Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis.Exo-GEM through electroporation,sonication,or incubation,and the loading efficiency was evaluated.The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays.RESULTS The isolated exosomes had an average size of 76.7 nm.The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation.The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02μM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells.Moreover,Exo-GEM enhanced the frequency of GEMinduced apoptosis in both cell lines.CONCLUSION Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis,offering a promising drug delivery system for improving therapeutic outcomes.

Clinical efficacy and safety of erlotinib combined with chemotherapy in the treatment of advanced pancreatic cancer:A meta-analysis

BACKGROUND Advanced pancreatic cancer is resistant to chemotherapeutic drugs,resulting in limited treatment efficacy and poor prognosis.Combined administration of the chemotherapeutic gemcitabine and erlotinib is considered a potential first-line treatment for advanced pancreatic cancer.However,their comparative benefits and potential risks remain unclear.AIM To assess the clinical efficacy and safety of erlotinib combined with other chemotherapy regimens for the treatment of advanced pancreatic cancer.METHODS Literature on the clinical efficacy and safety of erlotinib combined with chemotherapy for advanced pancreatic cancer was retrieved through an online search.The retrieved literature was subjected to a methodological qualitative assessment and was analyzed using the RevMan 5.3 software.Ten randomized controlled trials involving 2444 patients with advanced pancreatic cancer were included in the meta-analysis.RESULTS Compared with chemotherapeutic treatment,erlotinib combined with chemotherapy significantly prolonged the progression-free survival time of pancreatic cancer patients[hazard ratio(HR)=0.78,95%CI:0.66-0.92,P=0.003].Meanwhile,the overall survival(HR=0.99,95%CI:0.72-1.37,and P=0.95)and disease control rate(OR=0.93,95%CI:0.45-0.91,P=0.84)were not significantly favorable.In terms of safety,the erlotinib and chemotherapy combination was associated with a significantly higher risk of diarrhea(OR=3.59,95%CI:1.63-7.90,P<0.05)and rash(OR=3.63,95%CI:1.64-8.01,P<0.05)compared with single-agent chemotherapy.Moreover,the risk of vomiting(OR=1.27,95%CI:0.62-2.59,P=0.51),regurgitation/anorexia(OR=1.61,95%CI:0.25-10.31,P=0.62),and infection(OR=0.72,95%CI:0.28-1.87,P=0.50)were not significant in either group.CONCLUSION Compared with a single chemotherapeutic modality,erlotinib combined with gemcitabine can prolong progression-free survival in pancreatic cancer,but does not improve survival benefit or disease control rate,and can increase the risk of diarrhea and rash.

Early detection of pancreatic cancer in patients with recurrent pancreatitis:A case report

BACKGROUND Pancreatic cancer presents a challenge with its low early diagnosis and treatment rates,leading to high metastasis and mortality rates.The median survival time for advanced pancreatic cancer is a mere 3 months.However,there's hope:small pancreatic cancers diagnosed at an early stage(T1)or those less than or equal to 1 cm in diameter boast an impressive 5-year survival rate of nearly 100%.This underscores the critical importance of early pancreatic cancer detection for significantly improving prognosis.CASE SUMMARY Pancreatic cancer,a malignant tumor of the digestive tract,poses challenges in both diagnosis and treatment due to its occult and atypical clinical symptoms.Clinically,patients with recurrent pancreatitis should be vigilant,as it may be indicative of pancreatic cancer,particularly in middle-aged and elderly patients.Here,we presented the case of a patient who experienced recurrent acute pancreatitis within a span of 2 months.During the initial episode of pancreatitis,routine imaging failed to identify the cause of pancreatic cancer.However,upon recurrence of acute pancreatitis,endoscopic ultrasonography(EUS)revealed a space-occupying lesion approximately 1 cm in size in the pancreatic body.Subsequent EUS coupled with fine-needle aspiration examination demonstrated atypical pancreatic gland epithelium.Ultimately,the patient underwent surgery and was diagnosed with an intraductal papillary mucinous tumor of the pancreas(severe epithelial dysplasia,focal cancer).CONCLUSION We recommend EUS for patients with recurrent pancreatitis of unknown etiology to exclude early pancreatic cancer.

Thymoquinone affects hypoxia-inducible factor-1αexpression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways

BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination degradation.CONCLUSION The regulatory mechanism of TQ on HIF-1αprotein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90;Secondly,TQ reduced the initial expression of HIF-1αprotein by inhibiting the PI3K/AKT/mTOR pathway.

Extended survival with metastatic pancreatic cancer under fruquintinib treatment after failed chemotherapy:Two case reports

BACKGROUND Pancreatic cancer is a highly malignant disease.After decades of treatment progress,the current five-year survival rate for patients is still less than 10%.For later-line treatment,the treatment options are even more limited.Anti-angiogenic drugs can improve progression-free survival in patients with advanced pancreatic cancer.Preclinical data show that fruquintinib might improve the prognosis of advanced pancreatic cancer by targeting angiogenesis and lymphopoiesis,improving the abnormal vascular structure,and modulating the tumour immune microenvironment.CASE SUMMARY We present two cases of third-line fruquintinib monotherapy that brought an extraprolonged progress-free survival(PFS)of 10 months.Patient 1 took adjuvant gemcitabine-based and first-line nab-paclitaxel-based chemotherapy and then used local radiotherapy combined with programmed cell death 1 receptor(PD-1).Each line lasted approximately 7 months.Moreover,the patient took third-line fruquintinib,which was followed by stable disease for 10 months,during which no additional adverse effect was observed.The patient later refused to take fruquintinib due to difficulty urinating and lower abdominal pain after the coronavirus disease 2019(COVID-19)infection.The patient died in February 2023.Patient 2 also took two prior lines of chemotherapy and then local radiotherapy combined with S-1.After confirmed disease progression,the patient experienced a continuous partial response after using fruquintinib monotherapy in the third line.After the patient had COVID-19 in December 2022,fruquintinib was discontinued.The patient died in January 2023 due to disease progression.CONCLUSION Both cases achieved a PFS benefit from later-line single-agent fruquintinib therapy.With its better safety profile,fruquintinib may be worth exploring and studying in more depth as a later-line treatment for pancreatic cancer patients.

Identification of Prognosis-Related Genes and Key Target Genes for Pancreatic Cancer: A Bioinformatics Analysis

Objective: The mortality and morbidity rates associated with pancreatic cancer (PaCa) are extremely high. Various studies have demonstrated that pancreatic cancer will be the fourth cancer-related death by 2030, raising more concern for scholars to find effective methods to prevent and treat in order to improve the pancreatic cancer outcome. Using bioinformatic analysis, this study aims to pinpoint key genes that could impact PaCa patients’ prognosis and could be used as therapeutic targets. Methods: The TCGA and GEO datasets were integratively analyzed to identify prognosis-related differentially expressed genes. Next, the STRING database was used to develop PPI networks, and the MCODE and CytoNCA Cytoscape in Cytoscape were used to screen for critical genes. Through CytoNCA, three kinds of topology analysis were considered (degree, betweenness, and eigenvector). Essential genes were confirmed as potential target treatment through Go function and pathways enrichment analysis, a developed predictive risk model based on multivariate analysis, and the establishment of nomograms using the clinical information. Results: Overall, the GSE183795 and TCGA datasets associated 1311 and 2244 genes with pancreatic cancer prognosis, respectively. We identified 132 genes that were present in both datasets. The PPI network analysis using, the centrality analysis approach with the CytoNCA plug-in, showed that CDK2, PLK1, CCNB1, and TOP2A ranked in the top 5% across all three metrics. The independent analysis of a risk model revealed that the four key genes had a Hazard Ratio (HR) > 1. The monogram showed the predictive risk model and individual patient survival predictions were accurate. The results indicate that the effect of the selected vital genes was significant and that they could be used as biomarkers to predict a patient’s outcome and as possible target therapy in patients with pancreatic cancer. GO function and pathway analysis demonstrated that crucial genes might affect the P53 signaling pathway and FoxO signaling pathway, through which Meiotic nuclear division and cell cycle may have a significant function in essential genes affecting the outcome of patients who have pancreatic cancer. Conclusions: This study suggests that CDK2, CCNB1, PLK1 and TOP2A are four key genes that have a significant influence on PaCa migration and proliferation. CDK2, CCNB1, PLK1, and TOP2A can be used as potential PaCa prognostic biomarkers and therapeutic targets. However, experimental validation is necessary to confirm these predictions. Our study comes into contributions to the development of personalized target therapy for pancreatic cancer patients.

Surgical treatment of liver cancer and pancreatic cancer under the China Healthcare Security Diagnosis Related Groups payment system

BACKGROUND Data from the World Health Organization’s International Agency for Research on Cancer reported that China had the highest prevalence of cancer and cancer deaths in 2022.Liver and pancreatic cancers accounted for the highest number of new cases.Real-world data(RWD)is now widely preferred to traditional clinical trials in various fields of medicine and healthcare,as the traditional research approach often involves highly selected populations and interventions and controls that are strictly regulated.Additionally,research results from the RWD match global reality better than those from traditional clinical trials.AIM To analyze the cost disparity between surgical treatments for liver and pancreatic cancer under various factors.METHODS This study analyzed RWD 1137 cases within the HB1 group(patients who underwent pancreatectomy,hepatectomy,and/or shunt surgery)in 2023.It distinguished different expenditure categories,including medical,nursing,technical,management,drug,and consumable costs.Additionally,it assessed the contribution of each expenditure category to total hospital costs and performed cross-group comparisons using the non-parametric Kruskal–Wallis test.This study used the Steel–Dwass test for post-hoc multiple comparisons and the Spearman correlation coefficient to examine the relationships between variables.RESULTS The study found that in HB11 and HB13,the total hospitalization costs were significantly higher for pancreaticoduodenectomy than for pancreatectomy and hepatectomy.Although no significant difference was observed in the length of hospital stay between patients who underwent pancreaticoduodenectomy and pancreatectomy,both were significantly longer than those who underwent liver resection.In HB15,no significant difference was observed in the total cost of hospitalization between pancreaticoduodenectomy and pancreatectomy;however,both were significantly higher than those in hepatectomy.Additionally,the length of hospital stay was significantly longer for patients who underwent pancreaticoduodenectomy than for those who underwent pancreatectomy or liver resection.CONCLUSION China Healthcare Security Diagnosis Related Groups payment system positively impacts liver and pancreatic cancer surgeries by improving medical quality and controlling costs.Further research could refine this grouping system and ensure continuous effectiveness and sustainability.