Predictive factors of survival in patients with borderline resectable pancreatic cancer who received neoadjuvant therapy

Background/objectivesThis study aimed to develop the prognostic score (PS) based on clinical factors to stratify the prognosis in borderline resectable pancreatic cancer (BRPC) patients treated with neoadjuvant therapy (NAT).MethodsThis retrospective study included 57 BRPC patients who received NAT between April 2012 and December 2017. A score was assigned to each prognostic factor available before and after NAT, according to their β coefficients.ResultsMultivariate analysis identified the following six prognostic factors, and scores were assigned as follows: being a familial PC patient (HR 4.98, p = 0.029), post-NAT CA19-9 ≥37 U/ml (HR 3.08, p = 0.020), reduction rate of CA19-9 <70% (HR 3.71, p = 0.008), pre-NAT neutrophil-to-lymphocyte ratio ≥2.8 (HR 4.32, p = 0.003), and non-resection (HR 3.98, p = 0.009) were scored as 1; and post-NAT albumin-to-globulin ratio <1.33 (HR 8.31, p < 0.001) was scored as 2. The PS was calculated by summing the scores assigned to each prognostic factor. Patients were then classified into three risk groups (low- [0–1 points], moderate- [2–3 points], and high-risk [4–6 points] groups). Median overall survival in the low-, moderate-, and high-risk groups were not reached, 37.5 months, and 11.8 months, respectively, and there were significant differences in survival among the three groups (p < 0.01 in each group).ConclusionsThis study showed that the PS may be useful for predicting the prognosis of BRPC patients treated with NAT.     

Low MUC4 expression is associated with survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine

Background: Previous in vitro studies have shown that mucin 4 (MUC4) confers resistance toward gemcitabine in pancreatic cancer cells. To date, there are few clinical studies corroborating these findings. The aim of this study was to evaluate the predictive impact of MUC4 expression on survival in patients with resectable pancreatic cancer receiving adjuvant gemcitabine.

Materials and methods: MUC4 expression was investigated by immunohistochemistry in 78 tissue sections from patients with pancreatic ductal adenocarcinoma undergoing Whipple resection. The H-score was used to evaluate MUC4 expression. The Kaplan–Meier method and Cox proportional hazards regression analysis were used to assess the predictive role of MUC4 expression.

Results: The MUC4 protein was expressed in 93.6% (73/78) of pancreatic cancer tissue specimens. None of the normal control pancreatic tissues had any MUC4 expression. Low MUC4 expression (H-score ≤100) was detectable in 42 (53.8%) of tumors and high MUC4 expression (H-score >100) was detectable in 36 (46.2%) of tumors. Low expression of MUC4 was associated with favorable survival (p?=?.027), whereas high MUC4 expression did not correlate with survival (p?=?.87) in patients receiving adjuvant gemcitabine treatment.

Conclusions: This is the first study indicating a predictive role of MUC4 expression for gemcitabine treatment in the clinical setting.     

Strong prognostic value of nodal and bone marrow micro-involvement in patients with pancreatic ductal carcinoma receiving no adjuvant chemotherapy

INTRODUCTIONPancreatic adenocarcinoma is the fifth leading cause of death among all malignancies[1],leading to approximately40000deaths each year in Europe[2].Reported probabilities of five-year survival after curative surgery are still below10percent[3].Stage,grade and resection margin status are currently accepted as the most accurate pathologic variables predicting survival[4-10].Pathologic staging only insufficiently reflects the individual risk to develop tumor recurrence which is ev…     

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis

Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.     

Selection criteria in resectable pancreatic cancer: A biological and morphological approach

Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a low rate of survival. Surgery is the only curative treatment for PDA, although only 20% of patients are resectable at diagnosis. During the last decade there was an improvement in survival in patients affected by PDA, possibly explained by the advances in cancer therapy and by improve patient selection by pancreatic surgeons. It is necessary to select patients not only on the basis of surgical resectability, but also on the basis of the biological nature of the tumor. Specific preoperative criteria can be identified in order to select patients who will benefit from surgical resection. Duration of symptoms and level of carbohydrate antigen 19.9 in resectable disease should be considered to avoid R1 resection and early relapse. Radiological assessment can help surgeons to distinguish resectable disease from borderline resectable disease and locally advanced pancreatic cancer. Better patient selection can increase survival rate and neoadjuvant treatment can help surgeons select patients who will benefit from surgery.     

Prior history of acute pancreatitis predicts poor survival in patients with resectable pancreatic ductal adenocarcinoma

Background/objectivesMounting evidence has suggested that acute pancreatitis (AP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but its role in survival in PDAC patients was rarely investigated. The objective was to investigate the association of a history of AP with survival among PDAC patients who underwent surgical resection.MethodsA retrospective cohort study comprising 632 patients who were diagnosed with resectable PDAC was conducted. Survival was evaluated by history of AP prior to a diagnosis of PDAC using Kaplan-Meier methods and log-rank tests. Multivariate analyses for mortality were estimated using the Cox proportional hazards model. Propensity score matching methods were used to balance the difference of clinical characteristics between patients with and without AP history.ResultsThe log-rank tests showed that patients with a history of AP had a worse overall survival than those without a history of AP (p = 0.006). The multivariable-adjusted hazard ratio (HR) for mortality comparing participants with AP to those without AP was 1.808 (95% CI: 1.241–2.632, p = 0.002). Patients with a recent history of AP (<2 years), rather than patients with a remote history of AP (≥2 years), were found to have significantly worse survival (p = 0.014) than those without a history of AP. After adjusted for PSM, history of AP remained an independent survival predictor of PDAC following surgical resection.ConclusionsOur findings indicate that a history of AP, especially a recent history of AP, is associated with poor survival among patients with resectable pancreatic ductal adenocarcinoma.     

Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis

BackgroundChronic pancreatitis (CP) may cause tumor-like lesions, creating a challenge in distinguishing between CP and pancreatic ductal adenocarcinoma (PDAC) in a patient. Given that invasive surgery is a standard cancer treatment, we aimed to examine whether a noninvasive diagnostic tool utilizing serum cytokines could safely differentiate between PDAC and CP.MethodsA pre-operative serum panel comprising 48 inflammatory cytokines, CA19-9, and C-reactive protein (CRP) was analyzed, consisting of 231 patients, 186 with stage I–III PDAC and 45 with CP. We excluded PDAC patients who underwent neoadjuvant therapy and those CP patients with other active malignancies. The laboratory variables most associated with PDAC diagnosis were assessed using logistic regression and selected using the lasso method.ResultsThe cytokines CTACK, GRO-α, and β-NGF were selected alongside CA19-9 and CRP for our differential diagnostic model. The area under the curve (AUC) for our differential diagnostic model was 0.809 (95% confidence interval [CI] 0.738–0.880), compared with 0.791 (95% CI 0.728–0.854) for CA19-9 alone (not significant).ConclusionsWe found that inflammatory cytokines CTACK, GRO-α, and β-NGF alongside CA19-9 and CRP may help distinguish PDAC from CP.     

Evaluation of preoperative prognostic factors in patients with resectable pancreatic ductal adenocarcinoma

Abstract

Objective: Upfront surgery is the standard treatment for resectable pancreatic ductal adenocarcinomas (R-PDACs); however, these tumors often recur. We investigated the factors governing recurrence and prognosis in patients with R-PDAC.

Methods: We analyzed 359 patients who underwent upfront surgery for R-PDAC between 2000 and 2016, and evaluated the relationship between clinicopathological factors and recurrence/outcomes.

Results: The rate of recurrence was 74% while the median time to recurrence was 1.2 years. On multivariate analysis, carbohydrate antigen 19-9 (CA19-9) >37?U/mL (hazard ratio [HR]: 2.02), tumor size >2.6?cm (HR: 1.50), pathological grade 3 (HR: 2.58), lymph node metastasis (LNM; HR: 1.65), residual tumor (HR: 1.47) and forgoing adjuvant chemotherapy (HR: 1.31) were risk factors for a shorter recurrence-free survival; the median survival time (MST) was 2.8 years. On multivariate analysis, CA19-9?>?37?U/mL (HR: 1.99), tumor size >2.6?cm (HR: 1.43), pathological grade 3 (HR: 2.93), pathological portal vein invasion (HR: 1.48), LNM (HR: 1.79) and forgoing adjuvant chemotherapy (HR: 1.39) were risk factors for shorter disease-specific survival intervals. When examining outcomes according to preoperatively measurable factors (CA19-9?>?37?U/mL and tumor size >2.6?cm), the median time to recurrence and MSTs of patients with none (n?=?83), one (n?=?112) and both (n?=?164) risk factors were 3.2, 1.8 and 0.8 years; and 7.2, 4.0 and 1.7 years, respectively.

Conclusions: CA19-9?>?37?U/mL and tumor size >2.6?cm were preoperative independent risk factors for early recurrence and poor outcomes in patients with R-PDAC. Therefore, preoperative treatment should be considered for such patients.     

Preoperative risk factors for early recurrence in patients with resectable pancreatic ductal adenocarcinoma after curative intent surgical resection

Background: Postoperative early recurrence(ER) in patients with pancreatic ductal adenocarcinoma(PDAC) is frequently encountered after curative intent surgery. Nonetheless, clinical significance and risk factors of ER after surgery for PDAC have not been extensively investigated. The aim of this study was to determine preoperative risk predictors for ER in patients with PDAC after upfront surgery. Methods: Eighty-one consecutive patients with PDAC who underwent curative intent surgical resection at Kangbuk Samsung Hospital between January 2004 and May 2015 were enrolled. ER was defined as tumor relapse within 6 months after surgery. Results: ER occurred in 26 patients(32.1%), whereas 49 patients(60.5%) had late recurrence( ≥ 6 months after surgery), and 6 patients had no recurrence(7.4%). Univariate analysis showed that C-reactive protein(CRP) 3.0 mg/dL, modified Glasgow prognostic score(mGPS) = 2, decrease of total lymphocyte count by 50% of baseline value in the preoperative period, prognostic nutritional index(PNI) 45, neutrophilto-lymphocyte ratio(NLR) ≥ 3, and preoperative maximum standardized uptake value(SUVmax) were significantly associated with ER. Multivariate logistic regression analysis revealed that CRP 3.0 mg/dL, decrease of total lymphocyte count by 50% of baseline value, and preoperative SUVmax were significant and independent contributors of ER in patients with resectable PDAC who underwent curative intent surgery. Conclusions: Postoperative ER for resectable PDAC was frequent with poor prognosis after curative intent upfront surgery. It is reasonable to suggest that there is a subgroup of resectable PDAC patients at highrisk of ER and neoadjuvant therapy should be considered in these patients in a clinical trial setting.     

Significance of the inflammation-based prognostic score in recurrent pancreatic cancer

BackgroundAlthough the prognosis of recurrent pancreatic cancer (RPC) is improving with the appearance of new anticancer drugs, prognostic indicators for RPC are still poorly understood. The aim of this study was to evaluate significance of the inflammation-based prognostic score, including modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Prognostic Nutritional Index (PNI), in patients with RPC.MethodsThis study reviewed 263 patients of pancreatic ductal adenocarcinoma at our institution between 2006 and 2015. A receiver operating characteristics curve analysis was performed to determine the cut-off values. The prognostic significance of the inflammation-based prognostic scores were evaluated by a multivariate analysis.Results172 patients (65.4%) who had recurrence was included in this study. The optimal PNI for predicting 1-year survival after recurrence was 40 with higher area under receiver operating characteristics curve value (0.704) in comparison with other inflammation-based prognostic scores. A univariate and multivariate analysis revealed that liver metastasis (P < 0.001) and PNI < 40 (P < 0.001) were independently associated with the survival time after recurrence. When each of the two predictors was counted as one point and the points were calculated for all cases, a good stratified survival curve was obtained, showing the shorter survival in the higher points: median survival times of 2, 1, and 0 points were 4.3, 11.1, and 21.2 months, respectively (P < 0.001).ConclusionsInflammation-based prognostic scores, especially PNI is useful clinical biomarker for predicting the survival time after recurrence in patients with pancreatic adenocarcinoma.     

Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis

Objective

Adipophilin is a lipid droplet-associated protein, and its expression has been correlated with aggressive clinical behavior in some types of carcinomas, though its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the role of adipophilin in PDAC.

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.MethodsWe performed methylation-specific PCR of the SFRP1 genes’ promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.ResultsThe study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%–61.7%) and 19.8% (95% CI 1.9–37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-monthsConclusionsThis indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.     

Lumican蛋白在胰腺导管腺癌间质中的表达及其与Ki-67、VEGF及突变型P53表达的相关性

目的:观察细胞外基质蛋白Lumican在胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDA)中表达特征,分析Lumican与Ki-67、VEGF、突变型P53等肿瘤恶性表型相关分子的关联.方法:采用免疫组织化学染色(IHC)和逆转录-聚合酶链式反应(RT-PCR)检测PDA原发灶及对应癌旁胰腺组织中Lumican表达.IHC检测PDA原发灶Ki-67、VEGF及突变型P53表达.用SPSS软件行统计学分析.结果:PDA原发灶中,Lumican表达在mRNA及蛋白质水平均明显高于癌旁胰腺组织.就该蛋白在癌灶中的分布特性而言,Lumican蛋白主要定位于癌间质,阳性表达率为83.0%(83/100).低分化PDA中,癌间质过表达Lumican与TNM分期相关(x2=6.446,P<0.05),与年龄、性别、淋巴结转移、远处转移等无明显相关.高中分化PDA中,癌间质过表达Lumican与临床病理特征无关,而与Ki-67(r=-0.28,P=0.017)、VEGF(r=-0.264,P=0.025)及突变型P53(r=-0.253,P=0.032)表达呈明显负相关.结论:Lumican在PDA原发灶中表达高于癌旁胰腺组织,主要分布于癌间质.Lumican在癌间质过表达与低分化PDA的TNM分期相关,与高、中分化PDA的Ki-67、VEGF及突变型P53表达呈负相关.     

Improving the accuracy of pancreatic cancer clinical staging by exploitation of nanoparticle-blood interactions: A pilot study

Background

Pancreatic ductal adenocarcinoma (PDAC) early diagnosis is? crucial ?and new, cheap and user-friendly techniques for biomarker identification? are ?needed. “Protein corona” (PC) is emerging a new bio-interface potentially useful in tumor early diagnosis. In a previous investigation, we showed that relevant differences between the ?protein patterns of? PCs formed on lipid NPs after exposure to PDAC and non-cancer plasma? samples exist. To extend that research, We performed this pilot study to investigate the effect of PDAC tumor size and distant metastases on PC composition.

Molecular advances in pancreatic cancer: A genomic,proteomic and metabolomic approach

Pancreatic ductal adenocarcinoma (PDAC) represents a challenging pathology with very poor outcomes and is increasing in incidence within the general population. The majority of patients are diagnosed incidentally with insidious symptoms and hence present late in the disease process. This significantly affects patient outcomes: the only cure is surgical resection but only up to 20% of patients present with resectable disease at the time of clinical presentation. The use of “omic” technology is expanding rapidly in the field of personalised medicine - using genomic, proteomic and metabolomic approaches allows researchers and clinicians to delve deep into the core molecular processes of this difficult disease. This review gives an overview of the current findings in PDAC using these “omic” approaches and summarises useful markers in aiding clinicians treating PDAC. Future strategies incorporating these findings and potential application of these methods are presented in this review article.     

Glycoproteins and glycoproteomics in pancreatic cancer

Aberrations in protein glycosylation and polysaccharides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immunoresponse and chemoresistance. Abnormal expression in sugar moieties can impact the function of various glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their effectors and binding ligands, resulting in an increase in pancreatic cancer invasiveness and a cancerfavored microenvironment. Recent advance in glycoproteomics, glycomics and other chemical biology techniques have been employed to better understand the complex mechanism of glycosylation events and how they orchestrate molecular activities in genomics, proteomics and metabolomics implicated in pancreatic adenocarcinoma. A variety of strategies have been demonstrated targeting protein glycosylation and polysaccharides for diagnostic and therapeutic development.     

Management of pancreatic cancer in the elderly

Currently, pancreatic adenocarcinoma mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. The aging of the population will result in a rise in the incidence of pancreatic adenocarcinoma within the next years. Thus, the management of pancreatic cancer in the elderly population is gaining increasing relevance. Older cancer patients represent a heterogeneous group with different biological, functional and psychosocial characteristics that can modify the usual management of this disease, including pharmacokinetic and pharmacodynamic changes, polypharmacy, performance status, comorbidities and organ dysfunction. However, the biological age, not the chronological age, of the patient should be the limiting factor in determining the most appropriate treatment for these patients. Unfortunately, despite the increased incidence of this pathology in older patients, there is an underrepresentation of these patients in clinical trials, and the management of older patients is thus determined by extrapolation from the results of studies performed in younger patients. In this review, the special characteristics of the elderly, the multidisciplinary management of localized and advanced ductal adenocarcinoma of the pancreas and the most recent advances in the management of this condition will be discussed, focusing on surgery, chemotherapy, radiation and palliative care.