Prognostic significance of preoperative PNI and CA19-9 for pancreatic ductal adenocarcinoma: A multi-institutional retrospective study

BackgroundThe aim of this study was to investigate the clinical value of nutritional and immunological prognostic scores as predictors of outcomes and to identify the most promising scoring system for patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-institutional study.MethodsData were retrospectively collected for 589 patients who underwent surgical resection for PDAC. Prognostic analyses were performed for overall (OS) and recurrence-free survival (RFS) using tumor and patient-related factors, namely neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), modified GPS, C-reactive protein-to-albumin ratio, Controlling Nutritional Status score, and the Geriatric Nutritional Risk Index.ResultsCompared with PDAC patients with high PNI values (≥46), low PNI (<46) patients showed significantly worse overall survival (OS) (multivariate hazard ratio (HR), 1.432; 95% CI, 1.069–1.918; p = 0.0161) and RFS (multivariate HR, 1.339; 95% CI, 1.032–1.736; p = 0.0277). High carbohydrate antigen 19–9 (CA19-9) values (≥450) were significantly correlated with shorter OS (multivariate HR, 1.520; 95% CI, 1.261–2.080; p = 0.0002) and RFS (multivariate HR, 1.533; 95% CI, 1.199–1.961; p = 0.0007). Stratification according to PNI and CA19-9 was also significantly associated with OS and RFS (log rank, P < 0.0001).ConclusionsOur large cohort study showed that PNI and CA19-9 were associated with poor clinical outcomes in PDAC patients following surgical resection. Additionally, combining PNI with CA19-9 enabled further classification of patients according to their clinical outcomes.     

Pre-treatment carbohydrate antigen 19-9 does not predict the response to neoadjuvant therapy in patients with localized pancreatic cancer

BackgroundThe prognostic value of CA19-9 in patients with pancreatic cancer (PC) treated with neoadjuvant therapy has not been well described.MethodsPre-treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (≤35), low (36–200), moderate (201–1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery.ResultsPre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post-treatment CA19-9 normalized (≤ 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group (P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups (P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02].ConclusionsAmong patients who completed neoadjuvant therapy and surgery, pre-treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic.     

High CA19-9 level in resectable pancreatic cancer is a potential indication of neoadjuvant treatment

BackgroundPrevious studies on borderline resectable (BR) pancreatic cancer (PC) included patients with heterogenous preoperative states; however, the definition of resectability for PC has evolved. We aimed to investigate the prognostic factors for PC other than anatomical resectability in those who underwent upfront resection and discuss the optimal treatment strategy for PC.MethodsWe retrospectively examined 431 patients who underwent upfront surgery with curative intent between 2007 and 2014. The association between clinical characteristics and survival outcomes was assessed by stratifying patients according to risk factors. The patients were categorized into four groups based on anatomical (resectable [R]/BR) and biological features (CA19-9 ≤500/>500 U/mL): anatomical R with CA19-9 ≤500 U/mL (favorable-R); anatomical BR with CA19-9 ≤500 U/mL (favorable-BR); anatomical R with CA19-9 >500 U/mL (risky-R); and anatomical BR with CA19-9 >500 U/mL (risky-BR).ResultsOverall, 320 and 111 patients had anatomical R- and BR-PC, respectively. A modified Glasgow prognostic score = 2 (hazard ratio [HR]: 1.73), NLR>5 (hazard ratio [HR]: 1.54), CA19-9 >500 U/mL (HR: 1.86), and anatomical BR (HR: 1.38) were independent prognostic factors for overall survival. The risky-R group had likely worse prognosis (16 months vs. 19 months, P = 0.0605) and a significantly higher early recurrence rate (36% vs 18%, P = 0.0231) than the favorable-BR group.ConclusionsIt is essential to stratify and distinguish PC patients at a high risk of worse prognosis. Risky-R was an unfavorable prognostic factor and should thus be considered in the decision-making for treatment with neoadjuvant chemotherapy, in addition to anatomical BR-PC.     

Prognostic impact of the ratio of preoperative CA19-9 to liver enzyme levels in pancreatic cancer patients with jaundice (predictability of combined CA19-9/AST and CA19-9/γ-GGT for jaundiced PDAC patients)

BackgroundCarbohydrate antigen 19–9 (CA19-9) has been reported as the most significant survival predictor of patients with pancreatic ductal adenocarcinoma (PDAC). However, the elevation of CA19-9 could interfere with obstructive jaundice and the predictive value of CA19-9 in PDAC patients with jaundice remains to be analyzed and elucidated to find possible adjustments.ObjectiveTo evaluate the predictability of preoperative CA19-9 and its adjustments for the overall survival (OS) of PDAC patients by analyzing the relationship between preoperative serum CA19-9 and total bilirubin (TBIL).MethodsA total of 563 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma in our center between January 2015 and September 2018 were retrospectively reviewed. Clinicopathologic information was collected and preoperative parameters such as CA19-9, CEA, TBIL, γ-GGT, AST, ALT, and ALP were recorded as well as overall survival rates, which began from the date of operation to that of death or the last follow-up. Kaplan-Meier survival curves with log-rank test and Cox regression models were applied using SPSS and the survival and survminer packages in R software.ResultsUsing 39/390/1000 as the cut-off values for preoperative serum CA19-9, significant capability of OS stratification was found in the total cohort (p < 0.001, MST = 29.7/19.1/15.2/12.1 months) and patients with TBIL <102.6 μmol/L (p < 0.001, MST = 32.2/19.6/15.0/11.2 months). However, in the subgroup of TBIL≥102.6 μmol/L, this classification method was replaced by the combined scoring of CA19-9/AST and CA19-9/γ-GGT.ConclusionsAs an independent predictor of overall survival of PDAC patients, preoperative serum CA19-9 is defective in survival stratification when TBIL≥102.6 μmol/L but a positive survival prognosis could be achieved with the application of combined preoperative CA19-9/AST and CA19-9/γ-GGT.     

Induction chemotherapy in pancreatic cancer: CA 19-9 may predict resectability and survival

BackgroundPreoperative/Neoadjuvant treatment (NT) is increasingly used in unresectable pancreatic cancer (PDAC). However, ∼40% of patients cannot be resected after NT and reliable preoperative response evaluation is currently lacking. We investigated CA 19-9 levels and their dynamics during NT for prediction of resectability and survival.MethodsWe screened our institution's database for patients who underwent exploration or resection after NT with gemcitabine-based therapy (GEM) or FOLFIRINOX (FOL). Pre- and post-NT CA 19-9, resection rate and survival were analyzed.ResultsOf 318 patients 165 (51.9%) were resected and 153 (48.1%) received exploration. In the FOL group (n = 103; 32.4%), a post-NT CA 19-9 cutoff at 91.8 U/ml had a sensitivity of 75.0% and a specificity of 76.9% for completing resection with an AUC of 0.783 in the ROC analysis (95% CI: 0.692–0.874; p < 0.001. PPV: 84.2%, NPV: 65.2%). Resected patients above the cutoff did not benefit from resection. Post-NT CA 19-9 <91.8 U/ml (OR 11.63, p < 0.001) and CA 19-9 ratio of <0.4 (OR 5.77, p = 0.001) were independent predictors for resectability in FOL patients.DiscussionCA 19-9 levels after neoadjuvant treatment with FOLFIRINOX predict resectability and survival of PDAC more accurately than dynamic values and should be incorporated into response evaluation and surgical decision-making.     

Risk factors and outcomes for patients with pancreatic cancer undergoing surgical exploration without resection due to metastatic disease: A national cohort study

BackgroundUnresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to identify preoperative risk factors for metastatic disease diagnosed at surgical exploration and to investigate and compare survival in resected and non-resected patients.MethodsPatients were identified from the Swedish National Pancreatic and Periampullary Cancer Registry 2010-2018. Predictors of metastatic disease were evaluated with a multivariable logistic regression model, and survival was evaluated with Kaplan-Meier estimates and log-rank tests.ResultsIn total, 1938 patients with PDAC were scheduled for surgery. An unresectable situation was diagnosed intraoperatively in 399 patients (20.6%), including 234 (12.1%) with metastasized disease. Independent risk factors for metastasis were involuntary weight loss (OR = 1.72; 95% CI: 1.27-2.33) and elevated carbohydrate antigen 19-9 (CA19-9) (35-599 U/mL, OR = 1.79, 95% CI: 1.11-2.89; ≥ 600 U/mL, OR = 3.24, 95% CI: 2.04-5.17). Overall survival was lower among patients with metastasized disease than that among patients with a resectable tumor (P < 0.001).ConclusionsInvoluntary weight loss and an elevation of CA19-9 are preoperative risk factors for diagnosing metastasized disease during surgical exploration.     

Isolated pulmonary recurrence after resection of pancreatic cancer: the effect of patient factors and treatment modalities on survival

BackgroundThe literature suggests favorable survival for patients with isolated pulmonary recurrence after resection of pancreatic ductal adenocarcinoma (PDAC) as compared to other recurrence patterns. Within this cohort, it remains unclear what factors are associated with improved survival.MethodsPatients who developed pulmonary recurrence after pancreatectomy were selected from a prospective database. Predictors for post-recurrence survival (PRS) were analyzed using a multivariable Cox regression model.ResultsNinety-six patients were included. Median recurrence-free survival (RFS), PRS and overall survival (OS) were 16.3, 18.8 and 39.6 months, respectively. Further systemic treatment and/or metastasectomy (n = 64, 67%) was associated with significantly improved PRS and OS when compared to best supportive care (n = 35, 22%) (26.3 vs. 5.3 and 48.1 vs. 18.4, respectively; both P < 0.001). Patients who were able to undergo metastasectomy (n = 19) achieved a PRS and OS of 35.0 and 68.9 months, respectively. More than 5 pulmonary lesions, symptoms and CA 19-9 ≥100 U/mL at time of recurrence were predictive of decreased PRS. A recurrence-free interval of >16 months and treatment for recurrence were independently associated with improved PRS.ConclusionsIsolated pulmonary recurrence occurs in 13% of patients with recurrent PDAC and is associated with a median OS of 40 months. Aggressive treatment in highly selected patients was correlated with improved survival.     

Preoperative Serum CA125 Levels Predict the Prognosis in Hyperbilirubinemia Patients With Resectable Pancreatic Ductal Adenocarcinoma

Serum carbohydrate antigen 19-9 (CA19-9) is widely used to predict the prognosis for pancreatic ductal adenocarcinoma (PDAC). However, hyperbilirubinemia and the CA19-9 nonsecretor phenotype restrict the usage of serum CA19-9 alone. The goal of this study was to confirm the prognostic role of preoperative serum CA125 in PDAC, especially in patients with jaundice.A total of 211 patients with resected PDAC were eligible for this retrospective study, and were classified into 2 groups based on serum bilirubin levels. The prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses, and the performance of each factor in predicting overall survival (OS) and recurrence-free survival (RFS) was compared.High preoperative CA125, high TNM stage, and lymph node metastasis were independent risk predictors for OS and RFS in all patients and the 2 subgroups, but high CA19-9 was only significant when considering all patients and those with nonelevated bilirubin. Using time-dependent receiver-operating characteristic analysis, better predictive performance for OS and RFS was observed for serum CA19-9 as compared to serum CA125 in these patients.High serum CA125 can independently predict poor prognosis. Importantly, in PDAC patients with hyperbilirubinemia, preoperative serum CA125 can predict the prognosis, whereas CA19-9 cannot. Preoperative CA19-9 had better predictive performance for survival than CA125, and the performance of CA19-9 did not decline between all patients and those with nonelevated bilirubin, but was significantly affected by hyperbilirubinemia.     

Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer

Objectives

The purpose of this study was to determine the relationship between carbohydrate antigen (CA) 19-9 levels and outcome in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy (NT).

Methods

This study included all patients with borderline resectable pancreatic cancer, a serum CA 19-9 level of ≥40 U/ml and bilirubin of ≤2 mg/dl, in whom NT was initiated at one institution between 2001 and 2010. The study evaluated the associations between pre- and post-NT CA 19-9, resection and overall survival.

Results

Among 141 eligible patients, CA 19-9 declined during NT in 116. Following NT, 84 of 141 (60%) patients underwent resection. For post-NT resection, the positive predictive value of a decline and the negative predictive value of an increase in CA 19-9 were 70% and 88%, respectively. The normalization of CA 19-9 (post-NT <40 U/ml) was associated with longer median overall survival among both non-resected (15 months versus 11 months; P = 0.022) and resected (38 months versus 26 months; P = 0.020) patients. Factors independently associated with shorter overall survival were no resection [hazard ratio (HR) 3.86, P < 0.001] and failure to normalize CA 19-9 (HR 2.13, P = 0.001).

Conclusions

The serum CA 19-9 level represents a dynamic preoperative marker of tumour biology and response to NT, and provides prognostic information in both non-resected and resected patients with borderline resectable pancreatic cancer.     

Clinical significance and predictors of complete or near-complete histological response to preoperative chemoradiotherapy in patients with localized pancreatic ductal adenocarcinoma

BackgroundThe clinical value and predictors of a favorable histological response to preoperative chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC) remains undefined.ObjectiveTo assess the significance and predictors of a favorable histological response to preoperative CRT in patients with localized PDAC.MethodsThe study included 203 patients with localized PDAC undergoing curative-intent resection after CRT. The rate of R0 resection and overall survival (OS) and recurrence-free survival (RFS) were correlated with the grading of histological response to determine optimal stratification. Clinical factors associated with a significant histological response were evaluated using multivariate regression analysis.ResultsAmong all patients, eight patients (3.9%) had a grade 4 (pCR); 40 (19.4%) had a grade 3 estimated rate of residual neoplastic cells <10% (near-pCR); and 155 (76.7%) had a grade 1/2 limited response. The 48 patients with pCR/near-pCR achieved significantly higher R0 resection rate (100%) than those with grade 1/2 (80.0%). The 5-year OS and RFS rates were significantly higher in the patients with pCR/near-pCR (45.3% and 36.5%) than in those with grade 1/2 (27.1% and 18.5%). Gemcitabine plus S-1 based CRT, serum CA19-9 level after CRT <83 U/mL, and interval from initial treatment to surgery ≥4.4 months were independent predictive factors for pCR/near-pCR.ConclusionspCR or near-pCR to preoperative CRT contributed to achieving a high rate of R0 resection and improving survival for localized PDAC. The use of gemcitabine plus S-1 as a radiosensitizer, lower serum CA19-9 level after CRT, and longer preoperative treatment duration were significantly associated with pCR or near-pCR.     

Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma – An external validation study

BackgroundWe recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9.MethodsPatients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort.ResultsPatients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70–8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42–6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69–0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89–0.96) in the primary study and 0.85 (95% CI 0.79–0.91) in the validation study.ConclusionIn this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.     

Exosomal glypican-1 discriminates pancreatic ductal adenocarcinoma from chronic pancreatitis

Background and aimsPancreatic ductal adenocarcinoma (PDAC) diagnosis can be difficult in a chronic pancreatitis (CP) background, especially in its mass forming presentation. We aimed to assess the accuracy of glypican-1-positive circulating exosomes (GPC1⁺crExos) to distinguish PDAC from CP versus the state-of-the-art CA 19–9 biomarker.MethodsThis was a unicentric prospective cohort. Endoscopic ultrasound with fine-needle aspiration or biopsy and blood tests (GPC1⁺crExos and serum CA 19–9) were performed.ResultsThe cohort comprised 60 PDAC and 29 CP (7 of which mass forming - MF) patients. Median levels of GPC1⁺crExos were significantly higher in PDAC (99.7%) versus CP (28.4%; p<0.0001) with an AUROC of 0.96 with 98.3% sensitivity and 86.2% specificity for a cut-off of 45.0% (p<0.0001); this outperforms CA 19–9 AUROC of 0.82 with 78.3% sensitivity and 65.5% specificity at a cut-off of 37 U/mL (p<0.0001). The superiority of% GPC1+crExos over CA 19–99 in differentiating PDAC from CP was observed in both early (stage I) and advanced tumors (stages II-IV).ConclusionLevels of GPC1⁺crExos coupled to beads enable differential diagnosis between PDAC and CP including its mass-forming presentation.     

Comparing prognostic factors of Glut-1 expression and maximum standardized uptake value by FDG-PET in patients with resectable pancreatic cancer

BackgroundThis study aimed to assess the prognostic values of preoperative maximum standardized uptake value (SUVmax) of primary pancreatic tumors and Glut-1 expression in patients with resectable pancreatic ductal adenocarcinoma (R-PDAC), and to investigate whether Glut-1 expression is more effective than SUVmax in predicting survival in patients with R-PDAC.MethodsWe investigated 101 R-PDAC patients who underwent pancreatectomy for pancreatic cancer treatment. SUVmax analyzed through ¹⁸F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT), and Glut-1 expression, were assessed for predicting the prognosis of patients with R-PDAC.ResultsIn patients with R-PDAC, the high SUVmax group (≥4.25) had significantly shorter overall survival (OS) and disease-free survival (DFS) than the low SUVmax group (＜4.25). Surprisingly, Glut-1 expression was not significantly correlated with SUVmax. Moreover, the high Glut-1 expression group, which was related to higher levels of CA 19–9, had significantly shorter OS and DFS than the low Glut-1 expression group. Furthermore, among the high SUVmax group, OS and DFS were significantly shorter in the high Glut-1 expression group. Multivariate analyses revealed that Glut-1 overexpression was an independent prognostic factor in patients with R-PDAC. Glut-1 knockdown also induced cell cycle arrest in PDAC cells in vitro.ConclusionsThe study determined that Glut-1 overexpression is a more powerful prognostic factor than SUVmax for predicting OS and higher risk of recurrence in R-PDAC patients. Glut-1 overexpression is also more likely to be associated with malignant activity in PDAC patients.     

The impact of posthepatectomy liver failure on long-term survival after hepatectomy for colorectal liver metastasis

BackgroundPostoperative complications affect both the short-term and long-term outcomes. The aim of this study was to identify specific prognostic factors among complications after hepatectomy for colorectal liver metastasis (CRLM).MethodsBetween 2002 and 2014, 427 patients underwent initial hepatectomy for CRLM. The clinicopathological parameters including postoperative complications were evaluated to identify the prognostic factors for the overall (OS) and relapse-free survival (RFS).ResultsOne hundred and forty-nine patients (34%) developed postoperative complications, including surgical site infection (n = 49, 11.4%), bile leakage (n = 41, 9.6%), posthepatectomy liver failure (PHLF) (n = 26, 6.0%), and pulmonary complication (n = 20, 4.6%). The independent predictors of RFS included primary nodal metastasis, abnormal CA19-9 levels, extrahepatic metastasis, bilateral CRLMs, ≥5 CRLMs, preoperative chemotherapy, lack of adjuvant chemotherapy and PHLF. The 5-year RFS rates in patients with and without PHLF were 8% and 32%, respectively (P < 0.001). The independent prognostic factors for OS included primary nodal metastasis, abnormal CA19-9 levels, extrahepatic metastasis, positive surgical margins, preoperative chemotherapy, lack of adjuvant chemotherapy and PHLF. The 5-year OS rates in patients with and without PHLF were 31% and 63%, respectively (P = 0.004).ConclusionsAmong the complications, only PHLF was associated with decreased long-term survival after hepatectomy for CRLM as well as tumor-specific prognostic factors.     

Clinical implications of the serum CA19-9 level in “biological borderline resectability” and “biological downstaging” in the setting of preoperative chemoradiation therapy for pancreatic cancer

BackgroundBiological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and “biological downstaging” in chemoradiation therapy (CRT) for pancreatic cancer (PC).MethodsA total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. “Biological downstaging” was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor).ResultsThe 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986).ConclusionsBiological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated “biological downstaging” in b-BR in the preoperative CRT strategy.     

Mitochondrial expression of the DNA repair enzyme OGG1 improves the prognosis of pancreatic ductal adenocarcinoma

Background/Objectives: 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC).MethodsNinety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined.ResultsThe low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19–9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC.ConclusionsLow mitochondrial OGG1 expression might aggravate the PDAC prognosis.     

Prognostic impact of simultaneous venous resections during surgery for resectable pancreatic cancer

BackgroundThe aim of this study was to evaluate the prognostic impact of simultaneous venous resection during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) that was preoperatively staged resectable according to NCCN guidelines.MethodsA retrospective analysis of 153 patients who underwent PD for PDAC was performed. Patients were divided into standard PD and PD with simultaneous vein resection (PDVR). Groups were compared to each other in terms of postoperative morbidity and mortality, disease free (DFS) and overall survival (OS).Results114 patients received PD while 39 patients received PDVR. No differences in terms of postoperative morbidity and mortality between both groups were detected. Patients in the VR group presented with a significantly shorter OS in the median (13 vs. 21 months, P = 0.011). In subgroup analysis, resection status did not influence OS in the PDVR group (R0 13 vs. R1 12 months, P = 0.471) but in the PD group (R0 23 vs. R1 14 months, P = 0.043). PDVR was a risk factor of OS in univariate but not multivariable analysis.ConclusionPDVR for PDAC preoperatively staged resectable resulted in significantly shorter OS regardless of resection status. Patients who require PDVR should be considered for adjuvant chemotherapy in addition to other oncological indications.     

How do we interpret an elevated carbohydrate antigen 19-9 level in asymptomatic subjects?

AimThis prospective cohort study aimed to evaluate the etiology of elevated CA 19-9 levels and to present appropriate guidelines for the asymptomatic patients.MethodsBetween January 2004 and March 2007, we enrolled consecutive asymptomatic patients who had elevated CA 19-9 levels >37 U/mL. To evaluate the etiology, the CA 19-9 level was rechecked and further studies were carried out. If the CA 19-9 level decreased to the normal range, or if it showed a decreasing trend, then it was monitored annually. Yet, if the CA 19-9 level showed an increasing trend, then the level was monitored at intervals of 1, 3, and 6 months until no evidence of malignancy was proven.ResultsOf the 62,976 patients, 501 (0.8%) subjects showed an elevated CA 19-9 level. This prospective analysis was conducted on 353 subjects (70.5%) who were followed up for at least 6 months. Ten patients (2.8%) were diagnosed with malignancies. There were 97 patients (27.5%) with benign diseases and 246 patients (69.7%) were deemed non-specific.ConclusionsCA 19-9 should not be used as a screening tool. In the case of a persistently elevated CA 19-9 level, further work-up for determining the etiology should be done.     

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.     

Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer

BackgroundWe evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers.MethodsMaterials were derived from the prospective nationwide Dutch Pancreas Biobank (2015–2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed.ResultsMedian ADAM12 levels were 161 (IQR 79–352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P = 0.04), but not after adjustment. In distal cholangiocarcinoma (n = 33), high ADAM12 levels predicted poor OS in univariable analysis (P = 0.02), but not in PDAC (P = 0.63). PDAC patients (n = 135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P = 0.02), whereas those with low levels did not (21 vs 21 months, P = 0.87).ConclusionHigh circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies.