Simultaneous and sequential combination of genetic and epigenetic biomarkers for the presence of high-grade dysplasia in patients with pancreatic cyst: Discovery in cyst fluid and test in pancreatic juice.

BACKGROUND/OBJECTIVES: Screening patients with intraductal papillary mucinous neoplasms (IPMN) has the primary goal of identifying potentially curable noninvasive precursors. We aimed to evaluate the diagnostic impact of genetic and epigenetic biomarkers in the presence of noninvasive precursors. METHODS: Mutated KRAS/GNAS and methylated SOX17/TBX15/BMP3/TFPI2 DNA were assessed by droplet digital PCR in a discovery cohort of 70 surgically aspirated cyst fluids, and diagnostic performances for differentiating high-grade dysplasia (HGD) from low-grade dysplasia (LGD) was evaluated. We then tested these markers using an independent test cohort consisting of 156 serially collected pancreatic juice samples from 30 patients with IPMN. RESULTS: Mutated KRAS and GNAS are specific for IPMNs but are not helpful for the prediction of histological grades. Cyst fluids from IPMN with HGD showed higher methylation levels of SOX17 (median, 0.141 vs. 0.021; P = 0.086) and TBX15 (median, 0.030 vs. 0.003; P = 0.028) than those with LGD. The combination of all tested markers yielded a diagnostic performance with sensitivity of 69.6%, and specificity of 90.0%. Among the 30 pancreatic juice samples exhibiting the highest abundance of KRAS/GNAS mutations in each patient in the test cohort, patients with histologically proven HGD due to pancreatic resection had a significantly higher prevalence (100% vs. 31%, P = 0.018) and abundance (P = 0.037) of methylated TBX15 than those without cytohistological diagnosis undergoing surveillance. CONCLUSIONS: A simultaneous and sequential combination of mutated and methylated DNA markers in pancreatic cyst fluid and juice sample markers can help detect noninvasive pancreatic precursor neoplasms.

Prognostic impact of postoperative circulating tumor DNA as a molecular minimal residual disease marker in patients with pancreatic cancer undergoing surgical resection.

PURPOSE: We aimed to clarify the prognostic impact of postoperative circulating tumor DNA (ctDNA) shortly after pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Preoperative and paired postoperative blood samples were obtained from 66 patients in patients with PDAC. Cell-free DNA was extracted from the plasma, and KRAS mutations, as a benchmark of ctDNA, were examined using droplet digital PCR. Disease-free survival (DFS) and overall survival (OS) were compared between patients with presence and absence of ctDNA. RESULTS: In univariate analysis, patients with detectable postoperative ctDNA showed worse survival than those with undetectable in both DFS (P = .034) and OS (P = .022). Multivariate analysis also revealed that the presence of postoperative ctDNA was an independent risk factor for recurrence (hazard ratio: 2.677, P = .011). In contrast, preoperative ctDNA detection did not affect long-term outcomes. These trends persisted in 34 patients with resectable PDAC who underwent resection after neoadjuvant chemotherapy. Patients with detectable postoperative ctDNA were more prone to developing hepatic recurrence than those with undetectable postoperative ctDNA (P = .039). CONCLUSION: Postoperative ctDNA, as a minimal residual marker, can be useful for predicting the risk of recurrence in patients with PDAC even after curative resection.

Levels of tumor markers CEA/CA 19-9 in serum and peritoneal lavage predict postoperative recurrence in patients with pancreatic cancer.

Aim: This study aimed to clarify the usefulness of tumor markers from peritoneal lavage in selecting patients with a high risk of recurrence and predicting site-specific recurrence in patients with pancreatic cancer. Methods: The levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 (sCEA/sCA 19-9) and paired peritoneal lavage CEA and CA 19-9 (pCEA/pCA 19-9) were measured in 90 patients with pancreatic cancer who underwent surgery. Using the cutoff values determined by maximally selected rank statistics for disease-free survival (DFS), the risk of recurrence and its patterns were evaluated in combination with different markers and different test specimens. Results: In univariate and multivariate analysis, an elevated pCA 19-9 level (>1.3 U/mL) was an independent prognostic marker for both DFS (hazard ratio [HR], 2.391; P = .018) and overall survival (HR, 3.194; P = .033). Combination analyses contributed to further stratification of a very high risk of recurrence. Of the 58 patients with resectable pancreatic cancer who underwent curative resection, elevated pCA19-9 was also associated with inferior DFS and overall survival (OS). Patients with elevated pCA 19-9 levels were more likely to have an earlier onset of peritoneal recurrence than those with normal pCA 19-9 levels (P = .048, Gehan-Breslow-Wilcoxon test). Conclusion: pCA 19-9 is a reliable marker for predicting postoperative recurrence in patients with pancreatic cancer after surgery. Further risk stratification can be achieved by using combination assays. The combination of pCA 19-9 and sCA19-9 also serves as a predictor of recurrence site-specific recurrence.

Impact of Tumor-Derived DNA Testing in Peritoneal Lavage of Pancreatic Cancer Patients with and Without Occult Intra-Abdominal Metastases.

BACKGROUND: The fractional abundance of tumor-derived DNA in body fluids depends on the metastatic sites and the degree of expansion. We aimed to assess the clinical significance of tumor-derived DNA testing in the peritoneal lavage of patients with pancreatic cancer. METHODS: The prevalence and abundance of tumor-derived DNA was assessed in 204 subjects with ascites by peritoneal lavage (AS) and the evaluable paired plasma (PL) from 149 pancreatic cancer patients undergoing abdominal exploration. Genetic profiles were evaluated by next-generation sequencing, and prognostic impact was assessed using Cox proportional hazard models. RESULTS: Of 204 subjects, AS samples from patients with peritoneal dissemination (PER+) and positive cytology (CY+) showed significantly higher prevalence and abundance of tumor-derived DNA than those with negative counterparts. Tumor-derived DNA prevalence and abundance in AS were more likely to be higher than in paired PL in a subgroup of patients with PER+ and CY+, respectively. Next-generation sequencing revealed concordant or discrepant mutational patterns between the AS and PL samples. Multivariate analysis showed that both tumor-derived DNA in AS (hazard ratio [HR] 3.940, p = 0.009) and PL (HR 2.936, p = 0.026) were independently associated with poor survival in treatment-naïve patients. In patients who underwent resection, tumor-derived DNA positivity in the AS was more predictive of early recurrence than in PL. CONCLUSIONS: Tumor-derived DNA in AS can serve as characterizing the genetic profiles of tumor cells attributable to the development of PER+ and predicting the minimal residual disease and early recurrence in patients with pancreatic cancer.

Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population.

AIM: Cancer patients with personal/family histories of pancreatic/breast/ovarian/prostate cancer are associated with a higher likelihood of harboring DNA damage repair (DDR)-related germline mutations. Here, we aimed to obtain a better understanding of DDR-related germline mutations in Japanese pancreatic ductal adenocarcinoma (PDAC) patients with personal and/or family histories of BRCA-related cancers of the pancreas, breast, ovary, and prostate. METHODS: We performed next-generation sequencing (NGS) and evaluated germline mutations in nine DDR-related genes (BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2) in PDAC patients with personal and/or family histories. RESULTS: Of 196 patients with PDAC, 39 (19.9%) fulfilled the criteria for at least one family history of pancreatic/breast/ovarian/prostate cancer in first-degree relatives (sibling-sibling or parent-child) or the personal history of these malignancies. Targeted NGS revealed that four (10.2%) of 39 patients with personal/family histories harbored deleterious germline mutations-two in BRCA2, one in ATM, and one in MLH1. Both the BRCA2 variants showed frameshift mutations due to short insertion/deletions. In the 39 patients undergoing NGS, a similar distribution of the clinicopathological characteristics was observed between those with deleterious mutations/variants of unknown significance (VUSs) and with benign/wild types. Patients with deleterious germline mutations/VUSs in DDR-related genes showed a significantly more favorable prognosis than those with benign mutations/wild-type genes (hazard ratio: 0.160, P = .040). CONCLUSIONS: A significant fraction of PDAC patients with personal/family histories of BRCA-related cancers harbored deleterious germline mutations in DDR-related genes. DDR-related germline gene mutations might be a favorable prognostic factor in patients with pancreatic cancer.

Circulating tumor DNA as a predictive marker for occult metastases in pancreatic cancer patients with radiographically non-metastatic disease.

PURPOSE: To elucidate the effectiveness of circulating tumor DNA (ctDNA) for predicting occult metastases in patients with pancreatic cancer without apparent metastases. METHODS: Circulating tumor DNA was obtained from plasma samples of 165 patients with pancreatic cancer and analyzed using droplet digital PCR. The prevalence and allele frequencies of ctDNA were compared across different patterns and degrees of metastatic spread. RESULTS: Of the 142 patients without apparent metastases who underwent abdominal exploration, 39 (27.5%) harbored occult metastases including positive peritoneal lavage cytology. The prevalence of ctDNA was significantly higher in patients with occult metastases than in those without (41.0% vs 14.6%, P = .001). A markedly high prevalence of ctDNA was observed in patients with radiographically visible metastases (78.3%). ctDNA was found to be an independent predictor of the presence of occult metastases (odds ratio: 3.113, P = .039), and its diagnostic performance in combination with tumor markers had a sensitivity of 66.7% and a specificity of 81.6%. In 62 treatment-naïve patients without metastases, multivariate analysis identified the presence of ctDNA as an independent prognostic factor (hazard ratio: 6.311, P = .001). CONCLUSION: Circulating tumor DNA can help predict the presence of occult metastases in pancreatic cancer patients with radiographically non-metastatic disease.

Increased neutrophil-lymphocyte ratio predicts recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

BACKGROUND: The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms. METHODS: Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals. RESULTS: Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors. CONCLUSIONS: The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

Acinar Cell Carcinoma with Morphological Change in One Month.

A 64-year-old man was admitted to our hospital to undergo examination of a pancreatic tumor accompanied by sudden epigastric pain. The tumor had a well-defined oval shape that was mostly less enhanced, with the exception of part of the tumor on the pancreatic head side, on contrast enhanced (CE)-CT. However, CE-CT performed one-month later revealed that the viable part of the tumor grew toward the pancreatic tail with the reduction of necrotic tissue. We performed distal pancreatectomy and the tumor was diagnosed as acinar cell carcinoma (ACC). One important characteristic of ACC is that it may develop morphological changes within a short period of time.

MicroRNA-593-3p Expression in Peritoneal Lavage Fluid as a Prognostic Marker for Pancreatic Cancer Patients Undergoing Staging Laparoscopy.

BACKGROUND: Some presumed resectable pancreatic cancer patients harbor radiographically occult metastases that are incidentally identified at the time of abdominal exploration. This study aims to identify novel diagnostic or predictive microRNA (miRNA) markers for subclinical peritoneal dissemination in patients with pancreatic cancer undergoing abdominal exploration. METHODS: Peritoneal lavage fluid samples were harvested from 74 patients with pancreatic cancer at the time of staging laparoscopy. Microarray analysis was performed using peritoneal lavage fluids with positive and negative cytology. Candidate microRNA expression was quantified and validated by droplet-digital PCR assays. RESULTS: In the miRNA array analysis, miR-593-3p showed significant upregulation in peritoneal lavage fluids with positive cytology. Of the 74 patients validated, peritoneal lavage fluids with positive cytology had significantly higher expression of miR-593-3p than those with negative cytology (P < 0.001). Even in cases with no peritoneal dissemination and negative cytology, multivariate analysis revealed that elevated miR-593-3p expression was significantly correlated with worse overall survival than those with low expression (hazard ratio: 3.474, P = 0.042). Of the 48 patients who underwent pancreatectomy, multivariate analysis also demonstrated that higher expression of miR-593-3p in peritoneal lavage was the only significant poor prognostic marker influencing both overall survival (hazard ratio: 23.38, P = 0.005) and recurrence-free survival (hazard ratio: 5.700, P = 0.002). CONCLUSIONS: Elevated miR-593-3p expression in peritoneal lavage suggests the presence of subclinical micrometastasis even in cases with localized pancreatic cancer, and miR-593-3p could be a useful prognostic predictor for pancreatic cancer patients undergoing staging laparoscopy.

Intracholecystic papillary neoplasm arising in the cystic duct and extending into common bile duct: a case report.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

[A Successful Case of Pancreaticoduodenectomy after Neoadjuvant Therapy for Pancreatic Head Cancer with Acute Pancreatitis Due to Iatrogenic Injury of the Pancreatic Duct].

A 64-year-old woman was referred to our hospital for treatment of pancreatic head cancer with acute pancreatitis due to iatrogenic injury of the pancreatic duct during endoscopic retrograde cholangiopancreatography. In addition to a 28 mm pancreatic head tumor, soft tissue shadow and fluid collection surrounding the superior mesenteric artery(SMA)due to pancreatitis were observed in the abdominal CT scan. The tumor was histologically diagnosed as adenocarcinoma by endoscopic ultrasound-guided fine needle aspiration. Neoadjuvant chemotherapy with gemcitabine and S-1 was performed to control the progression of the pancreatic cancer and improve the inflammatory changes for reduction of the operative risk. After 2 courses of neoadjuvant chemotherapy, abdominal CT scan revealed stable disease according to the Response Evaluation Criteria in Solid Tumors and attenuation of the inflammatory changes surrounding the SMA. Then, subtotal stomach- preserving pancreaticoduodenectomy was performed without the difficulty of peeling around the SMA in spite of the old inflammatory changes. Histological examination of the resected specimen showed R0 resection. The patient was discharged 18 days after surgery without any complications and is surviving 9 months postoperatively without any recurrence. Neoadjuvant chemotherapy was helpful for disease control and improvement of the inflammatory changes.

Liver resections in patients with prior bilioenteric anastomosis are predisposed to develop organ/space surgical site infections and biliary leakage: results from a propensity score matching analysis.

PURPOSE: The aims of this study were to compare the perioperative outcomes after hepatectomy with prior bilioenteric anastomosis to those without prior anastomosis, and to elucidate the mechanisms and preventative measures of its characteristic complications. METHODS: The demographic data and perioperative outcomes of 525 hepatectomies performed between January 2007 and December 2018, including 40 hepatectomies with prior bilioenteric anastomosis, were retrospectively analyzed. RESULTS: A propensity score matching analysis demonstrated that hepatectomies with prior bilioenteric anastomosis were associated with a higher frequency of major complications (p = 0.015), surgical site infection (p = 0.005), organ/space surgical site infection (p = 0.003), and bile leakage (p = 0.007) compared to those without. A multivariate analysis also elucidated that prior bilioenteric anastomosis was one of the independent risk factors of organ/space surgical site infection. In the patients with prior bilioenteric anastomosis, bile leakage was associated with organ/space surgical site infection at a significantly higher rate than those without prior bilioenteric anastomosis (p < 0.001). CONCLUSIONS: Prior bilioenteric anastomosis is a strong risk factor for organ/space surgical site infections, which might be induced by bile leakage. To prevent infectious complications after hepatectomy with prior bilioenteric anastomosis, meticulous liver transection to reduce bile leakage rate is thus considered to be mandatory.

Staging laparoscopy is mandatory for the treatment of pancreatic cancer to avoid missing radiologically negative metastases.

PURPOSE: Staging laparoscopy is considered useful for determining treatment plans for advanced pancreatic cancer. However, the indications for staging laparoscopy are not clear. This study aimed to evaluate the safety of staging laparoscopy and its usefulness for detecting distant metastases in patients with pancreatic cancer. METHODS: A total of 146 patients with pancreatic cancer who underwent staging laparoscopy between 2013 and 2019 were analyzed. Staging laparoscopy was performed in all pancreatic cancer patients in whom surgery was considered possible. RESULTS: In this cohort, 42 patients (29%) were diagnosed with malignant cells on peritoneal lavage cytology, 9 (6%) had peritoneal dissemination, and 11 (8%) had liver metastases. A total of 48 (33%) had radiologically negative metastases. On a multivariate analysis, body and tail cancer [odds ratio (OR) 5.00, 95% confidence interval (CI) 2.15-11.6, p < 0.001], high CA19-9 level [OR 4.04, 95% CI 1.74-9.38, p = 0.001], and a resectability status of unresectable (OR 2.31, 95% CI 1.03-5.20, p = 0.04) were independent risk factors for radiologically negative metastases. CONCLUSIONS: Staging laparoscopy can be safely performed and is useful for the diagnosis of radiologically negative metastases. Staging laparoscopy should be routinely performed for the accurate diagnosis of pancreatic cancer patients before pancreatectomy and/or local treatment, such as radiotherapy.

Prognostic impact of intraoperative peritoneal cytology after neoadjuvant therapy for potentially resectable pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is considered a potential approach to improve survival for patients with pancreatic adenocarcinoma (PA). The objective of this study was to identify the clinical implications of washing peritoneal cytology (CY) status after NAT. METHODS: Between 2005 and 2016, 151 consecutive patients with resectable (R)/borderline resectable (BR) PA underwent NAT with intention of subsequent resection at our institution. Of them, 13 and 123 patients underwent pancreatectomies with positive (CY+) and negative (CY-) cytology, respectively, while the remaining 15 patients did not undergo resection due to gross metastases at laparotomy. The clinicopathological factors influencing overall survival were clarified by the uni- and multivariate analyses. RESULTS: The postoperative overall survival (OS) and disease-free survival (DFS) were markedly worse in patients who underwent resection with CY+, compared with those who were CY- (median OS, 14.8 m vs 30.8 m, p = 0.026, and median DFS 6.0 m vs 15.1 m, p = 0.008). According to the resectability by NCCN guidelines, CY+ indicates worse prognosis than CY- in R-PA patients (mOS: 30.1 m vs 71.1 m: p = 0.080). Similarly, in BR-PA patients, CY+ showed the significantly worse prognosis than CY- (mOS: 13.8 m vs 24.5 m: p = 0.048), which prognosis is comparable with patients who did not undergo resection. The multivariate analysis revealed that resectability, CY status and the induction of adjuvant therapy were significant predictors of postoperative OS (p = 0.007: Hazard ratio 2.264, 0.040:2.094 and 0.002:3.246, respectively). CONCLUSIONS: CY+ is a significant predictor of poorer prognosis in PA patients after NAT. The subsequent pancreatectomies with CY+ after NAT do not contribute to prolonged survival.

GNAS mutation detection in circulating cell-free DNA is a specific predictor for intraductal papillary mucinous neoplasms of the pancreas, especially for intestinal subtype.

Pancreatic cystic neoplasms (PCNs) are a heterogeneous group with varying risks of malignancy. To explore the clinical utility of liquid biopsy in cyst type classification, we analyzed the GNAS/KRAS mutations in circulating cell-free DNA (cfDNA) obtained from 57 patients with histologically diagnosed PCNs, including 34 with intraductal papillary mucinous neoplasms (IPMNs) and compared the mutant allele prevalence and variant patterns with the paired resected specimens using next-generation sequencing. The positive prevalence of GNAS mutations in cfDNA of patients with IPMN (n = 11, 32%) was significantly higher than that in those with other PCNs (0%, P = 0.002). Conversely, KRAS mutations were detected in cfDNA of only 2 (6%) IPMN patients. The paired-sample comparison revealed highly concordance between the GNAS mutation status of cfDNA and resected IPMN specimens. Similar distributions of GNAS mutation positivity in cfDNA were observed across the different histological grades, whereas IPMNs with intestinal subtype showed a significantly higher prevalence of GNAS mutations than other subtypes (P = 0.030). GNAS mutation positivity in cfDNA was significantly associated with the acellular mucin pool of histological findings in primary IPMN lesions (P = 0.017). Detection of GNAS mutation in cfDNA can serve as a novel biomarker for cyst type classification and differentiation of intestinal subtype IPMN from the other PCNs.

Epigenetic inactivation of IRX4 is responsible for acceleration of cell growth in human pancreatic cancer.

Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to loss of key cellular pathways in tumorigenesis. Methyl-CpG-targeted transcriptional activation (MeTA) reactivates hypermethylation-mediated silenced genes in a different way from DNA-demethylating agents. Microarray coupled with MeTA (MeTA-array) identified seven commonly hypermethylation-mediated silenced genes in 12 pancreatic ductal adenocarcinoma (PDAC) cell lines. Among these, we focused on IRX4 (Iroquois homeobox 4) because IRX4 is located at chromosome 5p15.33 where PDAC susceptibility loci have been identified through genome-wide association study. IRX4 was greatly downregulated in all of the analyzed 12 PDAC cell lines by promoter hypermethylation. In addition, the IRX4 promoter region was found to be frequently and specifically hypermethylated in primary resected PDACs (18/28: 64%). Reexpression of IRX4 inhibited colony formation and proliferation in two PDAC cell lines, PK-1 and PK-9. In contrast, knockdown of IRX4 accelerated cell proliferation in an IRX4-expressing normal pancreatic ductal epithelial cell line, HPDE-1. Because IRX4 is a sequence-specific transcription factor, downstream molecules of IRX4 were pursued by microarray analyses utilizing tetracycline-mediated IRX4 inducible PK-1 and PK-9 cells; CRYAB, CD69, and IL32 were identified as IRX4 downstream candidate genes. Forced expression of these genes suppressed colony formation abilities for both PK-1 and PK-9. These results suggest that DNA methylation-mediated silencing of IRX4 contributes to pancreatic tumorigenesis through aberrant transcriptional regulation of several cancer-related genes.

Duodenal Obstruction Caused by the Long-term Recurrence of Appendiceal Goblet Cell Carcinoid.

A 38-year-old Japanese man who had been diagnosed with appendiceal carcinoid and undergone ileocecal resection 8 years before presented with duodenal obstruction caused by a submucosal tumor-like appearance. He was diagnosed with long-term recurrence of appendiceal goblet cell carcinoid (GCC) with a multi-morphological pattern based on the histological assessment of a duodenal biopsy and his previously resected appendix. He underwent subtotal stomach-preserving pancreaticoduodenectomy combined with resection of an ileo-colic anastomotic lesion. The GCC recurred at the nearby ileo-colic anastomosis and invaded the duodenum. This late recurrence might have resulted from the unique features of his GCC, which contained cells with different degrees of malignancy.

Serum procalcitonin as an early diagnostic marker of severe postoperative complications after elective pancreaticoduodenectomy.

BACKGROUND/PURPOSE: To evaluate the clinical utility of serum procalcitonin (PCT) as a diagnostic marker for the severe postoperative complications associated with pancreaticoduodenectomy (PD). METHODS: A total of 387 patients were enrolled and the PCT and C-reactive protein (CRP) values were compared between the non-severe complications group (Clavien-Dindo classification Grade IIIb and lower) and severe complications (Grade IVa and higher). RESULTS: Severe complications occurred in 16 patients. In the severe complications group, CRP levels peaked on postoperative day (POD) 3, whereas PCT levels peaked on POD 1. The PCT levels on PODs 1-5 were significantly higher in the severe complications group. Regarding the diagnostic performance, the PCT value on POD 2 higher than 2.1 ng/mL revealed the highest performance, with 66.7% sensitivity and 78.6% specificity. Based on the postoperative kinetics and multivariate analysis, PCT and CRP both act independently of each other and the combination assay improved the diagnostic power (area under the curve 0.781; sensitivity 60.0%; specificity 85.6%). Preoperative biliary drainage was found to affect the perioperative PCT values and subgroup analysis stratified by the drainage procedure improved diagnostic sensitivity (~85%). CONCLUSIONS: Procalcitonin in the early postoperative period can serve as an earlier detector for the development of severe complications after PD.

Stromal expression of hemopexin is associated with lymph-node metastasis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.

Serum Anti-p53 Antibody Can Serve as a Predictive Marker for Histological Grade of Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: The aim of the study was to clarify the diagnostic impact of measuring serum anti-p53 antibody (S-p53Ab) in predicting the histological grades of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: We compared the measured values and positive prevalence of S-p53Ab across the different histological grades of 111 resected IPMN cases. We also evaluated the TP53 alterations using immunohistochemistry and next-generation sequencing. RESULTS: Serum anti-p53 antibody were detected in 6 of 111 cases, all of their histological grades were high-grade dysplasia (HGD) and invasive carcinoma (INV). Positive prevalence of S-p53Ab was higher in cases with INV (4/35 cases, 11.4%) than those with HGD (2/38 cases, 5.3%), whereas S-p53Abs were undetectable in cases with low-grade dysplasia. Measured S-p53Ab values were not correlated with either carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9). In 4 of 6 S-p53Ab-positive cases, the TP53 alterations-somatic pathogenic mutations or aberrant immunoreactivity-were identified in their IPMN lesions. A combination assay of S-p53Ab, CEA, and CA 19-9 revealed a 38.4% sensitivity and 81.6% specificity for predicting HGD/INV. CONCLUSIONS: Serum anti-p53 antibody can serve as a surrogate marker for TP53 alterations and help predict the presence of HGD/INV in cases with IPMN, in combination with CEA and CA 19-9.