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Background: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers., Methods: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort., Results: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%)., Conclusions: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer., (© 2024. The Author(s).)

Pancreas divisum (PD) represents a prevalent congenital pancreatic variant, typically arising from the failure of fusion between the ventral and dorsal pancreatic ducts. This condition is frequently associated with recurrent pancreatitis. We herein present a case involving an incomplete PD diagnosis following the identification of a refractory postoperative pancreatic fistula (POPF) after laparoscopic distal pancreatectomy (DP) for pancreatic cancer. A 74-year-old female patient, who had undergone laparoscopic DP for pancreatic cancer, developed a POPF accompanied by intraabdominal bleeding, necessitating urgent intervention radiology to avert life-threatening complications. Following this, intraabdominal drainage was performed through an intraoperative drainage root. Subsequent fistulography and endoscopic retrograde pancreatography unveiled the presence of an incomplete PD for the first time. Consequently, a stent was placed in the Santorini duct. However, the volume of pancreatic juice from the intraabdominal drainage tube exhibited no reduction. Despite repeated attempts to access the pancreatic duct via a guidewire through the drainage tube, these endeavors proved futile. Paradoxically, the removal of the external drainage tube led to a recurrence of intraabdominal abscess formation. Consequently, reinsertion of the drainage tube became imperative. Consideration was given to draining the abscess under endoscopic ultrasonography and performing pancreatic duct drainage. However, due to the diminution of the abscess cavity through the external fistula drainage procedure, coupled with the absence of pancreatic duct dilation and its tortuous course, it was deemed a formidable challenge. the patient necessitated a lifestyle adaptation with a permanently placed percutaneous drainage tube., (© 2024. Japanese Society of Gastroenterology.)

Background: Minimally invasive distal pancreatectomy has become a widely accepted procedure for tumors located in the pancreatic body or tail. However, pancreatic transection by linear stapler is generally avoided for pancreatic body tumors located above the portal vein because the surgical margin width is narrowed after taking into account the cutting allowance for insertion of the stapling device. Herein, we report a parenchymal clamp-crushing procedure that provides a sufficient surgical margin in pancreatic transection., Methods: Two patients with suspected early pancreatic cancer underwent pancreatic transection using the clamp-crushing procedure. The planned pancreatic transection line was set just to the left of the gastroduodenal artery in both cases. Robotic and laparoscopic distal pancreatectomy were performed in 1 patient each. Patients were positioned supine with split legs. Parenchymal transection was performed with crushing by VIO 3 (ERBE Elektromedizin) operated in softCOAG Bipolar mode with Effect 2/modulation 50. After crushing, remnant tissue was cut in autoCUT Bipolar mode operated by VIO 3 with Effect 2/modulation 50, or cut after secured by clipping., Results: The surgical duration was 253 and 212 minutes, and estimated blood loss was 0 and 50 mL in the 2 patients, and both were discharged with uneventful courses. Pathologic examination confirmed a negative surgical margin in both patients., Conclusion: Clamp-crushing pancreatic transection for distal pancreatectomy might be a suitable treatment option for achieving sufficient surgical margin in pancreatic body tumors located close to the portal vein., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

Background: /Objectives: This study aimed to evaluate the usefulness of three-dimensional (3D) immunohistochemistry for the Ki67 index of small tissue specimens of pancreatic neuroendocrine tumor (PanNET)., Methods: Clinicopathological materials from 17 patients with PanNET who underwent surgical resection at Jichi Medical University Hospital were analyzed. We compared the Ki67 index of endoscopic ultrasonography-fine-needle aspiration biopsy (EUS-FNAB) specimens, surgical specimens, and small tissue specimens hollowed from paraffin blocks of surgical specimens that were substituted for EUS-FNAB specimens ("sub-FNAB"). The sub-FNAB specimens were optically cleared using LUCID (IlLUmination of Cleared organs to IDentify target molecules) and analyzed using 3D immunohistochemistry., Results: The median Ki67 index in FNAB, sub-FNAB, and surgical specimens with conventional immunohistochemistry were 1.2% (0.7-5.0), 2.0% (0.5-14.6), and 5.4% (1.0-19.4), respectively. The median Ki67 index in sub-FNAB specimens with tissue clearing was calculated separately using the total number of cells on multiple images ("multiple slice"), with the image of the fewest positive cells ("coldspot"), and with the image of most positive cells ("hotspot"), which were 2.7% (0.2-8.2), 0.8% (0-4.8), and 5.5% (2.3-12.4), respectively. PanNET grade evaluated for the hotspot of the surgical specimens was significantly more consistent with those of the hotspot than multiple images of sub-FNAB specimens (16/17 vs. 10/17, p = 0.015). Hotspot evaluation using 3D immunohistochemistry of the sub-FNAB specimens showed agreement with the assessment of the surgical specimens (Kappa coefficient: 0.82)., Conclusions: Tissue clearing and 3D immunohistochemistry for the Ki67 index can potentially improve the preoperative evaluation of EUS-FNAB specimens of PanNET in routine clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Surgery plus adjuvant chemotherapy (AC) for resectable pancreatic ductal adenocarcinoma (PDAC) has been shown to prolong survival compared with surgery alone. Thus, it is of clinical importance that these patients receive a continuous dose of S-1. The aim of this study was to examine whether the geriatric nutritional risk index (GNRI) is a predictor for the completion of S-1 as AC for PDAC., Methods: Seventy-seven patients who were administered S-1 as AC after pancreatectomy for PDAC between January 2010 and October 2021 were retrospectively enrolled. Predictive markers were statistically analyzed for S-1 completion, which was defined as continued oral administration with relative dose intensity of >80%., Results: Patients were divided into the S-1 complete group (n = 55; 71.4%) and S-1 incomplete group (n = 22; 28.6%). There was a significant association of higher GNRI ( P = 0.013) at the onset of AC with the completion of S-1. Receiver operating characteristic curve analysis revealed 94.4 as the optimal cutoff value of GNRI for predicting the completion of S-1. Univariate and multivariate analyses confirmed that GNRI >94.4 was independently associated with the completion of S-1 ( P = 0.007)., Conclusions: High GNRI value is a predictive marker for the completion of S-1 as AC for PDAC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Postoperative pancreatic fistula (POPF) are major postoperative complications (POCs) following distal pancreatectomy (DP). Notably, POPF may worsen the prognosis of patients with pancreatic cancer. Previously reported risks for POCs include body mass index, pancreatic texture, and albumin levels. Moreover, the C-reactive protein-to-albumin ratio (CAR) is a valuable parameter for prognostication. On the other hand, POCs sometimes lead to a worse prognosis in several cancer types. Thus, we assumed that CAR could be a risk factor for POPFs. This study investigated whether CAR can predict POPF risk in patients with pancreatic cancer following DP. This retrospective study included 72 patients who underwent DP for pancreatic cancer at Ehime University between January 2009 and August 2022. All patients underwent preoperative CAR screening. Risk factors for POPF were analyzed. POPF were observed in 17 of 72 (23.6%) patients. POPF were significantly associated with a higher CAR (p = 0.001). The receiver operating characteristic curve analysis determined the cutoff value for CAR to be 0.05 (sensitivity: 76.5%, specificity: 88.9%, likelihood ratio: 6.88), indicating an increased POPF risk. Univariate and multivariate analysis revealed that CAR ≥ 0.05 was a statistically independent factor for POPF (p < 0.001, p = 0.013). Therefore, CAR has the potential to predict POPF following DP.

Loss of function in the BRCA2 gene exacerbates ovarian, breast, and pancreatic ductal cancer risk. Despite being implicated in the pancreatic ductal epithelium carcinogenesis, the involvement of a germline BRCA2 mutation in acinar and endocrine cells is less reported. A 45-year-old woman with a history of breast cancer was referred to our hospital for a detailed examination of epigastric pain. Her father had pancreatic cancer, and her paternal aunt had a history of breast cancer. Contrast-enhanced computed tomography revealed a round tumor with a contrast effect in the pancreatic head. The patient underwent pancreaticoduodenectomy, and postoperative pathology and genetic testing revealed amphicrine-type mixed acinar-neuroendocrine carcinoma with a germline BRCA2 mutation. Recent studies have reported the BRCA2 mutation in genome sequencing of pancreatic acinar cell carcinoma and neuroendocrine tumor; perhaps, genetic testing for the BRCA2 mutation is feasible for patients with mixed neuroendocrine-non-neuroendocrine neoplasm., (© 2022. Japanese Society of Gastroenterology.)

In pancreatic cancer, postoperative complications (POCs) are associated with disease outcomes. The geriatric nutritional risk index (GNRI) is known to predict POCs after pancreatoduodenectomy (PD) or distal pancreatectomy (DP) in patients with hepatobiliary pancreatic tumors, including pancreatic cancer. Through POC occurrence risk, we aimed to determine whether GNRI could predict prognosis in patients who underwent PD or DP for resectable pancreatic cancer. This retrospective study examined 139 patients who underwent radical pancreatectomy for resectable pancreatic cancer at Ehime University. All patients were subjected to nutritional screening using GNRI and were followed up for POC diagnosis and patient outcomes such as overall survival (OS). Patients were divided based on the GNRI value of 99 (Low group: N = 74, GNRI < 99; High group: N = 65, GNRI ≥ 99), which was determined by receiver operating characteristic curve analysis. Multivariate analysis showed that GNRI < 99 was statistically correlated with POCs after curative pancreatic resection (p = 0.02). Univariate and multivariate analyses confirmed that GNRI < 99 was significantly associated with long OS (p = 0.04). GNRI could be a potential prognostic marker for resectable pancreatic cancer after curative pancreatic resection despite being a simple and noninvasive approach., (© 2022. The Author(s).)

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) arises from several types of premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown., Methods: We performed studies with Hnf1b-Cre ERT2 ; Pten f/f ; Arid1a f/f mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of oncogenic PI3K/Akt pathway activation., Results: Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells resulted in the development of ITPN, which progressed to PDAC, in mice. Simultaneous loss of Arid1a and Pten induced dedifferentiation of pancreatic ductal cells and Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway activation. Consistent with the mouse data, TAZ expression was found elevated in human ITPNs and ITPN-derived PDACs but not in human intraductal papillary mucinous neoplasms, indicating that activation of the TAZ pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the dedifferentiation of pancreatic ductal cells and development of ITPN in Arid1a and Pten double-knockout mice., Conclusion: Concurrent loss of Arid1a and Pten in adult pancreatic ductal cells induced ITPN and ITPN-derived PDAC in mice through aberrant activation of the YAP/TAZ pathway, and inhibition of the YAP/TAZ pathway prevented the development of ITPN. These findings provide novel insights into the pathogenesis of ITPN-derived PDAC and highlight the YAP/TAZ pathway as a potential therapeutic target., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The perioperative management and technical details of laparoscopic clamp-crushing enucleation for low-malignant-potential pancreatic neuroendocrine neoplasms (PNENs) located close to the main pancreatic duct (MPD) in the body/tail of the pancreas using a perioperative MPD stent are reported. The procedure was performed in two patients with PNEN (13 and 10 mm in diameter) in the body/tail of the pancreas. A naso-pancreatic stent (NPS) was placed preoperatively in both patients. Resection was performed using Maryland-type bipolar forceps. The surgical duration was 139 and 55 min, and the estimated blood loss was 5 and 0 mL, respectively. One patient was discharged uneventfully on postoperative day (POD) 12. The other patient developed a grade B pancreatic fistula, but was discharged on POD 22. Laparoscopic clamp-crushing enucleation with an NPS might be a viable treatment option for tumors located close to the MPD., (© 2021. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and early diagnosis is challenging. Because patients who present with symptoms generally have advanced-stage diseases, analysis of asymptomatic PDAC provides invaluable information for developing strategies for early diagnosis. Here, we reviewed 577 patients with PDAC (372 diagnosed with symptoms [symptomatic group] and 205 without symptoms [asymptomatic group]) diagnosed at our institute. Among the 205 asymptomatic PDAC patients, 109 were detected during follow-up/work-up for other diseases, 61 because of new-onset or exacerbation of diabetes mellitus, and 35 in a medical check-up. Asymptomatic PDAC is characterized by smaller tumor size, earlier disease stage, and higher resectability than those of symptomatic PDAC. In 22.7% of asymptomatic cases, indirect findings, e.g., dilatation of the main pancreatic duct, triggered PDAC detection. Although pancreatic tumors were less frequently detected, overall abnormality detection rates on imaging studies were nearly 100% in asymptomatic PDAC. Asymptomatic PDAC had a better prognosis (median survival time, 881 days) than symptomatic PDAC (342 days, P < 0.001). In conclusion, diagnosis of PDAC in the asymptomatic stage is associated with early diagnosis and a better prognosis. Incidental detection of abnormal findings during the follow-up/work-up for other diseases provides important opportunities for early diagnosis of asymptomatic PDAC., (© 2022. The Author(s).)

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.

Background: Pancreatic body and tail cancer easily invades retroperitoneal tissue, including the transverse mesocolon. It is difficult to ensure a dissected peripancreatic margin with standard distal pancreatectomy for advanced pancreatic body and tail cancer. Thus, we developed a novel surgical procedure to ensure dissection of the peripancreatic margin. This involved performing dissection deeper than the fusion fascia of Toldt and further extensive en bloc resection of the root of the transverse mesocolon. We performed distal pancreatectomy with transverse mesocolon resection (DP-TCR) using a mesenteric approach and achieved good outcomes., Methods: There are two main considerations for surgical procedures using a mesenteric approach: 1) dissection deeper than the fusion fascia of Toldt (securing the vertical margin) and 2) modular resection of the pancreatic body and tail, with the root of the transverse mesocolon and adjacent organs in a horizontal direction (ensuring the caudal margin)., Results: From 2017 to 2019, we performed DP-TCR using a mesenteric approach for six patients with advanced pancreatic body and tail cancer. Histopathological radical surgery was possible in all patients who underwent DP-TCR. No Clavien-Dindo grade IIIa or worse perioperative complications were observed in any patient., Conclusions: We believe that DP-TCR is useful as a radical surgery for advanced pancreatic body and tail cancer with extrapancreatic invasion.

Background: Peripheral intravenous injection of gemcitabine often causes vascular pain; however, preventive measures have not yet been established., Objectives: This study focused on identifying predictive factors for gemcitabine-induced vascular pain., Methods: We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses., Results: Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose ( P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine ( P = 0.025), and hot pack use ( P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m 2 ), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%)., Conclusions and Relevance: High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for majority of pancreatic cancers, is one of the most lethal human malignancies. Most patients are diagnosed at an advanced stage after symptom development. Early diagnosis of PDAC in asymptomatic subjects is important to improve prognosis. Diabetes mellitus (DM) is a risk factor for PDAC, and DM, especially new-onset DM, has attracted attentions as a diagnostic clue to PDAC. However, the impact of DM as a diagnostic opportunity on the prognosis of PDAC is unclear. We here retrospectively reviewed 489 PDAC patients and compared the clinical characteristics and prognosis according to the opportunities for PDAC diagnosis. PDAC was diagnosed upon presentation of symptoms, such as pain and jaundice, in 318 cases including 151 DM patients, upon new-onset or exacerbation of long-standing DM in 53 asymptomatic patients, and upon incidental detection by medical check-up or follow-up/work-up of other diseases in 118 asymptomatic patients. Asymptomatic patients including those with DM had smaller tumors, earlier disease stage, and higher resectability rates than symptomatic patients. Asymptomatic patients diagnosed in association with DM had better prognosis (median survival time, 771 days) than those diagnosed due to symptoms (343 days, P < 0.001), and similar to those diagnosed by incidental detection (869 days). The survival advantage was not evident in symptomatic patients with DM-associated signs. In conclusion, patients diagnosed in association with DM at asymptomatic stages had better prognosis than those diagnosed with symptoms. DM-associated signs might provide a clue to the early diagnosis of PDAC among asymptomatic subjects.

Pancreatic cancer is one of the most dangerous solid tumors, but its early diagnosis is difficult. The abnormality of the main pancreatic duct (MPD), such as a single localized stricture and upstream dilatation, might be useful in the early detection of pancreatic cancer. However, these findings are often observed in benign inflammatory cases. This study aimed to clarify whether early pancreatic cancer presenting MPD abnormalities has characteristic features different from those of benign cases. This is a single-center, retrospective study. We analyzed 20 patients who underwent pancreatectomy presenting with a single, localized MPD stricture without identifiable masses on imaging: 10 patients with pancreatic ductal adenocarcinoma (cancer group; 6 with stage 0 and 4 with stage I) and 10 patients with benign strictures (benign group; 8 with inflammation and 2 with low-grade pancreatic intraepithelial neoplasms). Pancreatectomy was performed in these benign cases because high-grade intraepithelial neoplasm was suspected. Although the proportion of patients with diabetes mellitus tended to be higher in the cancer group (6/10) than that in the benign group (1/10) (P = 0.058), other clinical characteristics were not different between the groups. Preoperative cytological malignancies were detected in four patients in the cancer group (4/10) but not in the benign group (P = 0.09). Focal parenchymal atrophy and fat replacement were more frequently detected on computed tomography in the cancer group (7/10) than in the benign group (1/10) (P = 0.02). In conclusion, focal parenchymal atrophy and fat replacement may provide clues for the early diagnosis of pancreatic cancer.

A 67-year-old woman with a history of esophageal cancer(poorly-differentiated squamous cell carcinoma, pStageⅡ) was diagnosed with 2 liver tumors by regular checkup CT 10 years after her operation. We also observed elevated levels of tumor marker CEA. The tumors were suspected to be metastatic although no primary lesion was identified. We performed partial hepatectomy for diagnostic therapy. The pathological diagnosis was adenocarcinoma suggestive of metastatic tumors but the primary lesion remained unknown. Tumor marker levels were elevated 2 months after the operation and we detected a pancreatic tumor, multiple liver tumors, peritoneal dissemination, and para-aortic lymph node metastasis. Therefore, our clinical diagnosis was multiple metastases with primary pancreatic cancer and chemotherapy was performed. We conducted a thorough review of the diagnostic images and repeated the pathological analysis. Immunobiological staining showed that the tumor cells were positive for neuroendocrine markers such as chromogranin A, CD56, and Ki-67. We eventually diagnosed the liver tumors as metastasis from the pancreatic neuroendocrine carcinoma(Grade 3).

Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ≥5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ≥7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ≥9 and ≥10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30 mm, duodenal invasion, LN metastasis and an LVI-score ≥2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ≥9 and ≥10 were significantly associated with poor overall survival, and an LVI-score ≥10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.

Background: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established as a method to obtain tissues of various organs. To obtain sufficient tissue has clinical impact to facilitate the diagnosis by clinical pathologists, the assessment and subtyping of various neoplasms, and for further immunohistochemical investigations of tumor type. Recently, a novel 20G core trap with a forward-cutting beveled FNA needle (ProC-F) has become available. The aim of this prospective study was to evaluate the feasibility and diagnostic yield of EUS-FNA for pancreatic lesions using this needle., Patients and Method: In this study, the first puncture was performed using the ProC-F. Only tissue obtained with the first puncture using the ProC-F was used to evaluate diagnostic yield of ProC-F. The second puncture was performed using a 22G standard FNA needle using the same technique as for the first puncture. Second puncture was performed if the endosonographer did not feel that sufficient tissue had not been obtained by first puncture., Results: Fifty-three consecutive patients who underwent EUS-FNA for pancreatic lesions were prospectively enrolled. The technical success rate of EUS-FNA using the ProC-F was 98.1% (52/53). The rate of adequate tissue obtained by ProC-F was 96.2% (50/52). On the other hand, the rate of adequate tissue obtained by the standard needle was 71.1%. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of the ProC-F and the standard needle were 92.5, 100, 100, 76.9, and 94.0%, and 85.2, 100, 100, 55.6, and 87.5%, respectively. Diagnostic yield of ProC-F about sensitivity (P = 0.027), NPV (P = 0.035), and accuracy (P = 0.004) was significantly higher than of standard needle. Adverse events were not seen in any patients., Conclusions: Although only tissue obtained by the first puncture was evaluated, the rate of adequate tissue and the histologic diagnostic yield for pancreatic lesions were extremely high using the ProC-F.

The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce the robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.

Loss of primary cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose primary cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores primary cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of primary cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of primary cilium formation in PDAC cells., (© 2016 The Authors.)

Background: The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing, but only a subset of these heterogeneous tumors will progress to malignant disease, which is associated with a poor prognosis. Currently, there are limited data on the natural history of these tumors and it is difficult to determine which patients require surgical intervention because the risk of metastatic disease cannot be accurately determined., Study Design: We conducted a prospective study of 87 patients with von Hippel Lindau syndrome-associated solid pancreatic lesions to determine the natural history of these tumors with biochemical testing, follow-up anatomic and functional imaging, and advanced imaging analysis, with a median follow-up of 4 years., Results: Approximately 20% of consecutive tumor measurements during follow-up were decreased in size and 20% showed no change. This included 2 of 4 surgically proven malignant tumors, which had a net decrease in tumor size over time. Tumor volume, as derived from greatest diameter and volumetric measurements, showed good correlation to pathology tumor measurement of surgically resected tumors (Spearman rank correlation ρ = 0.72, p = 0.0011, and ρ = 0.83, p < 0.0001, respectively). Tumor density measurement had an inverse relationship with tumor size (Spearman rank correlation -0.22, p = 0.0047). A tumor density cutoff of 200 was 75% specific for malignant tumors., Conclusions: Pancreatic neuroendocrine tumors demonstrate a nonlinear growth pattern, which includes periods of no growth and apparent decrease in size by imaging. These growth patterns are variable and are not associated with tumor grade and malignancy. Tumor density, as measured in this cohort, may offer a specific diagnostic tool for malignant disease., (Published by Elsevier Inc.)

A 70-year-old female patient underwent pylorus-preserving pancreaticoduodenectomy for carcinoma of the ampulla of Vater in March 2007. In April 2009, multiple lung metastases were detected by CT scanning. The patient was treated with S-1 (80mg/day, day 1-28, followed by 2-weeks withdrawal)from April 2009. The shrinkage of lung metastases was diagnosed as a complete response based on the Response Evaluation Criteria in Solid Tumors(RECIST). No severe toxicities were observed. S-1 is an effective and safe anti-cancer agent available for lung metastases of carcinoma of the ampulla of Vater.

Introduction: There are limited data on the utility of 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) and (18)F-2-deoxy-d-glucose ((18)F-FDG) in the workup of patients with pancreatic neuroendocrine tumors (PNETs). The aim of our study was to determine the accuracy of (18)F-DOPA and (18)F-FDG to detect PNETs in patients with von Hippel-Lindau disease (vHL)., Methods: We studied prospectively 69 patients with a diagnosis of vHL and pancreatic lesion(s) using computed tomography (CT), magnetic resonance imaging (MRI), (18)F-FDG, and (18)F-DOPA. Clinical, genetic, and laboratory characteristics were analyzed to determine association with imaging study results., Results: In sum, 40 patients underwent evaluation by all 4 modalities; 98 PNETs and 55 PNETs were identified on CT and MRI, respectively. Only 11 of the 98 lesions (11%) were positive on (18)F-DOPA and 45 of the 98 (46%) lesions were positive on (18)F-FDG. There were 13 (18)F-DOPA and 26 (18)F-FDG avid extrapancreatic lesions. One patient underwent resection of an (18)F-DOPA avid extrapancreatic lesion in the lung, with pathology demonstrating a NET. There was no association between (18)F-DOPA and (18)F-FDG avidity and tumor size, age, gender, vHL mutation, or serum chromogranin A level., Conclusion: (18)F-FDG and MRI may be adjuncts to CT in identifying PNETs and metastatic disease. (18)F-DOPA has limited value in identifying PNETs in patients with vHL, but may be useful for identifying extrapancreatic NET lesions., (Published by Mosby, Inc.)

Background: Inflammation plays a multifaceted role in cancer progression, and NF-kappaB is one of the key factors connecting inflammation with cancer progression. We have shown that lipopolysaccharide (LPS) promotes NF-kappaB activation in colon cancer cells and pancreatic cancer cells. However, it is unclear why inflammatory stimuli can induce NF-kappaB activation in cancer cells., Methods: We used two human pancreatic cancer cells, Panc-1 and AsPC-1, as target cells. LPS was used as an inflammatory stimulus. To confirm the participation of TLR4/NF-kappaB signaling pathway, we used three different NF-kappaB inhibitors (PDTC, IkappaBalpha mutant, and NF-kappaB decoy ODN) and siRNAs (against TLR4, MyD88, and MMP-9). Effect of LPS on pancreatic cancer cell invasive ability was determined by Matrigel invasion assay., Results: LPS increased the invasive ability of pancreatic cancer cells, while blockade of NF-kappaB pathway decreased the LPS-dependent increased invasive ability. Blockade of TLR4 or MyD88 by siRNA also decreased the LPS-dependent increased invasive ability., Conclusion: These results suggest that TLR/MyD88/NF-kappaB signaling pathway plays a significant role in connecting inflammation and cancer invasion and progression., (Copyright 2009 Wiley-Liss, Inc.)

We report a case of pancreas head cancer with liver metastasis treated with uracil-tegafur (UFT) and gemcitabine combined chemotherapy. A 66-year-old man was referred to our hospital for obstructive jaundice. We planned to perform a pancreatoduodenectomy, but a small nodule was found at laparotomy on the liver surface. The histopathological diagnosis was adenocarcinoma, so we inserted a self-expandable metallic stent (EMS) in this inoperable pancreas head cancer. We performed 9 courses of UFT and gemcitabine (GEM) combination chemotherapy. Renewed liver metastases did not appear, and the pancreas head tumor partially responded. Pancreatoduodenectomy was performed, and EMS could not be separated from the common bile duct. After treatment with an additional 11 courses of chemotherapy, he took S-1 orally because of a tumor recurrence. He survived for 24 months from the first laparotomy. Combination chemotherapy and surgery enhanced the survival benefit in this case.

Background: The hedgehog (Hh) signaling pathway is aberrantly activated in many human carcinomas including pancreatic cancer and regulates tumor cell growth. Overproduction of sonic hedgehog (Shh), a ligand of the Hh signaling pathway, increases the Hh signaling activity through transmitting the signal to patched-1 (Ptch1), the receptor of the Hh signaling pathway., Materials and Methods: a-Ptch1 antibodies were raised against an oligo-peptide, designed according to the Ptch1 aminoacid sequence. The specificity of a-Ptch1 was examined by immunoblotting and immuno-fluorescence, and biological effects were detected by RT-PCR and cell proliferation assay using two pancreatic cancer cell lines, Panc1 and SUIT-2., Results: a-Ptch1 recognized a 160 kDa protein as shown by immunoblotting and cell surface staining of pancreatic cancer cells. Incubation with a-Ptch1 suppressed Hh signaling activity and proliferation of pancreatic cancer cells., Conclusion: These results provide a new strategy for controling Hh dependent development of pancreatic cancer and other Hh related carcinomas.

Although a 64-year-old man with pancreatic cancer was referred to our hospital due to difficulty in the bile drainage, he was initially planned to have an operation at another hospital after relief of obstructive jaundice. Laboratory tests on admission revealed obstructive jaundice, pancreatitis and malnutrition (T-Bil 12.1 mg/dL, AMY 1170 IU/L, Alb 2.0 g/dL). Abdominal computed tomography (CT) detected a pancreas tumor and multiple liver metastases. Then, we determined to carry out palliative therapy. Percutaneous transhepatic cholangiography (PTC) showed a common bile duct obstruction, and a biliary metallic stent was placed. Endoscopic examination revealed a tumorous duodenal stenosis. We performed percutaneous endoscopic gastrostomy with jejunal extension (PEG-J), which was used for both transintestinal nutrition and decompression gastrostomy. After these therapies, the patient's condition improved better in 2 weeks as such that he could have stayed away from our hospital for several days. PEG-J was useful to improve a quality of life in pancreatic cancer patient with duodenal stenosis.

Expression patterns of keratins (K), both simple epithelia-type (K7, K8, K18, K19) and complex/stratified epithelia-type (K1, K4, K5/6, K10, K13, K14, K15, K16, K17), and epithelial membrane antigen (EMA) were immunohistochemically studied in six pancreatoblastomas (PBL). In all six tumors, areas with overt acinar differentiation (AA), solid areas without any specific differentiation (SO), and squamoid corpuscles (SC) were diffusely positive for K8, K18, and K19. The AA and SO in all the tumors were diffusely positive for K7, but the SC were negative or displayed only scattered reactivity for K7. In three tumors, the AA and the SC showed scattered reactivity for K5/6. No reactivity for other complex/stratified epithelia-type K was found in any of the examined tumor. All tumors were reactive for EMA with consistent predominancy in the SC. Ultrastructurally, well-developed desmosome-tonofilament complexes were only partially observed in tumor cells comprising the SC. These results implied that (i) the SC usually lack a character of complete squamous metaplasia; and (ii) the SC have a characteristic phenotype (K8/K18/K19/EMA-positive, K7-negative or scatteredly positive) that can potentially be useful to delineate the SC in PBL.