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Cancer of the Pancreas

Pancreatic cancer is a disease in which the cells of the pancreas become malignant. The pancreas has two main functions; (i) it makes juices that help digest food and (ii) produces hormones (including insulin) that conrol how food is used and stored in the body. The vast majority of pancreatic cancers are associated with the part of the pancreas that makes digestive juices - these are known as "exocrine" pancreatic cancers. Only about 1/20 pancreatic cancers start in the hormone producing part of the pancreas ; these are known as "endocrine" pancreatic cancer or "islet cell cancer". There are several types of exocrine pancreatic cancers (based on how the cells appear under the microsope), most are classed as "ductal adenocarcinomas". Pancreatic cancer is rare before the age of 40 years, incidence increases sharply with increasing age.

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Pancreatic Neuroendocrine Tumours (Islet Cell Tumours)
Familial Pancreatic Cancer

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    MeSH term: Pancreatic Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Khare V, Alam N, Saneja A, et al.
Targeted drug delivery systems for pancreatic cancer.
J Biomed Nanotechnol. 2014; 10(12):3462-82 [PubMed] Related Publications
Pancreatic cancer is usually diagnosed at the advanced stages, responds poorly to the available chemotherapeutics and constitutes the major factor for high mortality rate. Selective delivery of therapeutics to their cellular targets, without side effects is the foremost objective of the current investigations for effective treatment of pancreatic cancer. The development of the drugs which can selectively target pancreatic cancer along with carriers that can deliver drugs specifically to the rapidly dividing cells is considered as magic bullet for the efficient treatment of this fatal disease. This review describes various factors hampering the efficacy of drug targeting to pancreatic cancer including stromal fortress, hypocascularity, hyaluronan and interstitial fluid pressure, and exploration of various cellular targets for the site specific drug delivery. An account of burgeoning applications of novel drug delivery systems including nanoparticles, liposomes, quantum dots, micelles and drug conjugates in the management of pancreatic cancer is also provided. Additionally, potential of target based therapeutic agents and nanomedicines in clinical trials for the pancreatic cancer therapy are highlighted.

Kurihara T, Kogo M, Ishii M, et al.
Practical prognostic index for survival in patients with unresectable pancreatic cancer treated with gemcitabine or S-1.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):478-84 [PubMed] Related Publications
BACKGROUND/AIMS: We performed this retrospective cohort study to identify prognostic factors for unresectable pancreatic cancer treated with current standard therapy using gemcitabine (GEM) or S-1 and to stratify patients prior to treatment using a prognostic index (PI).
METHODOLOGY: We analyzed 182 patients with unresectable pancreatic cancer, who had received GEM or S-1 as first-line chemotherapy. Factors that contributed to the prognosis were identified by univariate and multivariate analysis using a Cox proportional hazards model. The PI was constructed using the factors identified in the multivariate analysis.
RESULTS: By multivariate analysis, performance status (PS), stage, and absolute neutrophil count (ANC) were identified as factors that independently contributed to the prognosis of unresectable pancreatic cancer (P < 0.05). The hazard ratios were 1.69, 3.33, and 1.18, respectively. In addition, PI was calculated using these three factors. Patients were classified into three groups according to the PI values. A significant difference was observed among the survival curves of these three groups (P < 0.05).
CONCLUSIONS: We identified three prognostic factors in the population after the introduction of S-1, and have created a simple and useful PI. This index demonstrates the ability to accurately classify advanced pancreatic cancer patients before the start of treatment.

Aoyama T, Murakawa M, Katayama Y, et al.
Lymphatic invasion is an independent prognostic factor in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):472-7 [PubMed] Related Publications
BACKGROUND/AIMS: The objective of this retrospective study was to clarify prognostic factors in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1.
METHODOLOGY: Both overall survival (OS) and recurrence-free survival (RFS) were examined in 122 pancreatic cancer patients who underwent curative surgery and received adjuvant gemcitabine or S-1 after surgery between 2005 and 2014.
RESULTS: When the length of OS was evaluated according to the log-rank test, significant differences were observed in lymphatic invasion and the T status. Univariate and multivariate Cox's proportional hazard analyses demonstrated that lymphatic invasion was the only significant independent prognostic factor for both OS and RFS. The 5-year OS was 30.1% in the lymphatic invasion-negative group and 12.1% in the lymphatic invasion-positive group (p < 0.001). Moreover, the 5-year RFS was 20.5% in the lymphatic invasion-negative group and 10.4% in the lymphatic invasion- positive group (p = 0.006).
CONCLUSIONS: Lymphatic invasion is the most important prognostic factor for OS and RFS in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy. The present results suggest that adjuvant chemotherapy is not sufficient, especially in patients with risk factors. Such patients should be evaluated as a target group for clinical trials of novel treatments.

Tomizawa M, Shinozaki F, Motoyoshi Y, et al.
Diffusion-weighted whole body imaging with background body signal suppression/T2 image fusion is negative for patients with intraductal papillary mucinous neoplasm.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):463-5 [PubMed] Related Publications
BACKGROUND/AIMS: One major problem with Intraductal papillary mucinous neoplasm (IPMN) is the appearance of pancreatic duct adenocarcinoma. Diffusion-weighted whole body imaging with background body signal suppression (DWIBS) provides hyperintense signals in cases of cancer. DWIBS and T2 image fusion (DWIBS/T2) provides functional information in anatomical settings, and is useful for the detection of cancer with strong contrast against surrounding tissues. DWIBS/T2 signals were analyzed in patients with IPMN to investigate positive or negative results.
METHODOLOGY: Patient records were analyzed retrospectively regarding IPMN. None showed high-risk stigmata or worrisome features. To rule out T2 shine-through or differentiate malignant lesions from non-malignant causes of restricted diffusion, positive ADC maps were produced from the recorded ADC values.
RESULTS: None of the patients with IPMN had features of malignant progression. No mural nodules were detected by endoscopic ultrasonography. IPMN was hyperintense with DWIBS/T2 and the ADC map. This finding suggested that the hyperintense values of IPMN were T2 shine-through. These results showed that none of the IPMNs were positive with DWIBS/T2.
CONCLUSION: DWIBS/T2 was negative for patients with IPMN. DWIBS/T2 might be useful for the evaluation of malignant progression, in addition to observation.

Tsuchikawa T, Hirano S, Nakamura T, et al.
Detailed analysis of extra-pancreatic nerve plexus invasion in pancreatic body carcinoma analyzed by 50 consecutive series of distal pancreatectomy with en-bloc celiac axis resection.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):455-8 [PubMed] Related Publications
BACKGROUND/AIMS: Advanced pancreatic body carcinoma frequently accompany extra-pancreatic nerve plexus (PL) invasion, one of the poor indicator of patient prognosis. The present study aimed to reveal the progress of the PL invasion from cancer of the pancreas body toward the root of the celiac artery (CA) and superior mesenteric artery (SMA) followed by investigation of the relevance of diagnostic accuracy.
METHODOLOGY: Resected specimens from 50 consecutive patients who underwent distal pancreatectomy with en bloc celiac axis resection (DP-CAR) were pathologically analyzed for the direction of PL invasion. Diagnostic accuracy on CT imaging were also investigated.
RESULTS: Thirty seven of the 50 patients (74%) were positive for PL invasion around the CHA, SPA, CA and SMA. In terms of the diagnostic accuracy, positive predictive values for the PL invasion were 35%, 36%, 43% and 81% for the SPA, CHA, CA and SMA, respectively. Among 21 patients and 23 patients with PL invasion around CHA and SPA, 13 and 6 patients also accompanied PL invasion around CA, respectively.
CONCLUSIONS: Carcinoma of the pancreatic body is found to frequently accompany PL invasion around CA. Under the limitation of low diagnostic accuracy, DP-CAR might be feasible operation that increases the possibility of R0 resection.

Utsumi M, Umeda Y, Takagi K, et al.
Correlation of computed tomography imaging features and pathological features of 41 patients with pancreatic neuroendocrine tumors.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):441-6 [PubMed] Related Publications
BACKGROUND/AIMS: Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification.
METHODOLOGY: We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (G1), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system.
RESULTS: Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 ± 0.54, 4.90 ± 0.84, and 5.62 ± 1.18 cm, respectively, (P < 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors.
CONCLUSIONS: Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered.

Cao J, Xia C, Cui T, et al.
Correlations between serum trypsinogen-2 and pancreatic cancer.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):435-40 [PubMed] Related Publications
BACKGROUND/AIMS: To investigate associations be- tween serum trypsinogen-2, pancreatitis and pancreatic cancer (PC) and determine cutoff values for PC diagnosis.
METHODOLOGY: We recruited 88 patients from Internal Medicine/Surgical Departments of General Military Hospital of Beijing PLA between 12/2009 and 6/2010. Serum samples were collected preoperatively from 23 PC patients, 30 pancreatitis patients and 35 healthy controls. Enzyme-linked immunosorbent assay was used to detect trypsinogen-2 semiquantitatively.
RESULTS: Serum trypsinogen-2 levels of PC and pancreatitis patients were significantly higher than those of controls (51.2 ± 80.3, 107.7 ± 98.1 vs. 1.0 ± 0.5, p = 0.03, p < 0.001) and significantly higher in pancreatitis vs. PC patients (107.7 ± 98.1 vs. 51.2 ± 80.3, p = 0.01). Higher Balthazar CT grades correlated with higher trypsinogen-2 in pancreatitis group. ROC curves for trypsinogen-2 revealed optimal cutoff value 1.8 as lower PC detection limit with 95.7% sensitivity and 91.4% specificity, and optimal cutoff value 19.9 for upper PC detection limit with 87.0% sensitivity and 97.1% specificity. Trypsinogen-2 levels correlated with pancreatic injury level. An AUC of 0.73 (95% Cl: 0.59-0.84, p = 0.002) distinguished PC from pancreatitis.
CONCLUSION: Serum trypsinogen-2 is associated with PC and pancreatitis. Levels between 1.8 μg/L and 19.9 μg/L strongly suggest PC. Detection of serum trypsinogen-2 may provide simple, sensitive, specific non-invasive initial screening for early PC diagnosis.

Kim JC, Kim KT, Park JT, et al.
Expression of vasohibin-2 in pancreatic ductal adenocarcinoma promotes tumor progression and is associated with a poor clinical outcome.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):251-6 [PubMed] Related Publications
This study aimed to assess the expression of vasohibin-2 (VASH2) in pancreatic ductal adenocarcinoma (PDAC) as a marker of tumor aggressiveness and its impact on tumor angiogenesis, proliferation, and clinical outcome. We examined the expression of the VASH2 gene in human pancreatic cell lines PANC-1 and MiaPaCa-2 by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunocytochemistry. Fifty samples from patients with PDAC were immunostained with VASH2, CD34, and Ki-67 antibodies. Further, the immunoreactivity of VASH2 correlated with the pathological features, including microvessel density (MVD), tumor cell proliferation (Ki-67 labeling index), and survival. Forty-seven of the 50 samples from PDAC patients showed immunoreactivity for VASH2 along the tumor cell cytoplasm. Among the VASH2-positive samples, 22 were categorized as high VASH2 expression group, and this group had statistical significance with pN stage (p = 0.006), UICC stage (p = 0.033), tumor proliferation (p < 0.001), and MVD (p = 0.017). Moreover, patients with high VASH2 expression showed worse prognosis compared to those showing low VASH2 expression (overall logrank p = 0.003). Thus, our results suggested that overexpression of VASH2 accelerated the pace of tumor development toward a more serious malignant phenotype and was associated with a poor clinical outcome. VASH2 may be an important novel target for the management of PDAC after surgery.

Aoyama T, Katayama Y, Murakawa M, et al.
Clinical implication of peritoneal cytology in the pancreatic cancer patients who underwent curative resection followed by adjuvant gemcitabine or S-1 chemotherapy.
Hepatogastroenterology. 2015 Jan-Feb; 62(137):200-6 [PubMed] Related Publications
BACKGROUND/AIMS: The clinical implications of peritoneal lavage cytology (CY) status in the patients who received curative resection and adjuvant chemotherapy have not been established.
METHODOLOGY: We retrospectively analyzed clinical data from 143 consecutive patients who underwent macroscopically curative resection and received adjuvant gemcitabine or S-1 chemotherapy for pancreatic cancer from 2005 to 2014 in our institution. Correlations between CY status and survival and clinicopathological features were investigated.
RESULTS: Of the 143 patients, 21 patients were peritoneal washing cytology positive (CY+) (14.7%). Although significant difference was observed in the tumor size, no other correlation between cytology status and clinicopathological parameter existed. The recurrence free survival (RFS) rates at 3 and 5 years after surgery were 5.1% and 0% in CY+ patients, respectively, and were 21.5% and 16.1% in peritoneal washing cytology negative (CY-) patients, respectively, which were significantly different (p=0.001). The OS rates at 3 and 5 years after surgery were 17.1% and 8.6% in CY+ patients, respectively, and were 26.1% and 16.1% in CY- patients, respectively, which were trend to worse in the CY+ patients (p=0.254).
CONCLUSION: The patients with CY+ are likely to experience recurrence, even after they received curative resection and adjuvant Gemcitabine or S-1 adjuvant chemotherapy.

Ishii M, Kimura Y, Imamura M, et al.
Remnant pancreas reconstruction with duct-to-duct anastomosis after middle pancreatectomy: a report of two cases.
Hepatogastroenterology. 2015 Jan-Feb; 62(137):190-4 [PubMed] Related Publications
Reconstruction of a remnant pancreas after middle pancreatectomy has generally been performed with a pancreaticoenterostomy. We report here two cases in which physiological reconstructive procedures were performed. The reconstructive procedures included pancreatic duct-to-duct anastomosis and parenchymal sutures with absorbable monofilament interrupted stitches. A pancreatic tube was inserted for decompression at the anastomotic site in both cases. The patients comprised one with pancreatic metastasis from renal cell carcinoma and another with a non-malignant insulinoma. The tumors were located in the pancreatic body. Although an International Study Group on Pancreatic Fistula classification grade B-pancreatic fistula was observed in each patient, they both resolved with conservative therapy. The pancreatic duct at the anastomosis site was patent in both cases, and no atrophic changes developed in the remnant pancreas in either patient. These outcomes confirmed that, in selected cases, this reconstructive procedure is safe and feasible for physiological reconstruction without involvement of the digestive tract.

Hu HK, Ke NW, Li A, et al.
Clinical characteristics and prognostic factors of gastroenteropancreatic neuroendocrine tumors: a single center experience in China.
Hepatogastroenterology. 2015 Jan-Feb; 62(137):178-83 [PubMed] Related Publications
BACKGROUND/AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a unique subgroup of tumors in the digestive system but with great clinical heterogeneity. The information on clinical characteristics and prognostic factors of Chinese patients is rather limited.
METHODOLOGY: We retrospectively analyzed the clinical features, prognostic factors of this disease in a consecutive cohort (N=294) between January 2007 and December 2012.
RESULTS: Functioning tumors accounted for 9.2%. Rectum was the most predominant GEP-NETs locations. Abdominal pain occurred in 46.5% patients which was the most common initial symptom. G1, G2 and G3 tumors accounted for 41.5%, 34.7% and 23.8%, respectively. Endoscopy provided the highest detection rate of 95.7%. Consistence between endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNAB) and surgically obtained histological Ki-67 index was 36.4%. Serum CgA test showed a 80.0% consistence with the tissue biopsy. The median follow up duration was 2.8 years (0.02-5.90 years), the median survival was 4.8 years, overall 5-year survival rate was 69.6%. We found colonic localization, tumor size larger than 20 mm, G3 tumor and metastasis were associated with worse outcome (p<0.05).
CONCLUSION: We found both consistence and differences in GEP-NETs characteristics between our study and previous reports.

Shinkawa H, Uenishi T, Takemura S, et al.
Adjuvant S-1 chemotherapy after surgical resection for pancreatic adenocarcinoma.
Hepatogastroenterology. 2015 Jan-Feb; 62(137):169-74 [PubMed] Related Publications
BACKGROUND/AIMS: The aim of this study was determine the effectiveness of adjuvant S-1 chemotherapy for patients with resected pancreatic cancer.
METHODOLOGY: Patients with pancreatic carcinoma who underwent pancreatic resection without adjuvant S-1 chemotherapy (n = 11) or with adjuvant S-1 chemotherapy (n = 10) were included. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 consecutive days followed by a 14-day pause. The cycle was repeated 4 times. Overall and disease-free survival curves were generated using the Kaplan-Meier method, and statistical differences between groups were analyzed using the log-rank test.
RESULTS: The disease-free survival and overall survival were longer among recipients of adjuvant S-1 chemotherapy than among those who received surgery alone (P < 0.05; 5-year disease-free survival rate, 30% versus 0%; 5-year overall survival rate, 65% vs 0%). Although dose reduction was needed in 2 patients because of grade 2 anorexia, only 1 patient with grade 2 hypoalbuminemia discontinued adjuvant chemotherapy because of long-term hospitalization.
CONCLUSIONS: S-1 administered as a single agent showed promise as an adjuvant chemotherapy for resected pancreatic cancer.

Chirindel A, Alluri KC, Chaudhry MA, et al.
Prognostic Value of FDG PET/CT-Derived Parameters in Pancreatic Adenocarcinoma at Initial PET/CT Staging.
AJR Am J Roentgenol. 2015; 204(5):1093-9 [PubMed] Related Publications
OBJECTIVE: The purpose of this study is to evaluate the performance of PET-derived parameters as prognostic markers for overall survival (OS) and progression-free survival (PFS) outcome in patients with pancreatic adenocarcinoma.
MATERIALS AND METHODS: We conducted a retrospective study of 106 patients (62 men and 44 women) with histologically proven pancreatic adenocarcinoma who underwent initial staging FDG PET/CT before treatment. Peak standardized uptake value (SUV), maximum SUV (SUVmax), metabolic tumor volume, and tumor glycolytic activity of the primary pancreatic tumor were measured. Two segmentation methods were performed to obtain the metabolic tumor volume and tumor glycolytic activity for all tumors: a gradient-based segmentation model (metabolic tumor volume and tumor glycolytic activity by gradient edge detection) and a fixed-threshold model with a threshold of 50% of the lesion's SUVmax and peak SUV. Univariate and multivariate Cox regression models were developed including clinical and imaging parameters for OS and PFS.
RESULTS: Multivariate Cox regression analysis showed a statistically significant association between PFS and age, SUVmax, peak SUV, and tumor glycolytic activity by gradient edge detection. There was a statistically significant difference in PFS for patients with values above and below the median cutoff points for SUVmax (hazard ratio [HR], 1.12; p < 0.01), peak SUV (HR, 1.25; p < 0.02), and tumor glycolytic activity measured by gradient edge detection (HR, 1.00; p < 0.02) of the primary tumor. However, multivariate Cox regression analysis showed a statistically significant association only between tumor glycolytic activity by gradient edge detection and OS (p = 0.04), and there was a statistically significant difference in OS between patients with values above and below the median cutoff point for the tumor glycolytic activity by gradient edge detection of the primary tumor (HR, 1.42; p = 0.05).
CONCLUSION: Age, SUVmax, peak SUV, and total lesion glycolysis (i.e., tumor glycolytic activity) of the primary tumor are associated with PFS, and tumor glycolytic activity is associated with OS in patients with pancreatic adenocarcinoma.

Zhu Z, Xu Y, Zhao J, et al.
miR-367 promotes epithelial-to-mesenchymal transition and invasion of pancreatic ductal adenocarcinoma cells by targeting the Smad7-TGF-β signalling pathway.
Br J Cancer. 2015; 112(8):1367-75 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: Aberrant Smad7 expression contributes to the invasion and metastasis of pancreatic cancer cells. However, the potential mechanism underlying aberrant Smad7 expression in human pancreatic ductal adenocarcinoma (PDAC) remains largely unknown.
METHODS: Bioinformatic prediction programmes and luciferase reporter assay were used to identify microRNAs regulating Smad7. The association between miR-367 expression and the overall survival of PDAC patients was evaluated by Kaplan-Meier analysis. The effects of miR-367 and Smad7 on the invasion and metastasis of pancreatic cancer cells were investigated both in vitro and in vivo.
RESULTS: We found that miR-367 downregulated Smad7 expression by directly targeting its 3'-UTR in human pancreatic cancer cells. High level of miR-367 expression correlated with poor prognosis of PDAC patients. Functional studies showed that miR-367 promoted pancreatic cancer invasion in vitro and metastasis in vivo through downregulating Smad7. In addition, we showed that miR-367 promoted epithelial-to-mesenchymal transition by increasing transforming growth factor-β (TGF-β)-induced transcriptional activity.
CONCLUSIONS: The present study identified and characterised a signalling pathway, the miR-367/Smad7-TGF-β pathway, which is involved in the invasion and metastasis of pancreatic cancer cells. Our results suggest that miR-367 may be a promising therapeutic target for the treatment of human pancreatic cancer.

von Karstedt S, Conti A, Nobis M, et al.
Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis.
Cancer Cell. 2015; 27(4):561-73 [PubMed] Related Publications
Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.

Xu Y, Zhu F, Xu S, Liu L
Anti-tumor effect of the extract from qingyihuaji formula on pancreatic cancer by down-regulating Notch-4 and Jagged-1.
J Tradit Chin Med. 2015; 35(1):77-83 [PubMed] Related Publications
OBJECTIVE: To investigate, in terms of Notch signaling pathway, the effect on pancreatic cancer of the extract of an anti-tumor prescription--Qingyi-huaji formula (QYHJ)--from Traditional Chinese Medicine (TCM).
METHODS: Nude mice were implanted subcutaneously with human pancreatic cancer cell line SW1990 and then randomly divided into four groups: Control, QYHJ extract, Gemcitabine, and Combination of QYHJ extract and gemcitabine. Treatments were given for 21 days and tumor growth was evaluated simultaneously. Then, expression of Notch receptors (Notch-1, Notch-2, Notch-3, and Notch-4) and their Jagged ligands (Jagged-1 and Jagged-2) in dissected tumor tissue were detected by real-time quantitative reverse transcription-polymerase chain reaction and Western blot. Finally, immunohistochemistry was performed to detect CD133, a marker of pancreatic cancer stem cells (CSCs), to evaluate the impact of QYHJ extract on pancreatic CSCs.
RESULTS: QYHJ extract treatment effectively inhibited the tumor growth in nude mice. The expression of both Notch-4 and Jagged-1 were decreased significantly in QYHJ treatment groups (P < 0.05), while gemcitabine alone had no significant effect in down-regulating Jagged-1 (P > 0.05). No significant difference was observed in the ex- pression of Notch-1, Notch-2, Notch-3, and Jagged-2 between three treatment groups and control group (P > 0.05). Moreover, immunohistochemical analysis showed that the number of CD133 positive cells was significantly reduced by QYHJ treatment (P < 0.05), and the combined treatment was more effective than gemcitabine alone (P < 0.05).
CONCLUSION: The role of the extract in pancreatic cancer treatment was associated with down-regulation of Notch-4 and Jagged-1 in Notch signaling pathway. The extract could enhance the antitumor activity of gemcitabine and was more effective than gemcitabine in regulating Notch signaling pathway to some extent.

Schlarb HC, Schlarb AC, Ubert HA, Schlarb CA
Solid pseudopapillary tumor of the pancreas.
W V Med J. 2015 Mar-Apr; 111(2):22-4 [PubMed] Related Publications
Solid pseudopapillary tumor is a rare tumor accounting for 1-2% of exocrine neoplasms involving the pancreas. This typically benign tumor is predominately found in young females of non-Caucasian descent between the second and fourth decades of life. Despite the reported increasing incidence of this neoplasm, many physicians are unfamiliar with this tumor, which may lead to uncertainty of diagnosis and treatment. While further delineating the clinical and imaging features of this tumor, we present two cases with review of the literature.

Pandita A, Manvati S, Singh SK, et al.
Combined effect of microRNA, nutraceuticals and drug on pancreatic cancer cell lines.
Chem Biol Interact. 2015; 233:56-64 [PubMed] Related Publications
AIM: We proposed to investigate the combination effect of microRNA, nutraceuticals and drug (MND), in two pancreatic cancer cell lines to assess the therapeutic potential.
MATERIALS AND METHODS: MIA PaCa-2 and PANC-1 cells transfected with miR-101 or miR-24-2 were treated with Betulinic acid or Thymoquinone and gemcitabine independently and in combination and assessed for the extent of synergism in both experimental and control conditions, considering significance at the p value of <0.05.
RESULTS: miR-101 or miR-24-2 over-expressing cells when treated with lower than IC50 doses of the dietary compounds and drug showed a reduced (37-50%) viability in two cell lines with differential synergistic effect and the outcome for Pro-caspase3, Poly (ADP-ribose) polymerase (PARP) cleavage and PKM2 expression.
CONCLUSION: Two independent microRNA backgrounds showed promise in therapeutic intervention of gemcitabine sensitive, MIA PaCa-2 and resistant, PANC-1 pancreatic cancer cells, in combination with dietary agents and drug.

Marchegiani G, Mino-Kenudson M, Ferrone CR, et al.
Oncocytic-type intraductal papillary mucinous neoplasms: a unique malignant pancreatic tumor with good long-term prognosis.
J Am Coll Surg. 2015; 220(5):839-44 [PubMed] Related Publications
BACKGROUND: The different epithelial phenotypes of intraductal papillary mucinous neoplasms (IPMNs) are predictors of tumor biology and post-surgical outcomes. Oncocytic-type IPMN (O-IPMN) seems to have a unique natural history, but not much information is available because of its rarity. We sought to describe the characteristics of a cohort of patients resected for O-IPMNs, focusing on their long-term outcomes after surgery.
STUDY DESIGN: We conducted a retrospective review of the demographics, clinical presentation, pathology, and survival of a cohort of patients resected for IPMN between 1990 and 2013, comparing O-IPMN with other IPMN subtypes.
RESULTS: Eighteen of 400 patients (4.5%) who underwent resection for IPMN had the oncocytic subtype. Compared with other IPMN patients, those with O-IPMNs were more likely to be male (72% vs 45%; p = 0.02) and to have main pancreatic duct involvement (72% vs 42%; p = 0.01). Oncocytic IPMNs occurred in asymptomatic individuals in 67% of cases. They had either invasive carcinoma (61%) or high-grade dysplasia (39%), and the proportions in other epithelial subtypes were 19% and 21%, respectively (p < 0.001). After resection, the 10-year recurrence rate for O-IPMNs was 46%. Recurrences occurred up to 11 years after the initial resection and a completion total pancreatectomy was performed in 4 patients. At a median follow-up of 7 years, no patients with O-IPMN had died from the disease.
CONCLUSIONS: Oncocytic IPMN is a unique tumor subtype that occurs mostly in the main pancreatic duct and is malignant. Recurrences after resection are not uncommon and can occur more than 10 years after the initial resection. Reoperations for recurrent O-IPMN are often feasible and have excellent results in terms of survival.

Tan MC, Basturk O, Brannon AR, et al.
GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma.
J Am Coll Surg. 2015; 220(5):845-54.e1 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations.
STUDY DESIGN: Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43).
RESULTS: Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis.
CONCLUSIONS: Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.

Dokmak S, Ftériche FS, Aussilhou B, et al.
Laparoscopic pancreaticoduodenectomy should not be routine for resection of periampullary tumors.
J Am Coll Surg. 2015; 220(5):831-8 [PubMed] Related Publications
BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is a difficult procedure that has become increasingly popular. Nevertheless, comparative data on outcomes remain limited. Our aim was to compare the outcomes of LPD and open pancreaticoduodenectomy (OPD).
STUDY DESIGN: Between April 2011 and April 2014, 46 LPD were performed and compared with 46 OPD, which theoretically can be done by the laparoscopic approach. Patients were also matched for demographic data, associated comorbidities, and underlying disease. Patient demographics and perioperative and postoperative outcomes were studied from our single center prospective database.
RESULTS: Lower BMI (23 vs 27 kg/m(2), p < 0.001) and a soft pancreas (57% vs 47%, p = 0.38) were observed in patients with LPD, but there were no differences in associated comorbidities or underlying disease. Surgery lasted longer in the LPD group (342 vs 264 minutes, p < 0.001). One death occurred in the LPD group (2.1% vs 0%, p = 0.28) and severe morbidity was higher (28% vs 20%, p = 0.32) in LPD due to grade C pancreatic fistula (PF) (24% vs 6%, p = 0.007), bleeding (24% vs 7%, p = 0.02), and revision surgery (24% vs 11%, p = 0.09). Pathologic examination for malignant diseases did not identify any differences between the LPD and OPD as far as size (2.51 vs 2.82 cm, p = 0.27), number of harvested (20 vs 23, p = 0.62) or invaded (2.4 vs 2, p = 0.22) lymph nodes, or R0 resection (80% vs 80%; p = 1). Hospital stays were similar (25 vs 23 days, p = 0.59). There was no difference in outcomes between approaches in patients at a lower risk of PF.
CONCLUSIONS: This study found that LPD is associated with higher morbidity, mainly due to more severe PF. Laparoscopic pancreaticoduodenectomy should be considered only in the subgroup of patients with a low risk of PF.

Karunasiri D, Lowder F, Ostrzega N, Goldfinger D
Anti-Ge2: further evidence for lack of clinical significance.
Immunohematology. 2014; 30(4):156-7 [PubMed] Related Publications
Anti-Ge2 may be immune or naturally occurring, and it reacts with an antigen on glycophorin D. Ge2 is encoded by a gene, GYPC, which is located on the long arm of chromosome 2. Anti-Ge2 is usually an immunoblobulin G (IgG) antibody. In the available literature, we have not been able to find any reported cases of proven acute hemolytic transfusion reactions caused by Anti-Ge2. We present the case of a 67-year-old man with metastatic pancreatic carcinoma who had symptomatic anemia and a hemoglobin concentration of 6.3 g/dL. During pretransfusion testing, Anti-Ge2 was identified in his serum. Only a single unit of compatible, Ge:-2 frozen red blood cells (RBCs) could be provided by the blood supplier. A second unit of crossmatched, least-incompatible, leukocyte-reduced RBCs, presumably Ge:-2, was also transfused. The transfusion was completed without incident, and the patient's hemoglobin concentration rose appropriately. Posttransfusion values for haptoglobin, lactate dehydrogenase, and urine hemoglobin were within normal limits. A monocyte monolayer assay performed on this anti-Ge2 supports the data that antibodies of this specificity do not cause hemolysis. The clinical and laboratory data obtained in our patient clearly indicated that no hemolysis of transformed RBCs occurred during and for 24 hours after transfusion. We believe that this report adds to a limited experience with anti-Ge2 and provides further evidence for concluding that, to all likelihood, this is not a clinically important RBC antibody. The risk of transfusing apparently "incompatible" (Ge:2) RBCs seems remote and should allow for timely administration of RBCs when treating patients with serious anemia.

Yang M, Zeng L, Zhang Y, et al.
TNM staging of pancreatic neuroendocrine tumors: an observational analysis and comparison by both AJCC and ENETS systems from 1 single institution.
Medicine (Baltimore). 2015; 94(12):e660 [PubMed] Related Publications
We aimed to analyze the clinical characteristics and compare the surgical outcome of pancreatic neuroendocrine tumors (p-NETs) using the 2 tumor-node-metastasis (TNM) systems by both the American Joint Committee on Cancer (AJCC) Staging Manual (seventh edition) and the European Neuroendocrine Tumor Society (ENETS). Moreover, we sought to validate the prognostic value of the new AJCC criterion. Data of 145 consecutive patients who were all surgically treated and histologically diagnosed as p-NETs from January 2002 to June 2013 in our single institution were retrospectively collected and analyzed. The 5-year overall survival (OS) rates for AJCC classifications of stages I, II, III, and IV were 79.5%, 63.1%, 15.0%, and NA, respectively, (P < 0.005). As for the ENETS system, the OS rates at 5 years for stages I, II, III, and IV were 75.5%, 72.7%, 29.0%, and NA, respectively, (P < 0.005). Both criteria present no statistically notable difference between stage I and stage II (P > 0.05) but between stage I and stages III and IV (P < 0.05), as well as those between stage II and stages III and IV (P < 0.05). Difference between stage III and IV by ENETS was significant (P = 0.031), whereas that by the AJCC was not (P = 0.144). What's more, the AJCC Staging Manual (seventh edition) was statistically significant in both uni- and multivariate analyses by Cox regression (P < 0.005 and P = 0.025, respectively). Our study indicated that the ENETS TNM staging system might be superior to the AJCC Staging Manual (seventh edition) for the clinical practice of p-NETs. Together with tumor grade and radical resection, the new AJCC system was also validated to be an independent predictor for p-NETs.

Wu W, Hong X, Li J, et al.
Solid serous cystadenoma of the pancreas: a case report of 2 patients revealing vimentin, β-catenin, α-1 antitrypsin, and α-1 antichymotrypsin as new immunohistochemistry staining markers.
Medicine (Baltimore). 2015; 94(12):e644 [PubMed] Related Publications
Solid serous cystadenoma (SCA) of the pancreas is a rare type of pancreatic solid tumors. Postoperative pathological evaluation is of particular importance for distinguishing solid SCA of the pancreas from other pancreatic solid tumors. Here we present 2 cases of solid SCA of the pancreas, both preoperatively diagnosed with pancreatic neuroendocrine tumors. One case had positive OctreoScan test. Surgical resections were done for both cases. Postoperative immunohistochemistry assays were conducted with marker panels for SCA and 2 types of pancreatic solid tumors, which were neuroendocrine tumor (pNET) and solid pseudopapillary tumor (SPT). Two cases showed typical staining patterns for SCA markers. Notably, both cases showed positivity for 4 SPT markers (vimentin, β-catenin, α-1 antitrypsin, and α-1 antichymotrypsin). Emphasis should be paid to those 4 new markers for future pathological diagnosis of solid SCA of the pancreas.

He Z, Tian H, Song A, et al.
Quality appraisal of clinical practice guidelines on pancreatic cancer: a PRISMA-compliant article.
Medicine (Baltimore). 2015; 94(12):e635 [PubMed] Related Publications
Clinical practice guidelines (CPGs) play an important role in health care. The guideline development process should be precise and rigorous to ensure that the results are reproducible and not vague. To determine the quality of guidelines, the Appraisal of Guidelines and Research and Evaluation (AGREE) instrument was developed and introduced. The objective of this study is to assess the methodological quality of CPGs on pancreatic cancer. Five databases (included MEDLINE and EMBASE) and guideline websites were searched till April, 2014. The methodological quality of the guidelines was assessed by 4 authors independently using the AGREE II instrument. From 2526 citations, 21 relevant guidelines were included. The overall agreement among reviewers was moderate (intraclass correlation coefficient = 0.86, 95% confidence interval 0.64-0.96). The mean scores were moderate for the domains "scope and purpose" and "clarity of presentation"; however, they were low for the domains "stakeholder involvement" (31.22), "rigor of development", "applicability", and "editorial independence". These domain scores were lower when compared with international levels. There are 5 (23.81%) guidelines that described the systematic methods for searching. Moreover, only 5 (23.81%) guidelines reported that methodological expertise were included in the guideline developing teams. The quality and transparency of the development process and the consistency in the reporting of pancreatic cancer guidelines need to be improved. Many other methodological disadvantages were identified. In the future, pancreatic cancer CPGs should base on the best available evidence rigorously developed and reported. Greater efforts are needed to provide high-quality guidelines that serve as a useful and reliable tool for clinical decision making in this field.

Parisi A, Desiderio J, Cirocchi R, et al.
Road accident due to a pancreatic insulinoma: a case report.
Medicine (Baltimore). 2015; 94(12):e537 [PubMed] Related Publications
Insulinoma is a rare pancreatic endocrine tumor, typically sporadic and solitary. Although the Whipple triad, consisting of hypoglycemia, neuroglycopenic symptoms, and symptoms relief with glucose administration, is often present, the diagnosis may be challenging when symptoms are less typical. We report a case of road accident due to an episode of loss of consciousness in a patient with pancreatic insulinoma. In the previous months, the patient had occasionally reported nonspecific symptoms. During hospitalization, endocrine examinations were compatible with an insulin-producing tumor. Abdominal computerized tomography and magnetic resonance imaging allowed us to identify and localize the tumor. The patient underwent a robotic distal pancreatectomy with partial omentectomy and splenectomy. Insulin-producing tumors may go undetected for a long period due to nonspecific clinical symptoms, and may cause episodes of loss of consciousness with potentially lethal consequences. Robot-assisted procedures can be performed with the same techniques of the traditional surgery, reducing surgical trauma, intraoperative blood loss, and hospital stays.

Gharaibeh M, McBride A, Bootman JL, Abraham I
Economic evaluation for the UK of nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreas cancer.
Br J Cancer. 2015; 112(8):1301-5 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: The combination of nab-paclitaxel plus gemcitabine (NAB-P+GEM) has shown superior efficacy over GEM monotherapy in metastatic pancreas cancer (MPC). Independent cost-effectiveness/utility analyses of NAB-P+GEM from the payer perspective have not been conducted for the UK.
METHODS: A Markov model simulating the health outcomes and total costs was developed to estimate the life years gained (LYG) and quality-adjusted life years gained (QALY) and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) for patients with MPC in a base case and in a probabilistic (PSA) sensitivity analysis. Total cost included the cost of supportive care medications, administration, chemotherapy, disease monitoring, and adverse reactions; and was discounted at 3.5% per year. A full lifetime horizon and third party payer perspective was chosen.
RESULTS: The total cost of NAB-P+GEM was £5466 higher than the cost for GEM. Respectively, LYGs were 0.97 vs 0.79 and QALYs were 0.52 vs 0.45, with ICER of £30 367/LYG and ICUR of £78 086/QALY, confirmed by PSA.
CONCLUSIONS: The superior survival efficacy of NAB-P+GEM over GEM in the management of MPC is associated with positive cost-effectiveness and cost-utility.

Al Efishat M, Wolfgang CL, Weiss MJ
Stage III pancreatic cancer and the role of irreversible electroporation.
BMJ. 2015; 350:h521 [PubMed] Related Publications
About a third of patients with pancreatic cancer present with locally advanced disease that is not amenable to resection. Because these patients have localized disease, conventional ablative therapies (thermal ablation and cryoablation) have the potential to be beneficial, but their use is inherently limited in the pancreas. These limitations could be overcome by irreversible electroporation-a novel, non-thermal ablative method that is gaining popularity for the treatment of many soft tissue tumors, including those of the pancreas. This review summarizes the status of this technique in the treatment of locally advanced pancreatic cancer. Most of the evidence on efficacy and safety is based on non-randomized prospective series, which show that irreversible electroporation may improve overall survival and pain control in locally advanced pancreatic cancer. As experience with this procedure increases, randomized controlled trials are needed to document its efficacy in locally advanced pancreatic cancer more precisely.

Cromer MK, Choi M, Nelson-Williams C, et al.
Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.
Proc Natl Acad Sci U S A. 2015; 112(13):4062-7 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Liu X, Wang J, Wang H, et al.
REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop.
Cancer Lett. 2015; 362(1):45-60 [PubMed] Related Publications
Regenerating gene protein (REG) 3A is a 19 kD secretory pancreas protein with pro-growth function. Previously we demonstrated that overexpression of REG3A, acting as a key molecule for up-regulation of the JAK2/STAT3 pathway, contributed to inflammation-related pancreatic cancer (PaC) development. However the exact network associated with REG3A signaling still remains unclear. Here we determined that exposure of human PaC cells to cytokine IL-6 activated the oncogenic JAK2/STAT3 pathway, which directly upregulated REG3A expression, accelerated cell cycle progression by promoting CyclinD1 expression, and enhancing the expression of the anti-apoptosis Bcl family. Importantly, the activation of REG3A would instead enhance the JAK2/STAT3 pathway to constitute a REG3A-JAK2/STAT3 positive feedback loop, which leads to the amplification of the oncogenic effects of IL-6/JAK2/STAT3, a classic pathway linking to inflammation-related tumorigenesis, ultimately resulting in PaC cell over-proliferation and tumor formation both in vitro and in vivo. Moreover, EGFR was found to mediate the REG3A signal for PaC cell growth and JAK2/STAT3 activation, thus functioning as a REG3A receptor. Collectively, our results provide the first evidence for the presence of the synergistic effect of REG3A and IL-6 on PaC development via a REG3A-JAK2/STAT3 positive feedback loop.

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