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1.
JAMA ; 325(4): 382-390, 2021 Jan 26.
Article in English | MEDLINE | ID: mdl-33496779

ABSTRACT

IMPORTANCE: In the United States, acute pancreatitis is one of the leading causes of hospital admission from gastrointestinal diseases, with approximately 300 000 emergency department visits each year. Outcomes from acute pancreatitis are influenced by risk stratification, fluid and nutritional management, and follow-up care and risk-reduction strategies, which are the subject of this review. OBSERVATIONS: MEDLINE was searched via PubMed as was the Cochrane databases for English-language studies published between January 2009 and August 2020 for current recommendations for predictive scoring tools, fluid management and nutrition, and follow-up and risk-reduction strategies for acute pancreatitis. Several scoring systems, such as the Bedside Index of Severity in Acute Pancreatitis (BISAP) and the Acute Physiology and Chronic Health Evaluation (APACHE) II tools, have good predictive capabilities for disease severity (mild, moderately severe, and severe per the revised Atlanta classification) and mortality, but no one tool works well for all forms of acute pancreatitis. Early and aggressive fluid resuscitation and early enteral nutrition are associated with lower rates of mortality and infectious complications, yet the optimal type and rate of fluid resuscitation have yet to be determined. The underlying etiology of acute pancreatitis should be sought in all patients, and risk-reduction strategies, such as cholecystectomy and alcohol cessation counseling, should be used during and after hospitalization for acute pancreatitis. CONCLUSIONS AND RELEVANCE: Acute pancreatitis is a complex disease that varies in severity and course. Prompt diagnosis and stratification of severity influence proper management. Scoring systems are useful adjuncts but should not supersede clinical judgment. Fluid management and nutrition are very important aspects of care for acute pancreatitis.


Subject(s)
Enteral Nutrition , Fluid Therapy , Pancreatitis/therapy , APACHE , Alcohol Abstinence , Humans , Pancreatitis/diagnosis , Pancreatitis/etiology , Risk Reduction Behavior , Severity of Illness Index
2.
HPB (Oxford) ; 20(5): 418-422, 2018 05.
Article in English | MEDLINE | ID: mdl-29398424

ABSTRACT

BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.


Subject(s)
Pancreatectomy/adverse effects , Pancreatic Fistula/prevention & control , Pancreaticoduodenectomy/adverse effects , Somatostatin/analogs & derivatives , Aged , Case-Control Studies , Drug Administration Schedule , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Pancreatic Fistula/diagnostic imaging , Pancreatic Fistula/etiology , Prospective Studies , Risk Factors , Somatostatin/administration & dosage , Somatostatin/adverse effects , Time Factors , Treatment Outcome
3.
JAMA ; 325(23): 2403-2404, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34129002
4.
JAMA ; 315(17): 1882-93, 2016 05 03.
Article in English | MEDLINE | ID: mdl-27139061

ABSTRACT

IMPORTANCE: Cystic lesions of the pancreas are common and increasingly detected in the primary care setting. Some patients have a low risk for developing a malignancy and others have a high risk and need further testing and interventions. OBSERVATIONS: Pancreatic cysts may be intraductal mucinous neoplasms, mucinous cystic neoplasms, serous cystadenomas, solid pseudopapillary neoplasms, cystic variations of pancreatic neuroendocrine tumors, pancreatic ductal adenocarcinomas, or 1 of several types of nonneoplastic cysts. Mucinous (intraductal mucinous neoplasm or mucinous cystic neoplasm) lesions have malignant potential and should be distinguished from serous lesions (serous cystadenomas) that are nearly always benign. Symptomatic patients or those having high-risk features on initial imaging (eg, main pancreatic duct dilatation, a solid component, or mural nodule) require further evaluation with advanced imaging, possibly followed by surgical resection. Advanced imaging includes endoscopic ultrasound with cyst fluid analysis and cytology to confirm the type of cyst and determine the risk of malignancy. Small cysts (size <3 cm) in asymptomatic patients without any suspicious features may be observed with serial imaging because the risk for malignancy is low. CONCLUSIONS AND RELEVANCE: The management of pancreatic cysts requires risk stratification for malignant potential based on the presence or absence of symptoms and high-risk features on cross-sectional imaging. Because pancreatic cysts are becoming more frequently diagnosed, clinicians should have a systematic approach for establishing a diagnosis and determining which patients require treatment.


Subject(s)
Pancreatic Cyst/diagnosis , Pancreatic Neoplasms/diagnosis , Diagnosis, Differential , Humans , Risk Assessment
5.
J Surg Oncol ; 112(4): 396-402, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26303811

ABSTRACT

BACKGROUND: Lymph node (LN) involvement is a well-known poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). However, there have been conflicting results on the significance of the mechanism of LN involvement, "direct" tumor invasion versus "metastatic," disease on patient survival. METHODS: Clinicopathologic records from all patients who underwent resection for PDAC from 1990 to 2014 at a single-institution were reviewed. RESULTS: Of the 385 total patients, there was tumor invasion outside of the pancreas in 289 (75.1%) patients. Overall, 239 (62.1%) had node-positive disease: 220 (92.0%) by "metastatic" involvement, 14 (5.9%) by "direct" tumor extension, and five (2.1%) by a mix of "metastatic" and "direct". There were no significant differences in clinicopathologic factors associated with PDAC survival between "metastatic" and "direct" LN patients. The median overall survival for the whole cohort was 31.1 months. Compared to overall survival in patients with LN-negative disease (median 40.7 months), those with LNs involved by "metastatic" spread was significantly shorter (median 25.7 months, P < 0.001), yet "direct" LN extension was similar (median 48.1 months, P = 0.719). CONCLUSIONS: The mechanism of LN involvement affects PDAC prognosis. Patients with LNs involved by direct extension have similar survival to those with node-negative disease.


Subject(s)
Adenocarcinoma/mortality , Carcinoma, Pancreatic Ductal/mortality , Lymph Nodes/pathology , Pancreatectomy/mortality , Pancreatic Neoplasms/mortality , Adenocarcinoma/secondary , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/secondary , Carcinoma, Pancreatic Ductal/surgery , Female , Follow-Up Studies , Humans , Lymph Node Excision , Lymph Nodes/surgery , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis , Prospective Studies , Survival Rate , Young Adult
6.
Biochim Biophys Acta ; 1833(12): 2980-2987, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23954445

ABSTRACT

Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be an intriguing therapeutic strategy in PaCa.


Subject(s)
Apoptosis , Gene Knockdown Techniques , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolism , Apoptosis/drug effects , Caspases/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Enzyme Activation/drug effects , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Pancreatic Neoplasms/enzymology , Gemcitabine
7.
Biochim Biophys Acta ; 1823(2): 593-604, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22227579

ABSTRACT

Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.


Subject(s)
Apigenin/metabolism , Mutation , Pancreatic Neoplasms/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Apigenin/pharmacology , Apigenin/therapeutic use , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Benzothiazoles/metabolism , Cell Line, Tumor , Dietary Supplements , Humans , Male , Mice , Mice, Nude , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/therapy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Toluene/analogs & derivatives , Toluene/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , bcl-X Protein/genetics , bcl-X Protein/metabolism
8.
Biochem Biophys Res Commun ; 439(1): 6-11, 2013 Sep 13.
Article in English | MEDLINE | ID: mdl-23973710

ABSTRACT

Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3'-untranslated region (3'-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E2 (PGE2) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 µM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE2 levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE2, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.


Subject(s)
Cyclooxygenase 2/metabolism , Gene Expression Regulation, Neoplastic , MicroRNAs/metabolism , Pancreatic Neoplasms/metabolism , RNA Stability , Butadienes/pharmacology , Cell Line, Tumor , Cell Proliferation , DNA-Binding Proteins/metabolism , Dinoprostone/metabolism , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Humans , MAP Kinase Kinase Kinases/metabolism , Nitriles/pharmacology , Pancreatic Neoplasms/genetics , RNA, Messenger/metabolism , Signal Transduction , Time Factors , Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
9.
Ann Surg Oncol ; 20(13): 4322-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23943022

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data. METHODS: All patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system. RESULTS: We identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system. CONCLUSIONS: We were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system.


Subject(s)
Adenocarcinoma/pathology , Carcinoma, Pancreatic Ductal/pathology , Neoplasm Staging/standards , Pancreatic Neoplasms/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Aged , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/surgery , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Neoplasm Grading , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Prognosis , Prospective Studies , Survival Rate , Validation Studies as Topic
10.
Curr Opin Gastroenterol ; 29(5): 552-8, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23892537

ABSTRACT

PURPOSE OF REVIEW: To summarize published research on pancreatic surgery over the past year. RECENT FINDINGS: A number of studies aiming to reduce the costs associated with pancreatic surgery were reported. Retrospective analyses confirmed previous findings that neither the routine use of pancreatic duct stents decreases the rate of fistula formation nor does placement of a drain at the time of surgery change the morbidity in patients who develop one. Minimally invasive approaches, both laparoscopic and robot-assisted, are being performed more frequently to remove pancreatic cancers. A randomized trial confirmed that reinforcement of stapled closure during distal pancreatectomy reduces the rate of fistula formation. Controversy remains over whether small pancreatic neuroendocrine tumors need to be surgically resected or can be treated nonoperatively. Patients with chronic pancreatitis should be screened thoroughly before being offered surgical treatment; two studies reported preoperative factors that can be used to identify those most likely to experience pain relief. SUMMARY: Studies published on pancreatic surgery last year focused on a wide-range of topics. The morbidity and mortality of patients undergoing pancreatic surgery continues to improve, and we anticipate that incorporation of these new findings will lead to even better outcomes.


Subject(s)
Pancreatectomy/methods , Pancreatic Diseases/surgery , Carcinoma, Neuroendocrine/surgery , Cost-Benefit Analysis , Humans , Laparoscopy/methods , Pancreatectomy/adverse effects , Pancreatectomy/economics , Pancreatectomy/standards , Pancreatic Neoplasms/surgery , Pancreatitis, Chronic/surgery , Quality Indicators, Health Care , Robotics/methods
11.
Biochim Biophys Acta ; 1813(8): 1465-74, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21596068

ABSTRACT

Scutellaria baicalensis (SB) and SB-derived polyphenols possess anti-proliferative activities in several cancers, including pancreatic cancer (PaCa). However, the precise molecular mechanisms have not been fully defined. SB extract and SB-derived polyphenols (wogonin, baicalin, and baicalein) were used to determine their anti-proliferative mechanisms. Baicalein significantly inhibited the proliferation of PaCa cell lines in a dose-dependent manner, whereas wogonin and baicalin exhibited a much less robust effect. Treatment with baicalein induced apoptosis with release of cytochrome c from mitochondria, and activation of caspase-3 and -7 and PARP. The general caspase inhibitor zVAD-fmk reversed baicalein-induced apoptosis, indicating a caspase-dependent mechanism. Baicalein decreased expression of Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, presumably through a transcriptional mechanism. Genetic knockdown of Mcl-1 resulted in marked induction of apoptosis. The effect of baicalein on apoptosis was significantly attenuated by Mcl-1 over-expression, suggesting a critical role of Mcl-1 in this process. Our results provide evidence that baicalein induces apoptosis in pancreatic cancer cells through down-regulation of the anti-apoptotic Mcl-1 protein.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Flavanones/pharmacology , Pancreatic Neoplasms/drug therapy , Phytotherapy , Proto-Oncogene Proteins c-bcl-2/genetics , Scutellaria baicalensis/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/genetics , Apoptosis/physiology , Caspases/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Flavanones/isolation & purification , Flavonoids/isolation & purification , Flavonoids/pharmacology , Gene Knockdown Techniques , Genes, bcl-2/drug effects , Humans , Myeloid Cell Leukemia Sequence 1 Protein , Oncogene Proteins/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phenols/isolation & purification , Phenols/pharmacology , Polyphenols , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/physiology , Viral Proteins/metabolism
12.
Am J Pathol ; 178(3): 1340-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21356384

ABSTRACT

Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL5-mediated tumor angiogenesis and cancer growth. We report herein that CXCL5 is overexpressed in human pancreatic cancer compared with paired normal pancreas tissue. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival. Patients with pancreatic cancer and CXCL5 overexpression who underwent resection of cancer had a mean survival time 25.5 months shorter than that of patients who did not overexpress CXCL5. Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model. Finally, we demonstrated that CXCL5 mediates pancreatic cancer-derived angiogenesis through activation of several signaling pathways, including protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription (STAT) in human endothelial cells. These data suggest that CXCL5 is an important mediator of tumor-derived angiogenesis and that it may serve as a survival factor for pancreatic cancer. Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.


Subject(s)
Chemokine CXCL5/metabolism , Pancreatic Neoplasms/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Chemokine CXCL5/genetics , Disease Progression , Endothelial Cells/enzymology , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Mice , Mice, Nude , Neovascularization, Pathologic/metabolism , Neutralization Tests , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Interleukin-8B/metabolism , Survival Analysis , Xenograft Model Antitumor Assays
13.
Am J Pathol ; 176(2): 861-9, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20042670

ABSTRACT

The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta cells and islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by beta cells. It is increasingly appreciated that the toxic form of amyloidogenic proteins is not amyloid but smaller membrane-permeant oligomers. Using an antibody specific for toxic oligomers and cryo-immunogold labeling in human IAPP transgenic mice, human insulinoma and pancreas from humans with and without T2DM, we sought to establish the abundance and sites of formation of IAPP toxic oligomers. We conclude that IAPP toxic oligomers are formed intracellularly within the secretory pathway in T2DM. Most striking, IAPP toxic oligomers appear to disrupt membranes of the secretory pathway, and then when adjacent to mitochondria, disrupt mitochondrial membranes. Toxic oligomer-induced secretory pathway and mitochondrial membrane disruption is a novel mechanism to account for cellular dysfunction and apoptosis in T2DM.


Subject(s)
Amyloid/toxicity , Diabetes Mellitus, Type 2/pathology , Insulin-Secreting Cells/pathology , Amyloid/metabolism , Amyloid/pharmacology , Animals , Diabetes Mellitus, Type 2/metabolism , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/ultrastructure , Insulinoma/metabolism , Insulinoma/pathology , Intracellular Space/drug effects , Intracellular Space/metabolism , Islet Amyloid Polypeptide , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Islets of Langerhans/ultrastructure , Mice , Mice, Transgenic , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Protein Multimerization/physiology , Rats , Secretory Pathway/drug effects , Secretory Vesicles/drug effects , Secretory Vesicles/metabolism , Secretory Vesicles/pathology
14.
Curr Opin Gastroenterol ; 26(5): 499-505, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20651590

ABSTRACT

PURPOSE OF REVIEW: To summarize published research on pancreatic surgery over the past year. RECENT FINDINGS: Improvements in the treatment of patients with acute gallstone pancreatitis with regards to the timing of ERCP and cholecystectomy as well as management of pancreatic pseudocysts have been reported. It is often difficult to detect malignancy in neoplastic pancreatic cysts; however, a detailed cyst fluid analysis for protein and genetic markers may improve this accuracy. In order to continue to improve pancreatic cancer care in the United States, a standardized reporting system must be developed, and this was a focus of the American Hepato-Pancreatico-Biliary Association Consensus Conference on Resectable and Borderline Resectable Disease. The conference examined pretreatment assessment, surgical treatment, and combined modality treatment for pancreatic cancer. A multi-institutional randomized clinical trial revealed that routine preoperative decompression of malignant biliary obstruction is associated with a higher frequency of complications. Pancreatic fistulas are the most common source of perioperative morbidity following pancreatic surgery. Fortunately, most of these can be managed nonoperatively via interventional radiology techniques. SUMMARY: There is a broad spectrum of pancreatic diseases, which often require surgical treatment. Fortunately, the morbidity and mortality from each of them continues to decrease with more accurate diagnosis, improved management techniques, and standardized reporting systems.


Subject(s)
Cholangiopancreatography, Endoscopic Retrograde/methods , Pancreatectomy/methods , Pancreatic Diseases/surgery , Humans , Treatment Outcome
15.
J Comput Assist Tomogr ; 34(5): 732-8, 2010.
Article in English | MEDLINE | ID: mdl-20861777

ABSTRACT

OBJECTIVE: To evaluate the performance of multidetector computed tomographic angiography (MDCTA) in assessing the surgical resectability of pancreatic head adenocarcinoma. METHODS: With institutional review board approval, radiographic, surgical, and pathological records of 203 consecutive patients with adenocarcinoma of the pancreatic head were analyzed retrospectively. Patients were imaged with MDCT scanners using our institution's CTA pancreatic protocol. Images were compared with surgical outcomes to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MDCTA in determining resectability. RESULTS: Data were analyzed twice, once with equivocal findings on MDCTA assumed as resectable and again with equivocal cases assumed as unresectable. All equivocal cases were ultimately unresectable; when this was assumed, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were determined to be 100%, 71%, 85%,100% and 89%. Twelve patients deemed resectable by preoperative MDCTA were found to be unresectable on surgical exploration owing to vascular involvement (n = 4), liver metastases (n = 4), and peritoneal involvement (n = 4). CONCLUSIONS: Multidetector CT angiography offers accurate and valuable preoperative assessment of surgical resectability of pancreatic ductal adenocarcinoma. Liver and peritoneal metastases and vascular invasion still remain important pitfalls in preoperative evaluation.


Subject(s)
Adenocarcinoma/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Tomography, X-Ray Computed/methods , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Angiography/methods , Contrast Media/administration & dosage , Female , Humans , Iohexol/administration & dosage , Male , Middle Aged , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Patient Selection , Predictive Value of Tests , Sensitivity and Specificity
16.
Am Surg ; 76(10): 1071-4, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21105612

ABSTRACT

Chronic pancreatitis is a debilitating disease resulting in pain, intestinal malabsorption, endocrine dysfunction, and poor quality of life (QoL). Our aim was to analyze surgical outcomes for patients with chronic pancreatitis. Data for patients undergoing operations for chronic pancreatitis between 1990 and 2009 were reviewed. Demographics, operative and perioperative data, and survival were catalogued. QoL was determined (Short Form 36 and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire + PAN-26) and compared with historical controls. The mean age was 51 +/- 2 years, 38 patients were male (53%), the most common indication was pain (71%), the etiology of pancreatitis often was alcohol, and most patients underwent a Whipple procedure (56%). Operative time was 316 +/- 17 minutes and blood loss was 363 +/- 75 mL. There were 34 complications in 30 patients (42%) and one death. QoL surveys were administered for 25 of 55 (45%) surviving patients at a mean follow-up of 72 +/- 16 months. Mean survival was 99 +/- 9 months, whereas 5- and 10-year survival were 86 and 75 per cent. QoL scores were uniformly better than historical controls. Our data demonstrate that operations for chronic pancreatitis can be performed with acceptable morbidity and mortality. Patients have excellent survival and improved QoL compared with historical controls. Surgery is an effective and durable treatment option for patients with chronic pancreatitis.


Subject(s)
Pancreatitis, Chronic/surgery , Quality of Life , Digestive System Surgical Procedures , Female , Humans , Male , Middle Aged , Pancreaticoduodenectomy , Pancreatitis, Chronic/etiology , Pancreatitis, Chronic/mortality , Postoperative Complications/epidemiology , Retrospective Studies , Treatment Outcome
17.
Surgery ; 167(5): 803-811, 2020 05.
Article in English | MEDLINE | ID: mdl-31992444

ABSTRACT

BACKGROUND: Resection margin status has been recognized as an independent prognostic factor on overall survival in pancreatic cancer patients undergoing surgical resection. However, its impact after neoadjuvant treatment remains uncertain. METHODS: We analyzed 305 patients with resectable or borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatoduodenectomy at 3 tertiary referral centers between 2010 and 2017. Positive resection margin was defined as 1 or more cancer cells at any margin. Overall survival was measured from the date of surgery until death or last follow-up. RESULTS: One hundred and seventy-eight patients received neoadjuvant chemotherapy and 127 received neoadjuvant chemoradiotherapy. The median overall survival was 29.8 months. The 1-, 3-, and 5-year overall survival rates were 79.2%, 44.0%, and 23.5%, respectively. Negative margin was achieved in 275 (90.2%) patients. Negative margin resection patients had a significantly longer overall survival than positive resection margin patients (31.3 vs 16.3 months, P < .001). In univariate analyses, overall survival was associated with age, margin status, histologic grade, ypT, number of positive lymph nodes, perineural invasion, treatment effect, postoperative carbohydrate antigen 19-9, and adjuvant therapy. Positive margin resection, poorly differentiated carcinoma, treatment effect score of 3, postoperative carbohydrate antigen 19-9 of 37 U/mL or higher, and lack of adjuvant therapy were predictive of poor overall survival in multivariate Cox regression analysis. CONCLUSION: Margin status was an independent predictor of overall survival in patients treated with neoadjuvant therapy and pancreatoduodenectomy, supporting the use of a negative margin resection as a surrogate of adequate oncological resection in this setting. Our findings may also have significant implications for patient stratification in future randomized trials.


Subject(s)
Margins of Excision , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Staging , Pancreatic Neoplasms/diagnosis , Pancreaticoduodenectomy , Prognosis , Retrospective Studies , Treatment Outcome
18.
Curr Opin Gastroenterol ; 25(5): 460-5, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19550315

ABSTRACT

PURPOSE OF REVIEW: Surgery of the pancreas is evolving as the understanding of pancreatic disease improves. This report reviews the work published over the last year related to pancreatic surgery and the diseases addressed by surgical techniques. RECENT FINDINGS: Obesity is an important risk factor for many diseases of the pancreas, including pancreatic adenocarcinoma. Recent evidence suggests that obese patients with pancreatic cancer appear to have more advanced disease at the time of diagnosis and a worse outcome following resection. The issues surrounding adjuvant treatment for pancreatic cancer with chemotherapy and/or radiation therapy continue to be evaluated. Cystic lesions of the pancreas remain a vexing treatment dilemma, but as we learn more about their natural history, more thoughtful recommendations for management become possible. Resection of pancreatic endocrine neoplasms is often appropriate, even in the face of metastatic disease. Minimally invasive approaches to the drainage of infected pancreatic necrosis are beginning to gain acceptance. The pain of chronic pancreatitis may be lessened by operative intervention and possibly radiation. SUMMARY: Each year more is learned about the natural history of pancreatic lesion. For those dedicated to the study and treatment of this gland, several new advances help the clinician with treatment decisions.


Subject(s)
Pancreatic Diseases/surgery , Chemotherapy, Adjuvant , Humans , Minimally Invasive Surgical Procedures , Obesity/complications , Pancreatic Diseases/etiology , Pancreatic Neoplasms/etiology , Pancreatic Neoplasms/surgery , Radiotherapy, Adjuvant , Risk Factors
19.
Pancreatology ; 9(3): 197-9, 2009.
Article in English | MEDLINE | ID: mdl-19299908

ABSTRACT

Dr. Howard Reber is a world-renowned pancreatologist in the area of basic pancreatic physiology and the management of pancreatic diseases. He was leader in the development of the current recommendation for the treatment of pancreatic cancer. In this interview for Pancreatology, Dr. Reber shares his life experiences as a scientist in pancreatic research. and IAP.


Subject(s)
Pancreas/physiology , Pancreatic Diseases/therapy , Career Choice , Humans , Pancreas/physiopathology , Pancreatic Diseases/surgery , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/therapy , Students, Medical
20.
Dig Dis Sci ; 54(7): 1582-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-18958617

ABSTRACT

INTRODUCTION: Complications following pancreaticoduodenectomy (PD) often necessitate nutritional support. This study analyzes the utilization of parenteral nutrition (TPN) during the surgical admission as evidence for or against routine jejunostomy placement. METHODS: The California Cancer Registry (1994-2003) was linked to the California Inpatient File; PD for adenocarcinoma was performed in 1,873 patients. TPN use and enterostomy tube placement were determined and preoperative characteristics predictive of TPN use during the surgical admission were identified. RESULTS: Fourteen percent of patients received TPN, 23% underwent enterostomy tube placement, and 63% received no supplemental nutritional support. TPN was associated with longer hospital stay (18 vs. 13 days, P < 0.0001). The Charlson Comorbidity Index (CCI) > or = 3 had nearly two-fold greater odds of receiving TPN (odds ratio [OR] = 1.85, P < 0.005). CONCLUSION: Approximately 1 in 6 patients undergoing PD received TPN, which was associated with prolonged hospital stay. CCI > or = 3 was associated with increased odds of TPN utilization. Selected jejunostomy placement in patients with high CCI is worthy of consideration.


Subject(s)
Adenocarcinoma/surgery , Pancreatic Neoplasms/surgery , Pancreaticoduodenectomy/methods , Parenteral Nutrition, Total/statistics & numerical data , Adenocarcinoma/epidemiology , Aged , Comorbidity , Enteral Nutrition/statistics & numerical data , Enterostomy , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Length of Stay , Male , Middle Aged , Multivariate Analysis , Pancreatic Neoplasms/epidemiology , Pancreaticoduodenectomy/adverse effects , Pancreaticoduodenectomy/mortality , Postoperative Care/statistics & numerical data , Postoperative Complications/epidemiology , Postoperative Period
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