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1.
Transl Res ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442419

RESUMO

Pancreatic cancer is characterized by extremely high mortality and poor prognosis and is projected to be the leading cause of cancer deaths by 2030. Due to the lack of early symptoms and appropriate methods to detect pancreatic carcinoma at an early stage as well as its aggressive progression, the disease is often quite advanced by the time a definite diagnosis is established. The 5-year relative survival rate for all stages is approximately 8%. Therefore, detection of pancreatic cancer at an early surgically resectable stage is the key to decrease mortality and to improve survival. The traditional methods for diagnosing pancreatic cancer involve an imaging test, such as ultrasound or magnetic resonance imaging, paired with a biopsy of the mass in question. These methods are often expensive, time consuming, and require trained professionals to use the instruments and analyze the imaging. To overcome these issues, biosensors have been proposed as a promising tool for the early diagnosis of pancreatic cancer. The present review critically discusses the latest developments in biosensors for the early diagnosis of pancreatic cancer. Protein and microRNA biomarkers of pancreatic cancer and corresponding biosensors for pancreatic cancer diagnosis have been reviewed, and all these cases demonstrate that the emerging biosensors are becoming an increasingly relevant alternative to traditional techniques. In addition, we discuss the existing problems in biosensors and future challenges.

3.
Sci Transl Med ; 11(501)2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316009

RESUMO

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

4.
Mod Pathol ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285527

RESUMO

Germline pathogenic variants in the ATM serine/threonine kinase (ATM) gene are associated with an increased risk of pancreatic ductal adenocarcinoma. It is important to identify germline ATM pathogenic variants in pancreatic cancer patients because these alterations are potentially targetable with chemotherapeutic drugs and/or radiation and have implications for other family members. As germline pathogenic variants in other genes have been associated with distinct histologic subtypes of pancreatic cancer, we studied the histomorphology of pancreatic cancer in 23 patients with germline ATM pathogenic variants. The histologic subtype was ductal adenocarcinoma in 19/23 (83%) of the patients, adenosquamous carcinoma in 1/23 (4%), and colloid (mucinous non-cystic) carcinoma in 3/23 (13%). The percentage of colloid (mucinous non-cystic) carcinomas is higher than we have previously observed in patients with familial and sporadic pancreatic cancer (1 and 2% in prior reports, p < 0.01 and p < 0.01, respectively). Three carcinomas (2 colloid carcinomas, 1 ductal adenocarcinoma) arose in association with intraductal papillary mucinous neoplasms. Among the resected pancreata, non-invasive precursor lesions, including pancreatic intraepithelial neoplasia and incipient intraductal papillary mucinous neoplasms, were identified in 83%. We conclude that pancreatic cancers in patients with germline ATM pathogenic variants are more frequently of colloid (mucinous non-cystic) morphology but are overall morphologically diverse supporting the utility of universal germline genetic testing for patients with pancreatic cancer.

5.
Cancer Prev Res (Phila) ; 12(8): 527-538, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31164345

RESUMO

Patients with inflammatory bowel disease (IBD) colitis are at an increased risk of developing colorectal cancer and are currently recommended to undergo extensive annual or biennial colonoscopy, a costly and invasive procedure. Most surveillance colonoscopies are negative with no existing objective measures for assessing their risk of developing cancer. We have recently developed a less invasive, cost-effective and objective method to assess cancer risk by detecting the presence of colonic neoplasia via 3-dimensional (3D) nanoscale nuclear architecture mapping (nanoNAM) of normal-appearing rectal biopsies. To establish its translational relevance, we prospectively recruited 103 patients with IBD colitis undergoing surveillance colonoscopy and measured submicroscopic alterations in aberrant intrinsic nuclear architecture of epithelial cells from normal-appearing rectal biopsies with nanoNAM. The results were correlated with the histologic diagnoses from all random biopsies obtained during initial and follow-up colonoscopy within 3 years. Using nanoNAM-based structural characterization as input features into a soft margin-based ν-SVM risk classifier, we show that nanoNAM detects colonic neoplasia with AUC of 0.87 ± 0.04, sensitivity of 0.81 ± 0.09, and specificity of 0.82 ± 0.07 in the independent validation set. In addition, projecting nanoNAM features onto a 2-sphere reveals patients with low-risk and high-risk IBD colitis existing on separate hemispheres. Finally, we show that this ability to assess cancer risk translates to clinically-relevant estimation of individual-patient likelihood of being truly at risk. We demonstrate the potential of nanoNAM to identify patients with IBD at higher risk of developing cancer from normal-appearing rectum tissue, which may aid clinicians in patients with personalized IBD colitis surveillance.

6.
Clin Transl Gastroenterol ; 10(7): e00057, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232720

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

7.
EBioMedicine ; 42: 375-385, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30956167

RESUMO

BACKGROUND: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC. METHODS: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9. FINDINGS: The publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93) as well as CP (AUCTFF1+TFF2+TFF3+CA19.9 = 0.93). Notably, at 90% specificity (desired for blood-based biomarker panel), TFFs combination improved CA19.9 sensitivity by 10% and 25% to differentiate EPC from BC and CP respectively. In an independent blinded validation set, the combination of TFFs and CA19.9 (AUCTFF1+TFF2+TFF3+CA19.9 = 0.82) also improved the overall efficacy of CA19.9 (AUCCA19.9 = 0.66) to differentiate EPC from CP proving unique biomarker capabilities of TFFs to distinguish early stage of this deadly lethal disease. INTERPRETATION: In silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.


Assuntos
Antígeno CA-19-9/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Fatores Trefoil/sangue , Animais , Área Sob a Curva , Biomarcadores Tumorais , Bases de Dados Genéticas , Modelos Animais de Doenças , Detecção Precoce de Câncer , Imunofluorescência , Humanos , Imuno-Histoquímica , Camundongos , Neoplasias Pancreáticas/genética , Curva ROC , Reprodutibilidade dos Testes
8.
Pancreatology ; 19(4): 500-506, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30910452

RESUMO

BACKGROUND: We have previously reported that physicians under-recognize smoking as a chronic pancreatitis (CP) risk factor. We hypothesized that availability of empiric data will influence physician recognition of this relationship. METHODS: We analyzed data from 508 CP patients prospectively enrolled in the North American Pancreatitis Study-2 Continuation and Validation (NAPS2-CV) or NAPS2-Ancillary (AS) studies (2008-2014) from 26 US centers who self-reported ever-smoking. Information on smoking status, physician-defined etiology and identification of smoking as a CP risk factor was obtained from structured patient and physician questionnaires. We compared how often physician identified smoking as a CP risk factor in NAPS2-CV/NAPS2-AS studies with NAPS2-original study (2000-2006). RESULTS: Enrolling physician identified smoking as a risk factor in significantly (all p < 0.001) greater proportion of patients in NAPS2-CV/AS studies when compared with NAPS2-original study among ever (80.7 vs. 45.3%), current (91.3 vs. 53%), past (60.3 vs. 30.2%) smokers, in those who smoked ≤1 pack/day (79.3 vs. 39.5%) or ≥1 packs/day (83 vs. 49.8%). In multivariable analyses, the enrolling physician was 3.32-8.49 times more likely to cite smoking as a CP risk factor in the NAPS2-CV/NAPS2-AS studies based on smoking status and amount after controlling for age, sex, race and alcohol etiology. The effect was independent of enrolling site in a sub-analysis limited to sites participating in both phases of enrollment. CONCLUSIONS: Availability of empiric data likely enhanced physician recognition of the association between smoking and CP. Wide-spread dissemination of this information could potentially curtail smoking rates in subjects with and those at risk of CP.

9.
J Pediatr Gastroenterol Nutr ; 68(4): 566-573, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30897605

RESUMO

OBJECTIVES: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. METHODS: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables. RESULTS: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011). CONCLUSIONS: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

10.
Gastroenterology ; 156(8): 2242-2253.e4, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30836094

RESUMO

BACKGROUND & AIMS: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations. METHODS: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci. RESULTS: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs. CONCLUSIONS: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.


Assuntos
Adenocarcinoma Mucinoso/genética , Antineoplásicos/administração & dosagem , Carcinoma Ductal Pancreático/genética , Variação Genética/efeitos dos fármacos , Neoplasias Pancreáticas/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/epidemiologia , Mapeamento Cromossômico/métodos , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Adulto Jovem
11.
Clin Cancer Res ; 25(9): 2745-2754, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617132

RESUMO

PURPOSE: The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9. EXPERIMENTAL DESIGN: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set. RESULTS: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement (P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker. CONCLUSIONS: sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.

12.
Pancreas ; 47(10): 1262-1266, 2018 Nov/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30286010

RESUMO

OBJECTIVES: Presentation of pancreatic adenocarcinoma (PC) as acute pancreatitis (AP), association of chronic pancreatitis (CP) with PC, and role of inflammation in PC carcinogenesis are well recognized. We hypothesized that inflammatory changes associated with remote history of AP (≥2 years before PC diagnosis) would result in earlier age of PC diagnosis. METHODS: We evaluated PC patients prospectively enrolled in the Pancreatic Adenocarcinoma Gene Environment Risk (PAGER) study at the University of Pittsburgh for history of pancreatitis and reviewed relevant medical records and imaging studies. Univariate and multivariable linear regression analyses evaluated the relationship between PC and remote history of AP. RESULTS: Among 790 patients with histologically confirmed PC, 114 (14.4%) had a history of pancreatitis (AP within 2 years of PC diagnosis in 69 [8.7%], remote history of AP in 28 [3.5%], CP in 4 [0.5%], and unknown duration of pancreatitis in 13 [1.6%]). After controlling for age, sex, body mass index, smoking, alcohol history, and diabetic status at diagnosis, patients with a remote history of AP were diagnosed on average 4.7 years earlier with PC when compared with PC patients without history of AP (P < 0.035). CONCLUSIONS: Remote history of AP may accelerate carcinogenesis in PC.

13.
Pancreas ; 47(10): 1244-1248, 2018 Nov/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30325864

RESUMO

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

14.
J Immunol Methods ; 463: 39-46, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30218652

RESUMO

BACKGROUND: There are limited data on the immunological responsiveness of healthy intestinal tissue when it is cultured and stimulated ex vivo. Such an ex vivo model has the potential to be a valuable tool in understanding disease pathogenesis and as a preclinical tool for the assessment of candidate therapeutic agents used to treat inflammatory bowel disease (IBD). AIM: We undertook a comprehensive study to evaluate ex vivo immunological responses of intestinal tissue and isolated mucosal mononuclear cells (MMC) to a broad range of stimuli. METHODS: Colorectal biopsies (explants) were obtained from healthy participants by flexible sigmoidoscopy and were placed either directly into culture or digested to isolate MMC prior to placement in culture. Explants or MMC were treated with polyinosinic:polycytidylic acid (Poly IC), phytohemagglutinin (PHA), lipopolysacccharides from E Coli (LPS), anti-CD3/CD28 antibodies, or IL-1ß/TNF-α for 24 h. Supernatants were assayed for 40 inflammatory biomarkers using multiplexed enzyme-linked immunosorbent assay (ELISA). The isolated MMCs were further characterized using twelve color flow cytometry. RESULTS: Explants have greater weight adjusted constitutive expression of inflammatory biomarkers than MMCs. Biomarker responses varied as a function of immunogen and use of intact tissue or isolated cells. PHA applied to intact explants was the most effective agent in inducing biomarker changes. Stimulation induced activated and memory cellular phenotypes in both explants and MMCs. CONCLUSIONS: The breadth and magnitude of responses from intact and enzymatically digested intestinal tissue explants stimulated with exogenous immunogens are complex and vary by tissue form and treatment. Overall, PHA stimulation of intact explants produced the most robust responses in normal human colorectal tissue. This system could potentially serve as a preliminary model of the disease state, suitable for small scale screening of new therapeutic agents prior to using IBD patient derived tissue.

15.
Nutr Clin Pract ; 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30101991

RESUMO

BACKGROUND: Chronic pancreatitis (CP) patients frequently experience malabsorption and maldigestion, leading to micronutrient and macronutrient deficiencies. Comorbid diabetes and lifestyle habits, such as alcohol consumption, may impact nutrition status. METHODS: We compared micronutrient antioxidant, bone metabolism, serum protein, and inflammatory marker levels in 301 CP patients and 266 controls with no known pancreatic disease. We analyzed serum prealbumin and retinol binding protein; vitamins A, D, E, and B12; osteocalcin; tumor necrosis factor-α; and C-reactive protein (CRP). We also evaluated biomarkers among subsets of patients, examining factors including time since diagnosis, body mass index, alcohol as primary etiology, diabetes mellitus, vitamin supplementation, and pancreatic enzyme replacement. RESULTS: After correcting for multiple comparisons, CP patients had significantly lower levels than controls of the following: vitamin A (40.9 vs 45.4 µg/dL) and vitamin E (α-tocopherol [8.7 vs 10.3 mg/L] and γ-tocopherol [1.8 vs 2.2 mg/L]), as well as osteocalcin (7.9 vs 10 ng/mL) and serum prealbumin (23 vs 27 mg/dL). Both patients and controls who took vitamin supplements had higher serum levels of vitamins than those not taking supplements. Compared with controls, in controlled analyses, CP patients had significantly lower levels of vitamins A, D, and E (both α-tocopherol and γ-tocopherol). CP patients also had significantly lower levels of osteocalcin, serum prealbumin, and retinol binding protein, and higher CRP. CONCLUSIONS: CP patients demonstrated lower levels of selected nutrition and bone metabolism biomarkers than controls. Diabetes and alcohol did not impact biomarkers. Vitamin supplements and pancreatic enzyme replacement therapy improved nutrition biomarkers in CP patients.

16.
Pancreas ; 47(8): 924-936, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30113427

RESUMO

Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

17.
Gastroenterol Res Pract ; 2018: 2380596, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29967636

RESUMO

Background: Adolescent obesity is a national epidemic that recently has been shown to increase risk for pancreatic adenocarcinoma (PC) and is associated with an earlier age of PC onset. We hypothesized that PC patients who are overweight or obese at age 18 would have an earlier age of PC onset. Methods: Retrospective review of 531 patients in our PC registry was completed. Self-reported weight at age 18 and maximum lifetime weight were used to calculate body mass index (BMI) at age 18 (BMI-18) and maximum lifetime BMI. Results: Complete BMI and baseline covariate data was available in 319 PC patients. Mean age (in years) of PC diagnosis for patients whose BMI-18 was overweight (64.0) or obese (59.9) was significantly different when compared to patients with a normal BMI-18 (66.7). No significant difference was observed in the mean age of PC diagnosis in those patients who maintained a normal BMI-18 when compared to those patients who subsequently became overweight or obese (67.0 versus 66.6; p = 0.65). Conclusions: An elevated BMI at age 18 is associated with an earlier age of PC onset and should be factored into determining the optimal age of beginning screening for patients at high risk for PC.

18.
AIDS Res Hum Retroviruses ; 34(10): 838-848, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29936861

RESUMO

Ranpirnase (RNP) is a low molecular weight type III endoribonuclease, which demonstrates broad antiviral and antitumor properties. We sought to characterize the antiviral activity of RNP against HIV-1 and to determine whether RNP modulates local inflammatory changes associated with HIV infection in the colorectal explant model. Colorectal explants were incubated for 2 h with HIV-1BaL, in the presence of increasing concentrations of RNP (0-60 µg/mL). After washing, explants were cultured for 14 days, with supernatant collected at days 3, 7, 10, and 14. All samples were assayed for HIV-1 p24. Additionally, 30 soluble inflammatory biomarkers were assayed in the day 3 supernatant sample. Other biopsies were stimulated with lipopolysaccharides (LPS) (10 µg/mL) in the presence of RNP and soluble biomarkers assayed at day 3. RNP inhibited productive infection of the colorectal explants with HIV-1BaL and induced a dose-dependent decrease in 15/30 biomarkers. Affected biomarkers included IP-10, MDC, MIP-1α, MIP-1ß, TARC, IL12-p40, IL-15, IL-17, IL-1α, IL-7, IFNγ, IL12-p70, IL-1ß, IL-4, IL-5, and TNF-ß. Similarly, RNP dose-dependent inhibition was demonstrated in 7/30 biomarkers after LPS stimulation, all of which overlapped with HIV-1BaL-induced biomarker changes. The ability of RNP to inhibit both colorectal explant HIV-1BaL infection and inflammatory changes associated with HIV-1 infection makes RPN a promising agent for topical rectal pre-exposure prophylaxis.

19.
Mod Pathol ; 31(10): 1608-1618, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29884888

RESUMO

Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p < 0.001). This one patient had "Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

20.
Pancreatology ; 2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29859674

RESUMO

BACKGROUND: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US. METHODS: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA. Demographic and phenotypic information was obtained from structured questionnaires. Ancestry and admixture were evaluated by principal component analysis (PCA). Genotyping was performed for pathogenic genetic variants in PRSS1, SPINK1, CFTR and CTRC. Prevalence of disease-associated variants in NAPS2 subjects of AA and EA was compared. RESULTS: When compared with CP subjects of EA (n = 862), prevalence of established pathogenic genetic variants was infrequent in AA patients with CP, overall (29 vs. 8.19%, OR 4.60, 95% CI 2.74-7.74, p < 0.001), and after stratification by alcohol etiology (p < 0.001). On PCA, AA cases were more heterogeneous but distinct from EA subjects; no difference was observed between AA subjects with and without CP-associated variants. Of 19 A A patients with CP who had pathogenic genetic variants, 2 had variants in PRSS1 (R122H, R122C), 4 in SPINK1 (all N34S heterozygotes), 12 in CFTR (2 CFTRsev, 9 CFTRBD, 1 compound heterozygote with CFTRsev and CFTRBD), and 1 in CTRC (R254W). CONCLUSION: Pathogenic genetic variants reported in EA patients are significantly less common in AA patients. Further studies are needed to determine the complex risk factors for AA subjects with pancreatitis.

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