Absence of a pancreatic microbiome in intraductal papillary mucinous neoplasm.

OBJECTIVE: This study aims to validate the existence of a microbiome within intraductal papillary mucinous neoplasm (IPMN) that can be differentiated from the taxonomically diverse DNA background of next-generation sequencing procedures. DESIGN: We generated 16S rRNA amplicon sequencing data to analyse 338 cyst fluid samples from 190 patients and 19 negative controls, the latter collected directly from sterile syringes in the operating room. A subset of samples (n=20) and blanks (n=5) were spiked with known concentrations of bacterial cells alien to the human microbiome to infer absolute abundances of microbial traces. All cyst fluid samples were obtained intraoperatively and included IPMNs with various degrees of dysplasia as well as other cystic neoplasms. Follow-up culturing experiments were conducted to assess bacterial growth for microbiologically significant signals. RESULTS: Microbiome signatures of cyst fluid samples were inseparable from those of negative controls, with no difference in taxonomic diversity, and microbial community composition. In a patient subgroup that had recently undergone invasive procedures, a bacterial signal was evident. This outlier signal was not characterised by higher taxonomic diversity but by an increased dominance index of a gut-associated microbe, leading to lower taxonomic evenness compared with the background signal. CONCLUSION: The 'microbiome' of IPMNs and other pancreatic cystic neoplasms does not deviate from the background signature of negative controls, supporting the concept of a sterile environment. Outlier signals may appear in a small fraction of patients following recent invasive endoscopic procedures. No associations between microbial patterns and clinical or cyst parameters were apparent.

The role of the microbiome in pancreatic oncogenesis.

Bacterial dysbiosis is evolving as an advocate for carcinogenesis and has been associated with pancreatic cancer progression and survival outcomes. The gut and pancreas of cancer patients harbor a unique microbiome that differs significantly from that of healthy individuals. We believe that the pancreatic cancer microbiome regulates tumorigenesis by altering host cell function and modulating immune cells, skewing them toward an immunosuppressive phenotype. Moreover, altering this pathogenic microbiome may enhance the efficacy of current therapies in pancreatic cancer and improve survival outcomes. This review highlights the findings on microbial modulation across various pre-clinical and clinical studies and provides insight into the potential of targeting the microbiome for pancreatic cancer therapy.

pH-taxis drives aerobic bacteria in duodenum to migrate into the pancreas with tumors.

As oral or intestinal bacteria have been found in pancreatic cystic fluid and tumors, understanding bacterial migration from the duodenum into the pancreas via hepato-pancreatic duct is critical. Mathematical models of migration of aerobic bacteria from the duodenum to the pancreas with tumors were developed. Additionally, the bacterial distributions under the pH gradient and those under flow were measured in double-layer flow based microfluidic device and T-shaped cylinders. Migration of aerobic bacteria from the duodenum into pancreas is counteracted by bile and pancreatic juice flow but facilitated by pH-taxis from acidic duodenum fluid toward more favorable slightly alkaline pH in pancreatic juice. Additionally, the reduced flow velocity in cancer patients, due to compressed pancreatic duct by solid tumor, facilitates migration. Moreover, measured distribution of GFP E. coli under the pH gradient in a microfluidic device validated pH-tactic behaviors. Furthermore, Pseudomonas fluorescens in hydrochloride solution, but not in bicarbonate solution, migrated upstream against bicarbonate flow of > 20 µm/s, with an advancement at approximately 50 µm/s.

Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients.

Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.

Percutaneous endoscopic necrosectomy in a patient with emphysematous pancreatitis: A case report.

RATIONALE: Emphysematous pancreatitis, a rare complication of acute necrotizing pancreatitis with a high mortality rate, is associated with gas-forming bacteria. When using the step-up approach for treating emphysematous pancreatitis, it is preferable to delay drainage interventions for 4 weeks. However, percutaneous drainage may be necessary, even in the early phase of acute pancreatitis, for a patient whose sepsis deteriorates despite optimal medical management. Percutaneous drainage can then be followed by endoscopic necrosectomy through the percutaneous tract. PATIENT CONCERNS: A 52-year-old man was transferred to our hospital for treatment of sepsis and multiorgan failure associated with emphysematous pancreatitis. DIAGNOSIS: An abdominal computed tomography scan had shown pancreatic and peripancreatic necrosis, along with extensive gas bubbles. INTERVENTIONS: Despite optimal medical management, the patient's condition continued to deteriorate, and it became necessary to insert 2 percutaneous catheter drainages (PCDs), even though the patient was still in the early phase of pancreatitis. Each PCD was upsized and irrigated with sterile saline by an interventional radiologist twice a week. The infected necrosis around the tail of the pancreas was completely resolved after PCD. However, PCD through the transperitoneal route did not resolve necrosis around the pancreatic head. Following the PCDs, percutaneous pancreatic necrosectomy using an ultra-slim upper endoscope was performed, after which the patient recovered quickly and was discharged. OUTCOMES: Follow-up computed tomography was performed 12 weeks after the patient was discharged, and it showed complete resolution of the walled-off necrosis. The patient's condition improved without any fluid collection or complications. LESSONS: PCD can be used in the early phase of emphysematous pancreatitis for patients who continue to deteriorate due to sepsis. This can easily be followed, if necessary, by percutaneous pancreatic necrosectomy using an ultra-slim endoscope.

Implications of the microbiome in the development and treatment of pancreatic cancer: Thinking outside of the box by looking inside the gut.

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. As one of the most lethal cancer types, the prognosis for patients diagnosed with pancreatic cancer remains dismal and novel investigations are urgently needed. Evidence for an association of microbes with pancreatic cancer risk, development, treatment response, and post-treatment survivorship is rapidly developing. Herein, we provide an overview on the role of the microbiome as it relates to the natural history of pancreatic cancer, including host immune interactions, alterations in metabolism, direct carcinogenic effect, and its role in treatment response.

Peripancreatic Tuberculosis Lymphadenopathy: The Role of Endoscopic Ultrasound for Diagnosis.

Pancreatic and peripancreatic tuberculosis is a rare abdominal tuberculosis. Diagnosis for pancreatic tuberculosis can be challenging. Conventional imaging tools may show mass or malignancy in the pancreas. Endoscopic ultrasound (EUS) is an excellent tools for evaluating pancreas and peri pancreas region. It also allows us to obtain tissue sample for cytology and histopathology. Here we present a case of peripancreatic tuberculosis lymphadenopathy that mimic pancreatic mass. His symptoms were also nonspecific (weight loss, epigastric pain, and irregular fever). From EUS evaluation we found that there was no mass but multiple lymphadenopathy around the pancreas and then performed FNA. The result of the cytology was granuloma inflammation and caseous necrosis which is compatible with tuberculosis infection. From this case illustration we conclude that EUS is an important diagnostic tool for pancreatic lesion to avoid unnecessary surgery.

P. gingivalis Lipopolysaccharide Stimulates the Upregulated Expression of the Pancreatic Cancer-Related Genes Regenerating Islet-Derived 3 A/G in Mouse Pancreas.

Although epidemiological studies have shown a relationship between periodontal disease and pancreatic cancer, the molecular mechanisms involved remain unclear. In this study, the effects of systemic administration of Porphyromonas gingivalis lipopolysaccharide (PG-LPS) on gene expression were comprehensively explored in mouse pancreas that did not demonstrate any signs of inflammation. PG-LPS was prepared in physiological saline and intraperitoneally administered to male mice at a concentration of 5 mg/kg every 3 days for 1 month. After extracting total RNA from the excised mice pancreas, a comprehensive DNA microarray analysis of gene expression was performed. Tissue specimens were also subjected to hematoxylin-eosin staining and immunohistochemistry using anti-regenerating islet-derived 3A and G (Reg3A/G) antibody. ImageJ software was used to quantify the area of Reg3A/G positive cells in pancreatic islets by binarizing image date followed by area extraction. The results were compared using Mann-Whitney U test. Data are presented as mean ± standard deviation (SD) with p < 0.05 considered as significant. Reg3G, a gene related to pancreatic cancer, was one of the 10 genes with the highest levels of expression in the pancreas stimulated with PG-LPS. The comprehensive analysis revealed a 73-fold increase in Reg3G expression level in the PG-LPS group when compared with the control group; in addition, the expression level of Reg3A was increased by 11-fold in the PG-LPS group. Image analysis showed that the ratio of Reg3A/G positive cells was higher in the PG-LPS group than the control. Immunostaining showed the presence of Reg3A/G-positive cells in the alpha-cell equivalent areas around the islets of Langerhans in the PG-LPS group. These results support the notion that periodontal disease may be a risk factor for pancreatic cancer.

The microbiome in pancreatic diseases: Recent advances and future perspectives.

The human microbiota exerts multiple physiological functions such as the regulation of metabolic and inflammatory processes. High-throughput sequencing techniques such as next-generation sequencing have become widely available in preclinical and clinical settings and have exponentially increased our knowledge about the microbiome and its interaction with host cells and organisms. There is now emerging evidence that microorganisms also contribute to inflammatory and neoplastic diseases of the pancreas. This review summarizes current clinical and translational microbiome studies in acute and chronic pancreatitis as well as pancreatic cancer and provides evidence that the microbiome has a high potential for biomarker discovery. Furthermore, the intestinal and pancreas-specific microbiome may also become an integrative part of diagnostic and therapeutic approaches of pancreatic diseases in the near future.

Novel Discoveries Targeting Pathogenic Gut Microbes and New Therapies in Pancreatic Cancer: Does Pathogenic E. coli Infection Cause Pancreatic Cancer Progression Modulated by TUBB/Rho/ROCK Signaling Pathway? A Bioinformatic Analysis.

Pancreatic cancer (PC) is a pernicious cancer of the digestive system which remains a high degree of malignancy. Increasing studies demonstrated that regulating the gut microbiome may become a brand new strategy to improve the therapeutic outcomes of PC. This study is aimed at obtaining the pathway in the microbial tumorigenesis of PC. Microarray datasets GSE27890, GSE46234, and GSE17610 were downloaded from the GEO (Gene Expression Omnibus) database. Differential analysis was performed for every single gene chip using the R software package ("Limma" package), and functional enrichment analyses were carried out by DAVID (Database for Annotation, Visualization and Integrated Discovery). The PPI (protein-protein interaction) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING). The survival analysis was performed by GEPIA and USCS. A total of 84 differentially expressed genes (DEGs) were identified, and 3 of them were extracted (TUBB, TUBA4A, and TLR5). Biological process analysis revealed that these 3 genes were mainly enriched in pathogenic Escherichia coli (E. coli) infection. Survival analysis and pathway analysis revealed that TUBB (tubulin, beta class I) may be associated with the pathogenic E. coli infection, which may be involved in the carcinogenesis and progression of PC by activating the TUBB/Rho/ROCK signaling pathway. Elevated evidence indicated that a specific gut microbe could affect the progression of PC by suppressing immune response. However, little attention has been paid to the relationship and crosstalk between TUBB/Rho/ROCK signaling, microbes, and PC. This article is aimed at deducing that gut and tumor microbes are related to the development of PC by stimulating TUBB/Rho/ROCK signaling, while ablation of microbes by antibiotics cotreated with inhibitors of TUBB/Rho/ROCK signaling were identified as a novel target for PC therapy.

Emphysematous Pancreatitis in the Elderly.

BACKGROUND: Emphysematous pancreatitis (EP) is an unusual medical emergency that presents with intraparenchymal pancreatic air in the setting of necrotizing infection. We aimed to determine the differences in the epidemiology, etiology, clinical presentation, symptoms and outcome of EP between elderly and nonelderly patients. MATERIALS AND METHODS: A PubMed search was performed using the keywords "emphysematous pancreatitis," "gas-forming pancreatitis" and "pancreatitis and pneumoperitoneum" from March 1959 to February 2019. Forty-two EP articles with 58 patients were enrolled in our study. We divided the patients into ≥65 (elderly, n = 25) and <65-year age groups (non-elderly, n = 33). Data on patient age, sex, comorbidities, symptoms, clinical findings, etiologies, laboratory results, treatments, outcomes and mortality were collected and analyzed using the Student's t test and chi-square test using IBM SPSS 20. P values < 0.05 (2-tailed) indicated statistical significance. RESULTS: Alcohol- and biliary pancreatitis-related EP were 4.95- and 4-fold, respectively, more frequent in the elderly than in the nonelderly (36% versus [vs.] 9.1%, P < 0.05). Fever was more frequent in the nonelderly than in the elderly (69.7% vs. 36%, P < 0.05). The elderly presented with more severe shock status (68% vs. 33.3%, P < 0.05) and received more surgical interventions than the nonelderly (60% vs. 30.3%, P < 0.05). CONCLUSIONS: Biliary pancreatitis is the most common type of EP in the elderly and has an atypical presentation with less fever, more severe shock, and more surgical interventions. In treating elderly patients with pancreatitis, immediate administration of adequate antibiotics, assisted drainage and early surgical intervention are needed to prevent shock.

Pancreatic tuberculosis: A systematic review of symptoms, diagnosis and treatment.

INTRODUCTION: Although pancreatic tuberculosis (TB) is traditionally considered to be a rare clinical entity, in recent times, an increase in the number of reports of pancreatic TB has been noted. We conducted a systematic review in order to summarise currently available data on pancreatic TB. METHODS: A comprehensive literature search of Medline, Scopus and ISI Web of Science databases was conducted in order to identify papers reporting cases of pancreatic TB. The eligibility criteria for inclusion in the review required that the studies reported patient(s) affected by pancreatic TB and that individual data on age, sex, clinical presentation and outcome were available. RESULTS: In total, 116 studies reporting data on 166 patients were included in the analysis. The majority of patients were males (62.1%) diagnosed at a mean age of 41.61 ± 13.95 years. Most cases were diagnosed in Asia (50.0%), followed by North America (22.9%), Europe (20.5%), Africa (4.2%) and South America (2.4%). Human immunodeficiency virus (HIV) infection was diagnosed in 25.3% of those affected. Pancreatic TB most frequently presented itself in the form of a pancreatic mass (79.5%) localised mainly in the head (59.0%) and less frequently in the body (18.2%) and tail (13.4%). Extrapancreatic TB involvement most frequently affected the peripancreatic lymph nodes (47.3%). More than half of patients (55.2%) were subjected to laparotomy, while 21.08% underwent endoscopic ultrasound fine-needle aspiration biopsy. The presence of TB was identified most frequently through histological analysis (59.6%), followed by culture (28.9%), staining (27.7%) and, in a smaller number, by polymerase chain reaction (9.6%) and cytology (6.6%). Almost all patients received anti-tubercular pharmacological therapy (98.2%), while 24.1% underwent surgery. Despite treatment, 8.7% of patients died. CONCLUSION: Increased awareness of pancreatic TB is needed, not only in endemic areas but especially in relation to HIV infection and other clinical conditions associated with immunoincompetence.

Microbiota in pancreatic health and disease: the next frontier in microbiome research.

Diseases intrinsic to the pancreas such as pancreatitis, pancreatic cancer and type 1 diabetes mellitus impart substantial health and financial burdens on society but identification of novel mechanisms contributing to these pathologies are slow to emerge. A novel area of research suggests that pancreatic-specific disorders might be modulated by the gut microbiota, either through a local (direct pancreatic influence) or in a remote (nonpancreatic) fashion. In this Perspectives, we examine literature implicating microorganisms in diseases of the pancreas, specifically pancreatitis, type 1 diabetes mellitus and pancreatic ductal adenocarcinoma. We also discuss evidence of an inherent pancreatic microbiota and the influence of the intestinal microbiota as it relates to disease association and development. In doing so, we address pitfalls in the current literature and areas of investigation that are needed to advance a developing field of research that has clinical potential to reduce the societal burden of pancreatic diseases.

Microbiology of pancreatoduodenectomy and recommendations for antimicrobial prophylaxis.

BACKGROUND: The microbiology of pancreatoduodenectomy is challenging and published guidelines regarding perioperative antimicrobial prophylaxis are variable with poor adherence. METHODS: A retrospective analysis of the microbiological results of 294 consecutive patients who underwent pancreatoduodenectomy was performed. Intraoperative specimen culture results were available for 50 patients and their medical records were reviewed to determine the following demographics and factors; age; sex; tumour location, histopathology, grade and stage; neoadjuvant chemotherapy and radiotherapy; preoperative biliary stenting; surgeon; surgery type and antimicrobial prophylaxis coverage. Outcomes assessed included; post-operative infections, mortality (all and 90-day), and intensive care unit and hospital admission durations. Univariate analysis with chi-squared testing was performed. RESULTS: Intraoperative specimen cultures were positive in 48 (96%) patients and polymicrobial in 45 (90%) patients with a predominance of Enterobacteriaceae (38/76%), Enterococcus species (27/54%), and Candida species (25/50%). Isolates were potentially susceptible to the current perioperative antimicrobial prophylaxis regimen of ceftriaxone with or without metronidazole in only six patients. However, only neoadjuvant radiotherapy was associated with statistically significant increased intensive care unit and hospital admission durations. CONCLUSION: Although this study was probably underpowered to detect any statistically significant associations, perioperative antimicrobial prophylaxis coverage of the operative field microbiological milieu of pancreatoduodenectomy is logical and current guidelines may be inadequate.

Predrainage and Postdrainage Prognostic Nomograms to Predict Outcome of Percutaneous Drainage for Infected Pancreatic and Peripancreatic Necrotic Collections.

OBJECTIVES: This study aimed to identify factors affecting outcome of percutaneous catheter drainage (PCD) in management of infected pancreatic necrosis treated with step-up approach. METHODS: This was a single-center retrospective cohort study that included patients with infected necrosis undergoing PCD as initial intervention. Patients who did not respond underwent necrosectomy. Predictors of PCD failure (ie, mortality or need for necrosectomy) were analyzed. Models were constructed for predrainage and postdrainage use and were internally validated. RESULTS: Of 304 patients included, catheter drainage was successful in 59.8%, with overall mortality of 22%. Predrainage model consisted of Acute Physiologic and Chronic Health Evaluation II score at admission, early organ failure, and pancreatic necrosis of greater than 50%. Postdrainage model consisted of Acute Physiologic and Chronic Health Evaluation II at first PCD, early organ failure, pancreatic necrosis of greater than 50%, sepsis reversal within 1 week of PCD and Escherichia coli in PCD culture. Both models were internally validated with area under receiver operating characteristics curve of 71.2% for pre-PCD and 81.2% for post-PCD model. Prognostic nomograms were constructed using the models. CONCLUSIONS: Percutaneous catheter drainage alone was successful in 59.8% with mortality of 22%. The nomograms can help in guiding treatment strategy and referral of high-risk cases.

An endoscopic or minimally invasive surgical approach for infected necrotizing pancreatitis: a systematic review and meta-analysis

Background and aim: the incidence of acute pancreatitis is rising across the world, thus further increasing the burden on healthcare services. Approximately 10% of patients with acute pancreatitis will develop infected necrotizing pancreatitis (INP), which is the leading cause of high mortality in the late phase. There is currently no consensus with regard to the use of endoscopic or minimally invasive surgery as the first-line therapy of choice for INP. However, more clinical research with regard to the superiority of an endoscopic approach has been recently published. Therefore, we conducted a systematic review and meta-analysis to determine which of the two treatments leads to a better prognosis. Methods: four databases (Medline, SINOMED, EMBASE and Cochrane Library) were searched for eligible studies from 1980 to 2018, comparing endoscopic and minimally invasive surgery for INP. Results: two randomized controlled trials (RCTs) and seven clinical cohort studies were included. After the analysis of data amenable to polling, significant advantages were found in favor of the endoscopic approach in terms of pancreatic fistulas (OR = 0.10, 95% CI 0.04-0.30, p < 0.001) and the length of hospital stay (weighted mean difference [WMD] = -24.72, 95% CI = -33.87 to -15.57, p < 0.001). No marked differences were found in terms of mortality, multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, recurrence of pseudocysts, and length of stay (LOS) in the Intensive Care Unit (ICU), endocrine insufficiency and exocrine insufficiency. Conclusion: compared with minimally invasive surgery, an endoscopic approach evidently improved short-term outcomes for infected necrotizing pancreatitis, including pancreatic fistula and the length of hospital stay. Furthermore, relevant multicenter RCTs are eager to validate these findings

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Is Moxifloxacin a Treatment Option for Pancreatic Infections? A Pharmacometric Analysis of Serum and Pancreatic Juice.

Postoperative local infection is a major complication after pancreatic surgery. The aim of this prospective clinical trial was to assess the potential of moxifloxacin (MXF) to treat pancreatic infections from a pharmacokinetic (PK)/pharmacodynamic (PD) perspective. The PK of MXF in serum and pancreatic juice, via an inserted tube in the pancreatic duct, was determined in 19 patients up to day 7 after pancreatoduodenectomy. PK data in both specimens was analyzed with NONMEM 7.3. Intraoperative swipes were performed for microbiological examination. PK/PD target attainment was assessed in both matrices using unbound area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) targets of ≥30 and ≥100, for gram-positive and gram-negative pathogens, respectively. A 2-compartment population PK model in which the measurements in pancreatic juice were assigned to a scaled peripheral compartment best described the PK in both specimens simultaneously. Median (10th-90th percentile) area under the plasma concentration-time curve values after the third dose were 28.9 mg · h/L (18.6-42.0) in serum and 55.8 mg · h/L (23.7-81.4) in pancreatic juice. Target attainment rate for the intraoperatively isolated bacterial strains was ≥0.88 after the third MXF dose. For gram-negatives, high probability of target attainment ≥0.84 was observed in serum for MIC ≤ 0.125 mg/L and in pancreatic juice for MIC ≤ 0.25 mg/L. For gram-positives, the probability of target attainment was 0.84-1 in serum for MIC ≤ 0.5 mg/L and in pancreatic juice for MIC ≤ 1 mg/L. In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies.