Utilization of Pancreatic Endotherapy in Patients with Chronic Pancreatitis: Results From a Multicenter Cohort Study in the United States.

BACKGROUND AND AIMS: Although commonly used for treating complications of chronic pancreatitis (CP), data on the frequency and factors associated with the use of pancreatic endotherapy (PET) are limited. Our aim was to define the utilization and factors predictive for receiving PET in a well-characterized CP cohort. METHODS: This is a cross-sectional analysis of data from PROCEED, a multicenter US cohort study of CP. PET modalities primarily consisted of ERCP. A treatment course was defined as the number of sessions performed for a specific indication. A repeat course was defined as PET >1 year after completion of the last course. Multivariable logistic regression identified predictive factors for receiving PET, and proportional rates model assessed risk factors for repeat PET. RESULTS: Of a total of 681 subjects, 238 (34.9%) received PET. Factors associated with receiving PET included female sex (OR: 1.26, 95% CI: 1.03-1.53), lower education (OR: 1.30, 95% CI: 1.04-1.62), income ≤ $50,000 per year (OR: 1.35, 95% CI: 1.07-1.71) and prior acute pancreatitis (AP) (OR: 1.74, 95% CI: 1.31, 2.32). 103/238 subjects (43.3%) underwent repeat PET at a median duration of 2 years with 23.1% receiving 2 courses, 9.7% receiving 3 courses, and 10.4% receiving 4+ courses. CONCLUSIONS: Nearly half of patients with CP who undergo PET received one or more repeat courses within 2-3 years. In addition to a prior history of AP, demographic and socioeconomic factors were associated with receiving PET.

Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression.

Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. SIGNIFICANCE: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.

Peptide-based capture-and-release purification of extracellular vesicles and statistical algorithm enabled quality assessment.

Circulating extracellular vesicles (EVs) have gained significant attention for discovering tumor biomarkers. However, isolating EVs with well-defined homogeneous populations from complex biological samples is challenging. Different isolation methods have been found to derive different EV populations carrying different molecular contents, which confounds current investigations and hinders subsequent clinical translation. Therefore, standardizing and building a rigorous assessment of isolated EV quality associated with downstream molecular analysis is essential. To address this need, we introduce a statistical algorithm (ExoQuality Index, EQI) by integrating multiple EV characterizations (size, particle concentration, zeta potential, total protein, and RNA), enabling direct EV quality assessment and comparisons between different isolation methods. We also introduced a novel capture-release isolation approach using a pH-responsive peptide conjugated with NanoPom magnetic beads (ExCy) for simple, fast, and homogeneous EV isolation from various biological fluids. Bioinformatic analysis of next-generation sequencing (NGS) data of EV total RNAs from pancreatic cancer patient plasma samples using our novel EV isolation approach and quality index strategy illuminates how this approach improves the identification of tumor associated molecular markers. Results showed higher human mRNA coverage compared to existing isolation approaches in terms of both pancreatic cancer pathways and EV cellular component pathways using gProfiler pathway analysis. This study provides a valuable resource for researchers, establishing a workflow to prepare and analyze EV samples carefully and contributing to the advancement of reliable and rigorous EV quality assessment and clinical translation.

Infiltration of CD3+ and CD8+ lymphocytes in association with inflammation and survival in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins. METHODS: Tissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples. RESULTS: Our findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC. CONCLUSION: In this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment.

Heterogeneity of weight loss and transcriptomic signatures in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss. METHODS: Treatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss. RESULTS: Pancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours. CONCLUSIONS: Resectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes.

Prognosis and Treatment Outcomes of Bone Metastasis in Gallbladder Adenocarcinoma: A SEER-Based Study.

BACKGROUND: Gallbladder carcinoma (GBC) is a rare, aggressive malignancy comprising 0.5% of gastrointestinal cancers. It has poor survival outcomes due to its insidious onset, lack of standardized screening, and limited therapies. Advanced-stage diagnosis with liver, lymph node, and peritoneal metastasis is common, while bone metastasis is rare. The knowledge on bone metastasis in GBC is limited to case reports and small series, and its clinical significance is largely unexplored. METHODS: The study extracted the demographic and clinical variables of patients with metastatic (M1) gallbladder adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database between 2011 and 2020. Descriptive statistics were used to analyze the demographic characteristics. The multivariate Cox regression analysis was used to calculate the hazard ratio. The overall survival (OS) was assessed using the Kaplan-Meier method, and the log-rank test was utilized to compare the survival between the groups. RESULTS: A total of 2724 patients were included in the study. A total of 69% of the patients were female, and the median age was 68 (range 24-90+). A total of 7.4% of the patients had bone metastasis on diagnosis. The multivariate Cox analysis identified bone metastasis as an independent mortality risk factor in metastatic GBC (HR 1.50, p < 0.001). The patients were divided into two age groups: a younger age group (18-74 years) and an older age group (75+ years). In the younger group, the median OS with and without bone metastasis was 3 and 5 months, respectively (p < 0.0001). In the older age group, there was no significant difference in the OS between the patients with and without bone metastasis (p = 0.35). In the younger group who were treated with chemotherapy, the patients with bone metastasis had a significantly worse OS (median OS 5 months vs. 8 months, p < 0.0001). In the untreated group, the patients with bone metastasis in the younger age group had a significantly worse OS (median OS 1 month vs. 2 months, p = 0.014). In the patients with bone metastasis, those who did not receive chemotherapy had a significantly worse OS than those who were treated with chemotherapy in both age groups (younger age group: median OS 1 month vs. 5 months, p < 0.0001 and older age group: median OS 1 month vs. 5 months, p = 0.041). CONCLUSIONS: Our findings suggest that the presence of bone metastasis in gallbladder adenocarcinoma is an independent prognostic factor associated with unfavorable survival outcomes in the younger age group (18-74 years). However, in the older age group (75+ years), the presence of bone metastasis did not impact the survival. Treatment with chemotherapy was associated with extended survival in all patients. Thus, early detection and aggressive management of bone metastasis, including the consideration of chemotherapy, may be crucial in improving the OS and quality of life for individuals with gallbladder adenocarcinoma.

Changing Practice Patterns and Improving Survival for Patients with Pancreatic Ductal Adenocarcinoma.

Over the last two decades, there have been many reported advances in the clinical management of pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate changes in survival for patients diagnosed with PDAC between 2004 and 2017. The National Cancer Database was queried for patients diagnosed with PDAC between 2004 and 2017. There were 55,401 patients who underwent surgery and 109,477 patients who underwent non-surgical treatment for PDAC between 2004 and 2017. Patients were categorized into four groups by year of diagnosis. Median survival improved from 15.5 months to 25.3 months for patients treated with surgery between the years 2016 and 2017 compared with between 2004 and 2007 (p < 0.001). Median survival improved from 7.2 months to 10.1 months for patients treated without surgery during the same years (p < 0.001). On multivariable analysis, the hazard ratio for death was estimated to multiply by 0.975 per year for patients treated with surgery and 0.959 per year for patients treated without surgery (p < 0.001). This increase in survival in the setting of evolving care validates continued efforts aimed at improving survival for patients with this devastating disease.

A phase II study of neoadjuvant liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in pancreatic adenocarcinoma.

For patients with localized pancreatic cancer with minimal vascular involvement, optimal survivability requires a multidisciplinary approach of surgical resection and systemic chemotherapy. FOLFIRINOX is a combination chemotherapy regimen that offers promising results in the perioperative and metastatic settings; however, it can cause significant adverse effects. Such toxicity can negatively impact some patients, resulting in chemotherapy discontinuation or surgical unsuitability. In an effort to reduce toxicities and optimize outcomes, this investigation explores the safety and feasibility of substituting liposomal irinotecan (nal-IRI) for nonliposomal irinotecan to improve tumor drug delivery and potentially reduce toxicity. This regimen, NALIRIFOX, has the potential to be both safer and more effective when administered in the preoperative setting.

For patients with pancreatic cancer with little to no cancer near the blood vessels, the best life expectancy usually requires surgery and chemotherapy. FOLFIRINOX is a chemotherapy medicine that offers promising results for both patients getting surgery and for patients with widespread disease. However, it can cause harmful side effects. The side effects can be so bad that the chemotherapy has to be stopped or that surgery is no longer possible. In order to reduce the harmful side effects and improve outcomes, this investigation looks into the safety and practicality of using a different version of one of the medicines. The different version hopes to improve drug delivery and reduce harmful side effects. This regimen, NALIRIFOX, can be safer and more effective in patients awaiting surgery. Clinical Trial Registration: UF-STO-PANC-004 (NCT03483038) (ClinicalTrials.gov).

Impact of Biopsy Attempts, Race, and Access on Time to Initiation of Treatment for Pancreatic Cancer.

BACKGROUND: Biopsy of suspected pancreatic cancer (PDAC) in surgical candidates is informative however not always necessary. Biopsies impact treatment options as histological diagnosis are presently required for neo-adjuvant therapy, but not surgical resection. We explored the impact of pursuing tissue diagnosis by endoscopic ultrasound (EUS) biopsy on time to treatment in patients with resectable and borderline resectable PDAC. METHODS: A retrospective review of surgical patients with ultimately proven PDAC was performed (2011-2021). Milestone dates (cancer suspected, biopsy(ies), surgical or neo-adjuvant treatment) were collected. Mann-Whitney-Wilcoxon tests, Pearson's chi-squared tests, Fisher's exact tests, linear regressions, and Cox proportional hazard models were used for data analysis. RESULTS: Among 131 resectable and 58 borderline resectable patients, the borderline resectable group underwent more biopsies (1.2 vs 0.7, p < 0.0001), were more likely to undergo biopsy at tertiary care centers (67.2% vs 30.5%, p < 0.0001), and trended toward longer time to treatment (49 vs 44 days, p = 0.070). Significant increases in days to treatment were seen in patients with Black race (29 days, p = 0.0002) and Medicare insurance (22 days, p = 0.038) and no biopsies at a tertiary care center (10 days, p = 0.039). After adjusting for covariates, additional biopsies significantly delayed treatment (1 biopsy: 21 days, p = 0.0001; 2 biopsies: 44 days, p < 0.0001; 3 biopsies: 68 days, p < 0.0001). CONCLUSIONS: EUS biopsy significantly impacts time between suspicion and treatment of PDAC. This may be exacerbated by clinical practices increasingly favoring neo-adjuvant therapy that necessitates biopsy-proven disease. Time to treatment may also be impacted by access to tertiary centers and racial disparities.

Ethical Considerations of Biopsies in Early-Stage Pancreatic Cancer.

PURPOSE: The standard of care in resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) has evolved to include neoadjuvant treatment before surgical resection. Current guidelines call for obtaining histologic tissue diagnosis via endoscopic ultrasound fine-needle aspiration before administration of neoadjuvant therapy, which differ from guidelines discouraging delay in surgical resection for a biopsy. MATERIALS AND METHODS: Whether to proceed with treatment before a biopsy confirms that malignancy is a nuanced decision and includes considerations of physical and psychological risks entailed in both pursuing and forgoing a biopsy. RESULTS: Accuracy of imaging and biopsy results, the presence of contributing clinical signs/symptoms, and the existing precedents of considering biopsies as waivable such as in scenarios with high clinical suspicion and primary surgical resection. CONCLUSION: When considering the aspects of ethical medical practice including beneficence (doing good), nonmaleficence (avoiding harm), autonomy (allowing patients to make decisions about their care), and utilitarianism (doing the most good for the most people), analysis of whether guidelines guiding biopsies should continue to differ between resection and neoadjuvant treatments in PDAC is prudent.

A protein-based machine learning approach to the identification of inflammatory subtypes in pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: The inherently immunosuppressive tumor microenvironment along with the heterogeneity of pancreatic ductal adenocarcinoma (PDAC) limits the effectiveness of available treatment options and contributes to the disease lethality. Using a machine learning algorithm, we hypothesized that PDAC may be categorized based on its microenvironment inflammatory milieu. METHODS: Fifty-nine tumor samples from patients naïve to treatment were homogenized and probed for 41 unique inflammatory proteins using a multiplex assay. Subtype clustering was determined using t-distributed stochastic neighbor embedding (t-SNE) machine learning analysis of cytokine/chemokine levels. Statistics were performed using Wilcoxon rank sum test and Kaplan-Meier survival analysis. RESULTS: t-SNE analysis of tumor cytokines/chemokines revealed two distinct clusters, immunomodulating and immunostimulating. In pancreatic head tumors, patients in the immunostimulating group (N = 26) were more likely to be diabetic (p = 0.027), but experienced less intraoperative blood loss (p = 0.0008). Though there were no significant differences in survival (p = 0.161), the immunostimulating group trended toward longer median survival by 9.205 months (11.28 vs. 20.48 months). CONCLUSION: A machine learning algorithm identified two distinct subtypes within the PDAC inflammatory milieu, which may influence diabetes status as well as intraoperative blood loss. Opportunity exists to further explore how these inflammatory subtypes may influence treatment response, potentially elucidating targetable mechanisms of PDAC's immunosuppressive tumor microenvironment.

Translocation of Oral Microbiota into the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment.

Oral dysbiosis has long been associated with pancreatic ductal adenocarcinoma (PDAC). In this work, we explore the relationship between the oral and tumor microbiomes of patients diagnosed with PDAC. Salivary and tumor microbiomes were analyzed using a variety of sequencing methods, resulting in a high prevalence and relative abundance of oral bacteria, particularly Veillonella and Streptococcus, within tumor tissue. The most prevalent and abundant taxon found within both saliva and tumor tissue samples, Veillonella atypica, was cultured from patient saliva, sequenced and annotated, identifying genes that potentially contribute to tumorigenesis. High sequence similarity was observed between sequences recovered from patient matched saliva and tumor tissue, indicating that the taxa found in PDAC tumors may derive from the mouth. These findings may have clinical implications in the care and treatment of patients diagnosed with PDAC.

A one-pot isothermal Cas12-based assay for the sensitive detection of microRNAs.

The use of microRNAs as clinical cancer biomarkers is hindered by the absence of accurate, fast and inexpensive assays for their detection in biofluids. Here we report a one-step and one-pot isothermal assay that leverages rolling-circle amplification and the endonuclease Cas12a for the accurate detection of specific miRNAs. The assay exploits the cis-cleavage activity of Cas12a to enable exponential rolling-circle amplification of target sequences and its trans-cleavage activity for their detection and for signal amplification. In plasma from patients with pancreatic ductal adenocarcinoma, the assay detected the miRNAs miR-21, miR-196a, miR-451a and miR-1246 in extracellular vesicles at single-digit femtomolar concentrations with single-nucleotide specificity. The assay is rapid (sample-to-answer times ranged from 20 min to 3 h), does not require specialized instrumentation and is compatible with a smartphone-based fluorescence detection and with the lateral-flow format for visual readouts. Simple assays for the detection of miRNAs in blood may aid the development of miRNAs as biomarkers for the diagnosis and prognosis of cancers.

Low vs Standard-Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial.

BACKGROUND: Near-infrared fluorescence imaging using intravenous indocyanine green (ICG) facilitates intraoperative identification of biliary anatomy. We hypothesize that a much lower dose of ICG than the standard decreases hepatic and background fluorescence and improves bile duct visualization. STUDY DESIGN: In this multicenter randomized controlled trial, 55 adult patients undergoing laparoscopic cholecystectomy were randomized to low-dose (0.05 mg) or standard-dose (2.5 mg) ICG preoperatively on the day of surgery. A quantitative assessment was performed on recorded videos from the operation using ImageJ software to quantify the fluorescence intensity of the bile duct, liver, and surrounding/background fat. Operating surgeons blinded to ICG dose provided a qualitative assessment of various aspects of the visualization of the extrahepatic biliary tree comparing near-infrared fluorescence to standard visible light imaging using a scale of 1 to 5 (1, unsatisfactory; 5, excellent). Quantitative and qualitative scores were compared between the groups to determine any significant differences between the doses. RESULTS: The bile duct-to-liver and bile duct-to-background fat fluorescence intensity ratios were significantly higher for the low-dose group compared with the standard-dose group (3.6 vs 0.68, p < 0.0001; and 7.5 vs 3.3, p < 0.0001, respectively). Low-dose ICG had a slightly higher (ie better) mean score on the qualitative assessment compared to the standard dose, although the differences were not statistically significant. CONCLUSIONS: Low-dose ICG leads to quantitative improvement of biliary visualization using near-infrared fluorescence imaging by minimizing liver fluorescence; this further facilitates routine use during hepatobiliary operations.

The Impact of a Narcotic-Sparing Enhanced Recovery Protocol on Postoperative Narcotic Use Following Colectomy.

BACKGROUND: In the United States, 37% of all opioids are prescribed in the surgical setting, many of which report initial exposure in the postoperative period. OBJECTIVE: This study aimed to assess the impact of a narcotic-sparing enhanced recovery after surgery protocol on postoperative narcotic use by patients and to assess its impact on the narcotic-prescribing practices of physicians. DESIGN: Data regarding consecutive narcotic-naïve patients who underwent a surgical procedure from January 2013 to August 2017 were retrospectively reviewed. SETTINGS: Patients were divided into 2 cohorts: preimplementation (2013-2015) and postimplementation (2015-2017) of the enhanced recovery after surgery protocol. PATIENTS: This study included patients who underwent elective inpatient abdominal colorectal surgery at the University of Florida Health. MAIN OUTCOME MEASURES: The primary outcome measure was 30-day postoperative narcotic use (inpatient and outpatient). Other outcomes measured included pain scores, time to diet institution, length of hospital stay, cost of hospitalization, and postoperative complications. RESULTS: Baseline characteristics were similar between the preprotocol group (n = 537) and postprotocol group (n = 790). Protocol implementation was associated with a decrease in the total 30-day postoperative narcotic amount used by patients (2481 vs 31 morphine milligram equivalents; p = 0.05), inpatient patient-controlled analgesia use (63% vs 0.5%; p < 0.00001; dosage 1254 vs 5 morphine milligram equivalents), inpatient on-demand oral narcotic use (90% vs 32%; p = 0.001; dosage 47 vs 5 morphine milligram equivalents), and outpatient narcotic amount used (46 vs 6 morphine milligram equivalents; p = 0.001). Average pain scores were similar. LIMITATIONS: Retrospective nature of the study and possible underestimation of pre- and postoperative narcotic use. CONCLUSIONS: Implementation of a narcotic-sparing enhanced recovery after surgery protocol was associated with a decrease in both inpatient and 30-day outpatient postoperative narcotic use. Variation in resident physician prescribing practices suggests the need for ongoing education to accompany these protocols. See Video Abstract at http://links.lww.com/DCR/B936 . EL IMPACTO DE UN PROTOCOLO DE RECUPERACIN MEJORADO CON AHORRO DE NARCTICOS EN EL USO POSTOPERATORIO DE NARCTICOS DESPUS DE UNA COLECTOMA: ANTECEDENTES:En los Estados Unidos, el 37 % de todos los opioides se prescriben en el entorno quirúrgico. Entre los adictos a los narcóticos, muchos reportan una exposición inicial en el período posoperatorio.OBJETIVO:Nuestro objetivo fue evaluar el impacto de un protocolo de recuperación mejorada después de la cirugía que ahorra narcóticos en el uso de narcóticos postoperatorios por parte de los pacientes y evaluar su impacto en las prácticas de prescripción de narcóticos de los médicos.DISEÑO:Se revisaron retrospectivamente los datos de pacientes consecutivos sin tratamiento previo con narcóticos que se sometieron a un procedimiento quirúrgico colorrectal abdominal electivo para pacientes hospitalizados desde enero de 2013 hasta agosto de 2017.AJUSTE:Los pacientes se dividieron en 2 cohortes: antes de la implementación (2013-2015) y después de la implementación (2015-2017) del protocolo de recuperación mejorada después de la cirugía.PACIENTES:Pacientes de cirugía colorrectal abdominal electiva para pacientes internados en University of Florida Health.MEDIDAS DE RESULTADO PRINCIPALES:La medida de resultado primaria fue el uso de narcóticos postoperatorios de 30 días (pacientes hospitalizados y ambulatorios). Otros resultados medidos incluyeron puntuaciones de dolor, tiempo hasta la institución de la dieta, duración de la estancia hospitalaria, costo de la hospitalización y complicaciones postoperatorias.RESULTADOS:Las características iniciales fueron similares entre los grupos antes (n = 537) y después del protocolo (n = 790). La implementación del protocolo se asoció con una disminución en la cantidad total de narcóticos postoperatorios de 30 días utilizada por los pacientes (2481 mg frente a 31 mg de equivalentes de morfina, p = 0,05), uso de analgesia controlada por pacientes hospitalizados (63 % frente a 0,5 %, p < 0,00001; dosis 1254 mg frente a 5 mg), uso de narcóticos orales a demanda en pacientes hospitalizados (90 % frente a 32 %, p = 0,001; dosis de 47 mg frente a 5 mg) y cantidad de narcóticos utilizados en pacientes ambulatorios (46 mg frente a 6 mg, p = 0,001). Las puntuaciones medias de dolor fueron similares.LIMITACIONES:La naturaleza retrospectiva del estudio y la posible sub estimación del uso de narcóticos antes y después de la operación fueron limitaciones de los hallazgos del estudio.CONCLUSIÓN:La implementación de un protocolo de recuperación mejorada después de la cirugía que ahorra narcóticos se asoció con una disminución en el uso de narcóticos en el postoperatorio de pacientes hospitalizados y ambulatorios de 30 días. La variación en las prácticas de prescripción de los médicos residentes sugiere la necesidad de una educación continua que acompañe a estos protocolos. Consulte Video Resumen en http://links.lww.com/DCR/B936 . (Traducción-Dr. Mauricio Santamaria ).

Single-cell profiling of microenvironment components by spatial localization in pancreatic ductal adenocarcinoma.

Rationale: The biology of the pancreatic ductal adenocarcinoma (PDAC) is heterogenous, but how heterogenity of the tumor microenvironment contributes to disparate patient outcomes remains essentially unstudied. Methods: A strategy employing multiplex digital spatial profiling (mplxDSP) technology was employed to evaluate the nature and dynamics of microenvironment components including cancer associated fibroblasts (CAFs) and infiltrating immune cells at the single-cell level based upon their spatial relationship within the tumor. Results: We report that myofibroblasts directly adjacent to PDAC tumors comparatively overexpress genes (BATF3, IL12B, ITGB8, CD4 and IFNAR1), constructing pathways prone to stimulating an adaptive immune response. Markers of innate immune cells (Natural Killer cells, Dendritic Cells and macrophages) are predominant in CD45+ cells immediately adjacent to PDAC tumor, however, the checkpoint protein CTLA4 is also overwhelmingly expressed, fostering tolerance. Finaly, mRNA profiling of adjacent CAFs identified clusters of genes that correlate with survival. Conclusion: CAFs and leukocytes in close proximity to PDAC significantly differ from those remote from the tumor, providing insight into microenvironment influence on immune tolerance mediated through relative populations of leukocytes and subsets of CAFs and monocytes. mRNA expression profiling of CAFs adjacent to PDAC cells may hold promise for prognostication.

The oral microbiome, pancreatic cancer and human diversity in the age of precision medicine.

Pancreatic cancer is a deadly disease with limited diagnostic and treatment options. Not all populations are affected equally, as disparities exist in pancreatic cancer prevalence, treatment and outcomes. Recently, next-generation sequencing has facilitated a more comprehensive analysis of the human oral microbiome creating opportunity for its application in precision medicine. Oral microbial shifts occur in patients with pancreatic cancer, which may be appreciated years prior to their diagnosis. In addition, pathogenic bacteria common in the oral cavity have been found within pancreatic tumors. Despite these findings, much remains unknown about how or why the oral microbiome differs in patients with pancreatic cancer. As individuals develop, their oral microbiome reflects both their genotype and environmental influences. Genetics, race/ethnicity, smoking, socioeconomics and age affect the composition of the oral microbiota, which may ultimately play a role in pancreatic carcinogenesis. Multiple mechanisms have been proposed to explain the oral dysbiosis found in patients with pancreatic cancer though they have yet to be confirmed. With a better understanding of the interplay between the oral microbiome and pancreatic cancer, improved diagnostic and therapeutic approaches may be implemented to reduce healthcare disparities. Video Abstract.

The interleukin-1 axis and the tumor immune microenvironment in pancreatic ductal adenocarcinoma.

Interleukin-1 (IL-1) plays a key role in carcinogenesis and several IL-1-targeted therapeutics are under investigation for the treatment of pancreatic ductal adenocarcinoma (PDAC). We sought to broaden our understanding of how the family of IL-1 ligands and receptors impact the tumor immune landscape and patient survival in PDAC. Gene expression data and DNA methylation data for IL1A, IL1B, IL1RN, IL1R1, IL1R2, and IL1RAP was attained from The Cancer Genome Atlas (TCGA) database and cross validated using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Immune cell-type abundance was estimated using CIBERSORTx. Further confirmatory soluble protein analysis and peripheral blood immunophenotyping were performed on available tissue samples from our institution. 169 PDAC patients and 50 benign pancreatic TCGA-based samples were analyzed. IL1A (p < 0.001), IL1RN (p < 0.001), IL1R2 (p < 0.001), and IL1RAP (p = 0.006) were markedly increased in PDAC tumor tissue compared to benign pancreatic tissue. Furthermore, expression of IL1A, IL1B and IL1R1 were positively correlated with gene expression of immune checkpoints PVR, CD274, CD47, CD80, and HLA-A/B/C (p < 0.001). IL1B and IL1R1 were correlated to expression of PDCD1, CD86, CTLA4 and IDO1 (<0.001). Low expression of IL1RN (p = 0.020), IL1R2 (p = 0.015), and IL1RAP (p = 0.003) and high expression of IL1B (p = 0.031) were correlated with increased patient survival. At the protein level, IL-1ß was correlated with increased peripheral central memory CD4+ and CD8+ T-cells as well as decreased Th2 cells. These findings suggest that the IL-1 axis plays a complex and pivotal role in the host immune response to PDAC.