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Improved post-operative outcomes have been demonstrated in gastrointestinal procedures where a narcotic sparing strategy has been utilized. Data for pancreaticoduodenectomy (PD) patients is limited. This study reviews an institutional database for outcomes based on initial analgesic strategy.1004 consecutive patients who underwent PD at Emory University between 2010 and 2017, were included in the analysis. Patients were divided into groups based on primary analgesic strategy employed: epidural alone (EPI), patient controlled opiate analgesia (PCA), dual (dual-PCA/EPI) and other (non-PCA/EPI). Postoperative outcomes for each group were analyzed utilizing univariate and multivariate linear regression.448 (44.6%) patients were treated with EPI, 300 (29.9%) were given a PCA, 78 (7.8%) had dual-PCA/EPI and 178 (17.7%) had non-PCA/EPI analgesia. On univariate analysis, increased BMI (p = 0.030), PCA use (p 0.001), venous thromboembolism (VTE) (p 0.001), post-operative pancreatic fistula (POPF) (p 0.001) and Ileus/delayed gastric emptying (DGE) (p 0.001) were all correlated with increased LOS. On multivariate linear regression, VTE (b-coefficient 9.07, p = 0.004) POPF (8.846, p = 0.001), Ileus/DGE (4.464, p = 0.004) and PCA use (1.75, p = 0.003) were associated with significantly increased LOS.A primary narcotic sparing strategy is associated with a significantly reduced LOS and lower rates of Ileus/DGE. Mean opiate usage was significantly lower in the EPI and non-EPI/PCA groups.

Meningiomas are the most common type of primary brain tumor; they have a low risk for extracranial metastases, which are primarily associated with increased tumor grade. Hepatic metastases from cranial meningiomas are extremely rare, with only a paucity of cases reported in the literature and no standardized approach to management. Herein, we report a case of an incidentally discovered giant (>20 cm) metastatic meningioma to the liver treated with surgical resection 10 years following resection of a low-grade cranial meningioma. This report also highlights the use of (68Ga) DOTATATE PET/CT as the diagnostic imaging modality of choice when evaluating for meningioma metastases. To our knowledge, this report describes the largest hepatic metastasis from a cranial meningioma to undergo surgical resection in the literature.

Supplemental Figures S1-S7

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts >= 1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts >= 1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

Understanding students' development academic language skills within informational writing is only beginning to emerge. We evaluate Grade 5 and Grade 8 students' writing (in the genre of descriptive informational writing in response to a single text) to determine which metrics may be the most indicative of academic language and what role they play. The roles include contributions to writing quantity, quality, and level of narrativity. An individual differences design was used to compare several word and sentence-level features to determine the degree to which the features signal academic language at the beginning and end of middle school. Results suggest that frequency of longer words may be the most useful measure of academic language in informational writing and that several sentence-level measures may challenge our current conceptualization of quality writing. Results provide promising avenues for the measurement and assessment of academic language in writing that detects development as well as important finer grained malleable aspects of written composition.

Ion channels are potentially exploitable as pharmacological targets to treat asthma. This study evaluated the role of KCa3.1 channels, encoded by Kcnn4, in regulating the gene expression of mouse airway epithelium and the development of asthma traits. We used the ovalbumin (OVA) challenge as an asthma model in wild-type and Kcnn4−/− mice, performed histological analysis, and measured serum IgE to evaluate asthma traits. We analyzed gene expression of isolated epithelial cells of trachea or bronchi using mRNA sequencing and gene ontology and performed Ussing chamber experiments in mouse trachea to evaluate anion secretion. Gene expression of epithelial cells from mouse airways differed between trachea and bronchi, indicating regional differences in the inflammatory and transepithelial transport properties of proximal and distal airways. We found that Kcnn4 silencing reduced mast cell numbers, mucus, and collagen in the airways, and reduced the amount of epithelial anion secretion in the OVA-challenged animals. In addition, gene expression was differentially modified in the trachea and bronchi, with Kcnn4 genetic silencing significantly altering the expression of genes involved in the TNF pathway, supporting the potential of KCa3.1 as a therapeutic target for asthma.

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

The cause of most pancreatic and periampullary cancers (PAC) is unknown. Recently, anatomic variations such as pancreatobiliary maljunction have been recognized as risk factors, similar to Barrett-related gastro-esophageal cancers.Pre-operative MRI from 860 pancreatic/biliary resections, including 322 PACs, were evaluated for low-union (cystic duct joining the common hepatic duct inside of the pancreas or within 5 mm of the pancreatic border) RESULTS: Low-union, seen10% of the population, was present in 44% of PACs (73% distal bile duct/cholangiocarcinoma, 42% pancreatic head, and 34% ampullary). It was significantly lower(11%) in conditions without connection to the ductal system (thus not exposed to the ductal/biliary tract contents), namely mucinous cystic neoplasms and intrahepatic cholangiocarcinomas(p0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p0.0001).This study establishes an association between low-union and PACs, and points to an anatomy-induced chemical/bilious carcinogenesis. This may explain why most pancreas cancers are in the head. It is possible that the same chemical milieu, caused by conditions other than low-union/insertion, may also play a role in the remaining half of PACs. This opens various treatment opportunities including milieu modifications (chemoprevention), focused screening of at-risk patients, and early detection with possible corrective actions.

Existing research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system.From 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan-Meier survival curves and multivariate cox proportional regression analysis.Of 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p 0.001) and increasing age (p = 0.001) were associated with reduced survival.In contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC.

BACKGROUND. Pancreatoduodenectomy (PD) for duodenal adenoma (DA) resection may be associated with excessive surgical risk for patients with potentially benign lesions, given the absence of pancreatic duct obstruction. We examined factors associated with final malignant pathology and evaluated the postoperative course of patients with DA versus pancreatic ductal adenocarcinoma (PDAC). METHODS. We retrospectively analyzed patients with DA who underwent PD from 2008 to 2018 and assessed the accuracy rate of preoperative biopsy and factors associated with final malignant pathology. Complications for DA patients were compared with those of matched PDAC patients. RESULTS. Forty-five consecutive patients who underwent PD for DA were identified, and the preoperative biopsy false negative rate was 29. Factors associated with final malignant pathology included age over 70 years, preoperative biliary obstruction, and common bile duct diameter > 8 mm (p < 0.05). Compared with patients with PDAC (n = 302), DA patients experienced more major complications (31% vs. 15%, p < 0.01), more grade C postoperative pancreatic fistulas (9% vs. 1%, p < 0.01), and greater mortality (7% vs. 2%, p < 0.05). Propensity score matched patients with DA had more major complications following PD (32% vs. 12%, p < 0.05). CONCLUSIONS. Preoperative biopsy of duodenal adenomas is associated with a high false-negative rate for malignancy, and PD for DA is associated with higher complication rates than PD for PDAC. These results aid discussion among patients and surgeons who are considering observation versus PD for DA, especially in younger patients without biliary obstruction, who are less likely to harbor malignancy.

Resumen: Objetivo: establecer la prevalencia y la gravedad de la enfermedad periodontal en pacientes con síndrome coronario agudo sin comorbilidades, que ingresan al programa de rehabilitación cardíaca en la Fundación Clínica Shaio. Métodos: se examinaron 83 pacientes con diagnóstico de síndrome coronario agudo sin comorbilidades y los siguientes diagnósticos: angina inestable (n = 27), infarto de miocardio con elevación del segmento ST (STEMI) (n = 34) e infarto de miocardio sin elevación del segmento ST (NSTEMI) (n = 22). La prevalencia y la gravedad de la enfermedad periodontal fueron evaluadas con el índice periodontal de los Centros para el Control y la Prevención de Enfermedades (CDC). Se compararon entre los grupos índice clínico, placa, cálculo, hemorragia gingival, profundidad de sondaje y nivel de inserción clínica. Resultados: la prevalencia de enfermedad periodontal fue del 97,6% y se observó periodontitis avanzada en el 38,3%. Los pacientes con STEMI mostraron la mayor gravedad de la periodontitis. Los índices clínicos inflamatorios de la enfermedad periodontal se elevaron en todos los grupos sin diferencias significativas. El nivel de inserción clínica no mostró diferencias significativas entre las condiciones cardíacas. Sin embargo, se observó mayor porcentaje de sitios con pérdida de inserción clínica (PIC) ≥ 6 mm, y sitios con una profundidad de bolsas > 6 mm, en pacientes con STEMI. Conclusión: los pacientes con síndrome coronario agudo sin comorbilidades, que ingresaron al programa de rehabilitación cardíaca para completar su tratamiento, tuvieron alta prevalencia y gravedad de la enfermedad periodontal. Es necesario hacer énfasis en el control de la enfermedad periodontal en pacientes con enfermedad coronaria. Abstract: Objective: To determine the prevalence and severity of periodontal disease in patients with acute coronary syndrome with no comorbidities admitted to a cardiac rehabilitation programme in the Clínica Shaio Foundation, Colombia. Methods: The study included a total of 83 patients diagnosed with acute coronary syndrome with no comorbidities and the following diagnoses: unstable angina (n = 27), ST-segment elevation myocardial infarction (STEMI) (n = 34), and non-ST-elevation myocardial infarction (NSTEMI) (n = 22). The prevalence and severity of periodontal disease were evaluated using the Periodontal Index of the Centres for the Control and Prevention of Diseases. A between-group comparison was made of the clinical index, plaque, calculi, gingival bleeding, probing depth, and level of clinical attachment. Results: The prevalence of periodontal disease was 97.6%, and advance periodontitis was observed in 38.3% of subjects. The patients with a STEMI showed more severe periodontitis. The inflammatory clinical indices of periodontal disease were increased in all groups, with no significant differences being observed. There were no significant differences between clinical attachment and heart conditions. However, it was observed that there was a higher percentage of locations with a loss of clinical attachment ≥ 6 mm, and locations with bag depths > 6 mm in patients with a STEMI. Conclusion: The patients with acute coronary syndrome with no comorbidities, and who entered the cardiac rehabilitation programme to complete their treatment, had a high prevalence and severity of periodontal disease. The control of periodontal disease should be emphasised in patients with coronary disease..

Background Limited literature is available on the postoperative development of impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) following Distal Pancreatectomy (DP). We aimed to study the post-surgical clinical evolution of IGT/DM and its association with preoperative glycemic profiles of patients undergoing DP. Methods Pre- and postoperative glycemic laboratories were measured in patients undergoing DP by the senior author from 2007–2017. Multivariate risk factor analysis was performed to determine risk factors for new-onset IGT/DM after DP. Kaplan–Meier curves were constructed for development of NODM postoperatively. Results Of 216 included patients, n = 63, n = 68 and n = 85 were preoperatively diagnosed with no-diabetes (No-DM), pre-diabetes (Pre-DM), and diabetes (DM), respectively. At 2-year follow-up, n = 37, n = 80 and n = 99 were classified as No-DM, Pre-DM or DM, respectively. Pre-diabetics had a higher risk of developing postoperative dysglycemia (RR 2.230, 95% CI 1.732–2.870, p = 0.001). Preoperative OGTT>130, HbA1c >6.0, and chronic pancreatitis were risk factors for postoperative DM. Conclusion 40% of patients undergoing DP were unaware of their dysglycemic status (pre-DM or DM) pre-operatively. At 2-year follow-up, 36% non-diabetic and 57% pre-diabetic patients had developed NODM. Appropriate pre-operative diabetic assessment is warranted for all patients undergoing pancreatic resections.

Bile cultures (BC) have routinely been used to guide empiric antibiotic therapy for developing postoperative infections. The ability of BCs to predict sensitivity and resistance patterns (SRP) of site of infection cultures (SOIC) remains controversial. The aim was to assess the concordance of pathogens and SRPs between paired BC/SOICs.Medical records of consecutive patients undergoing pancreaticoduodenectomy were reviewed between 2014 and 2018. BC/SOIC pathogens and SRPs were compared on a patient-by-patient basis and concordance (K) was assessed.Common patient characteristics of 522 included patients were 65-years-old, Caucasian (75.5%), male (54.2%), malignant indication (79.3%), and preoperative biliary stent (59.0%). Overall, 275 (89.6%) BCs matured identifiable isolates with 152 (55.2%) demonstrating polymicrobial growth. Ninety-two (17.6%) SOICs were obtained: 48 and 44 occurred in patients with and without intraoperative BCs. Stents were associated with bacteriobilia (85.7%, K = 0.947, p 0.001; OR 22.727, p 0.001), but not postoperative infections (15.2%; K = 0.302, p 0.001; OR 1.428, p = 0.122). Forty-eight patients demonstrated paired BC/SOICs to evaluate. Pathogenic concordance of this group was 31.1% (K = 0.605, p 0.001) while SRP concordance of matched pathogens was 46.7% (K = 0.167, p = 0.008).Bile cultures demonstrate poor concordance with the susceptibility/resistance patterns of postoperative infections following pancreaticoduodenectomy and may lead to inappropriate antibiotic therapies.

After 43 years of dormancy, Taal Volcano violently erupted in January 2020 forming a towering eruption plume. The fall deposits covered an area of 8605 km2, which includes Metro Manila of the National Capital Region of the Philippines. The tephra fall caused damage to crops, traffic congestion, roof collapse, and changes in air quality in the affected areas. In a tropical region where heavy rains are frequent, immediate collection of data is crucial in order to preserve the tephra fall deposit record, which is readily washed away by surface water runoff and prevailing winds. Crowdsourcing, field surveys, and laboratory analysis of the tephra fall deposits were conducted to document and characterize the tephra fall deposits of the 2020 Taal Volcano eruption and their impacts. Results show that the tephra fall deposit thins downwind exponentially with a thickness half distance of about 1.40 km and 9.49 km for the proximal and distal exponential segments, respectively. The total calculated volume of erupted fallout deposit is 0.057 km3, 0.042 km3, or 0.090 km3 using the exponential, power-law, and Weibull models, respectively, and all translate to a VEI of 3. However, using a probabilistic approach (Weibull method) with 90% confidence interval, the volume estimate is as high as 0.097 km3. With the addition of the base surge deposits amounting to 0.019 km3, the volume translates to a VEI of 4, consistent with the classification for the observed height and umbrella radius of the 2020 main eruption plume. VEI 4 is also consistent with the calculated median eruption plume height of 17.8 km and sub-plinian classification based on combined analysis of isopleth and isopach data. Phreatomagmatic activity originated from a vent located in Taal Volcano’s Main Crater Lake (MCL), which contained 42 million m3 of water. This eruptive style is further supported by the characteristics of the ash grain components of the distal 12 January 2020 tephra fall deposits, consisting dominantly of andesitic vitric fragments (83–90%). Other components of the fall deposits are lithic (7–11%) and crystal (less than 6%) grains. Further textural and geochemical analysis of these tephra fall deposits contributes to better understand the volcanic processes that occurred at Taal Volcano, one of the 16 Decade Volcanoes identified by the International Association of Volcanology and Chemistry of the Earth’s Interior (IAVCEI) because of its destructive nature and proximity to densely populated areas. The crowdsourcing initiative provided a significant portion of the data used for this study while at the same time educating and empowering the community to build resilience.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is refractory to immunotherapy due in part to cellular cross-talk with cancer associated fibroblasts (CAFs). These interactions shape the microenvironment in a manner that is profoundly immunosuppressive. Our group is identifying novel targets in the PDAC stroma that can be manipulated to enhance immunotherapy efficacy. We hypothesize dysregulation of the serine protease, CD26/DPP4 in PDAC contributes to the limited efficacy of immunotherapy. Further, we posit targeting CD26 enzymatic activity using inhibitors that are FDA-approved for adult patients with Type 2 Diabetes Mellitus can enhance the efficacy of immunotherapy in PDAC.MethodsPrimary CAFs isolated from patient PDAC resection specimens under an IRB-approved protocol, were subject to NanoString analysis.1 CD26 protein expression was measured in primary and immortalized CAFs and PDAC cells by immunoblot, flow cytometry and immunofluorescence, while ELISA detected soluble CD26. For in vivo efficacy, luciferase-expressing KPC-tumor cells were implanted orthotopically in the pancreas of immune-competent C57BL/6 mice. Bioluminescence imaging (BLI) confirmed established tumors and mice were randomized to sitagliptin (75 mg/kg in drinking water, CD26/DPP4 inhibitor), anti-PD-L1 Ab (200 ug 2x/week), or both combined for 3 weeks. Controls received vehicle or isotype control Ab. BLI utilized to track tumor progression and tissues harvested for analysis at study endpoint (day 18 of treatment).ResultsNanoString analysis identified CD26/DPP4 as significantly upregulated in RNA transcripts from primary CAFs vs. fibroblasts from normal pancreas (figure 1). We confirmed abundant CD26 expression on patient-derived CAFs and immortalized CAF cell lines, however, lower CD26 expression was observed on human PDAC cell lines (HPAC, PANC-1) by immunoblot, flow cytometry and immunofluorescence (figure 5).Abstract 904 Figure 1(A) Schema for analysis of transcript from n=10 primary CAFs (PSC) from PDAC patients vs. normal human pancreatic fibroblasts (HPPFC) via NanoString nCounter PanCancer Immune Profiling Panel. (B) Heat map of gene expression with upregulate DPP4 or CD26 transcript detected. Adapted from Mace et al., 2016.Abstract 904 Figure 2Validation of CD26 protein expression in human PDAC-derived CAF and PDAC cell lines by immunoblot analysisAbstract 904 Figure 3Analysis of surface human CD26 expression in PBMCs, PDAC-derived CAFs (h-iPSC-PDAC-1), and PDAC cells (PANC-1) by flow cytometry. Histograms representing human surface CD26 expressionAbstract 904 Figure 4Immunofluorescence analysis of CD26/DPP4 cellular localization in a human PDAC-derived CAF cell lineAbstract 904 Figure 5Combined Sitagliptin and PD-L1 blockade in a murine orthotopic model of PDAC. Fold change in tumor volume, determined by BLI, comparing baseline (Day 0 of treatment) to Day 18 of treatment. Each bar represents fold change in BLI determined tumor volume for each animalConclusionsOur results are the first to describe CD26 expression on PDAC-derived CAFs and indicate that sitagliptin augments anti-tumor activity of anti-PD-L1 in PDAC tumor-bearing mice. Our ongoing work will provide insight into specific immune cell populations responsible for efficacy of immunotherapy in murine models of PDAC, and the role of CD26 in various cellular compartments within the PDAC microenvironment.ReferencesMace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, Nordquist E, Cruz-Monserrate Z, Yu L, Young G, Zhong X, Zimmers TA, Ostrowski MC, Ludwig T, Bloomston M, Bekaii-Saab T, Lesinski GB. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 2018;67(2):320–32.

Morbidity after pancreaticoduodenectomy (PD) has been reported to be about 30-53%. These complications can double hospital costs. We sought to explore the financial implications of complications after PD in a large institutional database.A retrospective analysis of patients undergoing PD from 2010-2017 was performed. Costs for index hospitalization were divided into categories: operating room, postoperative ward, radiology and interventional radiology. Complications were categorized according to the Clavien-Dindo classification. Univariable and mutivariable analysis were performed.Median cost of index admission for 997 patients who underwent PD was $23,704 (range $10,988-$528,531). Patients with major complications incurred significantly greater median costs compared to those without ($40,005 vs $21,306, p 0.001). Patients with postoperative pancreatic fistula (POPF) grade A, B and C had progressively increasing costs ($32,164, $50,264 and $102,013, p 0.001). On multivariable analysis ileus/delayed gastric emptying, respiratory failure, clinically significant POPF, thromboembolic complications, reoperation, duration of surgery240 minutes and male sex were associated with significantly increased costs.Complications after PD significantly increase hospital costs. This study identifies the major contributors towards increased cost post-PD. Initiatives that focus on prevention of complications could reduce associated costs and ease financial burden on patients and healthcare organizations.

After 43 years of repose, Taal Volcano erupted on 12 January 2020 forming hazardous base surges. Using field, remote sensing (i.e. UAV and LiDAR), and numerical methods, we gathered primary data to generate well-constrained observed information on dune bedform characteristics, impact dynamic pressures and velocities of base surges. This is to advance our knowledge on this type of hazard to understand and evaluate its consequences and risks. The dilute and wet surges traveled at 50-60 ms−1 near the crater rim and decelerated before making impact on coastal communities with dynamic pressures of at least 1.7 kPa. The base surges killed more than a thousand livestock in the southeast of Taal Volcano Island, and then traveled another ~ 600 m offshore. This work is a rare document of a complete, fresh, and practically undisturbed base surge deposit, important in the study of dune deposits formed by volcanic and other processes on Earth and other planets.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts ≥1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts ≥1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

The current SARS-CoV-2 pandemic is a historical event that has come to change the way of life for humanity; where the population is the main subject of cause and solution. Considering the global variation of propagation, each country has taken different positions, decisions and resources where the time for making different decisions has also been an important factor. In Mexico, the SARS CoV-2 situation has been confronted mainly with government decisions and the actions of the population. The successes or failures have impacted various dimensions of society in each of the states that make up the country. In this research, some impacted life dimensions are analyzed: Social, mental, educational, economic and environmental. It is possible to say that the impact of the pandemic were influenced, among other aspects; by the state of health and nutrition associated with the lifestyle in which the population was at the arrival of the pandemic. This impact is also influenced by commercial activities, which are linked to the economic mobility of those who buy and those who sell. Also, other aspects that have influenced the impact of this pandemic; it is possible to highlight the lack of culture on the part of the population in the use of face masks and the non-obligatory use of it by the leaders. This, added to various other factors, have had a great impact on the number of infected cases and deaths in the country; primarily in Mexico City and the State of Mexico. It is worth mentioning that, despite the negative impact due to the pandemic, there are also positive aspects. Finally, it is possible to say that it is necessary for the population to develop more awareness. The population has a definitive role in containing the pandemic and to incorporate the new changes, in its life in order to precisely preserve.

The endangered yellow-spotted river turtle (Podocnemis unifilis) has experienced a dramatic population decline in the Ecuadorian Amazonia, mainly due to overexploitation of its eggs. To reverse this trend, the Wildlife Conservation Society has developed a head-start program in Yasuní National Park since 2008, but the potential risk that microbes associated with its eggs might represent for hatching success has not been evaluated yet. Members of the Fusarium solani species complex (FSSC) are involved in egg failure in sea turtles under natural and hatchery conditions, but their role in infecting the eggs of P. unifilis is unknown. In this study, we collected eggshells of P. unifilis and obtained 50 fungal and bacterial isolates. Some potentially pathogenic fungi of the genera Fusarium, Penicillium and Rhizopus were identified based on molecular data. Most importantly, the sea turtle pathogenic species F. keratoplasticum not only was present, but it was the most frequently found. Conversely, we have also isolated other microorganisms, such as Pseudomonas or Phoma-like species, producing a wide spectrum of antifungal compounds that may have a protective role against fungal diseases. Our survey provides useful information on potential pathogens found in P. unifilis eggshells, upon which the success of conservation programs may depend., This research was funded by the Real Jardín Botánico (Spanish National Research Council, CSIC), and the MS program “Biodiversity and its Conservation in Tropical Areas” of the Menéndez Pelayo International University-CSIC.

OBJECTIVE To determine the associations of pancreatobiliary maljunction (PBM) in the West. BACKGROUND PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBC), attributed to reflux of pancreatic enzymes. METHODS Radiologic images of 840 patients in the U.S. who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan. RESULTS Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (

Background Both pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) have yet to widely benefit from T cell-targeted immunotherapy and have universally poor prognoses. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in preclinical models of PDAC.1 Mechanistically, Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade. Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic and colorectal cancers. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy. Methods During the phase II portion, PDAC or mCRC patients (n=16 each) were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies were obtained at baseline and at week two on treatment. A comprehensive panel of immunologic correlatives studies is being conducted to examine treatment-induced alterations in the tumor microenvironment and peripheral blood. Results As of August 23rd, 2020, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 15 patients (n=7 PDAC and n=8 mCRC). These specimens underwent single cell mass cytometry (CyTOF) analysis to assess immunophenotypic markers of T and myeloid cells. Using this approach, we have generated a comprehensive view of the immune landscape at baseline and following treatment. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. In addition to these correlative studies, using immortalized and primary CAF from PDAC patients, we have shown XL888 dampens production of IL-6 and other cytokines in vitro. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore also being assessed. Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients. Trial Registration This clinical trial is underway and registered with the ID NCT03095781. Ethics Approval The study was approved by Emory University’s Ethics Board, approval IRB00087397. Reference Zhang Y, Ware MB, Zaidi M, Ruggieri AN, Olson B, Komar H, Farren MR, Nagaraju GP, Zhang C, Chen Z, Sarmiento J, Ahmed R, Maithel SK, El-Rayes BF, Lesinski GB. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. Molecular Cancer Therapeutics 2020.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

BackgroundDifferent perspectives exist regarding the clinicopathologic characteristics, biology and management of gallbladder polyps. Size is often used as the surrogate evidence of polyp behavior and size of ≥1cm is widely used as cholecystectomy indication. Most studies on this issue are based on the pathologic correlation of polyps clinically selected for resection, whereas, the data regarding the nature of polypoid lesions from pathology perspective -regardless of the cholecystectomy indication- is highly limited.MethodsIn this study, 4231 gallbladders -606 of which had gallbladder carcinoma- were reviewed carefully pathologically by the authors for polyps (defined as ≥2 mm). Separately, the cases that were diagnosed as "gallbladder polyps" in the surgical pathology databases were retrieved.Results643 polyps identified accordingly were re-evaluated histopathologically. Mean age of all patients was 55 years (range: 20-94); mean polyp size was 9 mm. Among these 643 polyps, 223 (34.6%) were neoplastic: I. Non-neoplastic polyps (n = 420; 65.4%) were smaller (mean: 4.1 mm), occurred in younger patients (mean: 52 years). This group consisted of fibromyoglandular polyps (n = 196) per the updated classification, cholesterol polyps (n = 166), polypoid pyloric gland metaplasia (n = 41) and inflammatory polyps (n = 17). II. Neoplastic polyps were larger (mean: 21 mm), detected in older patients (mean: 61 years) and consisted of intra-cholecystic neoplasms (WHO's "adenomas" and "intracholecystic papillary neoplasms", ≥1 cm; n = 120), their "incipient" version (ConclusionsApproximately a third of polypoid lesions in the cholecystectomies (regardless of the indication) prove to be neoplastic. The vast majority of (90%) of polyps ≥1 cm and virtually all of those ≥2 cm are neoplastic confirming the current impression that polyps ≥1 cm ought to be removed. However, this study also illustrates that 30% of the neoplastic polyps are

Issue Decline in cervical cancer (CC) worldwide is attributed to coverage of screening programs, but there are barriers to achieve universal care and adherence, such as geographical accessibility, language, lack of knowledge and shame for the procedure. Description In indigenous populations barriers are stronger due to beliefs, customs and language. In multi-ethnic countries, it is necessary to use public health strategies that allow approaching communities by respecting their culture. This work proposed a strategy that respects cultures, strengthens community self-management and give sustainability to a CC prevention program. A study of Participatory Action Research with intercultural approach was done with five ethnic groups in a reserve of Colombian Amazon. It was approved by Research Ethics Committee, indigenous authorities and participating women. Indigenous female leaders participated in all phases of the project: 1) Training in qualitative research, ethics and CC; 2)ethnographic research for identifying beliefs and practices on sexuality, gender relations and attitudes towards western medicine and cytology; 3)educational campaign in ancestral languages; 4)training in CC prevention program to promote adherence, sustainability and self-management. Preliminary Results No beliefs or practices were found that could be negatively affected by the CC western screening program. Women's attitudes towards cytology are positive as long as it is carried out by female professionals, accompanied by female indigenous leaders and speaking their own languages. Lessons Womeńs leadership and reflection on health and prevention of CC were strengthened. Indigenous identity was reinforced and the gap in domination relationships by western culture reduced. A favorable setting for CC screening program was built with a culturally safe practice. In a few months screening campaign will start and it is expected that women feel more interested in their own health and comfortable to attend. Key messages Intercultural health prevention programs may be successful when focus on culturally safe practices through the involvement of local indigenous leaders. Cytology perception is positive in indigenous women as long as it is carried out by female professionals, accompanied by female indigenous leaders and speaking their own language.

UltimaGoldTM AB and OptiphaseTrisafe are two liquid scintillators made by Perkin Elmer and EG & G Company respectively. Both are commercially promoted as scintillation detectors for α and β particles. In this work, the responses to γ-rays and neutrons of UltimaGoldTM AB and OptiphaseTriSafe liquid scintillators, without and with reflector, have been measured aiming to use these scintillators as γ-rays and neutron detectors. Responses to γ-rays and neutrons were measured as pulse shape spectra in a multichannel analyzer. Scintillators were exposed to gamma rays produced by 137Cs, 54Mn, 22Na and 60Co sources. The response to neutrons was obtained with a 241AmBe neutron source that was measured to 25 and 50 cm from the scintillators. The pulse height spectra due to gamma rays are shifted to larger channels as the photon energy increases and these responses are different from the response due to neutrons. Thus, UltimaGoldTM AB and OptiphaseTrisafe can be used to detect γ-rays and neutrons.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were >= 1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

BACKGROUND The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). METHODS A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. RESULTS A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring

PD-1 targeted therapy has dramatically changed advanced cancer treatment. However many questions remain, including specificity of T cells activated by PD-1 therapy and how peripheral blood analysis correlates to effects at tumor sites. In this study, we utilized TCR sequencing to dissect the composition of peripheral blood CD8 T cells activated upon therapy, comparing it with tumor-infiltrating lymphocytes. We report on a nonagenarian melanoma patient who showed a prominent increase in peripheral blood Ki-67+ CD8 T cells following brain stereotactic radiation and anti-PD-1 immunotherapy. Proliferating CD8 T cells exhibited an effector-like phenotype with expression of CD38, HLA-DR and Granzyme B, as well as expression of the positive costimulatory molecules CD28 and CD27. TCR sequencing of peripheral blood CD8 T cells revealed a highly oligoclonal repertoire at baseline with one clonotype accounting for 30%. However, the majority of dominant clones - including a previously identified cytomegalovirus-reactive clone - did not expand following treatment. In contrast, expanding clones were present at low frequencies in the peripheral blood but were enriched in a previously resected liver metastasis. The patient has so far remained recurrence-free for 36 months, and several CD8 T cell clones that expanded after treatment were maintained at elevated levels for at least 8 months. Our data show that even in a nonagenarian individual with oligoclonal expansion of CD8 T cells, we can identify activation of tumor-infiltrating CD8 T cell clones in peripheral blood following anti-PD-1-based immunotherapies.