Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Simple Preoperative Imaging Measurements Predict Postoperative Pancreatic Fistula After Pancreatoduodenectomy.

OBJECTIVE: Postoperative pancreatic fistula is a potentially devastating complication after pancreatoduodenectomy (PD). The purpose of this study was to identify features on preoperative computed tomography (CT) imaging that correlate with an increased risk of postoperative pancreatic fistula (POPF). METHODS: Patients who underwent PD at our high-volume pancreatic surgery center from 2019 to 2021 were included if CT imaging was available within 8 weeks of surgical intervention. Pancreatic neck thickness (PNT), abdominal wall thickness (AWT), and intra-abdominal distance from pancreas to peritoneum (PTP) were measured by two board-certified radiologists who were blinded to the clinical outcomes. Radiographic measurements, as well as preoperative patient characteristics and intraoperative data, were assessed with univariate and multivariable analysis (MVA) to determine risk for clinically relevant POPF (CR-POPF, grades B and C). RESULTS: A total of 204 patients met inclusion criteria. Median PTP was 5.8 cm, AWT 1.9 cm, and PNT 1.3 cm. CR-POPF occurred in 33 of 204 (16.2%) patients. MVA revealed PTP > 5.8 cm (odds ratio [OR] 2.86, p = 0.023), PNT > 1.3 cm (OR 2.43, p = 0.047), soft pancreas consistency (OR 3.47, p = 0.012), and pancreatic duct size ≤ 3.0 mm (OR 4.55, p = 0.01) as independent risk factors for CR-POPF after PD. AWT and obesity were not associated with increased risk of CR-POPF. Patients with PTP > 5.8 cm or PNT > 1.3 cm were significantly more likely to suffer a major complication after PD (39.6% vs. 22.3% and 40% vs. 22.1%, p < 0.008). CONCLUSIONS: Patients with a thick pancreatic neck and increased intra-abdominal girth have a heightened risk of CR-POPF after pancreatoduodenectomy, and they experience more serious postoperative complications. We defined a simple CT scan-based measurement tool to identify patients at increased risk of CR-POPF.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Early experience with robotic central pancreatectomy with patient-reported outcomes and comparison with open central pancreatectomy.

BACKGROUND: Robotic central pancreatectomy (CP) has emerged in recent years as a noninferior approach to open CP and may offer improved patient-reported outcomes and reduction in incisional hernias. METHODS: All patients who underwent open and robotic CP between (2013 and 2022) were selected, and perioperative outcomes were analyzed. Patients who underwent robotic CP were interviewed over the phone to assess patient-reported postoperative outcomes. RESULTS: A total of 18 CP operations (56%-open vs. 44%-robotic) were identified. The overall median age was 67 years (interquartile range: 60-72), and 50% (n = 9) of patients were female. Median length of surgery was statistically longer for robotic CP (411 vs. 138 min, p = 0.002); all other intraoperative variables were similar. Postoperatively, a similar number of patients in the open and robotic cohorts developed clinically significant postoperative pancreatic fistulas (37.5% vs. 30%, p = 1) and major complications (37.5% vs. 20%, p = 0.60), respectively. No patients in the robotic cohort developed an incisional hernia, compared to 40% (n = 4) in open (p = 0.08). All patients returned to a baseline level of activity and reported a high quality of life. CONCLUSION: With the exception of longer operative times, robotic CP is a noninferior, definitive resection technique for select lesions of the middle pancreas. Additionally, the robotic approach may result in a reduction in incisional hernia development.

Robotic versus laparoscopic gastrectomy for adenocarcinoma in the US: a propensity score-matching analysis of 11,173 patients on oncological adequacy.

INTRODUCTION: Surgery remains the cornerstone treatment for gastric cancer. Previous studies have reported better lymphadenectomy with minimally invasive approaches. There is a paucity of data comparing robotic and laparoscopic gastrectomy in the US. Herein, we examined whether oncological adequacy differs between laparoscopic and robotic approaches. METHODS: The National Cancer Database was utilized to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2019. A propensity score-matching analysis between robotic gastrectomy (RG) versus laparoscopic gastrectomy (LG) was performed. The primary outcomes were lymphadenectomy ≥ 16 nodes and surgical margins. RESULTS: A total of 11,173 patients underwent minimally invasive surgery for gastric adenocarcinoma between 2010 and 2019. Of those 8320 underwent LG and 2853 RG. Comparing the unmatched cohorts, RG was associated with a higher rate of adequate lymphadenectomy (63.5% vs 57.1%, p < .0.0001), higher rate of negative margins (93.8% vs 91.9%, p < 0.001), lower rate of prolonged length of stay (26.0% vs 29.6%, p < .0.001), lower 90-day mortality (3.7% vs 5.0%, p < 0.0001), and a better 5-year overall survival (OS) (56% vs 54%, p = 0.03). A propensity score-matching cohort with a 1:1 ratio was created utilizing the variables associated with lymphadenectomy ≥ 16 nodes. The matched analysis revealed that the rate of adequate lymphadenectomy was significantly higher for RG compared to LG, 63.5% vs 60.4% (p = 0.01), respectively. There was no longer a significant difference between RG and LG regarding the rate of negative margins, prolonged length of stay, 90-day mortality, rate of receipt of postoperative chemotherapy, and OS. CONCLUSIONS: This propensity score-matching analysis with a large US cohort shows that RG was associated with a higher rate of adequate lymphadenectomy compared to LR. RG and LG had a similar rate of negative margins, prolonged length of stay, receipt of postoperative chemotherapy, 90-day mortality, and OS, suggesting that RG is a comparable surgical approach, if not superior to LG.

Pancreatobiliary Maljunction-associated Gallbladder Cancer Is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-induced Reflux-associated Physio-chemical Carcinogenesis.

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 US 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 (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.

Pancreatic ductal adenocarcinomas associated with intraductal papillary mucinous neoplasms (IPMNs) versus pseudo-IPMNs: relative frequency, clinicopathologic characteristics and differential diagnosis.

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.

Implications of leukocytosis following distal pancreatectomy splenectomy (DPS) and association with postoperative complications.

BACKGROUND: Early identification of complications after distal pancreatectomy splenectomy (DPS) poses challenges, as white blood cell count (WBC) is confounded by physiologic leukocytosis. We examined WBC patterns associated with complications after DPS. METHODS: Clinicopathologic data were collected for patients who underwent DPS in our system from 2009 to 2016. We examined WBC, temperature, platelet count (PC), and ratios of these variables as potential early indicators of patients at risk of infections or major complications (MCs). RESULTS: 348 patients met study inclusion, of whom 206 (59%) were women and the median patient age was 59 ± 15 years. Infectious and MC rates were 11% and 16%, respectively, with <1% 30-day mortality. Postoperative WBC peaks were higher in patients with infections and MCs compared with no complication (23 vs. 17, p < 0.0001). WBC peak timing occurred postoperative day (POD) 2-3 for uncomplicated cases while peaks occurred POD9 for patients with infections and MCs. DISCUSSION: These data define patterns of leukocytosis following DPS. Although differences in infection markers were identified for patients with and without complications, no obvious thresholds were identified. Clinical suspicion for complications after DPS remains our best tool for early identification.

The aborted Whipple: Why, and what happens next?

BACKGROUND: For patients with periampullary adenocarcinoma (PAC), pancreatoduodenectomy (PD) provides the best survival. Surgery on a subset of patients is aborted during PD. We analyzed these patients. METHODS: Patients who underwent laparotomy for planned PD for PAC were identified (2006-2019). From operative notes, we identified the subset with intraoperative decision to abort. Patient, treatment, and outcome data were analyzed. The subset with pancreatic ductal adenocarcinoma (PDAC) was analyzed for survival. RESULTS: Only 6.7% (n = 55/819) of cases were aborted. Majority 78% (n = 43) had pathologically-confirmed diagnoses at time of surgery, and 18.2% (n = 10) received preoperative chemotherapy. Reasons for aborted PD included: distant metastases (65.5%, n = 36) and local invasion (34.5%, n = 19). Of patients with metastatic disease, 75% (n = 27) had liver metastases. Eighty-nine percent (n = 49) of patients underwent at least one palliative bypass procedure and 81.8% (n = 45) had both gastric and biliary bypass. Patients with computed tomography (CT) scans before surgery more commonly had missed metastatic disease (79.2% CT compared to 54.8% magnetic resonance imaging [MRI], χ2 = 3.54, p = 0.059). In PDAC, 61.4% (n = 27/44) were aborted for metastatic disease and 38.7% (n = 17/44) for local invasion. Median overall survival for all PDAC patients after aborted PD was 334 days. CONCLUSION: Majority of pancreatoduodenectomies for periampullary adenocarcinoma are done to completion. Liver metastases is the most common reason for aborting. Preoperative MRI may help identify hepatic metastases.

Surgical resection for adrenocortical carcinoma: Current trends affecting survival.

INTRODUCTION: Adrenocortical carcinoma (ACC) is associated with a poor prognosis. We reviewed the National Cancer Database (NCDB) to analyze the prognostic factors in surgically resected ACC patients and the association of surgical approaches with overall survival (OS). METHODS: A retrospective NCDB (2004-2014) review of patients undergoing curative-intent surgical resection for ACC was performed. Effects of patient demographics, tumor characteristics, histopathology, and perioperative course on OS were analyzed. Log-rank statistics were used to associate clinical variables with OS. The multivariable Cox proportional hazard model included only statistically significant variables. RESULTS: A total of 1599 patients with ACC were included. A majority of patients were female (60.73%) and presented with a Charlson-Deyo score of zero (75.42%). A majority of the ACC cases were Grade 3 (45.69%), and almost a third (30.64%) underwent margin-positive resections. Univariate analysis demonstrated a decrease in OS associated with increasing age and comorbidities. A negative resection margin and lack of lymphovascular invasion predicted better OS. Multivariable analysis showed that age, grade, surgical resection margins, and hospital length of stay were associated with OS. CONCLUSIONS: Advanced age, grade, presence of lymphovascular invasion, and positive surgical margins predicted a worse overall survival for adrenocortical cancer in our analysis. Resection with negative margins improves outcomes.

Narcotic sparing postoperative analgesic strategies after pancreatoduodenectomy: analysis of practice patterns for 1004 patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Counting the cost: financial implications of complications following pancreaticoduodenectomy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 surgery >240 minutes and male sex were associated with significantly increased costs. CONCLUSION: 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.

Relationship between Cancer Diagnosis and Complications Following Pancreatoduodenectomy for Duodenal Adenoma.

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.

Unravelling the Complexity Myth for Minimally Invasive Right Hepatectomy: Liver Parenchymal Features and their Correlation to Objective Outcomes in Major Anatomical Resections.

BACKGROUND: Minimally invasive approaches to major liver resection have been limited by presumed difficulty of the operation. While some concerns arise from mastering the techniques, factors such as tumor size and liver parenchymal features have anecdotally been described as surrogates for operative difficulty. These factors have not been systematically studied for minimally invasive right hepatectomy (MIRH). METHODS: Seventy-five patients who underwent MIRH during 2007-2016 by the senior author were evaluated; these were compared to control group of open right hepatectomy. Demographics, operative, and post-operative variables were collected. Operative times and estimated blood loss, two objective parameters of operative difficulty were correlated to volume of hepatic resection, parenchymal transection diameter and liver parenchymal features using regression analysis. RESULTS: Thirty-eight (50.6%) resections were performed for malignant indications. Average tumor size was 5.7 cm (±3.6), mean operative time was 196 min (±74), and mean EBL was 220 mL (±170). Average transection diameter was 10.1 cm (±1.7). There was no correlation between operative difficulty with parenchymal transection diameter or presence of steatosis. Blood loss was higher with increased right hepatic lobe volume and body mass index. CONCLUSIONS: This analysis of a very defined anatomical resection suggests that the often quoted radiographic and pathologic features indicative of a challenging procedure were not significant in determining operative difficulty.

Aortic Aneurysm Natural Progression is Not Influenced by Concomitant Malignancy and Chemotherapy.

BACKGROUND: Aortic aneurysms occur concomitantly with malignancy in approximately 1.0-17.0% of patients. There is little published information regarding the effects of subsequent oncological therapies on aortic aneurysm growth. The aim of this study was to determine the effects of chemoradiation therapies on the natural progression of small abdominal aortic aneurysm (AAA), thoracic aortic aneurysm, and thoracoabdominal aortic aneurysm. METHODS: Patients with aortic aneurysms with and without malignancy between 2005 and 2017 were identified within institutional databases using Current Procedural Terminology and International Classification of Disease codes. Inclusion criteria included complete chemotherapy documentation, a minimum of 3 multiplanar axial/coronal imaging or ultrasonography before, during, and after receiving therapy or 2 studies for patients without malignancy. Propensity matching, Cox and linear regression, and Kaplan-Meier survival analyses were performed. RESULTS: A total of 159 (172 aneurysms) patients with malignancy and 127 (149 aneurysms) patients without malignancy were included. Average patient demographics were 74.4 ± 9.8-years-old, Caucasian (66.8%), male (70.3%), with hypertension (71.1%), current smoking (24.5%), coronary atherosclerotic disease (26.2%), and AAA (71.0%). The most common malignancy was lung cancer (48.4%) with most chemotherapy regimens including a platinum-based alkylating agent and concurrent antimetabolite (56.0%). The overall median follow-up time was 28.2 (range 3.1-174.4) months. Aortic aneurysms in patients without malignancy grew to larger sizes (4.43 ± 0.96 vs. 4.14 ± 1.00, P = 0.008) with similar median growth rates (0.12 vs. 0.12 cm/year, P = 0.090), had more atypical morphologic features (14.1% vs. 0.6%, P < 0.001), more frequently underwent repair (22.1% vs. 8.7%, P = 0.001), and more frequently required emergency repair for rupture (5.4% vs. 0.0%, P = 0.087). Cox regression identified initial aortic size ≥4.0 cm (hazard ratio [HR] 3.028), AAA (HR 2.146), chronic aortic findings (3.589), and the use of topoisomerase inhibitors (HR 2.694). Linear regression demonstrated increased growth rates predicted by antimetabolite chemotherapy (ß 0.170), initial aortic size (ß 0.086), and abdominal aortic location (ß 0.139, all P < 0.002). CONCLUSIONS: Small aortic aneurysms with concomitant malignancies are discovered at smaller initial sizes, grow at similar rates, require fewer interventions, and have fewer ruptures and acute dissections than patients without malignancy. Antimetabolite therapies modestly accelerate aneurysmal growth, and patients receiving topoisomerase inhibitors may require earlier repair. Patients with concomitant disease can be confidently treated according to standard institutional aneurysm surveillance protocols. Overall, we recommend treatment of the malignancy before small aortic aneurysm repair as these aneurysms behave similarly to those in patients without malignancy.

Economic valuation meta-analysis of freshwater improvement in developed and developing countries. Are they different?

The quality of drinking water differs across countries, so households show different levels of willingness to pay (WTP) to improve it, which is also influenced by their income levels. This study presents a meta-analysis using studies from 30 developed and developing countries, representing 4.7 billion inhabitants. At the international level, by standardizing these values (PPP) to international US dollars of 2011, developing countries show, on average, a greater WTP than developed countries relative to their income and an inverse correlation between their water footprint and their WTP.

Fumigant toxicity and biochemical effects of selected essential oils toward the red flour beetle, Tribolium castaneum (Coleoptera: Tenebrionidae).

Tribolium castaneum Herbst (Coleoptera: Tenebrionidae) is an insect popularly known as the red flour beetle, it is widely distributed worldwide and can cause serious damage to stored grains. Chemical control is the most used method for managing this pest, however, some substances are toxic to mammals and the environment. Therefore, the development of new effective and safe insecticides is necessary. Essential oils (EOs) can be considered as a potential alternative in the development of pesticides due to their physicochemical properties and varied effects against insects. In the current study, was determined the fumigant toxicity and biochemical effects of selected essential oils against T. castaneum. The 23 selected EOs were characterized by GC-MS and their fumigant lethal concentrations were determined. An exploratory Cluster analysis was performed to find a relationship between fumigant toxicity and chemical composition. Finally, the inhibition of the catalytic activity of acetylcholinesterase (AChE), glutathione S-transferase (GST) and catalase (CAT) was evaluated using protein homogenates obtained from T. castaneum. The results indicated that EOs with the highest fumigant potential were those with greater diversity in their composition, while the least active EOs presented mainly monoterpenes. The most active EOs were those obtained from Foeniculum vulgare and Zanthoxylum monophyllum with LC50 values of 16.23 and 18.54 µL/L air respectively. Regarding the inhibition of the enzymatic activity of the 23 EOs evaluated at 500 µL/L, only two caused an inhibition greater that 50% on AChE, which corresponded to EOs from Piper nigrum and Rosmarinus officinalis. Likewise, EOs from C. sinensis, Piper aduncum and Zanthoxylum monophyllum were the only ones able to inhibiting GST activity by more than 50%. Respecting CAT inhibition, 7 EOs caused and inhibition greater than 50%, highlighting those from Lavandula angustifolia, C. sempervirens and Eucalyptus sp. These results show that the EOs evaluated in this study seems to be a promising bio-controller of T. castaneum since have high fumigant toxicity and exert different mechanisms of action.

Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated.

BACKGROUND: The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. METHODS: In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. RESULTS: MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. CONCLUSIONS: In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

Influence of margin histology on development of pancreatic fistula following pancreatoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a potentially debilitating complication following pancreatoduodenectomy (PD). There are limited data correlating pancreatic parenchymal histopathologic features specifically fat and fibrosis content with development of POPF after PD. METHODS: Patients who underwent PD (January 2010-May 2015) with archived pathologic slides were included. Each pancreatic neck transection margin was histologically graded for fat and fibrosis, scored from 0 to 4, and grader was blinded to clinical outcomes. Main pancreatic duct diameter and duct wall thickness were microscopically measured. Patients were dichotomized into high and low categories with respect to pancreatic fat and fibrosis and primary outcome of POPF. RESULTS: Of 301 patients, 24 developed POPF (8.0%). One hundred ten patients (36.5%) had low fat (score <2), and 149 (49.5%) had low fibrosis (score <2), and average duct diameter was 3.9 ± 1.3 mm. Patients with low fibrosis had a higher rate of POPF (12.8% versus 3.3%, P = 0.005). Low fibrosis (odds ratio [OR] 4.29, 95% confidence interval [CI] 1.56-11.7, P = 0.005), nonpancreatic adenocarcinoma pathology (OR 3.25, 95% CI 1.25-8.43, P = 0.02), and increased body mass index (BMI) (OR 1.11, 95% CI 1.03-1.12, P = 0.007) were associated with POPF development on univariate analysis. Low fibrosis and increased BMI remained independently associated on multivariate analysis. High fat content was frequently concurrently identified in specimens with high fibrosis (67.8%). Surgeon-described gland consistency did not correlate with histopathologic findings (Spearman's rank correlation coefficients of -0.144 and 0.304, respectively) or to incidence of POPF. No patient who underwent preoperative chemotherapy developed POPF (n = 30, 10%). CONCLUSIONS: Low pancreatic neck fibrosis content and increased patient BMI are associated with increased rates of POPF following PD, while pancreatic fat content does not appear to influence this outcome. Pancreatic neck fat and fibrosis often coexist in the same specimen. The association between preoperative chemotherapy and low POPF rates needs further examination. Frozen section analysis of pancreatic neck margin for fibrosis content may be more accurate than surgeon assessment in identifying patients at risk for POPF. These assessments can potentially guide therapeutic interventions, including selective prophylactic drain placement and use of postoperative somatostatin analog therapy.

Diabetes development after distal pancreatectomy: results of a 10 year series.

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.