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Health care facilities represent a significant source of pollution, contributing to the growing problems associated with global warming. The resulting climate change impacts our health through worsening air and water quality, diminished access to nutritious food, and safe shelter. We outline here the not only the role of the surgeon in contributing to climate change, but also ways in which to minimize one's carbon footprint. Surgeons are leaders within healthcare systems. Adopting environmentally conscious practices can reduce solid waste, energy usage, and carbon emissions. Practices outside of the clinical setting can also incorporate sustainability, including the use of virtual recruitment and educational programs, as well as thoughtful and conscientious travel practices. Academic surgery combines clinical practice with an element of leadership, at all levels. Our recognition and action to reduce wasteful practices can help leave a better earth for generations to come. [ABSTRACT FROM AUTHOR]

The aggressive nature and metastatic potential of pancreatic cancer (PC) results in poor prognosis and high mortality. A better understanding of the underlying biology of PC and the ability of tumor cells to spread to distant sites is needed to advance the treatment of PC. The chemokine receptor CXCR4 has been heavily implicated in the spread and mobility of many solid cancers based on its role in cancer cell chemotaxis as well as increased metastatic potential. To better elucidate CXCR4's role in the metastatic spread of PC, we examined its expression on various tumor associated cells (TACs) in the peripheral blood of PC patients, including circulating tumor cells (CTCs), epithelial to mesenchymal transition cells (EMTs), and cancer associated macrophage-like cells (CAMLs). In this pilot study, blood samples were procured from 30 PC patients prior to the start of therapeutic intent. CXCR4 expression was analyzed on TACs captured from the blood samples and evaluated in relation to cell migration as well as patient clinical outcomes. In total, CTCs, EMTs, and CAMLs were found in 27%, 60%, and 97% of PC patients, respectively. High CXCR4 expression in CTCs, CAMLs, and EMTs was found to significantly relate to their increased numbers in circulation. Further, higher expression of CXCR4 in CAMLs and EMTs was significantly related to faster progression and worse survival. These data suggest that CXCR4 expression in PC is strongly related to the intravasation and presence of TACs into circulation, as well as being a possible biomarker for aggressive metastatic disease. [ABSTRACT FROM AUTHOR]

The altered anatomy in patients after bariatric surgery who have undergone a Roux-en-Y gastric bypass may pose a technical challenge for surgical removal of the pancreatic head. We treat patients with pancreas cancer with multimodality therapy in a neoadjuvant fashion followed by pancreaticoduodenectomy (PD). In patients with Roux-en-Y gastric bypass anatomy, the gastric remnant is preserved and used for pancreaticogastrostomy reconstruction and subsequently drained by the same jejunal limb used for the hepaticojejunostomy. This method of reconstruction takes advantage of the previous surgically altered anatomy and avoids the morbidity of a gastric remnant resection at the time of PD. [ABSTRACT FROM AUTHOR]

Historically, the clinical staging of pancreatic cancer has centered on the surgical management of the primary tumor, because few effective chemotherapeutic agents were available and long-term survival was only achieved in the context of surgical resection. Such a strategy of complete oncologic surgical care is reasonable when surgery is both the principal therapy and highly effective. However, complex surgery for pancreatic cancer--often performed in older patients after a lengthy period of induction therapy--can be associated with significant morbidity and mortality. The majority of patients with pancreatic cancer present either locally advanced or metastatic disease at the time of diagnosis. In this article, we will discuss the role of multimodality management of patients with borderline resectable and locally advanced pancreatic cancer. Considering that surgery has a modest impact on the natural history of pancreatic cancer in most patients, a neoadjuvant approach to treatment sequencing is favored for patients with borderline resectable pancreatic cancer, and this same rationale has been extended to select patients with locally advanced disease who demonstrate an exceptional response to induction therapy. [ABSTRACT FROM AUTHOR]

In pancreatic cancer, as with many other solid tumors, a commonly held surgical adage--a chance to cut is a chance to cure--has been promulgated throughout the years. Following such reasoning, surgical extirpation of a localized tumor would prevent tumor dissemination and metastatic tumor progression. However, decades of surgical experience have demonstrated that surgical resection alone provides a limited median survival benefit. Despite the optimization of surgical technique and perioperative management over the past three decades, little progress has been made to improve the limited survival of patients with localized pancreatic cancer who receive surgery. In this article, we discuss the rationale for a novel management strategy for patients with resectable pancreatic cancer, which may improve patient selection and the delivery of multimodality therapy. [ABSTRACT FROM AUTHOR]

Purpose Neoadjuvant chemoradiation is an alternative to the surgery-first approach for resectable pancreatic cancer (PDA) and represents the standard of care for borderline resectable (BLR). Materials and methods All patients with resectable and BLR PDA treated with neoadjuvant chemoradiation using IMRT between 1/2009 and 11/2011 were reviewed. Patients were treated to a customized CTV which included the primary mass and regional vessels. Results Neoadjuvant chemoradiation was completed in 69 patients (39 BLR and 30 resectable). Induction chemotherapy was used in 32 (82%) of the 39 patients with BLR disease prior to chemoXRT. All resectable patients were treated with chemoXRT alone. Following neoadjuvant treatment, 48 (70%) of the 69 patients underwent successful pancreatic resection with 47 (98%) being margin negative (RO). In 30 of the BLR patients who had arterial abutment or SMV occlusion, 19 (63%) were surgically resected and all had RO resections. The cumulative incidence of local failure at 1 and 2 years was 2% (95% CI 0–6%) and 9% (95% CI 0.6–17%) respectively. The median overall survival for all patients, patients undergoing resection, and patients without resection were 20, 26 and 11 months respectively. Sixteen (23%) of the 69 patients are alive without disease with a median follow-up of 47 months (36–60). Conclusion Neoadjuvant chemoXRT can facilitate a margin negative resection in patients with localized PCa. [ABSTRACT FROM AUTHOR]

Background: Resection of the superior mesenteric vein (SMV)-portal vein (PV)-splenic vein (SV) confluence during pancreatectomy for pancreatic cancer requires management of the SV. Discussion: Simple SV ligation can result in sinistral portal hypertension if the inferior mesenteric vein (IMV) enters the confluence and is thereby resected, or if the IMV is insufficient to drain the SV. We describe herein three patients whose clinical course confirms the importance of the IMV decompressing the SV to avoid sinistral hypertension. [ABSTRACT FROM AUTHOR]

Objective Topical latanoprost 0.005% is commonly used in dogs with primary angle closure glaucoma ( PACG), and marked miosis has been reported in the literature. To further explore the effect of topical latanoprost on anterior segment anatomy, we performed iridocorneal angle biometrics in normal beagle dogs. Methods Thirty-five normal female beagle dogs were assessed using anterior segment optical coherence tomography ( AS- OCT). One eye of each dog was scanned with the AS- OCT in the superotemporal quadrant. One drop of latanoprost 0.005% was applied topically, and the OCT scan was repeated 30 min later. Images were imported into ImageJ, and pupil diameter, anterior chamber angle, angle opening distance, angle recess area (ARA), anterior chamber hemifield, and anterior chamber depth were measured. Results A single drop of latanoprost resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. The anterior segment parameters demonstrated a significant reduction ( P-value ≤ 0.001) from baseline following latanoprost with the exception of the ARA ( P = 0.07). Conclusions Latanoprost significantly decreases pupil diameter and narrows the iridocorneal angle in normal female beagle dogs. Therefore, the utility of latanoprost as a prophylactic treatment for PACG in fellow eyes may be limited. Studies using quantitative iridocorneal angle measurements in goniodysgenic dogs are warranted to understand the changes in iridocorneal angle morphology that occur in PACG in response to topical application of latanoprost. [ABSTRACT FROM AUTHOR]

Objective Gonioscopy provides limited quantitative information to compare the iridocorneal anatomy across different species. In addition, the anatomic relationships by histologic examination are altered during processing. As a result, the comparative anatomy of the iridocorneal angle across several mammalian species was evaluated by Optical Coherence Tomography (OCT). Methods Cats, beagle dogs, minipigs, owl monkeys, cynomolgus monkeys, and rhesus monkeys (n = 6 or 7 per species) were evaluated. Imaging was performed using the OCT. The anterior chamber angle (ACA), angle opening distance (AOD), and the angle recess area (ARA) were evaluated. Results AC angle: cat (63 ± 6°) > owl monkey (54 ± 4°) > beagle dog (42 ± 4°) > minipig (40 ± 3°) > rhesus monkey (36 ± 1°) > cynomolgus monkey (34 ± 2°). AOD: cat (3.3 ± 0.5 mm) > owl monkey (2.05 ± 0.2 mm) > beagle dog (1.08 ± 0.1 mm) > rhesus monkey (0.92 ± 0.06 mm) > minipig (0.64 ± 0.04 mm) > cynomolgus monkey (0.43 ± 0.03 mm). ARA: cat (3.5 ± 0.1 mm2) > owl monkey (1.41 ± 0.2 mm2) > dog (0.88 ± 0.1 mm2) > rhesus monkey (0.62 ± 0.06 mm2) > minipig (0.21 ± 0.05 mm2) > cynomolgus monkey (0.15 ± 0.01 mm2). Conclusions This study benchmarks the normative iridocorneal angle measurements across different mammalian species by OCT. These data can be useful to compare iridocorneal angle measurements in disease states as OCT evolves as a common diagnostic tool in veterinary ophthalmic research and practice. [ABSTRACT FROM AUTHOR]

Introduction Episcleral venous pressure (EVP) has an important role in intraocular pressure (IOP) homeostasis and accounts for more than 70% of the IOP in the normal dog. A frequently used species in glaucoma research is the normotensive dog especially when evaluating the efficacy of prostaglandin analogues and prostamides; however, aqueous humor dynamic studies in normal dogs are lacking, and the effect of 0.005% latanoprost on canine EVP is not known. We sought to determine the effects to the EVP of topically applied 0.005% latanoprost in the normotensive beagle dog. Methods Female beagle dogs ( n = 14) were used and each had a normal ophthalmic examination on study entry. EVP was determined using a standard episcleral venomanometer. Animals were dosed in one eye with 0.005% latanoprost, and the effects on EVP were compared with the averaged baseline EVP's determined in the predosing phase and the fellow nondosed eye. The Mixed Model Repeated Measures method was used to analyze the EVP data. Results During the dosing phase of the study with topical 0.005% latanoprost, the mean EVPs of dosed eyes were significantly higher than that of nondosed eyes ( P < 0.0001). Conclusions The increase in EVP in the dog with exposure to topical 0.005% latanoprost has not been observed in other species that have been studied, such as in the mouse and in humans, where the drug had no significant effect on the EVP. This response may be unique to dogs and suggests that dogs may not fully mimic human aqueous humor dynamics with topical 0.005% latanoprost. Although frequently performed in human studies, EVP should not be regarded to be a constant value in aqueous humor dynamic studies in the normal beagle dog. [ABSTRACT FROM AUTHOR]

Objective Female dogs have approximately twice the risk of males for developing primary angle closure glaucoma (PACG). The cause of this gender difference is unknown, but one theory proposes that the gender differences in iridocorneal angle morphology are involved in this risk differential. Procedures Fifty beagles (25 males, 25 females) were included into this study and had normal baseline ophthalmic examinations. Normal dogs were selected so as to avoid any potentially confounding influence of goniodysgenesis. Standardized 20-MHz high-resolution ultrasound images of the iridocorneal angle were acquired from one eye of each dog with the scan plane perpendicular to the limbus in the superior temporal quadrant. Images were imported into ImageJ, and the angle opening distance (AOD) and angle recess area (ARA) were measured by a masked observer, and the analysis of variance method was used to compare differences. Results The mean (±SD) AOD was significantly smaller for female dogs (0.847 ± 0.241 mm) vs. male dogs (1.058 ± 0.322 mm) P-value = 0.012. The mean (±SD) ARA tended to be smaller for female dogs (0.584 ± 0.278 mm) vs. male dogs (0.748 ± 0.385 mm), but this difference was not significant ( P-value = 0.092). Conclusions Female dogs have a significantly smaller AOD vs. males. This difference may render the female iridocorneal angle more susceptible to closure and may partially explain the 2:1 female/male predisposition to PACG. Further studies using goniodysgenic dogs are warranted. [ABSTRACT FROM AUTHOR]

Background: Alagille syndrome is a multi-system developmental disorder associated with paucity of interlobular bile ducts and cholestasis, rarely associated with hepatocellular carcinoma. Associated syndromic co-morbidities may complicate surgical management. As such, we herein review the modern management of a large hepatocellular carcinoma in an adult patient with Alagille syndrome and review the literature of adult Alagille patients with hepatocellular carcinoma.Case Presentation: A 29-year-old woman with a history of Alagille syndrome was referred with biopsy-proven 12 × 8 cm hepatocellular carcinoma replacing her right liver. Biopsy of the contralateral liver demonstrated findings consistent with Alagille syndrome, but no underlying cirrhosis. CT volumetrics demonstrated a future liver remnant of 40%. Extensive hematologic and cardiac work-up was performed pre-operatively, given the syndrome's associated bleeding dyscrasias and cardiac abnormalities. The patient underwent a margin-negative right hepatectomy using the "hanging" technique through a thoracoabdominal approach. The patient developed a transient hyperbilirubinemia but no hepatic insufficiency and did well post-operatively.Conclusion: Since Alagille syndrome affects multiple organ systems, preoperative evaluation of cardiac, hematologic, and hepatic function should be considered. This case illustrates the peri-operative management of an Alagille patient, and highlights several key technical points that contributed to a successful resection. [ABSTRACT FROM AUTHOR]

Background: To examine the effect of body mass index (BMI) on clinicopathologic factors and long-term survival in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma.Methods: Data on BMI, weight loss, operative details, surgical pathology, and long-term survival were collected on 795 patients who underwent pancreaticoduodenectomy. Patients were categorized as obese (BMI > 30 kg/m(2)), overweight (BMI 25 to <30 kg/m(2)), or normal weight (BMI < 25 kg/m(2)) and compared using univariate and multivariate analyses.Results: At the time of surgery, 14% of patients were obese, 33% overweight, and 53% normal weight. Overall, 32% of patients had preoperative weight loss of >10%. There were no differences in operative times among the groups; however, higher BMI was associated with increased risk of blood loss (P < 0.001) and pancreatic fistula (P = 0.01). On pathologic analysis, BMI was not associated with tumor stage or number of lymph nodes harvested (both P > 0.05). Higher BMI patients had a lower incidence of a positive retroperitoneal/uncinate margin versus normal weight patients (P = 0.03). Perioperative morbidity and mortality were similar among the groups. Obese and overweight patients had better 5-year survival (22% and 22%, respectively) versus normal weight patients (15%; P = 0.02). After adjusting for other prognostic factors, as well as preoperative weight loss, higher BMI remained independently associated with improved cancer-specific survival (overweight: hazard ratio, 0.68; obese: hazard ratio, 0.72; both P < 0.05).Conclusion: Obese patients had similar tumor-specific characteristics, as well as perioperative outcomes, compared with normal weight patients. However, obese patients undergoing pancreaticoduodenectomy for pancreatic cancer had an improved long-term survival independent of known clinicopathologic factors. [ABSTRACT FROM AUTHOR]

PURPOSE: To update the American Society of Clinical Oncology (ASCO)-Oncology Nursing Society (ONS) standards for antineoplastic therapy administration safety in adult and pediatric oncology and highlight current standards for antineoplastic therapy for adult and pediatric populations with various routes of administration and location. METHODS: ASCO and ONS convened a multidisciplinary Expert Panel with representation of multiple organizations to conduct literature reviews and add to the standards as needed. The evidence base was combined with the opinion of the ASCO-ONS Expert Panel to develop antineoplastic safety standards and guidance. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: The standards presented here include clarification and expansion of existing standards to include home administration and other changes in processes of ordering, preparing, and administering antineoplastic therapy; the advent of immune effector cellular therapy; the importance of social determinants of health; fertility preservation; and pregnancy avoidance. In addition, the standards have added a fourth verification. STANDARDS: Standards are provided for which health care organizations and those involved in all aspects of patient care can safely deliver antineoplastic therapy, increase the quality of care, and reduce medical errors. [ABSTRACT FROM AUTHOR]

Background: We sought to define surgical outcomes among elderly patients with Alzheimer's disease and related dementias (ADRD) following major thoracic and gastrointestinal surgery. Methods: A retrospective cohort study was used to identify patients who underwent coronary artery bypass grafting (CABG), abdominal aortic aneurysm (AAA) repair, pneumonectomy, pancreatectomy, and colectomy. Individuals were identified from the Medicare Standard Analytic Files and multivariable regression was utilized to assess the association of ADRD with textbook outcome (TO), expenditures, and discharge disposition. Results: Among 1,175,010 Medicare beneficiaries, 19,406 (1.7%) patients had a preoperative diagnosis of ADRD (CABG: n = 1,643, 8.5%; AAA repair: n = 5,926, 30.5%; pneumonectomy: n = 590, 3.0%; pancreatectomy: n = 181, 0.9%; and colectomy: n = 11,066, 57.0%). After propensity score matching, patients with ADRD were less likely to achieve a TO (ADRD: 31.2% vs. no ADRD: 40.1%) or be discharged to home (ADRD: 26.7% vs. no ADRD: 46.2%) versus patients who did not have ADRD (both p < 0.001). Median index surgery expenditures were higher among patients with ADRD (ADRD: $28,815 [IQR $14,333–$39,273] vs. no ADRD: $27,101 [IQR $13,433–$38,578]; p < 0.001) (p < 0.001). On multivariable analysis, patients with ADRD had higher odds of postoperative complications (OR 1.32, 95% CI 1.25–1.40), extended length‐of‐stay (OR 1.26, 95% CI 1.21–1.32), 90‐day readmission (OR 1.37, 95% CI 1.31–1.43), and 90‐day mortality (OR 1.76, 95% CI 1.66–1.86) (all p < 0.001). Conclusion: Preoperative diagnosis of ADRD was an independent risk factor for poor postoperative outcomes, discharge to non‐home settings, as well as higher healthcare expenditures. These data should serve to inform discussions and decision‐making about surgery among the growing number of older patients with cognitive deficits. [ABSTRACT FROM AUTHOR]

Purpose/Objectives: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. Materials/Methods: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18months, and survival curves were estimated using the Kaplan– Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. Results: 121 patients were included with a median age of 62 years (37–86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n=41) were alive at 12months and 25% (n=31) were alive at 18months. Landmark analysis demonstrated a significant difference between patients surviving <18months and ≥18months regarding the presence of lung only metastases (36% vs. 16%, p=0.04), number of organs with metastases (≥2 vs. 1, p=0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p=0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p=0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p=0.004), metastasis only in the liver (p=0.04), and normalization of CA 19-9 (p<0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p=0.03). In those patients that normalized their CA 19-9, median overall survival was 16months. Conclusions: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions. [ABSTRACT FROM AUTHOR]

Background: Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer.Methods: We employed organoid culture methods and flow cytometric, cytologic, immunofluorescent and immunohistochemical methods to develop and characterize patient-derived pancreatic cancer organoids and multi-cell type organotypic co-culture models of the tumor microenvironment.Results: We describe the culture and characterization of human pancreatic cancer organoids from resection, ascites and rapid autopsy sources and the derivation of adherent tumor cell monocultures and tumor-associated fibroblasts from these sources. Primary human organoids displayed tumor-like cellular morphology, tissue architecture and polarity in contrast to cell line spheroids, which formed homogenous, non-lumen forming spheres. Importantly, we demonstrate the construction of complex organotypic models of tumor, stromal and immune components of the tumor microenvironment. Activation of myofibroblast-like cancer associated fibroblasts and tumor-dependent lymphocyte infiltration were observed in these models.Conclusions: These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors in the context of T-cell infiltration. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation (LT) is the preferred treatment for early hepatocellular carcinoma (HCC) in select patients. Differences in outcomes after LT have been previously described between recipient races, but the role of donor race is not well defined. This study sought to examine the effect of donor-recipient race-matching on overall survival after liver transplantation for HCC in African-American patients (AA).Study Design: Adult AA patients with HCC undergoing liver transplantation were identified using the Organ Procurement and Transplantation Network database (1994 to 2015). Recipient and donor demographic and clinical characteristics were collected. Patients were separated into unadjusted cohorts based on whether the liver donor was AA (matched) or another race (unmatched). The primary outcome was overall survival, which was analyzed by log-rank test and graphed using the Kaplan-Meier method. Multivariate regression modeling was used to determine adjusted hazard ratios (HR) for overall survival.Results: Of 1,384 AA patients identified, 325 (23.5%) were race-matched. Matched patients experienced significantly better median overall survival when compared with the unmatched cohort (135 vs 78 months, p = 0.007). Multivariate analysis revealed an adjusted hazard ratio of 0.66 for race-matched transplantation (95% CI 0.49 to 0.88; p = 0.004). Matched patients also experienced an improved 5-year survival (64.2% vs 56.9%; p = 0.019).Conclusions: African-American HCC patients undergoing liver transplantation experienced significantly improved overall survival when the donor race matched the recipient race. Donor-recipient race-matching remained an independent predictor of improved survival after adjusting for comorbidities and disease characteristics. Race-matching should be considered in the process of organ allocation because it may affect long-term survival in African-American HCC patients. [ABSTRACT FROM AUTHOR]

Early postoperative mortality risk prediction is crucial for clinical management of gastric cancer. This study aims to predict 90-day mortality in gastric cancer patients undergoing gastrectomy using automated machine learning (AutoML), optimize models for preoperative prediction, and identify factors influential in prediction. National Cancer Database was used to identify stage I–III gastric cancer patients undergoing gastrectomy between 2004 and 2016. 26 features were used to train predictive models using H2O.ai AutoML. Performance on validation cohort was measured. In 39,108 patients, 90-day mortality rate was 8.8%. The highest performing model was an ensemble (AUC = 0.77); older age, nodal ratio, and length of inpatient stay (LOS) following surgery were most influential for prediction. Removing the latter two parameters decreased model performance (AUC 0.71). For optimizing models for preoperative use, models were developed to first predict node ratio or LOS, and these predicted values were inputted for 90-day mortality prediction (AUC of 0.73–0.74). AutoML performed well in predicting 90-day mortality in a larger cohort of gastric cancer patients that underwent gastrectomy. These models can be implemented preoperatively to inform prognostication and patient selection for surgery. Our study supports broader evaluation and application of AutoML to guide surgical oncologic care. [ABSTRACT FROM AUTHOR]

Endometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-β. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis. [ABSTRACT FROM AUTHOR]

Background Transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) remains controversial. This systematic review sought to examine the role of TACE in the treatment of HCC with PVT in either the main portal vein (MPV) or portal vein branches (PVB). Methods PubMed was searched for “hepatocellular carcinoma” and “transarterial chemoembolization” from January 1, 2006 to August 31, 2016. Cohorts treated with TACE for HCC with PVT were included. Meta-analysis of overall survival (OS), mRECIST response, and complication incidence was performed. MPV and PVB subgroups were compared. Results Of 136 search results, 13 studies with 1933 TACE patients were included. Median OS (95% CI) was eight (5–15) months. Survival rates after one, three, and five years were 29% (20%–40%), 4% (1%–11%), and 1% (0%–5%), respectively. Only 1% experienced liver failure and 18% had post-treatment complications. Patients with MPV thrombosis had worse survival than PVB patients (p < 0.001), but similar mRECIST response rates (14% vs. 16%, p = 0.238). Conclusion TACE is a safe treatment for a highly selected population of HCC patients with PVT. Despite worse survival rates compared to PVB thrombosis, PVT in the MPV should not be considered an absolute contraindication to TACE. [ABSTRACT FROM AUTHOR]

Clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) has been associated with soft gland texture and/or small pancreatic duct. We hypothesized that selective use of pancreaticogastrostomy (PG) over pancreaticojejunostomy (PJ) in those scenarios would decrease the rate of CR-POPF. Review of prospective database of all PD's performed at a single institution between 2009 and 2019 was performed. The pancreatic remnant was deemed "high risk" if soft gland and/or small duct were present. PJ was performed in 199 (147 "low-risk" and 52 "high-risk") cases, and 110 patients (all "high-risk") had a PG. Overall CR-POPF rate was 11.9% with no difference between the groups. Risk-stratified analysis within PJ group showed CR-POPF rate of 5.4% versus 36% in "low-risk" versus "high risk" scenarios, respectively; the use of PG significantly decreased CR-POPF rate (9.1%, p < 0.0001). Gastrointestinal bleeding was more likely to occur following PG than PJ. Soft gland texture and gastrointestinal bleeding were the strongest predictors of CR-POPF in PJ and PG groups, respectively. Selective use of PG after PD in "high-risk" scenarios mitigates the risk of CR-POPF. Increased rate of gastrointestinal bleeding calls for further refinement of the technique and heightened postoperative vigilance. [ABSTRACT FROM AUTHOR]

In this series of talks and the accompanying panel session, leaders from the Society of Asian Academic Surgeons discuss issues faced by Asian Americans and the importance of the role of mentors and allyship in professional development in the advancement of Asian Americans in leadership roles. Barriers, including the model minority myth, are addressed. The heterogeneity of the Asian American population and disparities in healthcare and in research, specifically as relates to Asian Americans, also are examined. [ABSTRACT FROM AUTHOR]

Palliation is a controversial indication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients with peritoneal carcinomatosis (PC) are living longer, and the roles of palliative CRS and HIPEC are increasingly challenged. The purpose of this study is to evaluate indications, morbidity, and symptom improvement from CRS/HIPEC in advanced PC. A retrospective review of patients undergoing CRS and/or HIPEC with a palliative intent at a single institution from February 2008 to February 2018 was performed. Main end points included symptom improvement, symptom-free interval, and overall survival. Two hundred and seventy seven patients were referred for CRS/HIPEC during the study period and 17 underwent 20 palliative procedures. Appendiceal (n = 6) and colorectal cancers (n = 6) were the most common malignancies. Ascites (n = 8) and bowel obstruction (n = 8) were the most common indications for intervention. The postoperative complication rate was 50% and major complication rate was 20%. Partial symptom improvement or resolution of symptoms was achieved in 18 (90%) cases. A durable symptom control at 90 d was achieved in 13 (65%) cases. The median time to symptom recurrence was 5.1 mo (interquartile range: 2-11.4), and the median overall survival was 11.6 mo (interquartile range: 3.8-28.5). Palliative CRS and/or HIPEC achieve symptom improvement in patients with advanced PC. Risk assessment and expected time to recovery from surgery remain paramount for patient selection. • Advanced peritoneal carcinomatosis (PC) can cause debilitating symptoms. • To benefit patients, palliative surgery must be safe in terms of morbidity and mortality and effective in terms of symptom relief. • In highly selected patients, palliative CRS and/or HIPEC can offer durable symptom relief. • Important factors in patient selection include patient factors, disease characteristics, and operative approach. [ABSTRACT FROM AUTHOR]

Background Ablation for ≤ 3-cm hepatocellular carcinoma ( HCC) has been demonstrated to be an effective treatment strategy. The present study sought to examine the outcomes of patients with ≤3 cm HCC after ablation versus resection. Methods Patients treated by ablation or surgical resection for ≤ 3 cm T1 HCC were identified from the National Cancer Database (2002-2011). Survival outcomes were analysed according to propensity score modelling. Results A total of 2804 patients underwent ablation ( n = 1984) or a resection ( n = 820) for solitary HCC ≤ 3 cm. Patients treated with ablation as compared with a resection had a higher frequency in alpha-fetoprotein level (AFP) elevation (46.5% versus 39.1%, P < 0.01) and the presence of cirrhosis (22.2% versus 14.5%, P < 0.01). Unadjusted overall survival ( OS) at 3 and 5 years was greater after a resection (67%, 55%) versus ablation (52%, 36%, P < 0.01). After propensity score matching, the improved overall survival (OS) was sustained among the resection cohort (5 year OS: 54% versus 37%, P < 0.001). In multivariable models, a resection was independently associated with an improved OS [hazard ratio ( HR): 0.62, 95% confidence interval (CI): 0.48-0.81; P < 0.01]. Conclusion Resection of HCC ≤ 3 cm results in better long-term survival as compared with ablation. Treatment strategies for small solitary HCC should emphasize a resection first approach, with ablation being reserved for patients precluded from surgery. [ABSTRACT FROM AUTHOR]

Background: As indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated. Methods: Sarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling. Results: Median patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA ≤ 500 mm2/m2). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade ≥3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05). Conclusions: Sarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia. [ABSTRACT FROM AUTHOR]

Objective: To identify the incidence, location, etiology, and mortality of major vascular injuries in gynecologic laparoscopy for benign indications.Data Sources: A systematic review of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and MEDLINE was conducted.Methods Of Study Selection: One thousand ninety-seven studies were screened for inclusion with 147 full-text articles reviewed. Sixty-six studies published between 1978 and 2016 met inclusion criteria, representing 197,062 surgeries. Articles that were included reported the incidence of major vascular injuries during gynecologic laparoscopy for benign indications. Exclusion criteria included surgery for gynecologic malignancy, duplicated data, case series and reports, manuscripts not in English, and studies published only as abstracts.Tabulation, Integration, and Results: Injuries to the aorta, inferior vena cava, iliac (common, external, or internal), and inferior epigastric vessels were recorded, as were injuries denoted as major but not otherwise specified. A total of 179 major vascular injuries were reported with an incidence of 0.09% (95% CI 0.08-0.10). The inferior epigastric vessels were the most commonly injured vessel (0.04%, 95% CI 0.03-0.05), comprising 48% (95% CI 40-55) of all injuries. The majority of injuries occurred during abdominal entry (82%, 95% CI 76-89), and the remainder occurred during surgical dissection (18%, 95% CI 11-24). Most injuries were recognized intraoperatively (93%, 95% CI 87-100), and approximately half (55%, 95% CI 46-63) required laparotomy for repair. Only two of the 179 major vascular injuries resulted in death, for an overall mortality rate from vascular injuries of 0.001% (95% CI 0.000-0.004).Conclusion: The incidence of major vascular injury during gynecologic laparoscopy found in this review is very low, and the vast majority of injuries did not result in death. Laparoscopy remains a safe surgical technique in relation to vascular injuries when performed for benign gynecologic disease. [ABSTRACT FROM AUTHOR]

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-Cre ERT2 knock-in mouse. When crossed to CAG-LSL-Myc T58A mice, Msi2-Cre ERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2 + pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer. [Display omitted] • Development of Msi2-Cre ERT2 knock-in mouse to express MYC in stem/progenitor cells • MSI2+ cells are cells of origin for multiple cancers such as lung, brain, and pancreas • Msi2-Myc mice form diverse pancreatic cancer subtypes from a common tumor precursor • Mapping dependencies of adenosquamous tumors identifies HMMR as a potential target Rajbhandari et al. report the development of a Msi2-Cre ERT2 mouse model which shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful framework to understand the programs that shape divergent fates in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway. [ABSTRACT FROM AUTHOR]

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) Low-union, seen <10% 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(p < 0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p < 0.0001). 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. [ABSTRACT FROM AUTHOR]

Introduction: Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown.Methods: Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining.Results: NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens.Conclusion: Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low. [ABSTRACT FROM AUTHOR]

Abstract Background The postoperative outcomes of elderly patients undergoing resection of retroperitoneal sarcomas (RPS) have not been widely studied. Methods Patients undergoing surgical resection for primary or recurrent RPS between 2000 and 2015 at participating US Sarcoma Collaborative institutions were identified. Patient demographics, perioperative morbidity, mortality, length of stay, discharge to home, disease-specific survival, and disease-free survival were compared between elderly (≥70 y, n = 171) and nonelderly (<70 y, n = 494) patients. Results There was no difference in perioperative morbidity (total and major complications elderly versus nonelderly: 39% versus 35%; P = 0.401 and 18% versus 17%; P = 0.646, respectively) or mortality between elderly and nonelderly patients with each group experiencing a 1% 30-d mortality rate. Length of stay and 30-d readmission rates were similar (elderly versus nonelderly; 7 d interquartile range [IQR: 5-9] versus 6 d [IQR: 4-9], P = 0.528 and 11% versus 12%, P = 0.667). Elderly patients were more likely to be discharged to a skilled nursing or rehabilitation facility (elderly versus nonelderly; 19% versus 7%, P < 0.001). There was no difference in 3-y disease-free survival between the elderly and nonelderly patients (41% versus 43%, P = 0.65); however, elderly patients had a lower 3-y disease-specific survival (60% versus 76%, P < 0.001). In elderly patients, the presence of multiple comorbidities and high-grade tumors were most predictive of outcomes. Conclusions Advanced age was not associated with an increased risk of perioperative morbidity and mortality following resection of RPS in this multi-institutional review. Although short-term oncologic outcomes were similar in both groups, the risk of death after sarcoma recurrence was higher in elderly patients and may be related to comorbidity burden and tumor histology. [ABSTRACT FROM AUTHOR]

Background Surgical approach may influence morbidity following hepatectomy. This study sought to compare outcomes in minimally invasive surgery (MIS), conversion from MIS to open, and planned open hepatectomy patients and analyze factors leading to conversion. Methods The 2014 National Surgical Quality Improvement Program dataset was queried for patients undergoing hepatectomy. Patients were divided into three cohorts: MIS, open, or conversion. Propensity matching was performed to compare MIS vs. conversion (3:1) and open vs. conversion (8:1). The logistic regression model was used to identify odds ratios for conversion. Results Patients undergoing conversion had a higher transfusion rate (26% vs. 9%, p < 0.001), longer length of stay (5 vs. 3 days, p < 0.001), and higher morbidity (38% vs. 18%, p < 0.001) than MIS patients. Patients who underwent conversion had similar short-term outcomes to those who had planned open procedures. Independent predictors of conversion included hypertension (OR 1.91; 95% CI 1.12–3.26) and right lobectomy (OR 20.23; 95% CI 3.74–109.35). Conclusion Patients with hypertension and those undergoing right lobectomy had a higher risk of conversion to open procedure. Conversion resulted in higher morbidity and longer length of stay compared to MIS patients, but outcomes were similar to planned open procedures. [ABSTRACT FROM AUTHOR]

Background: In patients with newly diagnosed pancreatic cancer, the classification of indeterminate liver lesions is an unanswered clinical dilemma as misclassification of these lesions can impact the assignment of clinical stage and subsequent treatment planning. Our objective was to design a standardized classification system to more accurately define the risk of malignancy in indeterminate liver lesions.Methods: In this retrospective study, patients with localized, non-metastatic pancreatic cancer were identified and pre-treatment computed tomography (CT) scans were evaluated for the presence or absence of liver lesions. Liver lesions were defined as definitely benign (1) or indeterminate (2). Indeterminate lesions were further sub-classified as either indeterminate probably benign (2B) or indeterminate possibly malignant (2M). The index liver lesion was evaluated on follow-up imaging for stability or unequivocal disease progression.Results: From 2008 to 2015, 304 patients with localized, non-metastatic pancreatic cancer were identified and 125 (41%) patients had liver lesions. Of the 125 patients, the liver lesions in 35 (28%) were classified as definitely benign and in 90 (72%) patients they were classified as indeterminate. The 90 patients with indeterminate lesions included 80 (89%) classified as indeterminate probably benign (2B) and 10 (11%) classified as indeterminate possibly malignant (2M). After a median follow-up of 56 weeks, no patient with a definitely benign lesion had metastatic disease progression of the index lesion. Of the 90 patients with indeterminate liver lesions, the index lesion progressed to unequivocal liver metastasis in 8 (9%) patients; 5 (6%) of the 80 lesions classified as indeterminate probably benign (2B), and 3 (30%) of the ten lesions classified as indeterminate possibly malignant (2M). The sensitivity of the classification system was 38% and the specificity was 91%. The positive predictive value was 30% and the negative predictive value was 94%.Conclusions: A significant proportion of patients with localized pancreatic cancer will have liver lesions identified at the time of diagnosis and most of these lesions will have indeterminate characteristics. A classification system which further stratifies indeterminate liver lesions by malignant potential can assist clinicians in determining optimal treatment plan and is associated with a high negative predictive value. [ABSTRACT FROM AUTHOR]

Background: Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown.Methods: Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN-/LN+).Results: Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN-. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN- patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21-0.70; p = 0.002) but not in LN- patients (HR 0.89; 95% CI 0.53-1.52; p = 0.68).Conclusion: Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease. [ABSTRACT FROM AUTHOR]

Background Chemotherapy regimens for intrahepatic cholangiocarcinoma ( ICC) and gallbladder adenocarcinoma ( GC) remain interchangeable; however, response rates are frequently suboptimal. Biomarkers from ICC and GC patients were interrogated to identify actionable differences with potential therapeutic implications. Methods From 2009 to 2012, pathological specimens from 217 ICC and 28 GC patients referred to Caris Life Sciences were evaluated. Specific testing by immunohistochemical analysis for 17 different biomarkers was performed. Results In the collective cohort ( n = 245), actionable targets included: 95% low thymidylate synthase (TS), 82% low ribonucleotide reductase subunit M (RMM) 1 and 74% low excision repair cross complementation group (ERCC) 1, indicating potential susceptibility to fluoropyrimidines/capecitabine, gemcitabine and platinum agents, respectively. Additional targets included TOPO1 (53.3% high, Irinotecan), MGMT (50.3% low, temozolomide), TOP2A (33% high, anthracyclines) and PGP (30.1% low, taxanes). Subgroup analysis by tumour origin demonstrated a differential biomarker expression pattern with a higher frequency of ICC tumours showing low levels of TS (99% versus 72%, P < 0.01), and RRM1 (85% versus 64%, P = 0.02) when compared with GC. Conversely a greater frequency of GC demonstrated high levels of TOPO1 (76% versus 50%, P = 0.02) versus ICC, indicating a potential increased benefit from irinotecan. Discussion Differences in the molecular profiles between ICC and GC provide evidence that the two are distinct diseases, requiring different treatment strategies to optimize a response. [ABSTRACT FROM AUTHOR]

Objectives Cell free tumor DNA (cfDNA) circulating in blood has a great potential as biomarker for cancer clinical management. The objective of this study is to evaluate if cfDNA in blood plasma is detectable in early stage lung cancer patients. Materials and methods We extracted cfDNAs and tumor tissue DNAs from 8 lung adenocarcinoma patients. We also extracted cfDNAs from 8 normal controls. To evaluate copy number variations (CNV) and identify potential mutations, we performed low pass whole genome sequencing and targeted sequencing of 50 cancer genes. To accurately reflect the tumor-associated genomic abnormality burden in plasma, we developed a new scoring algorithm, plasma genomic abnormality (PGA) score, by summarizing absolute log2 ratios in most variable genomic regions. We performed digital PCR and allele-specific PCR to validate mutations detected by targeted sequencing. Results and conclusions The median yield of cfDNA in 400ul plasma was 4.9ng (range 2.25–26.98 ng) in patients and 2.32 ng (range 1.30–2.81 ng) in controls ( p = 0.003). The whole genome sequencing generated approximately 20 million mappable sequence reads per subject and 5303 read counts per 1 Mb genomic region. Log2 ratio-based CNV analysis showed significant chromosomal abnormality in cancer tissue DNAs and subtle but detectable differences in cfDNAs between patients and controls. Genomic abnormality analysis showed that median PGA score was 9.28 (7.38–11.08) in the 8 controls and 19.50 (5.89–64.47) in the 8 patients ( p = 0.01). Targeted deep sequencing in tumor tissues derived from the 8 patients identified 14 mutations in 12 different genes. The PCR-based assay confirmed 3 of 6 selected mutations in cfDNAs. These results demonstrated that the PGA score and cfDNA mutational analysis could be useful tool for the early detection of lung cancer. These blood-based genomic and genetic assays are noninvasive and may sensitively distinguish early stage disease when combined with other existing screening strategies including low-dose CT scanning. [ABSTRACT FROM AUTHOR]

Background The prognostic value of CA19-9 in patients with pancreatic cancer ( PC) treated with neoadjuvant therapy has not been well described. Methods Pre-treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (≤35), low (36-200), moderate (201-1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery. Results Pre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post-treatment CA19-9 normalized (≤ 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group ( P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups ( P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02]. Conclusions Among patients who completed neoadjuvant therapy and surgery, pre-treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic. [ABSTRACT FROM AUTHOR]

Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis. [ABSTRACT FROM AUTHOR]

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress--induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objectives Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy ( DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). Methods Decision tree modelling compared routine DL with exploratory laparotomy ( ExLap) at the time of curative resection in resectable cancer treated with surgery first, ( SF) and borderline resectable cancer treated with NAT. Costs ( US$) from the payer's perspective, quality-adjusted life months ( QALMs) and incremental cost-effectiveness ratios ( ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay ( WtP) was US$4166/ QALM (or US$50 000/quality-adjusted life year). Results Base case costs were US$34 921 for ExLap and US$33 442 for DL in SF patients, and US$39 633 for ExLap and US$39 713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10 695/ QALM in SF and US$4158/ QALM in NAT patients. Conclusions The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT. [ABSTRACT FROM AUTHOR]

Background Concerns for morbidity after a pancreaticoduodenectomy ( PD) has led to practitioners adopting endoscopic resection or ampullectomy in the treatment of T1 ampullary cancer ( AC). It was hypothesized that survival for patients undergoing local resection of AC was inferior to those undergoing a PD. Methods All the data of patients with AC reported in the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2010 were collected. Five-year survival rates according to nodal disease and histological type were compared. Results There were 1916 cases of AC; 421 (22%) had T1 disease. Among those with T1 disease, 217 (51%) received endoscopic surveillance, 21 (5%) underwent local resection/ampullectomy, 20 (5%) underwent ampullectomy with regional lymphadenectomy and 163 (39%) underwent PD. For patients with complete nodal staging ( PD, n = 163), 35 (22%) had metastatic disease in the nodes. Grade was significantly associated with node positivity ( P = 0.007). In multivariate models, survival was improved with either an ampullectomy with regional lymphadenectomy [hazard ratio ( HR) 0.19; 95% confidence interval ( CI) 0.05-0.61, P < 0.005] or a PD ( HR 0.23; 95% CI 0.15-0.36, P < 0.001). Conclusion Patients with T1 AC have a high risk for nodal metastases especially if they are higher-grade lesions. Nodal clearance with a lymphadenectomy or a PD is essential for long-term survival in these patients. [ABSTRACT FROM AUTHOR]

The role of adjuvant radiotherapy in the treatment of ampullary carcinoma (AC) remains unclear. We hypothesized that adjuvant radiotherapy (RT) does not improve survival following resection for AC. The SEER database was queried for patients with non-metastatic AC who underwent surgery (S) from 2004 to 2010. Propensity score (PS) modeling was applied to create balanced cohorts of patients that would be equally likely to receive RT. Cox proportional hazard models were used to compare survival. Of 1,287 patients, 329 (25.6 %) received adjuvant RT. Unadjusted median overall survival (OS) for patients receiving adjuvant RT compared to S alone was 27 vs. 36 months ( p = 0.14). Patients receiving RT were younger (63 vs. 69 years, p < 0.001), had more advanced tumors (69 vs. 53 % T3/T4, p < 0.001), and had more frequent lymph node metastasis (73 vs. 40 %, p < 0.001). Adjuvant RT failed to improve both overall survival (27 vs. 29 months, p = 0.58) and disease-specific survival (36 vs. 40 months, p = 0.92) in propensity-matched cohorts, although certain imbalances remained between treatment groups. Adjuvant RT does not confer a survival benefit for patients with ampullary tumors. The lack of disease-specific survival benefit suggests that it may also not be beneficial to prevent local recurrences. [ABSTRACT FROM AUTHOR]

Background The management of hepatic hemangiomas remains ill defined. This study sought to investigate the indications, surgical management and outcomes of patients who underwent a resection for hepatic hemangiomas. Methods A retrospective review from six major liver centres in the United States identifying patients who underwent surgery for hepatic hemangiomas was performed. Clinico-pathological, treatment and peri-operative data were evaluated. Results Of the 241patients who underwent a resection, the median age was 46 years [interquartile range ( IQR): 39-53] and 85.5% were female. The median hemangioma size was 8.5 cm ( IQR: 6-12.1). Surgery was performed for abdominal symptoms (85%), increasing hemangioma size (11.3%) and patient anxiety (3.7%). Life-threatening complications necessitating a hemangioma resection occurred in three patients (1.2%). Clavien Grade 3 or higher complications occurred in 14 patients (5.7%). The 30- and 90-day mortality was 0.8% ( n = 2). Of patients with abdominal symptoms, 63.2% reported improvement of symptoms post-operatively. Conclusion A hemangioma resection can be safely performed at high-volume institutions. The primary indication for surgery remains for intractable symptoms. The development of severe complications associated with non-operative management remains a rare event, ultimately challenging the necessity of additional surgical indications for a hemangioma resection. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) derived from primary tumors are believed to facilitate circulating tumor cell (CTC) seeding of distant metastases, but the mechanisms of these processes are poorly understood. Although many studies have focused on the migration of CTCs, less attention has been given to TAMs that, like CTCs, derive from tumor sites. Using precision microfilters under low-flow conditions, we isolated circulating cancer-associated macrophage-like cells (CAMLs) from the peripheral blood of patients with breast, pancreatic, or prostate cancer. CAMLs, which are not found in healthy individuals, were found to express epithelial, monocytic, and endothelial protein markers and were observed bound to CTCs in circulation. These data support the hypothesis that disseminated TAMs can be used as a biomarker of advanced disease and suggest that they have a participatory role in tumor cell migration. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites. [ABSTRACT FROM AUTHOR]