Contemporary approach to cardiogenic shock care: a state-of-the-art review.

Cardiogenic shock (CS) is a time-sensitive and hemodynamically complex syndrome with a broad spectrum of etiologies and clinical presentations. Despite contemporary therapies, CS continues to maintain high morbidity and mortality ranging from 35 to 50%. More recently, burgeoning observational research in this field aimed at enhancing the early recognition and characterization of the shock state through standardized team-based protocols, comprehensive hemodynamic profiling, and tailored and selective utilization of temporary mechanical circulatory support devices has been associated with improved outcomes. In this narrative review, we discuss the pathophysiology of CS, novel phenotypes, evolving definitions and staging systems, currently available pharmacologic and device-based therapies, standardized, team-based management protocols, and regionalized systems-of-care aimed at improving shock outcomes. We also explore opportunities for fertile investigation through randomized and non-randomized studies to address the prevailing knowledge gaps that will be critical to improving long-term outcomes.

Update on sex specific risk factors in cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of death worldwide and accounts for roughly 1 in 5 deaths in the United States. Women in particular face significant disparities in their cardiovascular care when compared to men, both in the diagnosis and treatment of CVD. Sex differences exist in the prevalence and effect of cardiovascular risk factors. For example, women with history of traditional cardiovascular risk factors including hypertension, tobacco use, and diabetes carry a higher risk of major cardiovascular events and mortality when compared to men. These discrepancies in terms of the relative risk of CVD when traditional risk factors are present appear to explain some, but not all, of the observed differences among men and women. Sex-specific cardiovascular disease research-from identification, risk stratification, and treatment-has received increasing recognition in recent years, highlighting the current underestimated association between CVD and a woman's obstetric and reproductive history. In this comprehensive review, sex-specific risk factors unique to women including adverse pregnancy outcomes (APO), such as hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus, preterm delivery, and newborn size for gestational age, as well as premature menarche, menopause and vasomotor symptoms, polycystic ovarian syndrome (PCOS), and infertility will be discussed in full detail and their association with CVD risk. Additional entities including spontaneous coronary artery dissection (SCAD), coronary microvascular disease (CMD), systemic autoimmune disorders, and mental and behavioral health will also be discussed in terms of their prevalence among women and their association with CVD. In this comprehensive review, we will also provide clinicians with a guide to address current knowledge gaps including implementation of a sex-specific patient questionnaire to allow for appropriate risk assessment, stratification, and prevention of CVD in women.

Ischemic heart disease in pregnancy: a practical approach to management.

Ischemic heart disease is a crucial issue during pregnancy. The term is composed of both preexisting conditions and acute coronary syndrome in pregnancy, including pregnancy-associated myocardial infarction, which can have a significant effect on maternal and fetal outcomes. This review provides a complete guide to managing ischemic heart disease in pregnant women, emphasizing the importance of multidisciplinary care and individualized treatment strategies. Cardiovascular disease, particularly ischemic heart disease, is now the leading cause of maternal mortality worldwide. Pregnancy introduces unique physiological changes that increase the risk of acute myocardial infarction, with pregnancy-associated myocardial infarction cases often associated with factors, such as advanced maternal age, chronic hypertension, and preexisting cardiovascular conditions. This review distinguishes between preexisting ischemic heart disease and pregnancy-associated myocardial infarction. It will emphasize the various etiologies of pregnancy-associated myocardial infarction, including coronary atherosclerosis and plaque rupture presenting as ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and other nonatherosclerotic causes, including spontaneous coronary artery dissection, vasospasm, and embolism. Our study discusses the practical management of ischemic heart disease in pregnancy, with a focus on preconception counseling, risk assessment, and tailored antenatal planning for women with preexisting ischemic heart disease. Moreover, this document focuses on the challenges of diagnosing cardiovascular disease, especially when presented with nonclassical risk factors and presentation. It provides insight into the appropriate diagnostic testing methods, such as electrocardiogram, cardiac biomarkers, and echocardiography. In addition, the review covers various treatment strategies, from medical management to more invasive procedures, including coronary angiography, percutaneous coronary intervention, and coronary artery bypass graft. Special attention is given to medication safety during pregnancy, including anticoagulation, beta-blockers, and antiplatelet agents. The complexities of delivery planning in women with ischemic heart disease are discussed, advocating for a multidisciplinary team-based approach and careful consideration of the timing and mode of delivery. Furthermore, the roles of breastfeeding and postpartum care are explored, emphasizing the long-term benefits and the suitability of various medications during lactation. Lastly, this review provides crucial insights into the management of ischemic heart disease in pregnancy, stressing the need for heightened awareness, prompt diagnosis, and tailored management to optimize maternal and fetal health outcomes.

Telehealth Support for Dementia Caregivers During the COVID-19 Pandemic: Lessons Learned From the NYU Family Support Program.

OBJECTIVES: In response to the needs of dementia caregivers during the COVID-19 pandemic, the NYU Langone Alzheimer's Disease and Related Disorders Family Support Program (FSP) quickly transitioned to providing most services online. To understand how dementia caregivers experienced FSP services after the switch to video telehealth, we conducted qualitative interviews of spouse or partner dementia caregivers. PARTICIPANTS: Ten participants were recruited from a convenience sample of dementia spouse or partner caregivers who used one or more online FSP services offered during the pandemic. DESIGN: Caregivers engaged in semi-structured interviews held via videoconference between May and June 2020. Qualitative analysis of interviews was conducted according to the principles of framework analysis. RESULTS: Caregivers reported high satisfaction with the FSP pre-pandemic and continued to feel supported when services were provided online. They transitioned to video telehealth services with little difficulty. CONCLUSIONS: While video telehealth is frequently cited as beneficial for those in rural communities, socioeconomically disadvantaged groups, or homebound individuals, our findings suggest that video telehealth is also advantageous for dementia caregivers, given their unique barriers, including lack of time due to caregiving responsibilities, lack of respite care for the person with dementia, and the additional burdens of travel time to access in-person services.

Presentation and survival of gastro-entero-pancreatic neuroendocrine tumors in young adults versus older patients.

BACKGROUND: A minority of patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) is diagnosed at younger age. This population-based study explores the broad clinical and pathologic features of the youngest 5% of adult patients with GEP-NETs. METHODS: A retrospective study of the National Cancer Database (NCDB) of patients with a primary GEP-NET was performed. Patients were stratified by age. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed. RESULTS: We identified 31,983 patients with a diagnosis of a GEP-NET and only 5% of patients were under the age of 35. Young patients were found to have greater proportions of localized, well differentiated disease. On multivariate analysis, young age, well differentiated histology, early stage, and surgical intervention were associated with lower risk of mortality. CONCLUSIONS: Young patients with GEP-NETs tend to have earlier stage of presentation and well differentiated tumors, which may be most amenable to surgical intervention.

Vision-related quality of life in patients with a history of congenital glaucoma.

PURPOSE: To assess the vision-related quality of life in adult patients with a history of primary congenital glaucoma. METHODS: In a cross-sectional hospital-based study eligible patients with a history of primary congenital glaucoma aged more than 18 were recruited in the study. Patients with secondary glaucoma and monocular patients were excluded. All patients underwent a complete ophthalmologic examination. The subjects were requested to answer a Persian approved version of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) questionnaire. RESULTS: A total of 23 congenital glaucoma patients have enrolled in the study. The mean age was 29.22 (9.3 SD) and mean IOP was 13.82 (5.19 SD) and 15.69 (5.26 SD) in right and left eyes, respectively. The mean number of medications was 1.13 (1.25 SD) in the right and 1.30 (1.18 SD) in the left eyes. Among all scores of NEI-VFQ-25, the lowest score belonged to mental health 53.71 (29.72) and the highest score was color vision score 83.69 (20.79). We found a significant influence of visual field defect on many subscales including general health and general vision (p = 0.007, R = +0.65) and (p = 0.002, R = +0.71) respectively. The Mean Defect (MD) was associated with low social functioning and peripheral vision too (p = 0.035, R = +0.53) and (p = 0.001, R = +0.76) respectively. Age had a negative impact on the general vision subscale (p = 0.003, R = -0.59). CONCLUSION: Our study showed that visual field defect was strongly associated with many subscales scores in (NEI VFQ-25) questionnaire.

Natural History of Renal Neuroendocrine Neoplasms: A NET by Any Other Name?

Renal neuroendocrine neoplasms are rare, with descriptions of cases limited to individual reports and small series. The natural history of this group of neuroendocrine neoplasms is poorly understood. In this study, we queried the Surveillance, Epidemiology and End Results (SEER) database over a four-decade period where we identified 166 cases of primary renal neuroendocrine neoplasms. We observed a 5-year overall survival of 50%. On multivariate analysis, survival was influenced by stage, histology, and if surgery was performed. We observed that patients managed by operative management had a greater frequency of localized or regional stage disease as well as a greater frequency of neuroendocrine tumor, grade 1 histology; whereas those managed non-operatively tended to have distant disease and histologies of neuroendocrine carcinoma, NOS and small cell neuroendocrine carcinoma. This is the largest description of patients with renal neuroendocrine neoplasms. Increased survival was observed in patients with earlier stage and favorable histologies.

Relationship of the Macular Ganglion Cell and Inner Plexiform Layers in Healthy and Glaucoma Eyes.

PURPOSE: To explore factors influencing the inner plexiform layer (IPL) in healthy subjects and to test the hypothesis that IPL thickness is preferentially decreased in glaucoma as compared with ganglion cell layer (GCL) thickness. METHODS: Ninety-nine glaucomatous eyes and 66 healthy eyes (165 subjects) underwent macular spectral-domain optical coherence tomography (SD-OCT) imaging and GCL and IPL were segmented creating 8 × 8 arrays of 3° × 3° superpixels. The central 24 superpixels were categorized into three levels of eccentricity (∼1.5°, 4.5°, and 7.5° from the foveal center). Linear mixed models were used to determine predictive parameters for IPL thickness in healthy subjects and to explore the influence of diagnosis of glaucoma on IPL thickness taking into account the effect of GCL thickness and other covariates. RESULTS: Being located at 4.5° eccentricity predicted thicker IPL compared with 1.5° eccentricity (P < 0.001) in multivariable models in healthy subjects, whereas older age (P = 0.001) and Asian ethnicity (P = 0.021) were associated with thinner IPL. Diagnosis of glaucoma was not associated with thinner IPL regardless of eccentricity after accounting for age and ethnicity. The results were similar when only eyes with mean deviation greater than -6 dB were analyzed. CONCLUSIONS: Ethnicity and distance from the fovea are the main determinants of IPL thickness in the central macula. Preferential thinning of the macular IPL, compared with GCL, could not be detected in this study regardless of glaucoma stage. TRANSLATIONAL RELEVANCE: There is no evidence for preferential thinning of the macular IPL in glaucoma compared with GCL based on currently available SD-OCT-imaging technology.

Neuroendocrine Tumors of Meckel's Diverticula: Rare but Fare Well.

Neuroendocrine tumors (NETs) are the most common malignancy arising in Meckel's diverticula (MDs). To date, there are no large series characterizing these tumors. The National Cancer Database was queried for patients with MD NETs (n = 162) from 2004 to 2014. Patient and tumor characteristics as well as outcomes were analyzed. MD NETs were more common in men (72.8%) at a median age of 62 years; 95.1 per cent of patients were white. All patients underwent surgery. Clinical M0 disease was present in 97.4 per cent of patients, and 88.2 per cent of tumors were well differentiated. Lymphovascular invasion was present in 13.2 per cent. Most (60.4%) tumors were less than 10 mm. Lymphadenectomy was performed in 32.9 per cent of patients, with 52.1 per cent of these found to have metastatic lymph node disease. Although most MD NETs are well differentiated, smaller than 10 mm, and do not have lymphovascular invasion, lymph node metastases are commonly found, suggesting that mesenteric lymphadenectomy with adequate resection of the small bowel may be necessary for adequate staging and disease clearance.

Defining Dysbiosis in Patients with Urolithiasis.

The prevalence of urinary stone disease (USD) is rapidly rising. However, the factors driving this increase are unknown. Recent microbiome studies suggest that dysbiosis may in part contribute to the increasing prevalence. The objective of the current study was to determine the nature and location of dysbiosis associated with USD. We conducted microbiome analysis from the gastrointestinal and urinary tracts, along with a metabolomic analysis of the urinary metabolome, from subjects with an active episode of USD or no history of the disease. Higher rates of antibiotic use among USD patients along with integrated microbiome and metabolomic results support the hypothesis that USD is associated with an antibiotic-driven shift in the microbiome from one that protects against USD to one that promotes the disease. Specifically, our study implicates urinary tract Lactobacillus and Enterobacteriaceae in protective and pathogenic roles for USD, respectively, which conventional, culture-based methods of bacterial analysis from urine and kidney stones would not necessarily detect. Results suggest that antibiotics produce a long-term shift in the microbiome that may increase the risk for USD, with the urinary tract microbiome holding more relevance for USD than the gut microbiome.

Endoscopic guided PCNL in the prone split-leg position versus supine PCNL: a comparative analysis stratified by Guy's stone score.

INTRODUCTION: The optimal patient positioning for percutaneous nephrolithotomy (PCNL) based on the complexity of stone burden is not yet defined. Thus, we aimed to evaluate the intraoperative parameters, effectiveness and complications of patients undergoing PCNL between the endoscopic-guided prone split-leg PCNL (ePSL) and the supine PCNL by stratifying patients according to Guy's stone score (GSS). MATERIALS AND METHODS: A retrospective chart review was conducted of patients undergoing PCNL at two high-volume tertiary referral centers. At one center, patients underwent PCNL using the ePSL technique, while at the second center, patients underwent PCNL in supine. Patient demographics and stone characteristics, operative details, complications and effectiveness were compared between groups. The impact of obesity was also investigated. RESULTS: Of 830 subjects, a total of 449 (54%) underwent PCNL in ePSL and 381 (46%) in supine. The ePSL group had a greater mean age and body mass index. No statistical differences were found in gender, serum chemistry and Charlson comorbidity index. After stratifying patients by GSS, the differences in baseline stone burden between PSL and supine lost significance and both groups could be compared. Complications were not statistically different between both groups. Univariate analysis demonstrated that multiple tracts and lower pole access were more prevalent in supine. In addition, for GSS1-3, ePSL was correlated with reduced operative time, radiation exposure, length of hospital stay and need for secondary procedure. Multivariate analysis correlated ePSL with lower radiation exposure and need for secondary procedures (p = 0.01). In comparison to the whole trial population, the same tendencies were appreciated for obese cohort. CONCLUSIONS: This is the first report focusing on the performance differences between ePSL and supine PCNL stratified by GSS. Both techniques are safe, with a low rate of complications. For GSS1-3, ePSL reduces radiation exposure and requires less need for both multiple access and secondary procedure.

Could Mesophases Play a Role in the Nucleation and Polymorph Selection of Zeolites?

Zeolites and mesoporous silicas are porous materials with important applications in catalysis, gas storage, and separation. Zeolite crystals form in the presence of cationic surfactants that act as structure directing agents (SDAs). The way SDAs control the nucleation and polymorphs selection in zeolites is not fully understood. The formation of mesoporous silica is templated by liquid crystalline mesophases that result from frustrated attraction between silicates and long-chain SDAs. Experiments indicate that surfactants C nH2 n+1(CH3)3N+ with n > 6 yield mesoporous silicas, and the one with n = 6 produces a zeolite. This suggests that the driving force toward mesophase formation is also present for small organocations, but is overcome by the ability of silica to wrap a crystal lattice around them. Here we use molecular dynamics simulations to investigate whether the existence of metastable mesophases can play a role in the nucleation and polymorph selection of zeolitic crystals. As a proof of concept, we investigate the phase behavior of simple mesogenic mixtures of SDAs and a network former T that favors tetracoordinated crystals. We represent the network-former T by Stillinger-Weber models of water and silicon, in lieu of silica, because a computationally efficient silica potential that would allow for the spontaneous nucleation of zeolites in molecular dynamics simulations is not yet available. The mixtures of T and SDA produce a rich phase diagram that encompasses the sII clathrate and at least six zeolites, including sigma-2 (SGT). We find that the nucleation of SGT is not assisted by a mesophase. The nucleation of the other five zeolites of this study, however, is facilitated by the existence of metastable mesophases that decrease the nucleation barriers and direct the selection of the crystal polymorph. Together with the experimental support for mesophases in mixtures of silicates and SDAs, our results for model systems suggest that metastable mesophases could play a prominent role in promoting the nucleation and polymorph selection of some zeolites.

The Fovea-BMO Axis Angle and Macular Thickness Vertical Asymmetry Across The Temporal Raphe.

PURPOSE: To test the hypothesis that the fovea-Bruch's membrane opening (FoBMO) axis angle influences the thickness symmetry of the macular ganglion cell/inner plexiform layer (GCIPL) across the temporal horizontal meridian in normal subjects. DESIGN: Cross-sectional diagnostic study at a tertiary academic center. METHODS: One hundred sixteen eyes of 60 normal subjects aged 40 to 85 years underwent spectral domain optical coherence tomography(SD-OCT) imaging. The FoBMO angle was estimated on en face infrared SD-OCT images. Posterior Pole algorithm images acquired with Spectralis SD-OCT were used to define vertical asymmetry as follows. The average thickness difference between the 3 most temporal superpixels above and below the horizontal meridian, the second row of superpixels from the horizontal meridian, and 3 central superpixels above and below the horizontal meridian were calculated. Factors influencing GCIPL thickness asymmetry were explored and changes in thickness asymmetry as a function of FoBMO angle were investigated. RESULTS: No demographic or clinical factors affected temporal GCIPL asymmetry (P>0.05 for all). A more (negatively) tilted FoBMO angle was associated with relatively thinner inferior compared with superior GCIPL thickness in superpixels immediately adjacent to the temporal raphe (P<0.001). The second row of temporal superpixels from the horizontal meridian (P=0.349) or central superpixels (P=0.292) did not show this tendency. CONCLUSIONS: Vertical GCIPL symmetry across the horizontal meridian is influenced by the FoBMO angle. SD-OCT algorithms using vertical asymmetry as a diagnostic index should be adjusted for the FoBMO angle.

Observational Outcomes of Initial Trabeculectomy With Mitomycin C in Patients of African Descent vs Patients of European Descent: Five-Year Results.

Importance: There is evidence that patients of African descent (AD) experience higher surgical failure rate after trabeculectomy without antimetabolites. Objective: To compare outcomes of initial trabeculectomy with mitomycin C in AD patients with those of patients of European descent (ED) and to identify prognostic factors for failure. Design, Setting, and Participants: In this retrospective matched cohort study, 135 eyes of 105 AD patients were matched with 135 eyes of 117 ED patients by age (within 5 years), surgeon, lens status, and follow-up time (within 1 year) from a single tertiary academic center. Interventions: Initial trabeculectomy with mitomycin C. Main Outcomes and Measures: Criteria A, B, and C defined qualified success rates as final intraocular pressure of 18 mm Hg or less, 15 mm Hg or less, and 12 mm Hg or less, respectively, in addition to 20% or more, 25% or more, and 30% or more reduction of intraocular pressure or reduction of 2 or more medications. Kaplan-Meier survival curves were compared with log-rank test in AD and ED patients, and Cox proportional hazard models were used to estimate the influence of race/ethnicity on surgical success accounting for confounding variables. Results: Of the 105 AD patients, 56 (53.3%) were female, and the mean (SD) age was 67.5 (10.4) years; of the 117 ED patients, 64 (54.7%) were female, and the mean (SD) age was 68.2 (10.0) years. For AD patients compared with ED patients, the qualified success rates at 5 years for criteria A were 61% and 67%, respectively (difference, 7.3%; 95% CI, 4.4-10.4); for criteria B, 43% and 60% (difference, 17.6%; 95% CI, 15.2-20.0); and for criteria C, 25% and 40% (difference, 15.8%; 95% CI, 11.1-20.5). On multivariable Cox regression analyses, AD was associated with higher failure rate with criteria B and C for qualified success and with all criteria for complete success (ie, no need for medications). Incidence of bleb leaks was higher in the AD group (29 vs 11 eyes; P = .002). Additionally, AD patients required additional glaucoma surgeries more often than ED patients (47 vs 26 eyes; P = .004). Conclusions and Relevance: African descent was associated with higher failure rates and higher incidence of bleb leaks after initial trabeculectomy with mitomycin C compared with European descent. If this is subsequently shown to be a cause and effect, the findings need to be considered when surgical treatment of glaucoma is contemplated in AD patients.

Role of stacking disorder in ice nucleation.

The freezing of water affects the processes that determine Earth's climate. Therefore, accurate weather and climate forecasts hinge on good predictions of ice nucleation rates. Such rate predictions are based on extrapolations using classical nucleation theory, which assumes that the structure of nanometre-sized ice crystallites corresponds to that of hexagonal ice, the thermodynamically stable form of bulk ice. However, simulations with various water models find that ice nucleated and grown under atmospheric temperatures is at all sizes stacking-disordered, consisting of random sequences of cubic and hexagonal ice layers. This implies that stacking-disordered ice crystallites either are more stable than hexagonal ice crystallites or form because of non-equilibrium dynamical effects. Both scenarios challenge central tenets of classical nucleation theory. Here we use rare-event sampling and free energy calculations with the mW water model to show that the entropy of mixing cubic and hexagonal layers makes stacking-disordered ice the stable phase for crystallites up to a size of at least 100,000 molecules. We find that stacking-disordered critical crystallites at 230 kelvin are about 14 kilojoules per mole of crystallite more stable than hexagonal crystallites, making their ice nucleation rates more than three orders of magnitude higher than predicted by classical nucleation theory. This effect on nucleation rates is temperature dependent, being the most pronounced at the warmest conditions, and should affect the modelling of cloud formation and ice particle numbers, which are very sensitive to the temperature dependence of ice nucleation rates. We conclude that classical nucleation theory needs to be corrected to include the dependence of the crystallization driving force on the size of the ice crystallite when interpreting and extrapolating ice nucleation rates from experimental laboratory conditions to the temperatures that occur in clouds.

Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.

Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.

Assessment of a Revised Management Strategy for Patients With Intraductal Papillary Mucinous Neoplasms Involving the Main Pancreatic Duct.

Importance: According to the 2012 International Consensus Guidelines, the diagnostic criterion of intraductal papillary mucinous neoplasms (IPMNs) involving the main duct (MD IPMNs) or the main and branch ducts (mixed IPMNs) of the pancreatic system is a main pancreatic duct (MPD) diameter of 5.0 mm or greater on computed tomography (CT) or magnetic resonance imaging (MRI). However, surgical resection is recommended for patients with an MPD diameter of 10.0 mm or greater, which is characterized as a high-risk stigma. An MPD diameter of 5.0 to 9.0 mm is not an indication for immediate resection. Objectives: To determine an appropriate cutoff (ie, one with high sensitivity and negative predictive value) of the MPD diameter on CT or MRI as a prognostic factor for malignant disease and to propose a new management algorithm for patients with MD or mixed IPMNs. Design, Setting, and Participants: This retrospective cohort study included 103 patients who underwent surgical resection for a preoperative diagnosis of MD or mixed IPMN and in whom IPMN was confirmed by surgical pathologic findings at a single institution from July 1, 1996, to December 31, 2015. Main Outcomes and Measures: Malignant disease was defined as high-grade dysplasia or invasive adenocarcinoma on results of surgical pathologic evaluation. An appropriate MPD diameter on preoperative CT or MRI to predict malignant disease was determined using a receiver operating characteristic curve analysis. The prognostic value of the new management algorithm that incorporated the new MPD diameter cutoff was evaluated. Results: Among the 103 patients undergoing resection for an MD or mixed IPMN (59 men [57.3%]; 44 women [42.7%]; median [range] age, 71 [48-86] years), 64 (62.1%) had malignant disease. Diagnostic accuracy for malignant neoplasms was highest at an MPD diameter cutoff of 7.2 mm (area under the receiver operating characteristic curve, 0.70; 95% CI, 0.59-0.81). An MPD diameter of 7.2 mm or greater was also an independent prognostic factor for malignant neoplasms (odds ratio, 12.76; 95% CI, 2.43-66.88; P = .003) on logistic regression analysis after controlling for preoperative variables. The new management algorithm, which included an MPD diameter of 7.2 mm or greater as one of the high-risk stigmata, had a higher sensitivity (100%), negative predictive value (100%), and accuracy (66%) for malignant disease than the 2012 version of the International Consensus Guidelines (95%, 57%, and 63%, respectively). Conclusions and Relevance: In this single-center, retrospective analysis, an MPD diameter of 7.2 mm was identified as an optimal cutoff for a prognostic factor for malignant disease in MD or mixed IPMN. These data support lowering the accepted criteria for MPD diameter when selecting patients for resection vs surveillance so as not to overlook cancer in IPMN.

Stiffness of pancreatic cancer cells is associated with increased invasive potential.

Metastasis is a fundamentally physical process in which cells are required to deform through narrow gaps as they invade surrounding tissues and transit to distant sites. In many cancers, more invasive cells are more deformable than less invasive cells, but the extent to which mechanical phenotype, or mechanotype, can predict disease aggressiveness in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here we investigate the invasive potential and mechanical properties of immortalized PDAC cell lines derived from primary tumors and a secondary metastatic site, as well as noncancerous pancreatic ductal cells. To investigate how invasive behavior is associated with cell mechanotype, we flow cells through micron-scale pores using parallel microfiltration and microfluidic deformability cytometry; these results show that the ability of PDAC cells to passively transit through pores is only weakly correlated with their invasive potential. We also measure the Young's modulus of pancreatic ductal cells using atomic force microscopy, which reveals that there is a strong association between cell stiffness and invasive potential in PDAC cells. To determine the molecular origins of the variability in mechanotype across our PDAC cell lines, we analyze RNAseq data for genes that are known to regulate cell mechanotype. Our results show that vimentin, actin, and lamin A are among the most differentially expressed mechanoregulating genes across our panel of PDAC cell lines, as well as a cohort of 38 additional PDAC cell lines. We confirm levels of these proteins across our cell panel using immunoblotting, and find that levels of lamin A increase with both invasive potential and Young's modulus. Taken together, we find that stiffer PDAC cells are more invasive than more compliant cells, which challenges the paradigm that decreased cell stiffness is a hallmark of metastatic potential.

CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer.

BACKGROUND: Compared to the widely adopted 2-4 months of pre-operative therapy for patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC), our institution tends to administer a longer duration before considering surgical resection. Using this unique approach, the aim of this study was to determine pre-operative variables associated with survival. METHODS: Records from patients with BR/LA PDAC who underwent attempt at surgical resection from 1992-2014 were reviewed. RESULTS: After a median duration of 6 months of pre-operative treatment, 109 patients with BR/LA PDAC (BR 63, LA 46) were explored; 93 (85.3 %) underwent pancreatectomy. Those who received at least 6 months of pre-operative treatment had longer median overall survival (OS) than those who received less (52.8 vs. 32.1 months, P = 0.044). On multivariate analysis, pre-operative treatment duration was the strongest predictor of survival (hazard ratio (HR) 4.79, P = 0.043). However, OS was similar in those whose CA19-9 normalized regardless of whether they received more or less than 6 months of chemotherapy (71.4 vs. 101.8 months, P = 0.930). CONCLUSIONS: Pre-operative CA19-9 decline can guide treatment duration in patients with BR/LA PDAC. We endorse 6 months of therapy except in those patients whose values normalize, where surgery can be considered after a shorter course.

Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naïve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF-conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens. IMPLICATIONS: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.