Permutations in pacer wire implantation in patients evaluated for transcatheter tricuspid valve interventions.

Pacer wire induced tricuspid regurgitation is not well-understood. The mechanisms behind pacer wired induced tricuspid regurgitation have not been clearly defined. This clinical vignette sets to identify different technical mechanisms behind cardiac lead induced tricuspid regurgitation to help optimize cardiac lead implantation strategies for future device implantation.

Demand-Side Factors in Maternal Health Outcomes: Evidence from a Community Health Worker Programme in Uganda.

While community health workers (CHWs) are a core feature of many low-resource healthcare systems, evidence on both their health impacts and the mechanisms behind these impacts remains limited. Using a difference-in-differences design with a control and treatment group, this study evaluated a CHW programme in southwestern Uganda aimed at improving maternal health outcomes. We found relatively little evidence of an overall programme effect on health behaviours, including antenatal care attendance and delivery under skilled supervision. Analysis of heterogeneity by gestational age at first antenatal visit - which should have modulated exposure to the intervention - provided suggestive evidence that treatment effects varied predictably with gestational age. Altogether, the absence of strong programme effects may have been due to suboptimal performance by CHWs, thus highlighting the importance of studying and instituting appropriate monitoring and incentive schemes for such programmes. Additionally, in contrast to the weak treatment effect findings, analysis of the entire study sample between the pre- and post-intervention periods showed large improvements in healthcare-seeking behaviour across both the treatment and control groups. These changes may have arisen from concurrent supply-side health facility improvements affecting the entire study population, spillover effects from the CHWs, or background health trends.

Outcomes of Patients Undergoing Elective Bowel Resection Before and After Implementation of an Anemia Screening and Treatment Program.

BACKGROUND: Patients with anemia undergoing elective colorectal cancer surgery are known to have significantly higher rates of postoperative complications and worse outcomes. OBJECTIVE: This study aimed to improve rates of anemia screening and treatment in patients undergoing elective colon and rectal resections through a quality improvement initiative. DESIGN: We compared a historical cohort of patients before implementation of our anemia screening and treatment quality improvement program to a prospective cohort after implementation. SETTINGS: This study was conducted at a tertiary care hospital. PATIENTS: This study included all adult patients with a new diagnosis of colon or rectal cancer without evidence of metastatic disease between 2017 and 2019. INTERVENTIONS: The interventions include the anemia screening and treatment quality improvement program. MAIN OUTCOME MEASURES: The primary outcome was hospital cost per admission. RESULTS: This study includes a total of 84 patients who underwent elective colon or rectal resection before implementation of our anemia quality improvement project and 88 patients who underwent surgery after. In the preimplementation cohort 44 of 84 patients (55.9%) were anemic compared to 47 of 99 patients (54.7%) in the postimplementation cohort. Rates of screening (25%-86.4%) and treatment (27.8%- 63.8%) were significantly increased in the postimplementation cohort. Mean total cost per admission was significantly decreased in the postimplementation cohort (mean cost $16,827 vs $25,796; p = 0.004); this significant reduction was observed even after adjusting for relevant confounding factors (ratio of means: 0.74; 95% CI, 0.65-0.85). The mechanistic link between treatment of anemia and reductions in cost remains unknown. No significant difference was found in rates of blood transfusion, complications, or mortality between the groups. LIMITATIONS: The study limitation includes before-after design subjected to selection and temporal biases. CONCLUSIONS: We demonstrate the successful implementation of an anemia screening and treatment program. This program was associated with significantly reduced cost per admission. This work demonstrates possible value and benefits of implementation of an anemia screening and treatment program. See Video Abstract at http://links.lww.com/DCR/C15 .RESULTADOS DE LOS PACIENTES SOMETIDOS A RESECCIÓN INTESTINAL ELECTIVA ANTES Y DESPUÉS DE LA IMPLEMENTACIÓN DE UN PROGRAMA DE DETECCIÓN Y TRATAMIENTO DE ANEMIA. ANTECEDENTES: Se sabe que los pacientes anémicos que se someten a una cirugía electiva de cáncer colorrectal tienen tasas significativamente más altas de complicaciones posoperatorias y peores resultados. OBJETIVO: Mejorar las tasas de detección y tratamiento de la anemia en pacientes sometidos a resecciones electivas de colon y recto a través de una iniciativa de mejora de calidad. DISEO: Comparamos una cohorte histórica de pacientes antes de la implementación de nuestro programa de detección de anemia y mejora de la calidad del tratamiento con una cohorte prospectiva después de la implementación. ENTORNO CLINICO: Hospital de atención terciaria. PACIENTES: Todos los pacientes adultos con un nuevo diagnóstico de cáncer de colon o recto sin evidencia de enfermedad metastásica entre 2017 y 2019. INTERVENCIONES: Detección de anemia y programa de mejora de la calidad del tratamiento. PRINCIPALES MEDIDAS DE RESULTADO: El resultado primario fue el costo hospitalario por ingreso. RESULTADOS: Un total de 84 pacientes se sometieron a resección electiva de colon o recto antes de la implementación de nuestro proyecto de mejora de calidad de la anemia y 88 pacientes se sometieron a cirugía después. En la cohorte previa a la implementación, 44/84 (55,9 %) presentaban anemia en comparación con 47/99 (54,7 %) en la cohorte posterior a la implementación. Las tasas de detección (25 % a 86,4 %) y tratamiento (27,8 % a 63,8 %) aumentaron significativamente en la cohorte posterior a la implementación. El costo total medio por admisión se redujo significativamente en la cohorte posterior a la implementación (costo medio $16 827 vs. $25 796, p = 0,004); esta reducción significativa se observó incluso después de ajustar los factores de confusión relevantes (proporción de medias: 0,74, IC del 95 %: 0,65 a 0,85). El vínculo mecánico entre el tratamiento de la anemia y la reducción de costos sigue siendo desconocido. No hubo diferencias significativas en las tasas de transfusión de sangre, complicaciones o mortalidad entre los grupos. LIMITACIONES: El diseño de antes y después está sujeto a sesgos temporales y de selección. CONCLUSIONES: Demostramos la implementación exitosa de un programa de detección y tratamiento de anemia. Este programa se asoció con un costo por admisión significativamente reducido. Este trabajo demuestra el valor y los beneficios posibles de la implementación de un programa de detección y tratamiento de la anemia. Consulte Video Resumen en http://links.lww.com/DCR/C15 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Clinical practice guideline: evidence, recommendations and algorithm for the preoperative optimization of anemia, hyperglycemia and smoking.

Preoperative optimization has not been explored comprehensively in the surgical literature, as this responsibility has often been divided among surgery, anesthesia and medicine. We developed an evidence-based clinical practice guideline to summarize existing evidence and present diagnostic and treatment algorithms for use by surgeons caring for patients scheduled to undergo major elective surgery. We focus on 3 common comorbid conditions seen across surgical specialties - anemia, hyperglycemia and smoking - as these conditions increase complication rates in patients undergoing major surgery and can be optimized successfully as soon as 6-8 weeks before surgery. With the ability to address these conditions earlier in the patient journey, surgeons can positively affect patient outcomes. The aim of this guideline is to bring optimization in the preoperative period under the existing umbrella of evidence-based surgical care.

Hospital cost associated with anemia in elective colorectal surgery: a historical cohort study.

PURPOSE: Anemia is highly prevalent in the colorectal surgery population, affecting 30-70% of patients. Anemia is associated with significant morbidity and mortality; however, there is a lack of evidence on how much anemia impacts healthcare costs. This study aims to determine the hospital cost of index surgical admission, postoperative length of stay, and transfusion rate associated with preoperative anemia in elective major colorectal surgery. METHODS: This historical cohort study included 851 adult inpatients having elective colorectal surgery at a tertiary care academic health sciences network between April 2010 and February 2016. Anemia was defined as hematocrit ≤ 39%. The primary outcome was total hospital costs standardized to 2016 CAD. Secondary outcomes were postoperative length of stay and transfusion. Multivariable regression analyses and propensity score methods were used to measure adjusted associations between anemia and outcomes. RESULTS: Before surgery, 381/851 (45%) patients were anemic. The mean (standard deviation [SD]) cost of index admission for an elective colorectal surgery was 20,040 (23,219) CAD. Anemia was associated with an adjusted 14% relative increase in costs (95% confidence interval [CI], 6 to 23; P < 0.001). The total hospitalization cost attributable to anemia was 3,027 CAD (95% CI, 2,670 to 3,388). Hospital costs and length of stay were highly associated; anemia was associated with an 18% increase in length of stay (95% CI, 7 to 30; P < 0.001) and increased transfusion rates (risk ratio, 4.7; 95% CI, 2.71 to 8.33; P < 0.001). CONCLUSION: Over 2,600 CAD per index surgical admission is attributable to preoperative anemia. Preoperative interventions with per patient cost of less than 2,600 CAD could be cost effective at the hospital level. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03476707); registered 26 March, 2018.

RéSUMé: OBJECTIF: La prévalence de l'anémie est très élevée dans la population subissant une chirurgie colorectale, touchant 30­70 % des patients. L'anémie est associée à une morbidité et une mortalité importantes; toutefois, nous manquons de données probantes pour estimer les coûts des soins de santé associés à l'anémie. Cette étude avait pour but de déterminer les coûts hospitaliers de l'admission chirurgicale initiale, la durée de séjour postopératoire et le taux de transfusion associés à une anémie préopératoire lors de chirurgie colorectale majeure non urgente. MéTHODE: Cette étude de cohorte historique a inclus 851 patients adultes hospitalisés et subissant une chirurgie colorectale non urgente dans un réseau hospitalier universitaire de soins tertiaires entre avril 2010 et février 2016. L'anémie était définie comme un hématocrite ≤ 39 %. Le critère d'évaluation principal était les coûts hospitaliers totaux standardisés à la valeur du dollar canadien en 2016. Les critères d'évaluation secondaires étaient la durée de séjour postopératoire et les transfusions. Des analyses de régression multivariée et des évaluations par score de propension ont été utilisées pour mesurer les associations ajustées entre l'anémie et nos critères d'évaluation. RéSULTATS: Avant la chirurgie, 381/851 (45 %) patients étaient anémiques. Le coût moyen (écart type [ÉT]) de l'admission initiale pour une chirurgie colorectale non urgente était de 20 040 (23 219) CAD. L'anémie a été associée à une augmentation relative ajustée de 14 % des coûts (intervalle de confiance [IC] 95 %, 6 à 23; P < 0,001). Les coûts d'hospitalisation totaux attribuables à l'anémie étaient de 3027 CAD (IC 95 %, 2670 à 3388). Les coûts hospitaliers et la durée de séjour étaient très fortement associés; l'anémie a été associée à une augmentation de 18 % de la durée de séjour (IC 95 %, 7 à 30; P < 0,001) et des taux de transfusion (risque relatif, 4,7; IC 95 %, 2,71 à 8,33; P < 0,001). CONCLUSION: Plus de 2600 CAD pour l'admission chirurgicale initiale sont attribuables à l'anémie préopératoire. Des interventions préopératoires ayant un coût par patient de moins de 2600 CAD pourraient être rentables au niveau hospitalier. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03476707); enregistrée le 26 mars 2018.

Genetic and phenotypic intra-species variation in Candida albicans.

Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity.

Reduced Myocardial Flow Reserve Is Associated With Diastolic Dysfunction and Decreased Left Atrial Strain in Patients With Normal Ejection Fraction and Epicardial Perfusion.

INTRODUCTION: Coronary microvascular dysfunction (MVD) may contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Using myocardial flow reserve (MFR) measured by positron emission tomography (PET) as an assessment of microvascular function, we hypothesized that abnormal MFR is associated with LV diastolic dysfunction (DD) and reduced LV and LA strain in patients with risk factors for HFpEF and normal epicardial perfusion on cardiac PET. METHODS AND RESULTS: Retrospective study of patients without heart failure who underwent cardiac rubidium-82 PET and echocardiography. Global MFR was calculated as the ratio of global stress to rest myocardial blood flow. Echocardiographic measures of diastolic function were recorded. Global longitudinal LA and LV strain were measured with a 2-dimensional speckle-tracking technique. Relationships among MFR and echocardiographic measures were assessed with linear regression, analysis of variance, and test for trend. Seventy-three patients (age 64 ± 11 years, 52% male) were identified with no epicardial perfusion defect on cardiac PET and an ejection fraction ≥50%. Decreased MFR was associated with LV DD (P = .02) and increased E/e', an estimation of LV filling pressure (low E/e' [<8] vs. high E/e' [>15], P < .001). MFR was associated with LA strain independent of age, gender, and common comorbidities (adjusted ß = 2.6% per unit MFR, P = 0.046); however, MFR was only marginally related to LV strain. CONCLUSIONS: In patients with risk factors for HFpEF, MVD assessed with MFR was associated with DD, increased estimated LV filling pressure, and abnormal LA strain.

Graft Infection Masquerading as Rheumatologic Disease: a Rare Case of Aortobifemoral Graft Infection Presenting as Hypertrophic Osteoarthropathy.

BACKGROUND: Prosthetic vascular graft procedures are a common treatment modality for peripheral vascular disease. A relatively common complication is graft infection, occurring at a rate of 0.5-5%. When they occur, graft infections are associated with significant morbidity and mortality. Vascular graft infections also represent a diagnostic and therapeutic challenge for the physician METHODS: Here, we report a case where the rare finding of secondary hypertrophic osteoarthropathy was an important indication of underlying aortic graft infection that was initially misdiagnosed. A review of the literature revealed 34 cases of vascular graft infection associated with hypertrophic osteoarthropathy. RESULTS: The mean interval from surgery to time of infection was approximately 5 years. Mortality was 35%. When combined with hypertrophic osteoarthropathy, vascular graft infection was complicated by an aortoenteric fistula in 53% of the cases. CONCLUSION: The complexity of this case highlights the challenges physicians face in order to diagnose and treat this condition.

Clinical practice guideline: management of acute pancreatitis.

ABSTRACT: There has been an increase in the incidence of acute pancreatitis reported worldwide. Despite improvements in access to care, imaging and interventional techniques, acute pancreatitis continues to be associated with significant morbidity and mortality. Despite the availability of clinical practice guidelines for the management of acute pancreatitis, recent studies auditing the clinical management of the condition have shown important areas of noncompliance with evidence-based recommendations. This underscores the importance of creating understandable and implementable recommendations for the diagnosis and management of acute pancreatitis. The purpose of the present guideline is to provide evidence-based recommendations for the management of both mild and severe acute pancreatitis as well as the management of complications of acute pancreatitis and of gall stone-induced pancreatitis.

RESUME: Une hausse de l'incidence de pancréatite aiguë a été constatée à l'échelle mondiale. Malgré l'amélioration de l'accès aux soins et aux techniques d'imagerie et d'intervention, la pancréatite aiguë est toujours associée à une morbidité et une mortalité importantes. Bien qu'il existe des guides de pratique clinique pour la prise en charge de la pancréatite aiguë, des études récentes sur la vérification de la prise en charge clinique de cette affection révèlent des lacunes importantes dans la conformité aux recommandations fondées sur des données probantes. Ces résultats mettent en relief l'importance de formuler des recommandations compréhensibles et applicables pour le diagnostic et la prise en charge de la pancréatite aiguë. La présente ligne directrice vise à fournir des recommandations fondées sur des données probantes pour la prise en charge de la pancréatite aiguë, qu'elle soit bénigne ou grave, ainsi que de ses complications et de celles de la pancréatite causée par un calcul biliaire.

Computed tomography-guided reoperation for neurogenic thoracic outlet syndrome.

OBJECTIVE: Persistent or recurrent symptoms after surgical treatment for neurogenic thoracic outlet syndrome (nTOS) is a problem commonly encountered by high-volume referral centers. The mechanical etiology patterns at reoperation include (1) inadequate previous rib resection, (2) rib regrowth, (3) scar tissue formation, or (4) intact scalene muscle. Reoperative TOS surgery has significant potential morbidity, and therefore, careful patient selection and meticulous planning are required. This study evaluated the utility of multidetector computed tomography (CT) in the differential diagnosis of patients with recurrent or persistent nTOS. METHODS: A retrospective record review was performed of a nTOS referral practice of patients treated from 2003 to 2012 to focus on patients reoperated on for recurrent or persistent symptoms. In 2003, a dedicated high-resolution multidetector TOS CT protocol was established to assist in clinical decision making and reoperative planning. A single designated radiologist interpreted all CT images. Imaging, patient clinical characteristics, interventions, and outcomes were reviewed. RESULTS: The study group included 20 reoperations for recurrent (n = 15) or persistent (n = 5) symptoms. Mean age was 35 years, and 60% of redo cases were in women. Preoperative CT imaging demonstrated the following anatomic patterns: inadequate previous rib resection in 5 (25%), rib regrowth in 5 (25%), scar tissue formation in 10 (50%), and intact scalene muscle in 3 (15%). Operative findings concurred with preoperative imaging in 85% of patients. There were no neurovascular injuries and no major complications. At a mean follow-up of 43 months, improvement or resolution of symptoms was significant in nine patients (45%), moderate in seven (35%), and minimal in four (20%). CONCLUSIONS: Recurrent/persistent nTOS is an often-vexing problem with challenging solutions. These results demonstrate the utility of a TOS protocol CT scan in providing correlative objective findings and in assisting with reoperative planning. Positive radiographic findings that correlate with patient symptoms inform the decision to reoperate.

Vascular injury is associated with increased mortality in winter sports trauma.

BACKGROUND: Trauma is the leading cause of injury and death for individuals aged 1-44 years. Up to 8% of the US population participates in winter sports, and although vascular injuries are uncommon in these activities, little is published in this area. We sought to identify the incidence, injury patterns, and outcomes of vascular injuries resulting from winter sports trauma. METHODS: Patients with winter sports trauma and the subset with vascular injuries were identified by accessing the National Trauma Data Bank querying years 2007-2010. Patients with and without vascular injuries were then compared. Admission variables included transport time, emergency department hypotension (systolic blood pressure < 90), Glasgow Coma Scale ≤ 8, Injury Severity Score ≥ 25, fractures, solid organ injury, and vascular injury. Outcomes were analyzed and associations with vascular injuries were determined. RESULTS: A total of 2,298 patients were identified with winter sports-related trauma and 28 (1.2%) had associated vascular injuries. Overall, the top 3 injuries were head trauma (16.7%), thoracic vertebral fractures (5.5%), and lumbar vertebral fractures (5.1%). The most common associated vascular injures were to the popliteal artery (17.7%), splenic artery (14.7%), and brachial blood vessels (14.7%). In the entire cohort, 1 patient (0.04%) suffered an amputation and 15 patients (0.7%) died. There were no amputations in the vascular injury group. Mortality was 0.6% in patients without a vascular injury compared with 7.1% of those with a vascular injury (P = 0.01). CONCLUSIONS: Although vascular injury is an uncommon associated finding in winter sports trauma, it is associated with a significant increase in mortality. These findings highlight the need for rapid identification of traumatic vascular injuries, which predicts worse overall outcomes in this patient population.

Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.

Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression.

A role for VEGF as a negative regulator of pericyte function and vessel maturation.

Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rbeta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation.

Minimal thoracotomy thoracic bifemoral bypass in the endovascular era.

BACKGROUND: Endoluminal revascularization has supplanted open techniques for most aortoiliac occlusive disease with open surgery reserved for endovascular failure or long-segment aortoiliac occlusions. A number of clinical and anatomic issues can preclude the use of the infrarenal aorta for inflow. Our approach in these select patients is minimal thoracotomy thoracic bifemoral (mini-TBF) bypass. METHODS: Mini-TBF bypass used a 2-team approach. The cardiac surgery team focused on arterial inflow from the distal descending aorta via a ≤8-cm thoracotomy at ninth interspace. The vascular surgery team focused on groin reconstruction and graft tunneling. The body of the graft was tunneled through the posterior left hemidiaphragm. The left limb was tunneled retroperitoneal over the psoas and the right limb anterior to the abdominal fascia below the umbilicus to the groin. RESULTS: Thirteen patients (mean age, 64; 82% male) underwent mini-TBF bypass between 2009 and 2012 for claudication in 9 (69%) and critical limb ischemia in 4 (31%). Five patients had prior failed iliac endovascular revascularizations and 2 patients had failed prior infrarenal aortobifemoral bypass. The indication for use of thoracic aortic inflow was prior abdominal operations in 4 (31%), pelvic anatomy with a critical inferior mesenteric artery (IMA) in 5 (38%), and the condition of the infrarenal/juxtarenal aorta in 4 (31%). Median operative time was 240 min (range 181-513 min). Median length of stay was 8 days. There was no perioperative mortality. Postoperative complications occurred in 5 patients, stroke 1, pulmonary 2 (both contralateral lung issues), and 2 limb occlusion secondary to outflow disease. At median follow-up of 18 months, 2 patients required amputations, both from preexisting tissue loss despite secondary patent grafts. CONCLUSIONS: Mini-TBF bypass provides another alternative to successfully revascularize Trans-Atlantic Inter-Society Consensus II type D lesions in patients with prior abdominal revascularization, pelvic anatomy with a critical IMA, or calcification/thrombus of the infrarenal/juxtarenal aorta precludes control.

SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRbeta/B-RAF.

Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRbeta and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRbeta and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRbeta and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.

Early experience with the snorkel technique for juxtarenal aneurysms.

OBJECTIVE: The lack of readily available branched and fenestrated endovascular aneurysm repair (EVAR) options has created an opportunity for creative deployment of endograft components to treat juxtarenal aneurysms. We present our early experience with "snorkel" or "chimney" techniques in the endovascular management of complex aortic aneurysms. METHODS: We retrospectively reviewed planned snorkel procedures for juxtarenal aneurysms performed from September 2009 to August 2011. Our standardized technique included axillary or brachial cutdown for delivery of covered snorkel stents and mostly percutaneous femoral access for the main body endograft. RESULTS: Fifty-six snorkel grafts were successfully placed in 28 consecutive patients (mean age, 75 years) with juxtarenal aneurysms. Mean aneurysm size was 64.8 mm (range, 53-87 mm). The snorkel configuration extended the proximal seal zone from an unsuitable infrarenal neck for standard EVAR (median diameter, 33.5 mm; length, 0.0 mm) to a median neck diameter of 24.5 mm and length of 18.0 mm. Five patients had unilateral renal snorkels, 17 had bilateral renal snorkels, and six had celiac/superior mesenteric artery/renal combinations. Technical success of snorkel placements was 98.2%, with loss of wire access leading to one renal stent deployment failure. Thirty-day mortality was 7.1%: one patient was readmitted 1 week postoperatively with pneumonia and died of sepsis; one patient died at 1 week of a right hemispheric stroke. Other major complications included perinephric hematomas, 7.1%; permanent hemodialysis, 3.6%; iliac artery injury requiring endoconduit placement, 3.6%; and brachial plexus nerve injury, 3.6%. Cardiac complications included self-limited arrhythmias (14.3%) and one non-Q-wave myocardial infarction (3.6%), with all recovering without coronary intervention. Mean follow-up was 10.7 months (range, 3-25 months). One patient died of nonaneurysmal-related causes at 3 months (89.3% survival). Postoperative imaging revealed one renal snorkel graft occlusion occurring at 3 months (98.2% overall primary patency). Seven (25%) early endoleaks were noted on the first follow-up computed tomography angiography: two type I, three type II, and two type III (25%), leading to one secondary intervention (3.6%) with bridging cuff placement (type III). The small type Ia endoleaks and other type III endoleak resolved at the 6-month scan. Mean sac regression at the latest follow-up was 7.3 mm. No aneurysm has enlarged on postoperative imaging. CONCLUSIONS: Early success with the snorkel technique for juxtarenal aneurysms has made it our procedure of choice for complex short-neck to no-neck EVAR. Although long-term follow-up is needed, the flexibility of the snorkel technique and lack of requirement for custom-built devices may make this approach more attractive than branched or fenestrated stent grafts.

Results of a double-barrel technique with commercially available devices for hypogastric preservation during aortoilac endovascular abdominal aortic aneurysm repair.

OBJECTIVE: To assess technical feasibility and short-term outcome of a novel hypogastric preservation technique in patients with aortoiliac aneurysms using commercially available endografts without device modification. METHODS: Multi-institution review of prospectively acquired database of patients undergoing double-barrel endograft repair of aortoiliac aneurysms. RESULTS: Twenty-two patients underwent endovascular aneurysm repair for aortoiliac aneurysms from 2010 to 2011, with 23 double-barrel hypogastric preservation procedures successfully completed in 21 patients. The technique involved bifurcated main body placement followed by simultaneous deployment of parallel endograft limbs into the external iliac (ipsilateral approach) and hypogastric (contralateral femoral or brachial approach) arteries. Bilateral hypogastric branches were performed in two patients, and unilateral branches with and without contralateral coil embolization were performed in nine and ten patients, respectively. Procedural success rate was 96%, technical success rate (successful implantation with immediate aneurysm exclusion and no observed endoleak) was 88%, and access was fully-percutaneous in 86%. Two type III endoleaks between branch components were noted on completion angiograms, but both resolved spontaneously on follow-up imaging. One type Ib endoleak was noted on postoperative imaging (contralateral to hypogastric branch, repaired with limb extension), as were three type II endoleaks (14%) without sac expansion. Early (<2 weeks) limb occlusion (one external iliac, two hypogastric) occurred in two patients, though no subsequent occlusions have occurred (mean follow-up, 7.2 months; range, 1-20 months). Primary patency for external iliac and hypogastric limbs at 6 months was 95% and 88%, respectively. There were no deaths; complications included groin hematoma in 10% and acute renal insufficiency in 5%. Buttock claudication (n = 4) only occurred in patients who had ipsilateral coil embolization of hypogastric arteries (n = 9) for bilateral iliac aneurysms in which only unilateral hypogastric preservation was performed, resulting in rate of 44% in these patients. CONCLUSIONS: The double-barrel technique for hypogastric preservation is technically feasible across multiple interventionalists using commercially available endografts without device modification. These procedures are associated with minimal morbidity, acceptable short-term limb-patency rates, and reduced buttock claudication compared with those involving contralateral hypogastric embolization.