Transcatheter mitral valve repair for inotrope dependent cardiogenic shock - Design and rationale of the CAPITAL MINOS trial.

BACKGROUND: Functional mitral regurgitation (MR) is an important clinical consideration in patients with heart failure. Transcatheter edge-to-edge repair (TEER) has emerged as a useful therapeutic tool for patients with chronic heart failure, however the role of TEER in patients with cardiogenic shock (CS) and MR has not yet been studied in a randomized trial. The Transcatheter Mitral Valve Repair for Inotrope Dependent Cardiogenic Shock (CAPITAL MINOS) trial was therefore designed to determine if TEER improves clinical outcomes in the CS population. METHODS AND DESIGN: The CAPITAL MINOS trial is an open-label, multi-center randomized clinical trial comparing TEER to medical therapy in patients with CS and MR. A total of 144 patients with Society for Cardiovascular Angiography and Interventions (SCAI) class C or D CS and at least 3+ MR will be randomized in a 1:1 ratio to TEER or medical therapy alone. The primary outcome will be a composite of in-hospital all-cause mortality, cardiac transplantation, implantation of durable left ventricular assist device, or discharge on palliative inotropic therapy. Patients will be followed for the duration of their index hospitalization for the primary outcome. Secondary outcomes include 6 month mortality. IMPLICATIONS: The CAPITAL MINOS trial will determine whether TEER improves outcomes in patients with CS and MR and will be an important step in optimizing treatment for this high-risk patient population.

Impact of sex on outcomes after percutaneous repair of functional mitral valve regurgitation.

BACKGROUND: The role of percutaneous repair of functional mitral regurgitation (MR) is evolving. Left ventricle remodeling is known to be different between men and women; however, outcomes following percutaneous repair of functional MR have not considered the impact of sex. METHODS: Between 2012 and 2018, 175 patients underwent percutaneous repair of functional MR with the Mitra Clip NT/NTR (Abbott) at our institution. Patients were assessed in a dedicated clinic with a follow-up that averaged 0.7 ± 1.2 years and extended to 5.7 years. RESULTS: Men had a larger body surface area than women (p < .001), and were more likely than women to have diabetes preoperatively (p = .02). There were no deaths or instances of single leaflet detachment. Immediate postprocedure MR was ≤2+ in 158 (90%) with a mean trans-mitral valve repair gradient of 3.4 ± 1.0 and 3.5 ± 2.1 mmHg, respectively for women and men (p = .8). One- and 2-year freedom from MR ≥3+ was 86.0 ± 3.5% and 77.6 ± 5.1%, respectively. After adjusting for differences between male and female patients, women were more likely to have recurrent MR ≥3+ (hazard ratio, 4.7; 95% confidence interval, 1.2-18.4; p = .03). Upon adjusted analysis, there was also no association between gender and survival (p = .2). One- and 2-year survival was 69.8 ± 4.3% and 54.3 ± 5.5%, respectively. CONCLUSION: Women are more likely to have recurrent severe MR after percutaneous repair of functional MR. The mechanism for this remains undetermined.

Computed Simulation of Transcatheter Edge-to-Edge Mitral Valve Repair - A Proof of Concept Study.

AIMS: As transcatheter mitral valve (MV) interventions are expanding and more device types and sizes become available, a tool supporting operators in preprocedural planning and the clinical decision-making process is highly desirable. We sought to develop a finite element (FE) computational simulation model to predict results of transcatheter edge-to-edge (TEER) interventions. METHODS AND RESULTS: We prospectively enrolled patients with secondary mitral regurgitation (MR) referred for a clinically indicated TEER. Three-dimensional (3D) transesophageal echocardiograms performed at the beginning of the procedure were used to perform the simulation. On the 3D dynamic model of the MV that was first obtained, we simulated the clip implantation using the same clip(s) type, size, number, and implantation location that was used during the intervention. The 3D model of the MV obtained after simulation of the clip implantation was compared to the clinical results obtained at the end of the intervention. We analyzed the degree and location of residual MR and the shape and area of the diastolic mitral valve area. We performed computational simulation on 5 patients. Overall, the simulated models predicted well the degree and location of the residual regurgitant orifice(s) but tended to underestimate the diastolic mitral orifice area. CONCLUSIONS: In this proof-of-concept study, we present preliminary results on our algorithm simulating clip implantation in 5 patients with functional MR. We show promising results regarding the feasibility and accuracy in terms of predicting residual MR and the need to improve the estimation of the diastolic mitral valve area.

c-Met is a marker of pancreatic cancer stem cells and therapeutic target.

BACKGROUND & AIMS: Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. METHODS: We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice. RESULTS: c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases. CONCLUSIONS: c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.

Repair of quadricuspid aortic valve associated with ascending aorta dilatation.

Quadricuspid aortic valve is a rare congenital anomaly that may require surgical intervention because of valvular dysfunction. Rarely, it may be associated with enlargement of the ascending aorta. Here, the case is presented of a quadricuspid aortic valve-associated enlargement of the ascending aorta and functional aortic annulus dilatation in a 36-year-old patient. The patient subsequently underwent a successful aortic valve repair and replacement of the ascending aorta.

Transcatheter Mitral Valve Repair in Cardiogenic Shock and Mitral Regurgitation: A Patient-Level, Multicenter Analysis.

OBJECTIVES: The aim of this study was to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR). BACKGROUND: Patients in cardiogenic shock with severe MR have a poor prognosis in the setting of conventional medical therapy. Because of its favorable safety profile, TMVr is being increasingly used as an acute therapy in this population, though its efficacy remains unknown. METHODS: A multicenter, collaborative, patient-level analysis was conducted. Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success. RESULTS: Between January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03). CONCLUSIONS: TMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock.

Frequency and surgical management of complex posterior leaflet prolapse of the mitral valve.

BACKGROUND AND AIM OF THE STUDY: Isolated posterior leaflet prolapse of the mitral valve may present with more complex anatomy than limited middle scallop prolapse (P2). The study aim was to describe the incidence and surgical management of extensive or commissural posterior leaflet prolapse, in addition to long-term outcomes following repair. METHODS: Between October 2001 and May 2008, among 481 patients operated on for mitral valve prolapse, 201 consecutive patients underwent mitral valve repair for isolated posterior leaflet prolapse. Of the latter patients, only 81 (40%) had limited P2 prolapse, while the remaining 120 (60%) showed complex posterior leaflet prolapse, including either extensive (n = 105) or commissural (n = 15) prolapse. Extensive leaflet prolapse was treated with aggressive leaflet resection and sliding plasty, combined with a longitudinal annular plication using polytetrafluoroethylene running sutures. Commissural prolapse was repaired with an edge-to-edge technique or commissuroplasty. The clinical and echocardiographic follow up was complete for all patients, and extended up to 6.8 years (mean 2.4 +/- 1.9 years). RESULTS: There was no hospital mortality. Repair was successful in 200 patients (99%), who showed no or trivial mitral regurgitation (MR) intraoperatively. The five-year freedom from recurrent MR (grade > 1+) was 91.5 +/- 4.2% in patients with isolated P2 prolapse, compared to 98.8 +/- 1.2% in patients with complex posterior leaflet prolapse (p = 0.07). The repair of complex posterior leaflet prolapse was also similar to that of isolated P2 prolapse with regard to five-year freedom from reoperation (98.9 +/- 5.9% versus 100%; p = 0.4), and survival (92.1 +/- 3.3% versus 88.9 +/- 8.0%; p = 0.9). CONCLUSION: In the present series, posterior leaflet prolapse offered more complexity than usually reported, requiring surgical skills beyond simple quadrangular resection. However, the surgical approach, which typically involved extensive leaflet resection and sliding plasty, offered high repair rates and acceptable durability, considering the initial severity of the prolapse anatomy.

Atorvastatin induces apoptosis in vitro and slows growth of tumor xenografts but not polyp formation in MIN mice.

BACKGROUND: Despite the availability of effective surveillance for colorectal cancer with colonoscopy, relatively few at-risk individuals utilize this option. Colon cancer chemoprevention might be a more acceptable alternative. Some epidemiologic studies have suggested that statins may have chemopreventive effects without the risks of nonsteroidal anti-inflammatory drugs, but other epidemiologic studies have found no effect of statins. METHODS: We aimed to evaluate the efficacy of atorvastatin in inducing apoptosis in vitro, in preventing polyp formation in the min mouse, and in preventing tumor growth in nude mice. RESULTS: Atorvastatin rapidly induces apoptosis in the HCT116 colon cancer cell line in vitro, and this effect is reversible with mevalonate and geranylgeranyl pyrophosphate, but less so by farnesyl pyrophosphate. Atorvastatin chow was ineffective in reducing polyp formation in the min mouse model, with no significant effect on polyp number. Atorvastatin was effective in significantly slowing the growth of HCT116 colon cancer cell xenografts in nude mice (p = 0.008). Further, this reduction is due to increased levels of apoptosis. CONCLUSIONS: Atorvastatin can induce apoptosis in vitro, through mevalonate and prenylation pathways. Atorvastatin, while not effective in preventing polyp formation in the min mouse model, was very effective in slowing tumor growth in a nude mouse model. Consistent with in vitro findings, increased apoptosis accounted for decreased tumor growth. Statins may have benefit in cancer by slowing tumor growth, rather than preventing tumor initiation.

Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury.

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.

Clinical Diagnostic Tests versus Medial Branch Blocks for Adults with Persisting Cervical Zygapophyseal Joint Pain: A Systematic Review and Meta-Analysis.

Purpose: A systematic review and meta-analysis were performed to identify clinical tests for diagnosing cervical zygapophyseal joint pain (CZP) and to determine their diagnostic accuracy. Method: A search strategy was carried out to find relevant evidence published in CINAHL, Embase, MEDLINE, and PEDro from 1980 to January 1, 2015, pertaining to the clinical diagnosis of CZP. Quality assessment was completed using the Quality Assessment of Diagnostic Accuracy Studies-2. Results were analyzed to pool sensitivity and specificity and clarify diagnostic value. Results: Seven articles (n=463) were included for data synthesis and review. Intersegmental mobility tests were found to have the highest diagnostic accuracy, with pooled sensitivity of 0.91 (95% CI: 0.85, 0.94) and specificity of 0.74 (95% CI: 0.65, 0.81). The pooled sensitivity for mechanical sensitivity (palpation) was 0.88 (95% CI: 0.78, 0.95), and specificity was 0.61 (95% CI: 0.50, 0.71). Conclusion: Limited studies are available that discuss the clinical diagnosis of CZP, and significant heterogeneity is present in the available data. In this review, intersegmental mobility tests were found to be the most accurate. Clustering of tests, agreement on a reference standard, and further exploration of CZP referral patterns are recommended.

Objectif : analyse systématique et méta-analyse afin de déterminer les tests cliniques nécessaires pour diagnostiquer des douleurs des articulations zygapophysaires cervicales (AZC) et en établir l'exactitude diagnostique. Méthodologie : les chercheurs ont adopté une stratégie de recherche pour extraire les données probantes pertinentes publiées dans CINAHL, Embase, Medline et PEDRo entre 1980 et le 1er janvier 2015, à l'égard du diagnostic clinique d'AZC. Ils en ont évalué la qualité au moyen des études d'exactitude diagnostique des évaluations de la qualité­2. Ils ont analysé les résultats pour en regrouper la sensibilité et la spécificité ainsi que pour en confirmer la valeur diagnostique. Résultats : les auteurs ont conservé sept articles (n=463) pour la synthèse et l'analyse des données. Ils ont découvert que les tests de mobilité intersegmentaire possédaient la plus grande précision diagnostique. En effet, la sensibilité groupée s'établissait à 0,91 (IC à 95% : 0,85, 0,94) et la spécificité, à 0,74 (IC à 95 % : 0,65, 0,81). La sensibilité mécanique groupée (palpation) était de 0,88 (IC à 95 % : 0,78, 0,95), et la spécificité, à 0,61 (IC à 95 % : 0,50, 0,71). Conclusion : peu d'études portent sur le diagnostic clinique des AZC, et les données disponibles sont très hétérogènes. Dans la présente analyse, les tests de mobilité intersegmentaire étaient les plus précis. Il est recommandé de regrouper les tests, de s'entendre sur une norme de référence et d'approfondir l'examen des profils d'orientation des AZC vers d'autres spécialistes.

Papillary fibroelastoma of the pulmonary valve.

There is a lack of information regarding the diagnosis and management of papillary fibroelastoma of the pulmonary valve due to the rarity of the tumour at this location. A case of pulmonary valve papillary fibroelastoma in a 60-year-old woman is reported and the approach for diagnosis and management is described.

Canadian guidelines for training in adult perioperative transesophageal echocardiography. Recommendations of the Cardiovascular Section of the Canadian Anesthesiologists' Society and the Canadian Society of Echocardiography.

PURPOSE: To establish Canadian guidelines for training in adult perioperative transesophageal echocardiography (TEE). METHODS: Guidelines were established by the Canadian Perioperative Echocardiography Group with the support of the cardiovascular section of the Canadian Anesthesiologists' Society in conjunction with the Canadian Society of Echocardiography. Guidelines for training in echocardiography by the American Society of Echocardiography, the American College of Cardiology and the Society of Cardiovascular Anesthesiologists were reviewed, modified and expanded to produce the 2003 Quebec expert consensus for training in perioperative echocardiography. The Quebec expert consensus and the 2005 guidelines for the provision of echocardiography in Canada formed the basis of the Canadian training guidelines in adult perioperative TEE. RESULTS: Basic, advanced and director levels of expertise were identified. The total number of echocardiographic examinations to achieve each level of expertise remains unchanged from the 2002 American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists guidelines. The increased proportion of examinations personally performed at basic and advanced levels, as well as the level of autonomy at the basic level suggested by the Quebec expert consensus are retained. These examinations may be performed in a perioperative setting and are not limited to intraoperative TEE. Training 'on-the-job', the role of the perioperative TEE examination, the requirements for maintenance of competence and the duration of training are also discussed for each level of training. The components of a TEE report and comprehensive TEE examination are also outlined. CONCLUSION: The Canadian guidelines for training in adult perioperative TEE reflect the unique Canadian practice profile in perioperative TEE and address the training requirements to obtain expertise in this field.

How Does Mitral Valve Repair Fail in Patients With Prolapse?-Insights From Longitudinal Echocardiographic Follow-Up.

BACKGROUND: Repair of mitral regurgitation (MR) caused by prolapse has been well validated. Although favorable early and late results after repair have been reported, few data are available that mechanistically describe how a mitral repair fails beyond the mere need for mitral valve reoperation. We therefore sought to determine the modes of valve repair failure in patients who underwent surgical correction of MR caused by prolapse. METHODS: Between 2001 and 2015, 855 patients underwent repair of MR caused by prolapse. Patients were a mean age of 63.7 ± 12.7 years, and 380 (44%) had bileaflet prolapse. The overall repair rate was 97.2%. These patients were monitored as part of a cohort initiative and underwent serial clinical and echocardiographic assessments at 1, 3 to 6, and 12 months after the operation. Beyond the first year of the MR repair, patients were assessed by echocardiography every 1 to 2 years or when clinically indicated. Clinical and echocardiographic follow-up averaged 4.3 ± 3.5 years. RESULTS: Freedom from recurrent MR of 2+ or higher was 92.4% ± 1.3% at 5 years and 86.6% ± 2.4% at 10 years. Overall, recurrent MR of 2+ or higher developed in 49 patients (5.7%) at a mean of 3.1 ± 2.5 years after the repair, of whom 14 (1.6%) had recurrent MR of 3+ or 4+. Among patients with bileaflet prolapse, recurrent MR of 2+ or higher was observed in 24, of whom 9 had 3+ or 4+ MR., The development of recurrent MR of 2+ or higher was categorized as prolapse in 6 and nonprolapse in 43. Severe mitral stenosis occurred in 3 patients at 8.2 years after the MR repair. Mitral reoperation was ultimately performed in 21 patients. Patients who had recurrent MR 2+ or higher within the first year after the operation were more likely to undergo a subsequent mitral valve reoperation (incident rate ratio, 5.2 ± 2.9; p = 0.003), although no association between recurrent MR and reoperation was observed after the first year. CONCLUSIONS: Severe MR after repair is rare, although some may have recurrent moderate MR. Patients who required a subsequent mitral valve reoperation were most likely to have recurrent MR of 2+ or higher within the first year after the operation.

Mitral valve repair in acquired dextrocardia.

Surgical correction of valvular heart disease in patients with dextrocardia is extremely rare. We report a surgical case of mitral valve repair in a patient with acquired dextrocardia. Successful mitral valve repair was performed through a right lateral thoracotomy. We describe our surgical strategy and summarize the literature.

Aortic root geometry in bicuspid aortic insufficiency versus stenosis: implications for valve repair.

OBJECTIVES: The contribution of aortic annular and root disease in bicuspid aortic valve (BAV) insufficiency remains unclear. We compared aortic root geometry between BAV stenosis and aortic insufficiency (AI), before and after repair. METHODS: Patients presenting for surgery for BAV insufficiency (n = 58) were compared with patients with BAV stenosis (n = 58). Clinical and transoesophageal echocardiographic data were collected, including end-diastolic diameters of the ventriculo-aortic junction (VAJ), aortic root, sinotubular junction (STJ) and ascending aorta (AA). RESULTS: AI patients were younger and more likely to be male compared with aortic stenosis (AS) patients. VAJ, aortic root and STJ diameters were significantly larger in AI compared with AS patients (30 ± 0.5 vs 25 ± 0.4 mm, P < 0.001; 41 ± 0.8 vs 34 ± 0.6 mm, P < 0.001; 36 ± 0.9 vs 30 ± 0.6 mm, P < 0.001, respectively). Following multivariable adjustment for age, sex, body surface area and ascending aortic diameter, these diameters remained larger in AI patients with a mean difference of 3, 6 and 4 mm, respectively (all P < 0.001). Mean AA diameter in the AI group was similar to the AS group (37 ± 1.0 vs 34 ± 0.8 mm, P = 0.06). Forty (69%) AI patients had BAV repair with a mean reduction in VAJ and STJ diameters of 5 and 9 mm compared with prerepair (P < 0.0001). CONCLUSIONS: Despite the absence of aortic aneurysms, aortic annulus and root dimensions are significantly larger in patients with BAV insufficiency compared with stenosis. Alterations in aortic root geometry contribute to the pathophysiology of BAV insufficiency and require correction for a successful repair.

Occurrence of a second primary papillary fibroelastoma.

Papillary fibroelastomas are rare, benign cardiac tumours that most commonly arise from cardiac valves, and often present with signs and symptoms of embolization. A patient presented initially with transient ischemic attacks. He was found to have a papillary fibroelastoma on his tricuspid valve, which was successfully resected. Nine years later, he presented again with cerebral embolic symptoms and was found to have a new fibroelastoma on his mitral valve. The presence of a new lesion should be considered if signs or symptoms recur.

Perioperative deaths after mitral valve operations may be overestimated by contemporary risk models.

BACKGROUND: Percutaneous therapies to manage mitral regurgitation are emerging as an alternative to conventional operations, especially for patients with a high estimated perioperative risk. However, contemporary risk models may not accurately reflect outcomes at reference mitral valve centers. The purpose of this study was to describe perioperative mortality rates after mitral valve operations in a contemporary cohort. METHODS: Between 2001 and 2011, 1,154 patients underwent mitral valve operations at a reference center. Of these, 851 underwent repair and 303 underwent replacement. Concomitant coronary artery bypass grafting was performed in 201 (17%). The Society of Thoracic Surgeons (STS) risk score version 2.73 and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II were used to estimate the number of perioperative deaths. RESULTS: The observed perioperative mortality was 1.0%. The STS score was 2.3%±2.6% and was higher than the observed mortality rate for each of the STS subgroups (all p<0.001). The EuroSCORE II expected mortality was 3.0%±3.4% and was greater than the observed mortality rate for isolated and combined procedures (both p<0.001). The STS and EuroSCORE II provided fair death discrimination, with an area under the receiver operating characteristic curve of 0.74 and 0.67, respectively. CONCLUSIONS: Although current risk models aid in risk stratifying patients, the contemporary perioperative mortality rate at a reference mitral valve center is significantly lower than expected. The use of alternate therapies must therefore take into consideration differences in perioperative risk based on the treating center.

The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer.

BACKGROUND: Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized. METHODS: Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth. RESULTS: Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population. CONCLUSION: The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.

Novel neutralizing hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine hedgehog signaling.

The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.