Publications by authors named "Lars Stangenberg"

24 Publications

  • Page 1 of 1

Wound location is independently associated with adverse outcomes following first-time revascularization for tissue loss.

J Vasc Surg 2020 Aug 29. Epub 2020 Aug 29.

Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Electronic address:

Objective: Few studies adequately evaluate the impact of wound location on patient outcomes after lower extremity revascularization. Consequently, we evaluated the relationship between lower extremity wound location and long-term outcomes.

Methods: We reviewed all patients at our institution undergoing any first-time open surgical bypass or percutaneous transluminal angioplasty with or without stenting for tissue loss between 2005 and 2014. We categorized wounds into three distinct groups: forefoot (ie, toes and metatarsal heads), midfoot (ie, dorsal, plantar, lateral, medial surfaces excluding toes, metatarsal heads, or heel), and heel. Limbs with multiple wounds were excluded from analyses. We compared rates of perioperative complications, wound healing, reintervention, limb salvage, amputation-free survival, and survival using χ, Kaplan-Meier, and Cox regression analyses.

Results: Of 2869 infrainguinal revascularizations from 2005 to 2014, 1126 underwent a first-time revascularization for tissue loss, of which 253 patients had multiple wounds, 197 had wounds proximal to the ankle, 100 had unreliable wound information, and 576 (forefoot, n = 397; midfoot, n = 61; heel, n = 118) fit our criteria and had a single foot wound with reliable information regarding wound specifics. Patients with forefoot, midfoot, and heel wounds had similar rates of coronary artery disease, hypertension, diabetes, and smoking history (all P > .05). Conversely, there were significant differences in patient age (71 vs 69 vs 70 years), prevalence of gangrene (41% vs 5% vs 21%), and dialysis dependence (18% vs 17% vs 30%) (all P < .05). There were no statistically significant differences in perioperative mortality (1.3% vs 4.9% vs 4.2%; P = .06) or postoperative complications among the three groups. Between forefoot, midfoot, and heel wounds, there were significant differences in unadjusted 6-month rates of complete wound healing (69% vs 64% vs 53%), 3-year rates of amputation-free survival (54% vs 57% vs 35%), and survival (61% vs 72% vs 41%) (all P < .05). After adjustment, compared with forefoot wounds, heel wounds were associated with higher rates of incomplete 6-month wound healing (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.]), major amputation or mortality (HR, 1.7; 95% CI, 1.1-2.7), and all-cause mortality (HR, 1.8; 95% CI, 1.1-3.0), but not major amputation alone (HR, 2.1; 95% CI, 0.9-4.5). In open surgical bypass-first patients, heel wounds were solely associated with an increased risk of all-cause mortality (HR, 1.7; 95% CI, 1.1-2.8), whereas heel wounds in percutaneous transluminal angioplasty-first patients were associated with an increased risk of incomplete wound healing (HR, 2.2; 95% CI, 1.3-3.7), major amputation or mortality (HR, 2.3; 95% CI, 1.1-5.4), and all-cause mortality (HR, 2.8; 95% CI, 1.1-7.2).

Conclusions: Heel wounds confer considerably higher short- and long-term morbidity and mortality compared with midfoot or forefoot wounds in patients undergoing any first-time lower extremity revascularization.
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http://dx.doi.org/10.1016/j.jvs.2020.07.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914284PMC
August 2020

Commentary: Spinal cord ischemia following aortic surgery: Survey says?

J Thorac Cardiovasc Surg 2020 Mar 31. Epub 2020 Mar 31.

Division of Cardiac Surgery, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, RI. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.03.058DOI Listing
March 2020

Five-year survival following endovascular repair of ruptured abdominal aortic aneurysms is improving.

J Vasc Surg 2020 07 21;72(1):105-113.e4. Epub 2020 Feb 21.

Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Electronic address:

Objective: Increasing experience and improving technology have led to the expansion of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysms (AAA). We investigated whether the 5-year survival after both EVAR and open repair for ruptured AAA changed over the last 14 years.

Methods: We identified repairs for ruptured infrarenal AAA within the Vascular Quality Initiative registry between 2004 and 2018. We compared the 5-year survival of both EVAR and open repair between the early (2004-2012) and late (2013-2018) cohorts. In addition, we compared EVAR with open repair in the early and late cohorts. We used propensity score modeling to create matching cohorts for each analysis. Kaplan-Meier analysis was used to estimate survival proportions and univariate Cox proportional hazards analysis was used to compare differences in hazard of mortality in the matched cohorts.

Results: We identified 4638 ruptured AAA repairs. This included 409 EVARs in the early cohort and 2250 in the late cohort, as well as 558 open repairs in the early cohort and 1421 in the late cohort. Propensity matching resulted in 366 matched pairs of late vs early EVAR and 391 matched-pairs of late vs early open repair. When comparing EVAR with open repair, propensity matching resulted in 277 matched pairs of early EVAR versus open, and 1177 matched pairs of late EVAR versus open. In matched EVAR patients, 5-year survival was higher in the late cohort (63% vs 49%; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61-0.97; P = .027), whereas there was no difference between matched late vs early for open repair patients (52% vs 59%; HR, 1.04; 95% CI, 0.85-1.28; P = .69). In the early cohort, there was no survival difference between EVAR and open repair (51% vs 46%; HR, 0.88; 95% CI, 0.69-1.11; P = .28). However, in the late cohort EVAR was associated with higher survival compared with open repair (63% vs 54%; HR, 0.69; 95% CI, 0.60-0.79; P < .001).

Conclusions: The 5-year survival after EVAR for ruptured AAA has improved over time, whereas survival after open repair remained constant. Consequently, the relative survival benefit of EVAR over open repair has increased over time, which should encourage further adoption of EVAR for ruptured AAA.
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http://dx.doi.org/10.1016/j.jvs.2019.10.074DOI Listing
July 2020

Endovascular Versus Surgical Revascularization for Acute Limb Ischemia: A Propensity-Score Matched Analysis.

Circ Cardiovasc Interv 2020 01 17;13(1):e008150. Epub 2020 Jan 17.

Division of Cardiology, Lifespan Cardiovascular Institute, Warren Alpert Medical School of Brown University, Providence, RI (S.T.M., O.N.H., P.S., H.D.A.).

Background: The optimal revascularization strategy for acute limb ischemia (ALI) remains unclear, and contemporary comparative effectiveness data on endovascular versus surgical revascularization are lacking.

Methods: We used the 2010 to 2014 National Inpatient Sample databases to identify hospitalizations with a primary diagnosis of ALI. Patients were propensity-score matched on the likelihood of undergoing endovascular versus surgical revascularization using a logistic regression model. The primary outcome was in-hospital mortality. Secondary outcomes included myocardial infarction, stroke, composite of death/myocardial infarction/stroke, any amputation, fasciotomy, acute kidney injury, major bleeding, transfusion, vascular complications, length of stay, and hospital costs.

Results: Of 10 484 (weighted national estimate=51 914) hospitalizations for ALI, endovascular revascularization was performed in 5008 (47.8%) and surgical revascularization in 5476 (52.2%). In the propensity-score matched cohort (n=7746; 3873 per group), patients who underwent endovascular revascularization had significantly lower in-hospital mortality (2.8% versus 4.0%; =0.002), myocardial infarction (1.9% versus 2.7%; =0.022), composite of death/myocardial infarction/stroke (5.2% versus 7.5%; <0.001), acute kidney injury (10.5% versus 11.9%; =0.043), fasciotomy (1.9% versus 8.9%; <0.001), major bleeding (16.7% versus 21.0%; <0.001), and transfusion (10.3% versus 18.5%; <0.001), but higher vascular complications (1.4% versus 0.7%; =0.002), compared with those undergoing surgical revascularization. Rates of any amputation were similar between the 2 groups (4.7% versus 5.1%; =0.43). Median length of stay was shorter and hospital costs higher with endovascular versus surgical revascularization.

Conclusions: In patients with ALI, endovascular revascularization was associated with better in-hospital clinical outcomes compared with surgical revascularization. Contemporary randomized controlled trials are needed to determine the optimal revascularization strategy for ALI.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008150DOI Listing
January 2020

Commentary: Hybrid thoracoabdominal aortic aneurysm repair: One step closer with the SPIDER graft.

J Thorac Cardiovasc Surg 2019 09 12;158(3):704-705. Epub 2018 Dec 12.

Division of Cardiothoracic Surgery, Department of Surgery, Alpert Medical School, Brown University, Providence, RI. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2018.11.112DOI Listing
September 2019

Image Fusion and 3-Dimensional Roadmapping in Endovascular Surgery.

Ann Vasc Surg 2018 Oct 22;52:302-311. Epub 2018 May 22.

Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Electronic address:

Practitioners of endovascular surgery have historically used 2-dimensional (2D) intraoperative fluoroscopic imaging, with intravascular contrast opacification, to treat complex 3-dimensional (3D) pathology. Recently, major technical developments in intraoperative imaging have made image fusion techniques possible, the creation of a 3D patient-specific vascular roadmap based on preoperative imaging which aligns with intraoperative fluoroscopy, with many potential benefits. First, a 3D model is segmented from preoperative imaging, typically a computed tomography scan. The model is then used to plan for the procedure, with placement of specific markers and storing of C-arm angles that will be used for intraoperative guidance. At the time of the procedure, an intraoperative cone beam computed tomography is performed, and the 3D model is registered to the patient's on-table anatomy. Finally, the system is used for live guidance in which the 3D model is codisplayed with overlying fluoroscopic images. There are many applications for image fusion in endovascular surgery. We have found it to be particularly useful for endovascular aneurysm repair (EVAR), complex EVAR, thoracic EVAR, carotid stenting, and for type 2 endoleaks. Image fusion has been shown in various settings to lead to decreased radiation dose, less iodinated contrast use, and shorter procedure times. In the future, fusion models may be able to account for vessel deformation caused by the introduction of stiff wires and devices, and the user-dependent steps may become more automated. In its current form, image fusion has already proven itself to be an essential component in the planning and success of complex endovascular procedures.
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http://dx.doi.org/10.1016/j.avsg.2018.03.032DOI Listing
October 2018

Liver perfusion dependent on superior mesenteric artery aneurysm.

J Vasc Surg 2018 02;67(2):618-619

Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jvs.2017.01.045DOI Listing
February 2018

Modern Fixed Imaging Systems Reduce Radiation Exposure to Patients and Providers.

Vasc Endovascular Surg 2018 Jan 21;52(1):52-58. Epub 2017 Nov 21.

1 Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

High-definition fluoroscopic imaging is required to perform endovascular procedures safely and precisely, especially in complex cases, resulting in longer procedures and increased radiation exposure. This is of importance for training institutions as trainees, even with sound instruction in as low as reasonably achievable (ALARA) principles, tend to have high radiation exposures. Recently, there was an upgrade in the imaging system allowing for comparison of radiation exposure to patients and providers. We performed an analysis of consecutive endovascular aneurysm repair (EVAR) and superficial femoral artery (SFA) interventions in the years 2013 to 2014. We recorded body mass index (BMI) and fluoroscopy time (FT) and subsequently matched 1:1 based on BMI, FT, or both. We determined radiation dose using air kerma (AK) and also recorded individual surgeons' badge readings. Allura Xper FD20 was upgraded to AlluraClarity with ClarityIQ. We identified a total of 77 EVARs (52 pre and 25 post) and 134 SFA interventions (99 pre and 35 post). Unmatched results for EVAR were BMI pre 26.2 versus post 25.8 (kg/m, P = .325), FT 28.1 versus 21.2 (minutes, P = .051), and AK 1178.5 versus 581 (mGy, P < .001), respectively. After matching, there was a 53.2% reduction in AK (846.1 vs 395.9 mGy; P = .004) for EVAR. Unmatched results for SFA interventions were BMI pre 28.1 versus post 26.6 ( P = .327), FT 18.7 versus 16.2 ( P = .282), and AK 285.6 versus 106.0 ( P < .001), respectively. After matching, there was a 57.0% reduction in AK (305.0 vs 131.3, P < .001). The total deep dose equivalent from surgeons' badge readings decreased from 39.5 to 17 mrem ( P = .029). Aortic and peripheral endovascular interventions can be performed with reduced radiation exposure to patients and providers, employing modern fixed imaging systems with advanced dose reduction technology. This is of particular importance in the light of the increasing volume and complexity of endovascular and hybrid procedures as well as the prospect of decades of radiation exposure during training and practice.
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http://dx.doi.org/10.1177/1538574417742211DOI Listing
January 2018

Development of a risk prediction model for transfusion in carotid endarterectomy and demonstration of cost-saving potential by avoidance of "type and screen".

J Vasc Surg 2016 Dec 16;64(6):1711-1718. Epub 2016 Jul 16.

Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Electronic address:

Objective: Preoperative testing for carotid endarterectomy (CEA) often includes blood typing and antibody screen (T&S). In our institutional experience, however, transfusion for CEA is rare. We assessed transfusion rate and risk factors in a national clinical database to identify a cohort of patients in whom T&S can safely be avoided with the potential for substantial cost savings.

Methods: With use of the National Surgical Quality Improvement Program database, transfusion events and timing were established for all elective CEAs in 2012-2013. Comorbidities and other characteristics were compared for patients receiving intraoperative or postoperative transfusion and those who did not. After random assignment of the total data to either a training or validation set, a prediction model for transfusion risk was created and subsequently validated.

Results: Of 16,043 patients undergoing CEA in 2012-2013, 276 received at least one transfusion before discharge (1.7%); 42% of transfusions occurred on the day of surgery. Preoperative hematocrit <30% (odds ratio [OR], 57.4; 95% confidence interval [CI], 29.6-111.1), history of congestive heart failure (OR, 2.8; 95% CI, 1.1-7.1), dependent functional status (OR, 2.7; 95% CI, 1.5-5.1), coagulopathy (OR, 2.5; 95% CI, 1.7-3.6), creatinine concentration ≥1.2 mg/dL (OR, 2.3; 95% CI, 1.6-3.3), preoperative dyspnea (OR, 2.0; 95% CI, 1.4-3.1), and female gender (OR, 1.6; 95% CI, 1.1-2.3) predicted transfusion. A risk prediction model based on these data produced a C statistic of 0.85; application of this model to the validation set demonstrated a C statistic of 0.81. In the validation set, 93% of patients received a score of 6 or less, corresponding to an individual predicted transfusion risk of 5% or less. Omitting a T&S in these patients would generate a substantial annual cost saving for National Surgical Quality Improvement Program hospitals.

Conclusions: Whereas T&S are commonly performed for patients undergoing CEA, transfusion after CEA is rare and well predicted by a transfusion risk score. Avoidance of T&S in this low-risk population provides a substantial cost-saving opportunity without compromise of patient care.
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http://dx.doi.org/10.1016/j.jvs.2016.04.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121067PMC
December 2016

A novel tool for three-dimensional roadmapping reduces radiation exposure and contrast agent dose in complex endovascular interventions.

J Vasc Surg 2015 Aug 10;62(2):448-55. Epub 2015 Jun 10.

Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. Electronic address:

Objective: The volume and complexity of endovascular procedures are increasing. Multidetector computed tomography (CT) made precise three-dimensional (3D) planning of these procedures possible, but intraoperative imaging, even with the use of modern flat-panel detectors, is limited to two dimensions. Flat detectors, however, allow C-arm cone-beam CT. This technology can be used to generate a 3D data set that can be fused with a preoperative high-resolution CT scan, thus generating a live 3D roadmap. We hypothesized that use of a novel image fusion software, VesselNavigator (Philips Healthcare, Best, The Netherlands), facilitates precise and expeditious procedures and therefore reduces radiation exposure and contrast agent dose.

Methods: A retrospective review of patients undergoing standard aortobi-iliac endovascular aneurysm repair at our institution between January 2011 and April 2014 was performed. Conventional imaging was compared with VesselNavigator-assisted imaging, and a matched analysis based on body mass index (BMI) was performed because of the dependence of radiation dose on body habitus. Outcome parameters were procedure time, fluoroscopy time, radiation, and contrast agent dose.

Results: A total of 75 patients were identified. After matching based on BMI, control and VesselNavigator groups each had 16 patients with BMI of 27.0 ± 3.6 kg/m(2) and 27.0 ± 3.6 kg/m(2), respectively (mean ± standard deviation). R(2) was 6.37 × 10(-7). Radiation dose measured as air kerma was lower with VesselNavigator (1067 ± 470.4 mGy vs 1768 ± 696.2 mGy; P = .004). Fluoroscopy time was shorter (18.4 ± 6.8 minutes vs 26.8 ± 10.0 minutes; P = .01) and contrast agent dose was lower (37.4 ± 21.3 mL vs 77.3 ± 23.0 mL; P < .001) with VesselNavigator compared with control. Procedure time was also shorter with VesselNavigator (80.4 ± 21.2 minutes vs 110.0 ± 29.1 minutes; P = .005).

Conclusions: Image fusion using VesselNavigator enhances the functionality of conventional fluoroscopy in standard endovascular aneurysm repair. It reduces radiation exposure to patients and providers. It also limits the amount of contrast agent and shortens the overall procedure length. The benefit of this technology is demonstrated on this typically straightforward procedure but may be even more useful for complex procedures.
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http://dx.doi.org/10.1016/j.jvs.2015.03.041DOI Listing
August 2015

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature.

Proc Natl Acad Sci U S A 2014 Aug 21;111(31):11419-24. Epub 2014 Jul 21.

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115

Two-way communication between the mammalian nervous and immune systems is increasingly recognized and appreciated. An intriguing example of such crosstalk comes from clinical observations dating from the 1930s: Patients who suffer a stroke and then develop rheumatoid arthritis atypically present with arthritis on only one side, the one not afflicted with paralysis. Here we successfully modeled hemiplegia-induced protection from arthritis using the K/BxN serum-transfer system, focused on the effector phase of inflammatory arthritis. Experiments entailing pharmacological inhibitors, genetically deficient mouse strains, and global transcriptome analyses failed to associate the protective effect with a single nerve quality (i.e., with the sympathetic, parasympathetic, or sensory nerves). Instead, there was clear evidence that denervation had a long-term effect on the limb microvasculature: The rapid and joint-localized vascular leak that typically accompanies and promotes serum-transferred arthritis was compromised in denervated limbs. This defect was reflected in the transcriptome of endothelial cells, the expression of several genes impacting vascular leakage or transendothelial cell transmigration being altered in denervated limbs. These findings highlight a previously unappreciated pathway to dissect and eventually target in inflammatory arthritis.
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http://dx.doi.org/10.1073/pnas.1410854111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128122PMC
August 2014

Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.

Cancer Discov 2013 Oct 1;3(10):1190-205. Epub 2013 Aug 1.

1Abramson Family Cancer Research Institute; 2Perelman School of Medicine, University of Pennsylvania; 3The Wistar Institute, Philadelphia, Pennsylvania; Departments of 4Pharmacology and Cancer Biology and 5Radiation Oncology, Duke University Medical Center, Durham, North Carolina; 6Howard Hughes Medical Institute; 7Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; and 8Memorial Sloan-Kettering Cancer Center, New York, New York.

Unlabelled: Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.

Significance: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.
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http://dx.doi.org/10.1158/2159-8290.CD-13-0118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822914PMC
October 2013

Low degree of formal education and musical experience predict degree of music-induced stress reduction in relatives and friends of patients: a single-center, randomized controlled trial.

Ann Surg 2013 May;257(5):834-8

Department of Surgery, Massachusetts General Hospital, Boston, MA 021114, USA.

Objective: To determine the factors that may predict music-induced relaxation in friends and family of patients in the emergency department.

Background: It remains unclear to date which demographic and experiential factors predict the effectiveness of music-induced relaxation. Furthermore, in-hospital stressors for friends and family of patients rather than patients themselves are underresearched and deserve in-depth investigation to improve this group's experience in health care environments.

Methods: A total of 169 relatives and friends of patients in the emergency department-waiting area completed a series of questionnaires, including the Spielberger State-Trait Anxiety Inventory (STAI), the Music Experience Questionnaire (MEQ), and a demographic survey. They were then randomly assigned to either Case Group (1 hour in the waiting area with classical music in the background) or Control Group (1 hour with no music) before completing a second, identical copy of the STAI to measure change from baseline. Data were analyzed for associations between music intervention, change in STAI scores, MEQ scores, and demographic characteristics.

Results: Participants who underwent the music intervention experienced a 9.8% decrease in overall mean State Anxiety, whereas those in the Control Group experienced no change over time (P = 0.001). Higher education significantly inversely correlated with the effectiveness of music intervention: participants with no formal education beyond high school showed a greater overall mean decrease in State Anxiety than those with a college education or beyond in response to classical music (P = 0.006). Furthermore, MEQ scores indicated that the Social Uplift scale (a measure of one's tendency to be uplifted in a group-oriented manner by music) was highly predictive of the effectiveness of music intervention.

Conclusions: Music is an effective and inexpensive means of reducing anxiety in friends and family of patients, who are underresearched in medicine. Moreover, low educational attainment and tendency to respond positively to music in a group setting can predict the effectiveness of music-induced relaxation.
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http://dx.doi.org/10.1097/SLA.0b013e31828ee1daDOI Listing
May 2013

In vivo optical molecular imaging of matrix metalloproteinase activity following celecoxib therapy for colorectal cancer.

Mol Imaging 2012 Sep-Oct;11(5):417-25

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.

We present an optical molecular imaging approach to measure the efficacy of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumor growth rate through its effect on matrix metalloproteinase (MMP) activity. A xenograft model of colorectal cancer was generated in nude mice, which were then randomized to receive celecoxib versus vehicle. MMP activity was measured by an enzyme-activatable optical molecular probe. A novel genetically engineered mouse (GEM) model of colorectal cancer was also used to assess celecoxib's effect on MMP activity, which was measured by quantitative fluorescence colonoscopy. Subcutaneously implanted xenograft tumors were 84% (SD 20.2%) smaller in volume in the treatment group versus the control group. Moreover, treated animals exhibited only a 7.6% (SEM 9%) increase in MMP activity versus 106% (SEM 8%) for untreated animals. There was an apparent linear relationship (r  =  .91) between measured MMP activity and tumor growth rate. Finally, in the GEM model experiment, treated murine tumors remained relatively unchanged in volume and MMP activity; however, untreated tumors grew significantly and showed an increase in MMP activity. This method may provide for the improved identification of patients for whom COX-2 inhibition therapy is indicated by allowing one to balance the patient's cardiovascular risk with the cancer's responsiveness to celecoxib.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683544PMC
September 2013

A quality improvement study on avoidable stressors and countermeasures affecting surgical motor performance and learning.

Ann Surg 2012 Jun;255(6):1190-4

Harvard Medical School, Massachusetts General Hospital, Department of Surgery, Boston, MA 02114, USA.

Objective: To explore how the 2 most important components of surgical performance--speed and accuracy-are influenced by different forms of stress and what the impact of music is on these factors.

Background: On the basis of a recently published pilot study on surgical experts, we designed an experiment examining the effects of auditory stress, mental stress, and music on surgical performance and learning and then correlated the data psychometric measures to the role of music in a novice surgeon's life.

Methods: Thirty-one surgeons were recruited for a crossover study. Surgeons were randomized to 4 simple standardized tasks to be performed on the SurgicalSIM VR laparoscopic simulator (Medical Education Technologies, Inc, Sarasota, FL), allowing exact tracking of speed and accuracy. Tasks were performed under a variety of conditions, including silence, dichotic music (auditory stress), defined classical music (auditory relaxation), and mental loading (mental arithmetic tasks). Tasks were performed twice to test for memory consolidation and to accommodate for baseline variability. Performance was correlated to the brief Musical Experience Questionnaire (MEQ).

Results: Mental loading influences performance with respect to accuracy, speed, and recall more negatively than does auditory stress. Defined classical music might lead to minimally worse performance initially but leads to significantly improved memory consolidation. Furthermore, psychologic testing of the volunteers suggests that surgeons with greater musical commitment, measured by the MEQ, perform worse under the mental loading condition.

Conclusions: Mental distraction and auditory stress negatively affect specific components of surgical learning and performance. If used appropriately, classical music may positively affect surgical memory consolidation. It also may be possible to predict surgeons' performance and learning under stress through psychological tests on the role of music in a surgeon's life. Further investigation is necessary to determine the cognitive processes behind these correlations.
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http://dx.doi.org/10.1097/SLA.0b013e318250b332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354736PMC
June 2012

Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.

PLoS One 2009 Nov 30;4(11):e8075. Epub 2009 Nov 30.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008075PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779485PMC
November 2009

Ocular melanoma metastatic to the pancreas after a 28-year disease-free interval.

Surgery 2010 Jul 29;148(1):151-4. Epub 2009 Jul 29.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.surg.2009.06.013DOI Listing
July 2010

Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell function.

Arthritis Rheum 2009 Aug;60(8):2314-24

Department of Radiology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114, USA.

Objective: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis.

Methods: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin-selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil-endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay.

Results: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor alpha was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration.

Conclusion: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.
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http://dx.doi.org/10.1002/art.24704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080016PMC
August 2009

Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.

Int J Radiat Oncol Biol Phys 2009 Jul;74(4):1207-16

Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS).

Methods And Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed.

Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis.

Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.
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http://dx.doi.org/10.1016/j.ijrobp.2009.02.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733223PMC
July 2009

Improved detection of ovarian cancer metastases by intraoperative quantitative fluorescence protease imaging in a pre-clinical model.

Gynecol Oncol 2009 Mar 8;112(3):616-22. Epub 2009 Jan 8.

Center for Molecular Imaging Research, Massachusetts General Hospital, Simches 8226, 185 Cambridge St., Boston, MA 02114, USA.

Objectives: Cytoreductive surgery is a cornerstone of therapy in metastatic ovarian cancer. While conventional white light (WL) inspection detects many obvious tumor foci, careful histologic comparison has shown considerable miss rates for smaller foci. The goal of this study was to compare tumor detection using WL versus near infrared (NIR) imaging with a protease activatable probe, as well as to evaluate the ability to quantify NIR fluorescence using a novel quantitative optical imaging system.

Methods: A murine model for peritoneal carcinomatosis was generated and metastatic foci were imaged using WL and NIR imaging following the i.v. administration of the protease activatable probe ProSense750. The presence of tumor was confirmed by histology. Additionally, the ability to account for variations in fluorescence signal intensity due to changes in distance between the catheter and target lesion during laparoscopic procedures was evaluated.

Results: NIR imaging with a ProSense750 significantly improved upon the target-to-background ratios (TBRs) of tumor foci in comparison to WL imaging (minimum improvement was approximately 3.5 fold). Based on 52 histologically validated samples, the sensitivity for WL imaging was 69%, while the sensitivity for NIR imaging was 100%. The effects of intraoperative distance changes upon fluorescence intensity were corrected in realtime, resulting in a decrease from 89% to 5% in signal variance during fluorescence laparoscopy.

Conclusions: With its molecular specificity, low background autofluorescence, high TBRs, and quantitative signal, optical imaging with NIR protease activatable probes greatly improves upon the intraoperative detection of ovarian cancer metastases.
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http://dx.doi.org/10.1016/j.ygyno.2008.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664404PMC
March 2009

Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase.

Proc Natl Acad Sci U S A 2008 Nov 14;105(47):18584-9. Epub 2008 Nov 14.

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, CNY-149, 13th Street, Charlestown, MA 02129, USA.

Inflammation can extend ischemic brain injury and adversely affect outcome in experimental animal models. A key difficulty in translating animal studies to humans is the lack of a definitive method to confirm and track inflammation in the brain in vivo. Myeloperoxidase (MPO), a key inflammatory enzyme secreted by activated neutrophils and macrophages/microglia, can generate highly reactive oxygen species to cause additional damage in cerebral ischemia. We report here that a functional, enzyme-activatable MRI agent can accurately track the oxidative activity of MPO noninvasively in stroke in living animals. We found that MPO is widely distributed in ischemic tissues, correlates positively with infarct size, and is detected even 3 weeks postinfarction. The peak level of MPO activity, determined by activation of the MPO-sensing agent in vivo and confirmed by MPO activity and quantitative RT-PCR assays, occurred on day 3 after ischemia. Both neutrophils and macrophages/microglia contribute to secrete MPO in the ischemic brain, although neutrophils peak earlier (days 1-3) whereas macrophages/microglia are most abundant later (days 3-7). In contrast to the conventional MRI agent diethylenetriamine-pentatacetate gadolinium, which reports blood-brain barrier disruption, MPO imaging is able to additionally track MPO activity and confirm inflammation on the molecular level in vivo, information that was previously only possible to obtain on ex vivo brain sections and impossible to assess in living human patients. Our findings could allow efficient noninvasive serial screening of therapies targeting inflammation and the use of MPO imaging as an imaging biomarker to risk-stratify patients.
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http://dx.doi.org/10.1073/pnas.0803945105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587593PMC
November 2008

Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction.

Eur Heart J 2008 Feb;29(4):445-54

Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Room 5406, Charlestown, MA 02129, USA.

Aims: The transglutaminase factor XIII (FXIII) emerges as a key enzyme in healing after myocardial infarction (MI). Here we assess the impact of transglutaminase-modulating therapies on healing and evolution of heart failure using a novel, non-invasive molecular imaging technique.

Methods And Results: Immunoblotting revealed lower FXIII levels in the myocardium of nine patients with infarct rupture when compared to MI patients without rupture (P < 0.0045). In a murine model of MI, we assessed healing while modulating local FXIII activity. Infarct tissue activity was monitored with molecular in vivo single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and activity was found to be increased by 80% in FXIII-treated mice (400 IU FXIII/kg iv.), and decreased by 65% in dalteparin (DP)-treated mice (600 IU/kg DP sc., P < 0.05). DP-treated mice exhibited increased mortality due to infarct rupture (64% by day 7, P < 0.018). Serial Magnetic Resonance Imaging (MRI) showed that left ventricular dilation post-MI was attenuated by FXIII treatment when compared to saline control-treated mice with MI (P = 0.04). Quantitative histological and reverse transcription-polymerase chain reaction analyses revealed that FXIII treatment induced a faster resolution of the neutrophil response, enhanced macrophage recruitment, increased collagen content and augmented angiogenesis in the healing infarct (P < 0.05 vs. control-treated mice with MI).

Conclusion: FXIII tissue levels are decreased in patients with insufficient healing. Therapeutic strategies that modulate FXIII activity impact murine myocardial healing. Molecular imaging of FXIII activity predicts prognosis in mice with experimental MI.
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http://dx.doi.org/10.1093/eurheartj/ehm558DOI Listing
February 2008

The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.

J Exp Med 2007 Nov 19;204(12):3037-47. Epub 2007 Nov 19.

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6C(hi) and -6C(lo) monocytes via CCR2 and CX(3)CR1, respectively. Ly-6C(hi) monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6C(lo) monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular-endothelial growth factor. Consequently, Ly-6C(hi) monocytes digest damaged tissue, whereas Ly-6C(lo) monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6C(hi) monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.
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http://dx.doi.org/10.1084/jem.20070885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118517PMC
November 2007

Differentiation of osteoblasts in three-dimensional culture in processed cancellous bone matrix: quantitative analysis of gene expression based on real-time reverse transcription-polymerase chain reaction.

Tissue Eng 2005 May-Jun;11(5-6):855-64

Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany.

Processed bovine cancellous bone (PBCB) is an attractive material for tissue engineering of bone. It is biocompatible, osteoconductive, nonimmunogenic, and porous and its biomechanical properties are close to those of native bone. In this study, differentiation of primary rat osteoblasts (rOBs) incubated on PBCB was investigated in vitro. rOBs were isolated and expanded in two-dimensional culture. Expanded rOBs were seeded into PBCB disks and cultured either in basal medium (BM) or differentiation medium (DM) containing ascorbic acid, beta-glycerol phosphate, and dexamethasone. Alkaline phosphatase (ALP) activity and RNA expression of ALP, bone sialoprotein (BSP), collagen type I (COL1), osteocalcin (OC), and osteopontin (OPN) were assessed by chemiluminescence assay and quantitative real-time RT-PCR over 14 days. Histologic analysis was performed on day 14. ALP increased over the observation period independent of stimulation. OPN and BSP expression was significantly higher in the DM group whereas COL1 and OC expression was significantly higher in the BM group. Matrix calcification was detectable only in the DM group by von Kossa stain. The observed expression patterns suggest a physiological response of rOBs to the differentiation stimulus. PBCB is a suitable matrix for in vitro differentiation of osteoblasts. Cell-seeded PBCB is a potential osteogenic construct for in vivo application.
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http://dx.doi.org/10.1089/ten.2005.11.855DOI Listing
May 2006