Mobile Smartphone Thermal Imaging Characterization and Identification of Microvascular Flow Insufficiencies in Deep Inferior Epigastric Artery Perforator Free Flaps.

BACKGROUND: Mobile smartphone thermal imaging (MTI) devices correlate with blood flow, which makes them appealing adjuncts during reconstructive surgery. MTI was assessed in the setting of deep inferior epigastric artery perforator (DIEAP) free flaps. We hypothesized that MTI can be a surrogate for blood flow to identify microvascular flow insufficiencies. METHODS: Nineteen patients underwent 30 DIEAP flaps for breast reconstruction. Images were obtained preoperatively, intraoperatively, and at instances of concern for flap viability. Three groups were evaluated: normal DIEAP flaps (NDFs), flaps with arterial insufficiency (AI), and flaps with venous congestion (VC). RESULTS: All flaps were successful. There were significant temperature increases from max ischemia (24.5 ± 2.1°C) to 1 min after anastomosis (27.2 ± 1.6°C, P < 0.001). NDFs continued to warm until the final MTI was taken when leaving the operating room. There were no differences between MTI flap temperatures before transfer to the chest and after completion of microanastomosis. With questionable flap viability, VC and AI temperatures were found to be significantly colder than the NDF group (28.3 ± 1.9°C versus 32.2 ± 1.8°C, P = 0.003) in the VC group and (27.2 ± 0.7°C versus 32.2 ± 1.8°C, P = 0.001) in the AI group. After correction of the identified flow insufficiency, VC and AI rewarmed and temperatures were no different compared with NDF. CONCLUSIONS: MTI recognizes microanastomotic failure and is a practical adjunct in the evaluation of free flap perfusion.

Preperitoneal balloon tamponade and resuscitative endovascular balloon occlusion of the aorta: Alternatives to open packing for pelvic fracture-associated hemorrhage.

BACKGROUND: The objective of this study was to compare the efficacy of preperitoneal balloon tamponade (PPB), resuscitative endovascular balloon occlusion of the orta (REBOA), and open preperitoneal packing (OP) in a realistic animal model of pelvic fracture-associated hemorrhage. METHODS: Thirty-nine swine underwent creation of open-book pelvic fracture and iliac vascular injury. Animals were randomized to no intervention (n = 7), OP (n = 10), PPB (n = 9), zone 1 REBOA (n = 7), and zone 3 REBOA (n = 6) at a mean arterial pressure less than 40 mm Hg from uncontrolled hemorrhage. Primary outcome was survival at 1 hour. Secondary outcomes included survival in the immediate 10 m following intervention reversal, peak preperitoneal pressure (PP), blood loss, bleed rate, and peak lactate. RESULTS: Prior to injury, no difference was measured between groups for weight, hemodynamics, lactate, and hematocrit (all p = NS). The injury was uniformly lethal without intervention, with survival time (mean) of 5 m, peak PP of 14 mm Hg, blood loss of 960 g, bleed rate of 450 g/m, and peak lactate of 2.6 mmol/L. Survival time (m) was extended to 44 with OP, 60 with PPB, and 60 with REBOA (p < 0.01). Peak PP (mm Hg) was 19 with OP, 23 with PPB, 10 with zone 1 REBOA, and 6 with zone 3 REBOA (p < 0.05). Blood loss (g) was 850 with OP, 930 with PPB, 610 with zone 1 REBOA, and 370 with zone 3 REBOA (p < 0.01). Peak lactate (mmol/L) was 3.3 with OP, 4.3 with PPB, 13.4 with zone 1 REBOA, and 5.3 with zone 3 REBOA (p < 0.01). Only 33% of zone 1 REBOA animals survived the initial 10 m after balloon deflation, compared to 60% for OP, 67% for PPB, and 100% for zone 3 REBOA (p < 0.01). CONCLUSION: Preperitoneal balloon tamponade and zone 3 REBOA are effective alternatives to OP in this animal model of lethal pelvic fracture-associated hemorrhage. Zone 1 REBOA extends survival time but with high mortality upon reversal.

Lifesaving interventions in blackout conditions using night vision technology: Come to the dark side.

BACKGROUND: During military combat operations and civilian night-time aeromedical transport, medical providers are frequently required to perform lifesaving interventions (LSIs) in low-light environments. Because definitive surgical care is often delayed until a white light environment is permissible, we sought to determine if night optical device (NOD) technology could enable surgical capabilities in blackout conditions. METHODS: Using a crossover design, six surgeons performed 11 different procedures on six swine, three in normal light conditions (LC) and 3 in blackout conditions (BC) using two-chamber NODs after familiarization with the procedures in both conditions on manikins. Successful completion and procedural times were compared between groups. RESULTS: Blackout conditions were confirmed with ambient light reading of 0.2 lux during BC versus 3962.9 lux for LC (p < 0.001). There were no significant differences in success rates for any procedure. There were no differences in operative times between BC and LC for extremity tourniquet placement, femoral artery cut-down and clamping, resuscitative thoracotomy, or percutaneous resuscitative endovascular balloon occlusion of the aorta placement. The following procedures took significantly longer in BC vs. LC: Focused Assessment with Sonography for Trauma examination (98 seconds vs. 62 seconds), peripheral IV placement (140 seconds vs. 35 seconds), intraosseous access (51 seconds vs. 26 seconds), jugular vein cut-down and access (237 seconds vs. 104 seconds), laparotomy and packing (71 seconds vs. 51 seconds), stapled splenectomy (137 seconds vs. 74 seconds), resuscitative endovascular balloon occlusion of the aorta placement via cutdown (1,008 seconds vs. 338 seconds), and cricothyroidotomy (177 seconds vs. 109 seconds) (all p < 0.05). CONCLUSION: Lifesaving interventions can be safely and effectively performed in blackout conditions using NODs, although increased difficulty with select procedure types was identified. Focused training and technological improvements to currently available devices are needed. LEVEL OF EVIDENCE: Basic science.

Minimally invasive preperitoneal balloon tamponade and abdominal aortic junctional tourniquet versus open packing for pelvic fracture-associated hemorrhage: Not all extrinsic compression is equal.

BACKGROUND: Minimally invasive preperitoneal balloon tamponade (PPB) and abdominal aortic junctional tourniquets (AAJT) have been proposed as alternatives to open preperitoneal packing (OP) for the management of pelvic fracture-associated hemorrhage. We hypothesized that the PPB (SpaceMaker Pro) and AAJT would result in similar rates of survival and blood loss versus OP. METHODS: Thirty-two swine underwent creation of a combined open-book pelvic fracture and major iliac vascular injuries. Animals were randomized to no intervention (n = 7), OP (n = 10), PPB (n = 9), or AAJT (n = 6) at a mean arterial pressure <40 mm Hg following initiation of uncontrolled hemorrhage. Survival (up to 60 minutes + 10 minutes after intervention reversal), hemodynamics, extraperitoneal pressures, blood loss, and associated complications were compared between groups. RESULTS: Prior to injury, no difference was measured between groups for weight, hemodynamics, lactate, and hematocrit (all p > 0.05). The injury was uniformly lethal without intervention, with survival time (mean) of 5 minutes, peak preperitoneal pressure (PP) of 14 mm Hg, blood loss of 960 g, and peak lactate of 2.6 mmol/L. Survival time was 44 minutes with OP versus 60 minutes with PPB and AAJT (p < 0.01). Peak PP (mm Hg) was 19 with OP, 23 with PPB, and 23 with AAJT (p > 0.05). Blood loss (g) was 850 with OP, 930 with PPB, and 600 with AAJT (p > 0.05). Peak lactate (mmol/L) was 3.3 with OP, 4.3 with PPB, and 6.3 with AAJT (p < 0.01). Only 33% of AAJT animals survived intervention reversal versus 60% for OP and 67% for PPB (p < 0.01). Necropsy revealed bowel/bladder injury in 50% of AAJT subjects versus 0% in all other arms (p < 0.01). CONCLUSION: Preperitoneal balloon tamponade is a safe and potentially effective alternative to OP for the management of lethal pelvic fracture-associated hemorrhage. Abdominal aortic junctional tourniquet offers a similar survival benefit to PPB but has concerning rates of ischemia-reperfusion and compressive abdominal organ injury.

Mobile forward-looking infrared technology allows rapid assessment of resuscitative endovascular balloon occlusion of the aorta in hemorrhage and blackout conditions.

INTRODUCTION: Objective assessment of final resuscitative endovascular balloon occlusion of the aorta (REBOA) position and adequate distal aortic occlusion is critical in patients with hemorrhagic shock, especially as feasibility is being increasingly investigated in the prehospital setting. We propose that mobile forward-looking infrared (FLIR) thermal imaging is a fast, reliable, and noninvasive method to assess REBOA position and efficacy in scenarios applicable to battlefield and prehospital care. METHODS: Ten swine were randomized to a 40% hemorrhage group (H, n = 5) or nonhemorrhage group (NH, n = 5). Three experiments were completed after Zone I placement of a REBOA catheter. Resuscitative endovascular balloon occlusion of the aorta was deployed for 30 minutes in all animals followed by randomized continued deployment versus sham in both light and blackout conditions. Forward-looking infrared images and hemodynamic data were obtained. Images were presented to 62 blinded observers for assessment of REBOA inflation status. RESULTS: There was no difference in hemodynamic or laboratory values at baseline. The H group was significantly more hypotensive (mean arterial pressure 44 vs. 60 mm Hg, p < 0.01), vasodilated (systemic vascular resistance 634 vs. 938dyn·s/cm, p = 0.02), and anemic (hematocrit 12 vs. 23.2%, p < 0.01). Hemorrhage group animals remained more hypotensive, anemic, and acidotic throughout all three experiments. There was a significant difference in the temperature change (ΔTemp) measured by FLIR between animals with REBOA inflated versus not inflated (5.7°C vs. 0.7°C, p < 0.01). The H and NH animals exhibited equal magnitudes of ΔTemp in both inflated and deflated states. Blinded observer analysis of FLIR images correctly identified adequate REBOA inflation and aortic occlusion 95.4% at 5 minutes and 98.8% at 10 minutes (positive predictive value at 5 minutes = 99% and positive predictive value at 10 minutes = 100%). CONCLUSIONS: Mobile thermal imaging is an easy, rapid, and reliable method for assessing distal perfusion after occlusion by REBOA. Smartphone-based FLIR technology allows for confirmation of adequate REBOA placement at the point of care, and performance was not degraded in the setting of major hemorrhage or blackout conditions.

The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.

BACKGROUND: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model. METHODS: The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage. RESULTS: Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 µg/mL. CONCLUSION: Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations. LEVEL OF EVIDENCE: Therapeutic, level II.

Smartphone-based mobile thermal imaging technology to assess limb perfusion and tourniquet effectiveness under normal and blackout conditions.

BACKGROUND: Over the past decade, there has been a resurgence of tourniquet use in civilian and military settings. Several key challenges include assessment of limb perfusion and adequacy of tourniquet placement, particularly in the austere or prehospital environments. We investigated the utility of thermal imaging to assess adequacy of tourniquet placement. METHODS: The FLIR ONE smartphone-based thermal imager was utilized. Ten swine underwent tourniquet placement with no associated hemorrhage (n = 5) or with 40% hemorrhage (n = 5). Experiment 1 simulated proper tourniquet application, experiment 2 had one of two tourniquets inadequately tightened, and experiment 3 had one of two tourniquets inadequately tightened while simulating blackout-combat conditions. Static images were taken at multiple time points up to 30 minutes. Thermal images were then presented to blinded evaluators who assessed adequacy of tourniquet placement. RESULTS: The mean core temperature was 38.3 °C in non-hemorrhaged animals versus 38.2 °C in hemorrhaged animals. Hemorrhaged animals were more hypotensive (p = 0.001), anemic (p < 0.001), vasodilated (p = 0.008), and had a lower cardiac output (p = 0.007) compared to non-hemorrhaged animals. The thermal imaging temperature reading decreased significantly after proper tourniquet placement in all animals, with no difference between hemorrhaged and non-hemorrhaged groups at 30 minutes (p = 0.23). Qualitative thermal image analysis showed clearly visible perfusion differences in all animals between baseline, adequate tourniquet, and inadequate tourniquet in both hemorrhaged and non-hemorrhaged groups. Ninety-eight percent of blinded evaluators (n = 62) correctly identified adequate and inadequate tourniquet placement at 5 minutes. Images in blackout conditions showed no adverse impact on thermal measurements or in the ability to accurately characterize perfusion and tourniquet adequacy. CONCLUSIONS: A simple handheld smartphone-based forward looking infrared radiometry device demonstrated a high degree of accuracy, reliability, and ease of use for assessing limb perfusion. Forward looking infrared radiometry also allowed for rapid and reliable identification of adequate tourniquet placement that was not affected by major hemorrhage or blackout conditions.

"The missing LINX" for gastroesophageal reflux disease: Operative techniques video for the Linx magnetic sphincter augmentation procedure.

In 2012 the FDA approved a magnetic sphincter augmentation (MSA) device (LINX, Torax Medical, Inc) for placement around the lower esophageal sphincter as an alternative approach to fundoplication for gastroesophageal reflux disease (GERD). This is a relatively new procedure and there is not widespread familiarization with the standard indications and techniques of device placement. We present two operative videos to highlight the standard surgical technique and technical points needed for successful LINX placement. First will be placement in a standard indications setting of uncomplicated GERD with no hiatal hernia. Second will be placement with complicated anatomy due to alterations from prior gastric surgery and a hiatal hernia. Our experience has revealed that the LINX device can be placed safely in patients with normal or significantly altered anatomy but requires adherence to several key principles and technical points. This procedure offers a new option that is anatomically and physiologically unique compared to standard fundoplication, and that offers highly effective control of GERD with a less invasive approach.

The routine use of prosthetic mesh in austere environments: dogma vs data.

BACKGROUND: Mesh repair has become the standard in adult hernia repairs. Mesh infection is an uncommon but potentially devastating complication. Currently, there is widespread dogma against the use of prosthetic mesh (PM) in deployed or austere environments but little available data to support or refute this bias. METHODS: Retrospective review of all hernia repairs over 1 year in a forward deployed surgical unit in Afghanistan. Demographics, hernia type, repair performed, and mesh type were evaluated. Follow-up was completed up to 6 weeks and then as needed for up to a year, and complications to include infection were recorded. RESULTS: Sixty-six patients were identified, mean age was 38 (range 3 to 80) and 98% were male. Single-dose perioperative antibiotics and standard sterile technique were used in all cases. The majority (70%) had PM placed. The mean operative time was 54 min, and mean estimated blood loss was less than 25 cm(3). The vast majority of our hernias were inguinal (95%) with 1 ventral and 2 umbilical hernias. In the PM group, there were no surgical site infections, no mesh infections, and no mesh explantation or reoperation. There were no recurrences in either group identified at up to 1-year postoperation. There was no statistically significant difference in any outcome measure between the PM and no-PM groups. CONCLUSIONS: The use of PM for hernia repairs in the austere or forward environment appears safe and did not increase the risk of wound infection, mesh infections, or recurrence.

Does PET with CT Have Clinical Utility in the Management of Patients with Intraductal Papillary Mucinous Neoplasm?

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are well-established pancreatic precancerous lesions. Indications for resection are outlined in the 2012 International Consensus Guidelines (ICG). Because of the low specificity of the ICG, many patients will undergo potentially unnecessary surgery for nonmalignant IPMNs. Several retrospective studies have reported that positron emission tomography (PET) with CT (PET/CT) is highly sensitive and specific in detecting malignant IPMNs. We hypothesized that PET/CT complements the ICG in identification of malignant IPMNs. STUDY DESIGN: From 2009 to 2013, patients with a suspected clinical or cytopathologic diagnosis of IPMN were prospectively enrolled in a clinical trial at a single center. Results of preoperative PET/CT on determination of IPMN malignancy (ie, high-grade dysplastic and invasive) was compared with surgical pathology. PET/CT uptake was considered increased if the standardized uptake value was ≥3. RESULTS: Of the 67 patients enrolled, 50 patients met all inclusion criteria. Increased PET/CT uptake was associated with significantly more malignant and invasive IPMNs (80% vs 13%; p < 0.0001 and 40% vs 3%; p = 0.004). When patients were divided into branch duct and main duct IPMNs, increased PET/CT uptake was also associated with more malignancy (60% vs 0%; p = 0.006 for branch duct IPMN and 100% vs 23%; p = 0.003 for main duct IPMN). Patients with ICG criteria (eg, worrisome features and high-risk stigmata) and increased PET/CT uptake had more malignant and invasive IPMNs than patients with ICG criteria, but no increased uptake (78% vs 17%; p = 0.001 and 33% vs 3%; p = 0.03). The sensitivity and specificity of the ICG criteria for detecting malignancy were 92% and 27%, respectively, and PET/CT was less sensitive (62%) but more specific (95%). When PET/CT was added to ICG criteria, the association resulted in 78% sensitivity and 100% specificity. CONCLUSIONS: The addition of PET/CT to preoperative workup improves the performance of the ICG for predicting malignant risk in patients with IPMN.

MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-ß signaling.

Pancreatic cancer is associated with a pronounced fibrotic reaction that was recently shown to limit delivery of chemotherapy. To identify potential therapeutic targets to overcome this fibrosis, we examined the interplay between fibrosis and the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14), which is required for growth and invasion in the collagen-rich microenvironment. In this article, we show that compared with control mice (Kras(+)/MT1-MMP(-)) that express an activating Kras(G12D) mutation necessary for pancreatic cancer development, littermate mice that express both MT1-MMP and Kras(G12D) (Kras(+)/MT1-MMP(+)) developed a greater number of large, dysplastic mucin-containing papillary lesions. These lesions were associated with a significant amount of surrounding fibrosis, increased α-smooth muscle actin (+) cells in the stroma, indicative of activated myofibroblasts, and increased Smad2 phosphorylation. To further understand how MT1-MMP promotes fibrosis, we established an in vitro model to examine the effect of expressing MT1-MMP in pancreatic ductal adenocarcinoma (PDAC) cells on stellate cell collagen deposition. Conditioned media from MT1-MMP-expressing PDAC cells grown in three-dimensional collagen enhanced Smad2 nuclear translocation, promoted Smad2 phosphorylation, and increased collagen production by stellate cells. Inhibiting the activity or expression of the TGF-ß type I receptor in stellate cells attenuated MT1-MMP conditioned medium-induced collagen expression by stellate cells. In addition, a function-blocking anti-TGF-ß antibody also inhibited MT1-MMP conditioned medium-induced collagen expression in stellate cells. Overall, we show that the bona fide collagenase MT1-MMP paradoxically contributes to fibrosis by increasing TGF-ß signaling and that targeting MT1-MMP may thus help to mitigate fibrosis.

Visualization of mouse pancreas architecture using MR microscopy.

Pancreatic diseases, which include diabetes, pancreatitis, and pancreatic cancer, are often difficult to detect and/or stage, contributing to a reduced quality of life and lifespan for patients. Thus, there is need for a technology that can visualize tissue changes in the pancreas, improve understanding of disease progression, and facilitate earlier detection in the human population. Because of low spatial resolution, current clinical magnetic resonance imaging (MRI) at low field strength has yet to fully visualize the exocrine, endocrine, vascular, and stromal components of the pancreas. We used high field strength magnetic resonance microscopy (µMRI) to image mouse pancreas ex vivo without contrast agents at high spatial resolution. We analyzed the resulting high-resolution images using volume rendering to resolve components in the pancreas, including acini, islets, blood vessels, and extracellular matrix. Locations and dimensions of pancreatic components as seen in three-dimensional µMRI were compared with histological images, and good correspondence was found. Future longitudinal studies could expand on the use of in vivo µMRI in mouse models of pancreatic diseases. Capturing three-dimensional structural changes through µMRI could help to identify early cellular and tissue changes associated with pancreatic disease, serving as a mode of improved detection in the clinic for endocrine and exocrine pathologies.

Alteration of strain background and a high omega-6 fat diet induces earlier onset of pancreatic neoplasia in EL-Kras transgenic mice.

Diets containing omega-6 (ω-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of ω-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in ω-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras(G12D) (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high ω-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in ω-6 fatty acid.

Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2.

One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine.

Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer.

To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.