Minimally invasive versus open pancreatoduodenectomy (LEOPARD-2): Study protocol for a randomized controlled trial

Background: Data from observational studies suggest that minimally invasive pancreatoduodenectomy (MIPD) is superior to open pancreatoduodenectomy regarding intraoperative blood loss, postoperative morbidity, and length of hospital stay, without increasing total costs. However, several case-matched studies failed to demonstrate superiority of MIPD, and large registry studies from the USA even suggested increased mortality for MIPDs performed in low-volume (< 10 MIPDs annually) centers. Randomized controlled multicenter trials are lacking but clearly required. We hypothesize that time to functional recovery is shorter after MIPD compared with open pancreatoduodenectomy, even in an enhanced recovery setting. Methods/design: LEOPARD-2 is a randomized controlled, parallel-group, patient-blinded, multicenter, phase 2/3, superiority trial in centers that completed the Dutch Pancreatic Cancer Group LAELAPS-2 training program for laparoscopic pancreatoduodenectomy or LAELAPS-3 training program for robot-assisted pancreatoduodenectomy and have performed ≥ 20 MIPDs. A total of 136 patients with symptomatic benign, premalignant, or malignant disease will be randomly assigned to undergo minimally invasive or open pancreatoduodenectomy in an enhan

Identification and Specification of the Mouse Skeletal Stem Cell

SummaryHow are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues

Minimally invasive versus open pancreatoduodenectomy (LEOPARD-2) : Study protocol for a randomized controlled trial

BACKGROUND: Data from observational studies suggest that minimally invasive pancreatoduodenectomy (MIPD) is superior to open pancreatoduodenectomy regarding intraoperative blood loss, postoperative morbidity, and length of hospital stay, without increasing total costs. However, several case-matched studies failed to demonstrate superiority of MIPD, and large registry studies from the USA even suggested increased mortality for MIPDs performed in low-volume (<10 MIPDs annually) centers. Randomized controlled multicenter trials are lacking but clearly required. We hypothesize that time to functional recovery is shorter after MIPD compared with open pancreatoduodenectomy, even in an enhanced recovery setting. METHODS/DESIGN: LEOPARD-2 is a randomized controlled, parallel-group, patient-blinded, multicenter, phase 2/3, superiority trial in centers that completed the Dutch Pancreatic Cancer Group LAELAPS-2 training program for laparoscopic pancreatoduodenectomy or LAELAPS-3 training program for robot-assisted pancreatoduodenectomy and have performed ≥ 20 MIPDs. A total of 136 patients with symptomatic benign, premalignant, or malignant disease will be randomly assigned to undergo minimally invasive or open pancreatoduodenectomy in an enhanced recovery setting. After the first 40 patients (phase 2), the data safety monitoring board will assess safety outcomes (not blinded for treatment allocation) and decide on continuation to phase 3. Patients from phase 2 will then be included in phase 3. The primary outcome measure is time (days) to functional recovery. All patients will be blinded for the surgical approach, at least until postoperative day 5, but preferably until functional recovery has been attained. Secondary outcome measures are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life, and costs. DISCUSSION: The LEOPARD-2 trial is designed to assess whether MIPD reduces time to functional recovery, as compared with open pancreatoduodenectomy in an enhanced recovery setting. TRIAL REGISTRATION: Netherlands Trial Register, NTR5689 . Registered on 2 March 2016

<i>Del1</i> Knockout Mice Developed More Severe Osteoarthritis Associated with Increased Susceptibility of Chondrocytes to Apoptosis

<div><p>Objective</p><p>We identified significant expression of the matricellular protein, DEL1, in hypertrophic and mature cartilage during development. We hypothesized that this tissue-specific expression indicated a biological role for DEL1 in cartilage biology.</p><p>Methods</p><p><i>Del1</i> KO and WT mice had cartilage thickness evaluated by histomorphometry. Additional mice underwent medial meniscectomy to induce osteoarthritis, and were assayed at 1 week for apoptosis by TUNEL staining and at 8 weeks for histology and OA scoring. <i>In vitro</i> proliferation and apoptosis assays were performed on primary chondrocytes.</p><p>Results</p><p>Deletion of the <i>Del1</i> gene led to decreased amounts of cartilage in the ears and knee joints in mice with otherwise normal skeletal morphology. Destabilization of the knee led to more severe OA compared to controls. <i>In vitro</i>, DEL1 blocked apoptosis in chondrocytes.</p><p>Conclusion</p><p>Osteoarthritis is among the most prevalent diseases worldwide and increasing in incidence as our population ages. Initiation begins with an injury resulting in the release of inflammatory mediators. Excessive production of inflammatory mediators results in apoptosis of chondrocytes. Because of the limited ability of chondrocytes to regenerate, articular cartilage deteriorates leading to the clinical symptoms including severe pain and decreased mobility. No treatments effectively block the progression of OA. We propose that direct modulation of chondrocyte apoptosis is a key variable in the etiology of OA, and therapies aimed at preventing this important step represent a new class of regenerative medicine targets.</p></div

Video Grading of Pancreatic Anastomoses During Robotic Pancreatoduodenectomy to Assess both Learning Curve and the Risk of Pancreatic Fistula - A Post Hoc Analysis of the LAELAPS-3 Training Program

OBJECTIVE: To assess the learning curve of pancreaticojejunostomy during robotic pancreatoduodenectomy(RPD) and to predict the risk of postoperative pancreatic fistula(POPF) by using the objective structured assessment of technical skills(OSATS) score, taking the fistula risk score into account. SUMMARY BACKGROUND DATA: RPD is a challenging procedure that requires extensive training and confirmation of adequate surgical performance. Video grading, modified for RPD, of the pancreatic anastomosis could assess the learning curve of RPD and predict the risk of POPF. METHODS: Post-hoc assessment of patients prospectively included in four Dutch centers in a nationwide LAELAPS-3 training program for RPD. Video grading of the pancreaticojejunostomy was performed by two graders using OSATS (attainable scores 12-60). The main outcomes were the combined OSATS of the two graders and POPF (grade B/C). CUSUM analyzed a turning point in the learning curve for surgical skill. Logistic regression determined the cut-off for OSATS. Patients were categorized for POPF risk (i.e. low, intermediate, high) based on the updated alternative fistula risk scores (uaFRS). RESULTS: Videos from 153 pancreatic anastomoses were included. Median OSATS score was 48 (IQR 41-52) points and with a turning point at 33 procedures. POPF occurred in 39 patients (25.5%). An OSATS score below 49, present in 77 patients (50.3%), was associated with an increased risk of POPF, OR 4.01, P=0.004. The POPF rate was 43.6% with OSATS < 49 versus 15.8% with OSATS ≥49. The uaFRS category "soft pancreatic texture" was the second strongest prognostic factor of POPF (OR 3.37, P=0.040). Median cumulative surgical experience was 17 years (IQR 8-21) at their first anastomosis. CONCLUSIONS: Video grading of the pancreatic anastomosis in RPD using OSATS identified a learning curve and a reduced risk of POPF in case of better surgical performance. Video grading may provide a valid method to surgical training, quality control and improvement

<i>Del1</i> KO phenoptype.

<p>Appearance of the ear in WT (A) and KO (B) mice. Ears were harvested from 10-week old, male mice and stained (C) for measurement of auricular cartilage thickness (D, n = 12 WT and 18 KO). Width and length are measurements of the pinna. Photomicrographs shown are 40x magnification. Knees were harvested from 10-week old, male mice and stained (E) for measurement of tibial articular cartilage thickness (F, n = 4 for all groups). All values were normalized to tibial length. There was no difference in weight or tibial length between WT and KO mice. A bounding box at 200x magnification as shown was created and the area of cartilage within determined. Due to the variable thickness present within the ear and the undulating boundary between cartilage and bone in the knee, thickness was calculated by measuring the length and dividing into area. p value refers to difference between WT and KO mice. Picrosirius red staining of KO (G) and WT (H) ears and the medial surface of KO (I) and WT (J) knees. Representative sections are shown at 25x magnification.</p

Osteoarthritis susceptibility.

<p>(A) 25x magnification view of knee joints from WT and KO mice after sham operation or medial meniscectomy (MM). (B) Box and whiskers plot of histologic scoring of medial tibial and femoral surfaces for OA. *p = 0.0206 for tibia, p = 0.0003 for femur, n = 18 WT and 17 KO. Representative photomicrographs of TUNEL staining of articular surfaces at 1 week after knee destabilization in the injured (C), and sham operated (D) knees. Apoptotic cells seen in the same area of the articular cartilage were counted at 200x magnification as shown and quantified (E). *p<0.001 for femur and p<0.00001 for tibia, n = 5 WT and 6 KO.</p

Biomechanical testing of cartilage.

<p>Articular surfaces were tested to measure (A) stiffness, (B) elasticity, and (C) resistance to penetration. Numerical values are shown (D) and statistical significance calculated with Student’s t test with p<0.05 seen to be significant, n = 10 WT and 10 KO.</p

Minimally invasive versus open pancreatoduodenectomy (LEOPARD-2): study protocol for a randomized controlled trial

Abstract Background Data from observational studies suggest that minimally invasive pancreatoduodenectomy (MIPD) is superior to open pancreatoduodenectomy regarding intraoperative blood loss, postoperative morbidity, and length of hospital stay, without increasing total costs. However, several case-matched studies failed to demonstrate superiority of MIPD, and large registry studies from the USA even suggested increased mortality for MIPDs performed in low-volume