Martin J. Dib

BMP4 is a novel paracrine inhibitor of liver regeneration

Transforming growth factor (TGF)-β family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-β family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high-dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration.

Technique and outcomes of robot-assisted median arcuate ligament release for celiac artery compression syndrome

OBJECTIVE Celiac artery compression by the median arcuate ligament (MAL) is a potential cause of postprandial abdominal pain and weight loss that overlaps with other common syndromes. Robotic technology may alter the current paradigm for surgical intervention. Open MAL release is often performed with concurrent bypass for celiac stenosis due to the morbidity of reintervention, whereas the laparoscopic approach is associated with high rates of conversion to open due to bleeding. We hypothesized that a robot-assisted technique might minimize conversion events to open, decrease perioperative morbidity, and defer consideration of vascular bypass at the initial operative setting. METHODS We retrospectively analyzed patients treated for MAL syndrome by a multidisciplinary team at a tertiary medical center between September 2012 and December 2013. Diagnosis was based on symptom profile and peak systolic velocity (PSV) >200 cm/s during celiac artery duplex ultrasound imaging. All patients underwent robot-assisted MAL release with simultaneous circumferential neurolysis of the celiac plexus. Postoperative celiac duplex and symptom profiles were reassessed longitudinally to monitor outcomes. RESULTS Nine patients (67% women) were evaluated for postprandial pain (100%) and weight loss (100%). All patients had celiac stenosis by mesenteric duplex ultrasound imaging (median PSV, 342; range, 238-637 cm/s), and cross-sectional imaging indicated a fishhook deformity in five (56%). Robot-assisted MAL release was completed successfully in all nine patients (100%) using a standardized surgical technique. Estimated blood loss was <50 mL, with a median hospital stay of 2 days (range, 2-3 days). No postoperative complications of grade ≥3, readmissions or reoperations were observed. All patients (100%) improved symptomatically at the 25-week median follow-up. Three patients experienced complete resolution on postoperative celiac duplex ultrasound imaging, and six patients showed an improved but persistent stenosis (PSV >200 cm/s) compared with preoperative velocities (P < .05 by Wilcoxon signed rank). No patients required additional treatment. CONCLUSIONS Robot-assisted MAL release can be performed safely and effectively with avoidance of conversion events and minimal morbidity. Potential factors contributing to success are patient selection by a multidisciplinary team and replication of the open surgical technique by means of robot-assisted dexterity and visualization. The need for delayed reintervention for persistently symptomatic celiac stenosis is uncertain.

Specific Activin Receptor-Like Kinase 3 Inhibitors Enhance Liver Regeneration

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor–like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.

Roux limb volvulus after pancreas transplantation: an unusual cause of pancreatic graft loss

Abstract:  Pancreas transplantation with enteric drainage avoids the long‐term urological complications of bladder drainage. Increasing use of this technique raises the possibility of complications from the enteric reconstruction. This report describes a patient five yr after left‐sided pancreas transplant with Roux‐en‐Y enteric drainage, presenting with abdominal pain, leukocytosis and radiological evidence of bowel obstruction. Exploration revealed a volvulus of the Roux limb as it passed through the mesocolon, with necrosis of the allograft duodenum and marked congestion of the pancreas. This is the first report of pancreas graft loss due to this entity, which should be recognized as an unusual cause of abdominal pain after pancreas transplantation. Potential bowel complications related to the sigmoid mesentery in left‐sided pancreas transplantation are additional reasons for right‐sided placement of the pancreas allograft.

Robotic Pancreaticoduodenectomy (Whipple Procedure)

Technological innovations in robotic-assisted surgery have allowed complex resections and anastomotic reconstructions. We present the selection criteria, technical description, and preliminary outcomes of robotic-assisted pancreaticoduodenectomy (RAPD). RAPD is offered to patients with low-predicted risk of a non-R0 outcome, based on tumor diameter, endoscopic ultrasound, and CT evidence of vascular involvement. Early outcomes of RAPD are comparable to laparoscopic and open approaches, bringing the well-recognized advantages of minimally invasive surgery to major pancreatic resections.

Endovascular management of critical limb ischemia in renal transplant patients.

BACKGROUND End-stage renal disease is a significant negative predictor of limb salvage and patient survival in patients with limb ischemia, but little is known of the overall effects of renal transplantation. Endovascular management may be less morbid than open surgery, but technical success and durability in these patients is not well established. METHODS All patients with functioning renal transplants and critical limb ischemia (CLI) treated with endovascular techniques between 2003 and 2010 were retrospectively reviewed for limb salvage, reintervention, pre- and postprocedure creatinine, and estimated glomerular filtration rate (eGFR), and overall survival. Contralateral common femoral access, low-profile techniques, and isosmolar contrast were standard for all interventions. RESULTS Endovascular interventions were performed on 57 limbs in 28 patients with renal transplants. Mean age was 54 years, 78% were male, 85% were diabetic, 100% were hypertensive, and 64% had a positive smoking history. All patients were treated for CLI. Treated regions included 16 iliac, 19 superficial femoral, 16 popliteal, and 12 tibial arteries, as well as 1 bypass graft with initial technical success of 100% and 0% 30-day mortality. Of all lesions, 43% required reintervention during the follow-up period, the majority in the first year. There was no significant change in eGFR or creatinine comparing pre- and post-angiogram value. Limb salvage and 1-year survival were 83% and 82%, respectively. CONCLUSIONS Endovascular management of CLI in renal transplant patients results in good technical success and can be accomplished without a measurable change in transplant kidney function, although it requires repeat interventions. Endovascular therapy is a reasonable first-line treatment option for this high-risk group.