Research Spotlight

Naziruddin, B., M. A. Kanak, C. A. Chang, M. Takita, M. C. Lawrence, A. R. Dennison, N. Onaca and M. F. Levy (2018). “Improved outcomes of islet autotransplant after total pancreatectomy by combined blockade of IL-1beta and TNFalpha.” Am J Transplant 18(9): 2322-2329.

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The efficacy of islet transplant is compromised by a significant loss of islet mass posttransplant due to an innate inflammatory reaction. We report the use of a combination of etanercept and anakinra (ANA+ETA) to block inflammatory islet damage in 100 patients undergoing total pancreatectomy with islet autotransplant. The patients were divided into 3 groups: no treatment (control [CTL]), etanercept alone (ETA), or a combination of etanercept and anakinra (ANA+ETA). Peritransplant serum samples were analyzed for protein markers of islet damage and for inflammatory cytokines. Graft function was assessed by fasting blood glucose, basal C-peptide, secretory unit of islet transplant objects (SUITO) index, and hemoglobin A1c . Administration of both antiinflammatory drugs was well tolerated without any major adverse events. Reductions in interleukin-6, interleukin-8, and monocyte chemoattractant protein 1 were observed in patients receiving ANA+ETA compared with the CTL group, while also showing a modest improvement in islet function as assessed by basal C-peptide, glucose, hemoglobin A1c , and SUITO index but without differences in insulin dose. These results suggest that double cytokine blockade (ANA+ETA) reduces peritransplant islet damage due to nonspecific inflammation and may represent a promising strategy to improve islet engraftment, leading to better transplant outcomes.

Moisan, F., B. Gayet, M. A. Ward, N. Tabchouri and D. Fuks (2018). “Segment 7 Laparoscopic Liver Resection: Is It Possible to Resect When Metastatic Lesions Border Suprahepatic Veins?” J Gastrointest Surg 22(9): 1643-1644.

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INTRODUCTION: After nearly 25 years of experience, laparoscopic liver resection (LLR) is now recognized as being feasible and safe.1 However, laparoscopic resections of the posterosuperior segments are more technically demanding. They are associated with higher conversions rates, more intraoperative bleeding, and increased operating time.2 Appropriate training is required to approach these resections safely.3 This video demonstrates the technical maneuvers to laparoscopically approach a segment 7 tumor in contact with the right supra hepatic vein. METHOD: The pertinent aspect to perform a segment 7 metastasis resection using minimally invasive techniques is shown. The main steps of this operation include (1) complete release of the right liver from the coronary and triangular ligament, (2) dissection of the retrohepatic vena cava and transection of the hepatocaval ligament, (3) the use of intercostal trocars for direct vision of the inferior vena cava and the right suprahepatic vein,4,5 (4) the use of intraoperative ultrasound to evaluate the position and limits of vascular structures compared to the lesion, (5) careful transection of the hepatic parenchyma, and (6) dissection of the right hepatic vein to separate it from the lesion. RESULTS: The surgery was performed in a 68-year-old male patient. The patient developed synchronous metastases to the liver from a sigmoid colon tumor. Two lesions were identified; a 15 mm subcapsular lesion located in segment 5 and a 45 mm lesion located in segment 7 in contact with the right hepatic vein and inferior vena cava confluence. Previously, laparoscopic sigmoidectomy was performed without complications (TNM classification of the specimen: T3N0, with 31 resected lymph nodes, KRAS gene mutated). Following chemotherapy with FOLFOX + bevacizumab, a good response to the liver lesion was noted on imaging. Subsequently, a laparoscopic resection of the metastases in segment 7 and 5 was performed. The surgery lasted 210 min, intraoperative blood loss was 200 cm(3), no Pringle maneuver was required, and the postoperative period was uneventful with the patient being discharged on postoperative day number four. Pathology of the liver specimens confirmed metastases from colon adenocarcinoma with free surgical margins. DISCUSSION: Some important points achieving easier and safer approach of the posterior segments of the liver by laparoscopic route should be discussed. First, the patient’s semi-lateral position showed in the video allows placing the ports and the optic in a more comfortable position since the lateral portion of the abdominal and thoracic wall becomes anterior. Another important point is the complete liberation of the hepatorenal, falciform, triangular, and right coronary ligaments in order to fully mobilize the liver and convert a segment that is posterior in the anatomical position to an anterior segment for the surgeon. And finally, the use of intercostal trocars that allows a direct and perpendicular view of the right hepatic vein and vena cava represents the most important point. Interestingly, these specific trocars should be inserted through the pleural cavity, during a forced expiration or apnea to avoid lung injury. In this context, the trocar balloon helps the surgeon to avoid displacement or that pneumoperitoneum enters the pleural cavity. At the end of the procedure, we strongly recommend to stitch laparoscopically these diaphragmatic openings after removing the trocars in order to avoid migration of abdominal fluid or bowel incarceration into the pleural cavity during the postoperative period and also to avoid future diaphragmatic hernia. In the present case, the parenchymal transection was performed with Thunderbeat (Olympus(R), Japan), a device integrating both ultrasound dissection and advanced bipolar energy. We use this device because it saves time by sealing vessels up to 7 mm in diameter avoiding the need to use clips in the majority of intrahepatic veins and portal branches. However, currently, several techniques and devices are equivalent for parenchymal transection in laparoscopic liver resection and should be left to the surgeon’s preference, as in open liver procedures. CONCLUSION: Using laparoscopy to remove lesions in the posterior segments of the liver is safe and feasible. Vision from transthoracic port has the added benefit of making the dissection of right hepatic vein and inferior vena cava safer. Mastery of the anatomy is paramount before attempting this approach with minimally invasive techniques. Surgeons who attempt this operation should have expertise with both laparoscopy and liver surgery.

Messika-Zeitoun, D., G. Nickenig, A. Latib, K. H. Kuck, S. Baldus, R. Schueler, G. La Canna, E. Agricola, F. Kreidel, M. Huntgeburth, M. Zuber, P. Verta, P. Grayburn, A. Vahanian and F. Maisano (2018). “Transcatheter mitral valve repair for functional mitral regurgitation using the Cardioband system: 1 year outcomes.” Eur Heart J Aug 16. [Epub ahead of print].

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Aims: The Cardioband (Edwards Lifesciences) is a transcatheter implant designed to reduce mitral annulus size and mitral regurgitation (MR) severity. We report the 1-year outcomes of consecutive patients who underwent the Cardioband procedure between 2013 and 2016. Methods and results: Sixty patients with moderate or severe secondary MR (72 +/- 7 years, 60% ischaemic origin) on guideline-recommended medical therapy were treated and analyzed at 11 European institutions. There were two in-hospital deaths (none device-related), one stroke, two coronary artery complications, and one tamponade. Anchor disengagement, observed in 10 patients (all but one in the first half of the population), resulted in device inefficacy in five patients and led to device modification half way through the study to mitigate this issue. Technical, device, and procedural successes, assessed based on Mitral Valve Academic Research Consortium (MVARC) criteria, were 97% (58/60), 72% (43/60), and 68% (41/60), respectively. At 1-year, overall survival, survival free of readmission for heart failure, and survival free of reintervention (performed in seven patients) were 87%, 66%, and 78%, respectively. In the overall population, MR grade at 12 months was moderate or less 61% and moderate or less in 95% of the 39 patients who underwent a transthoracic echocardiography at 1-year [but worsened by at least one grade in 11 patients (22%)]. Functional status (79% vs. 14% in New York Heart Association Class I/II), quality of life (-19 points on the Minnesota Living with Heart Failure Questionnaire score), and exercise capacity (+58 m by 6MWT) improved significantly (all P < 0.01). Conclusion: In this multicentre trial, the Cardioband mitral system demonstrated reasonable performance and safety. At 1 year, most patients had moderate or less MR and experienced significant functional improvements. A randomized controlled trial is underway to demonstrate the impact of Cardioband in patients on guideline-directed medical therapy.

Meng, F., L. Kennedy, L. Hargrove, J. Demieville, H. Jones, T. Madeka, A. Karstens, K. Chappell, G. Alpini, A. Sybenga, P. Invernizzi, F. Bernuzzi, S. DeMorrow and H. Francis (2018). “Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2(-/-) mice and human primary sclerosing cholangitis.” Lab Invest Aug 24. [Epub ahead of print].

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Ursodeoxycholic acid (UDCA) is used to treat biliary disorders; and, bile acids alter mast cell (MC) histamine release. MCs infiltrate Mdr2(-/-) mice liver (model of primary sclerosing cholangitis (PSC)). MC-derived histamine increases inflammation, hepatic stellate cell (HSC) activation and fibrosis. The objective was to determine the effects of UDCA treatment on MC infiltration, biliary damage, inflammation and fibrosis in Mdr2(-/-) mice and human PSC. Wild-type and Mdr2(-/-) mice were fed bile acid control diet or UDCA (0.5% wt/wt). Human samples were collected from control and PSC patients treated with placebo or UDCA (15 mg/kg/BW). MC infiltration was measured by immunhistochemistry and quantitative polymerase chain reaction (qPCR) for c-Kit, chymase, and tryptase. The HDC/histamine/histamine receptor (HR)-axis was evaluated by EIA and qPCR. Intrahepatic bile duct mass (IBDM) and biliary proliferation was evaluated by CK-19 and Ki-67 staining. Fibrosis was detected by immunostaining and qPCR for fibrotic markers. Inflammatory components were measured by qPCR. HSC activation was measured by SYP-9 staining. Inflammation was detected by qPCR for CD68. In vitro, MCs were treated with UDCA (40 muM) prior to HA secretion evaluation and coculturing with cholangiocytes or HSCs. BrDU incorporation and fibrosis by qPCR was performed. UDCA reduced MC number, the HDC/histamine/HR-axis, IBDM, HSC activation, inflammation, and fibrosis in Mdr2(-/-) mice and PSC patients. In vitro, UDCA decreases MC-histamine release, which was restored by blocking ASBT and FXRbeta. Proliferation and fibrosis decreased after treatment with UDCA-treated MCs. We conclude that UDCA acts on MCs reducing histamine levels and decreases the inflammatory/hyperplastic/fibrotic reaction seen in PSC. Ursodeoxycholic acid (UDCA) is used to treat biliary disorders; and, bile acids alter mast cell (MC) histamine release. Following liver injury like primary sclerosing cholangitis in mice and humans, MCs infiltrate. MC-derived histamine increases biliary damage, fibrosis, and inflammation. UDCA treatment decreases these parameters via reduced MC activation.

Mazharuddin, S., A. Chattopadhyay, M. Y. Levy and R. L. Redner (2018). “IRF2BP2-RARA t(1;17)(q42.3;q21.2) APL blasts differentiate in response to all-trans retinoic acid.” Leuk Lymphoma 59(9): 2246-2249.

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To date three reports of IRF2BP2-RARA have been published. Response to ATRA has been inconsistent. In the first publication, Yin et al. reported a 19-year-woman who initially responded to a combination of ATRA, arsenic, and gemtuzumab ozogamicin (though the patient exhibited an atypically prolonged time for normalization of her coagulopathy). She received an 8-month course of consolidation with ATRA and arsenic, but relapsed 2 months later, and received salvage therapy with ATRA, arsenic, and idarubicin, followed by allogeneic bone marrow transplant. The second case, reported by Shimomura et al. was of a 68-year-woman initially treated with ATRA, in which idarubicin and cytarabine was added on day 12. She did not achieve a complete remission, and was re-induced with gemtuzumab ozogamicin, only to relapse 1 year later. The third case was of a 37-year-man who achieved a morphological, but not molecular remission with single agent ATRA; he achieved molecular remission only after addition of Programa para el Tratamiento de Hemopatías Malignas (PETHEMA)-based induction chemotherapy. Herein, we describe the fourth case of t(1;17) APL. A 34-year-old white male presented in March 2016 with WBC 4100 × 106/L, hemoglobin 9.3 g/dL, and platelets 23,000 × 106/L with 40% neutrophils, 9% bands, 45% lymphocytes, 2% monocytes, and 4% blasts. Prothrombin time (PT) was 15.9 s, d-dimer 37.21 mg/L, fibrinogen 397 mg/dL. Over the first week of his hospitalization, the patient was given single agent ATRA 24 mg/m2 daily while the diagnosis of APL was being confirmed. Over this time, the white blood cells (WBC) rose to over 30,000 × 106/L. A bone marrow aspirate and biopsy revealed 89% immature cells expressing CD13, CD33, CD38(dim), CD45, CD117, CD123(dim), and myeloperoxidase[bright]; negative for HLA-DR. Cytogenetics revealed 45, X, -Y, t(1;17)(q42;q21), i(8)(q19). FISH and PCR did not reveal PML-RARA rearrangement. FISH using Vysis LSI RARA Dual Color, Break Apart Rearrangement Probe revealed one orange, one green and one fusion (1O1G1F) signal pattern, consistent with a variant RARA rearrangement. FISH also revealed a gain of RUNX1T1, consistent with the finding of iso(8)(q19). (Excerpt from text, p. 2246; no abstract available.)