Sealive: the use of technical vessel-sealing devices for recipient hepatectomy in liver transplantation: study protocol for a randomized controlled trial

Background: The surgical technique used in liver transplantation has undergone constant evolution in an effort to develop a safe, highly standardized procedure. Despite this, the initial step of recipient hepatectomy has not been the focus of clinical research thus far. Due to advanced coagulopathy in liver transplant recipients, this part of the operation still carries the risk of severe hemorrhage. This trial is designed to compare an electrothermal bipolar vessel sealing device (LigaSure™) and an ultrasound dissector (HARMONIC ACE®+7) with standard surgical techniques during the recipients’ hepatectomy in liver transplantation. Methods/design: In a single-center, prospective, randomized, controlled, parallel, three-armed, confirmatory, open trial, LigaSure™ and HARMONIC ACE®+7 will be compared with standard surgical techniques that use titanium clips and conventional knot-tying ligations during recipient hepatectomy in liver transplantation. Intraoperative total blood loss is the primary endpoint of the trial. Secondary endpoints include blood loss during hepatectomy, the duration of both the hepatectomy and the entire surgical procedure, and blood transfusion requirements of the procedure. To generate reliable data, intraoperative blood loss will be recorded with respect to all rinse fluids during surgery, ascites, and by weighing used swabs. At 80% power and an alpha of 0.025 for both of the experimental groups, 23 subjects will be analyzed per protocol in each study arm in order to detect clinically relevant reduction of intraoperative blood loss. The intention-to-treat analysis will include 69 patients. The follow-up period for each patient will be 90 days for safety reasons, whereas all clinical outcomes will be measured within the first 10 postoperative days. Discussion: To our knowledge, this is the first prospective, randomized trial comparing two innovative technical methods of vessel sealing and dissection with standard techniques for recipient hepatectomy. This will be done to detect relevant reduction of intraoperative blood loss during liver transplant. The results of the trial are expected to improve patient outcome and safety after liver transplant and to increase the general safety of this procedure. Trial registration: ClinicalTrials.gov, NCT 03323242 . Registered on October 26, 2017

Randomized controlled trial on PRIngle MAneuver to reduce blood Loss during STapler HEPatectomy - PriMal StHep

Background: Extended liver resections still bear the risk of severe haemorrhage. Moreover, the amount of blood loss during liver resection determines the need for perioperative blood transfusions and is of prognostic relevance in oncologic surgery. Even though there is an ongoing debate about its effectiveness and tolerable duration, the Pringle Maneuver (PM) as an occlusion of the hepatic inflow is routinely applied to reduce blood loss during parenchymal dissection. In combination with the stapler resection technique, PM is expected to minimize blood loss during major liver resection safely due to the short parenchymal dissection duration. Methods: In a single center prospective, randomized, controlled, parallel, confirmatory trial the combination of PM and stapler resection technique in patients undergoing right and left hepatectomies will be tested against the control group that applies stapler resection without the use of PM. The primary endpoint of the study is the total intraoperative blood loss. The measurement of the intraoperative blood loss is conducted with respect to all handled rinse fluids during surgery and by weighing used swabs to generate accurate and comparable data. Secondary endpoints include intra- and postoperative blood transfusion requirements, liver function parameters and the 90-day mortality rate. A sample size of fifty-three patients in either group was calculated to detect a clinically significant difference in blood loss of at least 450 ml with an α of 5% at 80% power. The individual follow-up will be 90 days. Discussion: This is the first clinical trial to test the combination of PM and stapler resection technique as a means to reduce intraoperative blood loss in hepatic left or right resection. Given the short parenchymal dissection duration in stapler resection, PM is expected to be applied shortly without compromising liver function postoperatively. Trial registration: The PriMaL StHep trial has been prospectively registered to the German Clinical Trial Registry (WHO ID: DRKS00010427 ) on April 21st. 2016

Expression of 3q Oncogene SEC62 Predicts Survival in Head and Neck Squamous Cell Carcinoma Patients Treated with Primary Chemoradiation

Primary chemoradiotherapy (CRT) is an established treatment option for locally advanced head and neck squamous cell carcinomas (HNSCC) usually combining intensity modified radiotherapy with concurrent platinum-based chemotherapy. Though the majority of patients can be cured with this regimen, treatment response is highly heterogeneous and can hardly be predicted. SEC62 represents a metastasis stimulating oncogene that is frequently overexpressed in various cancer entities and is associated with poor outcome. Its role in HNSCC patients undergoing CRT has not been investigated so far. A total of 127 HNSCC patients treated with primary CRT were included in this study. The median follow-up was 5.4 years. Pretherapeutic tissue samples of the primary tumors were used for immunohistochemistry targeting SEC62. SEC62 expression, clinical and histopathological parameters, as well as patient outcome, were correlated in univariate and multivariate survival analyses. High SEC62 expression correlated with a significantly shorter overall survival (p = 0.015) and advanced lymph node metastases (p = 0.024). Further significant predictors of poor overall and progression-free survival included response to therapy (RECIST1.1), nodal status, distant metastases, tobacco consumption, recurrence of disease, and UICC stage. In a multivariate Cox hazard proportional regression analysis, only SEC62 expression (p = 0.046) and response to therapy (p < 0.0001) maintained statistical significance as independent predictors of the patients’ overall survival. This study identified SEC62 as an independent prognostic biomarker in HNSCC patients treated with primary CRT. The role of SEC62 as a potential therapeutic target and its interaction with radiation-induced molecular alterations in head and neck cancer cells should further be investigated

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS/DESIGN: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 10(6) cfu up to 10(10) cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications. TRIAL REGISTRATION: EudraCT No.: 2011-000222-29, NCT01486329, ISRCTN6880927

Hand-Assisted laparoscopic donor nephrectomy PERiumbilical versus Pfannenstiel incision and return to normal physical ACTivity (HAPERPACT): study protocol for a randomized controlled trial

Background: Hand-assisted laparoscopic living donor nephrectomy (HALDN) using a periumbilical or Pfannenstiel incision was developed to improve donor outcome after a kidney transplant. The aim of this study was to investigate two methods of hand assistance and kidney removal during HALDN and their effect on the time it takes for the donor to return to normal physical activity. Methods/design: This study was initiated in November 2017 and is expected to last for 2 years. To be eligible for the study, donors must be more than 20 years of age and must not be receiving permanent pain therapy. Only donors with a single artery and vein in the graft are being enrolled in this trial. Donors with infections or scars in the periumbilical or hypogastric area, bleeding disorders, chronic use of immunosuppressive agents, or active infection will be excluded. Donors will be randomly allocated to either a control arm (periumbilical incision) or an intervention arm (Pfannenstiel incision). The sample size was calculated as 26 organ donors in each group. The primary endpoint is the number of days it takes the donor to return to normal physical activity (up to 4 weeks after the operation). Secondary endpoints are intraoperative outcomes, including estimated blood loss, warm ischemia time, and duration of the operation. Postoperative pain will be assessed using the visual analog scale, rescue analgesic use, and peak expiratory flow rate. Length of hospital stay, physical activity score, time to return to work, donor satisfaction, cosmetic score, postoperative complications, and all-cause mortality in living donors will also be reported. Delayed graft function, primary non-function, serum creatinine levels, and glomerular filtration rate will also be assessed in the recipients after transplantation. Discussion: This is the first randomized controlled trial to compare the time it takes the living donor to return to normal physical activity after HALDN using two different types of incision. The comprehensive findings of this study will help decide which nephrectomy procedure is best for living donors with regard to patient comfort and satisfaction as well as graft function in the recipient after transplantation. Trial registration: ClinicalTrials.gov, NCT03317184 . Registered on 23 October 2017

Prognostic impact of intra- and peritumoral immune cell subpopulations in head and neck squamous cell carcinomas – comprehensive analysis of the TCGA-HNSC cohort and immunohistochemical validation on 101 patients

BackgroundDue to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells.MethodsThe overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4+CXCR5, Foxp3 and CD68.ResultsOverall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients’ overall survival in the TCGA-HNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p&lt;0.0001), macrophages (p=0.0042), regulatory T cells (p=0.0306), lymphocytes (p=0.0001), and cytotoxic T cells (p=0.0242) were identified as highly significant predictors of improved patient survival. Using immunohistochemical detection of these immune cells in a second independent validation cohort of 101 HNSCC patients, we confirmed the prognostic relevance of follicular T helper cells, cytotoxic T cells and lymphocytes. In multivariable analysis, HPV negativity and advanced UICC stages were identified as additional prognostic biomarkers associated with poor outcome.ConclusionOur study highlights the prognostic relevance of the immunological tumor environment in head and neck cancer and demonstrates that a more detailed analysis of immune cell composition and immune cell subtypes is necessary to accurately prognosticate. We observed the highest prognostic relevance for lymphocytes, cytotoxic T cells, and follicular T helper cells, suggesting further investigations focusing on these specific immune cell subpopulations not only as predictors of patient prognosis but also as promising targets of new immunotherapeutic strategies

Quantum Criticality in Heavy Fermion Metals

Quantum criticality describes the collective fluctuations of matter undergoing a second-order phase transition at zero temperature. Heavy fermion metals have in recent years emerged as prototypical systems to study quantum critical points. There have been considerable efforts, both experimental and theoretical, which use these magnetic systems to address problems that are central to the broad understanding of strongly correlated quantum matter. Here, we summarize some of the basic issues, including i) the extent to which the quantum criticality in heavy fermion metals goes beyond the standard theory of order-parameter fluctuations, ii) the nature of the Kondo effect in the quantum critical regime, iii) the non-Fermi liquid phenomena that accompany quantum criticality, and iv) the interplay between quantum criticality and unconventional superconductivity.Comment: (v2) 39 pages, 8 figures; shortened per the editorial mandate; to appear in Nature Physics. (v1) 43 pages, 8 figures; Non-technical review article, intended for general readers; the discussion part contains more specialized topic