Clinical Research in Renal Transplantation: A Bibliometric Perspective on a Half-century of Innovation and Progress.

BACKGROUND: Groundbreaking biomedical research has transformed renal transplantation (RT) into a widespread clinical procedure that represents the mainstay of treatment for end-stage kidney failure today. Here, we aimed to provide a comprehensive bibliometric perspective on the last half-century of innovation in clinical RT. METHODS: The Web of Science Core Collection was used for a comprehensive screening yielding 123 303 research items during a 50-y period (January 1973-October 2022). The final data set of the 200 most-cited articles was selected on the basis of a citation-based strategy aiming to minimize bias. RESULTS: Studies on clinical and immunological outcomes (n = 63 and 48), registry-based epi research (n = 38), and randomized controlled trials (n = 35) dominated the data set. Lead US authors have signed 110 of 200 articles. The overall level of evidence was high, with 84% of level1 and -2 reports. Highest numbers of these articles were published in New England Journal of Medicine, Transplantation, and American Journal of Transplantation. Increasing trend was observed in the number of female authors in the postmillennial era (26% versus 7%). CONCLUSIONS: This study highlights important trends in RT research of the past half-century. This bibliometric perspective identifies the most intensively researched areas and shift of research interests over time; however, it also describes important imbalances in distribution of academic prolificacy based on topic, geographical aspects, and gender.

Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements.

Risk factors and management of biliary leakage after Endocystectomy for hepatic cystic echinococcosis.

BACKGROUND: Endocystectomy is a conservative surgical approach to managing cystic echinococcosis. Bile leakage is the main complication of this technique. The aim of this study was to evaluate the factors associated with bile leakage and to assess the outcomes and cost efficiency of strategies used to treat bile leakage. METHODOLOGY/PRINCIPAL FINDINGS: Patients who underwent endocystectomy between 2005 and 2020 were included. The preoperative characteristics, intra- and postoperative outcomes, hospital costs, and cost efficiency (the Diagnosis-Related Group reimbursement minus the overall cost) were evaluated prospectively. A total of eighty patients with 142 cysts were included. Postoperative complications occurred in 17 patients (21%), including 11 patients with bile leakage (type A: 1, type B: 6 and type C: 4 patients, total 13%). Bile leakage was more frequent in patients with preoperative MRI signs of cysto-biliary fistulas or intraoperative visible cysto-biliary fistulas (p = 0.03 and p = 0.04, respectively) and in patients with cysts larger than 8 cm (p = 0.03). Patients with bile leakage who underwent reoperation (type C) had significantly shorter hospital stays (9 vs. 16 days, p<0.01) and better cost efficiency than those who received radiologic or endocscopic interventions (€2,072 vs. -€2,097 p = 0.01). No mortality was observed, and recurrence was seen in two patients. CONCLUSIONS/SIGNIFICANCE: Endocystectomy is a safe and efficient technique. Preoperative and intraoperative cysto-biliary fistulas and a cyst diameter larger than 8 cm are correlated to postoperative bile leakage. Early operative management of bile leakage reduces hospital stay and improves cost efficiency compared with radiologic or endoscopic treatments.

Assessing textbook outcomes following major liver surgery in association with obesity at a referral academic center.

INTRODUCTION: Outcomes of major surgeries in tertiary educational hospitals have been complicated by the referral of high-risk patients and the participation of trainees in surgical procedures. We analyzed outcomes of major hepatectomies in a tertiary academic setting emphasizing the role of training and obesity on textbook outcomes (TO). MATERIALS AND METHODS: 971 adult patients who underwent open major hepatectomy (Mesohepatectomy [n = 111], hemihepatectomy [n = 610], and extended hepatectomy [n = 250]) were evaluated. A TO was defined as: a negative resection margin, no grade B/C bile leak, no major complications, no in-hospital mortality, and no 30-day readmission. TOs were compared following operations performed by senior surgeons and those performed by junior surgeons under the supervision of senior surgeons and between patients with and without obesity. RESULTS: TO was achieved in 70.1% of patients overall (78.4% in mesohepatectomy, 73.1% in hemihepatectomy, and 59.2% in extended hepatectomy). The rate of TO was similar following operations performed by and supervised by a senior surgeon (69.3% vs 71.0%, p = 0.570). The rate of TO was significantly lower in patients with obesity (41.5% vs 74.6%, p < 0.001). Factors including increased age (odds ratio [OR] for 10-year increase = 0.83, 95% confidence interval [CI]: 0.73-0.96, p = 0.009), obesity (OR = 0.25, 95%CI: 0.16-0.37, p < 0.001), biliodigestive anastomosis (OR = 0.27, 95%CI: 0.19-0.40, p < 0.001), and portal vein resection (OR = 0.49, 95%CI: 0.28-0.87, p = 0.014) lower the rate of TO. CONCLUSION: Promising outcomes are possible after major hepatectomy in an academic setting. Obese patients and those undergoing more complex surgeries had a higher risk of poor postoperative outcomes.

Surgical management of primary liver cancers during the COVID-19 pandemic: overcoming the dilemma with standardization.

BACKGROUND: The present study evaluates the impact of the pandemic on outcomes after surgical treatment for primary liver cancer in a high-volume hepatopancreatobiliary surgery center. METHODS: Patients, who underwent liver resection for primary liver resection between January 2019 and February 2020, comprised pre-pandemic control group. The pandemic period was divided into two timeframes: early pandemic (March 2020-January 2021) and late pandemic (February 2021-December 2021). Liver resections during 2022 were considered as the post-pandemic period. Peri-, and postoperative patient data were gathered from a prospectively maintained database. RESULTS: Two-hundred-eighty-one patients underwent liver resection for primary liver cancer. The number of procedures decreased by 37.1% during early phase of pandemic, but then increased by 66.7% during late phase, which was comparable to post-pandemic phase. Postoperative outcomes were similar between four phases. The duration of hospital stay was longer during the late phase, but not significantly different compared to other groups. CONCLUSION: Despite an initial reduction in number of surgeries, COVID-19 pandemic had no negative effect on outcomes of surgical treatment for primary liver cancer. The structured standard operating protocol in a high-volume and highly specialized surgical center can withstand negative effects, a pandemic may have on treatment of patients.

Declined Organs for Liver Transplantation: A Right Decision or a Missed Opportunity for Patients with Hepatocellular Carcinoma?

BACKGROUND: Liver transplantation is the only promising treatment for end-stage liver disease and patients with hepatocellular carcinoma. However, too many organs are rejected for transplantation. METHODS: We analyzed the factors involved in organ allocation in our transplant center and reviewed all livers that were declined for transplantation. Reasons for declining organs for transplantation were categorized as major extended donor criteria (maEDC), size mismatch and vascular problems, medical reasons and risk of disease transmission, and other reasons. The fate of the declined organs was analyzed. RESULTS: 1086 declined organs were offered 1200 times. A total of 31% of the livers were declined because of maEDC, 35.5% because of size mismatch and vascular problems, 15.8% because of medical reasons and risk of disease transmission, and 20.7% because of other reasons. A total of 40% of the declined organs were allocated and transplanted. A total of 50% of the organs were completely discarded, and significantly more of these grafts had maEDC than grafts that were eventually allocated (37.5% vs. 17.7%, p < 0.001). CONCLUSION: Most organs were declined because of poor organ quality. Donor-recipient matching at time of allocation and organ preservation must be improved by allocating maEDC grafts using individualized algorithms that avoid high-risk donor-recipient combinations and unnecessary organ declination.

Perioperative prothrombin complex concentrate and fibrinogen administration are associated with thrombotic complications after liver transplant.

Background: Use of intraoperative prothrombin complex concentrates (PCC) and fibrinogen concentrate administration has been linked to thrombotic events. However, it is unknown if its use is associated with thrombotic events after liver transplant. Methods and analysis: We conducted a post hoc analysis of a prospectively conducted registry database study on patients who underwent liver transplant between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariate and multivariate analyses were used to determine the association between PCC and fibrinogen concentrate administration and thrombotic complications. Results: Data from 939 transplantations were included in the analysis. Perioperative PCC or fibrinogen administration was independently associated with the primary composite endpoint Hepatic artery thrombosis (HAT), Portal vein thrombosis (PVT), and inferior vena cava thrombosis [adjusted HR: 2.018 (1.174; 3.468), p = 0.011]. PCC or fibrinogen administration was associated with the secondary endpoints 30-day mortality (OR 4.225, p < 0.001), graft failure (OR 3.093, p < 0.001), intraoperative blood loss, red blood cell concentrate, fresh frozen plasma and platelet transfusion, longer hospitalization, and longer length of stay in intensive care units (ICUs) (all p < 0.001). PCC or fibrinogen administration were not associated with pulmonary embolism, myocardial infarction, stroke, or deep vein thrombosis within 30 days after surgery. Conclusion: A critical review of established strategies in coagulation management during liver transplantation is warranted. Perioperative caregivers should exercise caution when administering coagulation factor concentrate during liver transplant surgery. Prospective randomized controlled trials are needed to establish causality for the relationship between coagulation factors and thrombotic events in liver transplantation. Further studies should be tailored to identify patient subgroups that will likely benefit from PCC or fibrinogen administration.

Prognostic Value of Red Blood Cell Distribution Width (RDW) in the Recurrence of Hepatocellular Carcinoma Following Curative Resection.

Purpose: Although surgery is associated with an acceptable cure rate, tumor recurrence is still a challenging issue in hepatocellular carcinoma (HCC) patients. Red blood cell distribution width (RDW) is considered an inflammatory marker for predicting overall mortality in a wide spectrum of malignancies. In the current study, the prognostic role of pre- and postoperative RDW in HCC recurrence after liver resection (LRx) is investigated. Patients and Methods: In 395 patients, RDW levels were evaluated preoperatively as well as six and twelve months after curative LRx. The RDW cutoff values were determined using receiver operating characteristic curves (ROCs) according to the recurrence-free survival (RFS). Survival analyses were performed using the Kaplan-Meier, and differences were compared using the Log rank test. Results: The RFS was significantly higher among patients with low RDW at the 6th month and 12th month, postoperatively (P < 0.001 and P = 0.028). RDW levels of higher than 16.15% at the 6th (HR: 2.047, P <0.001) and higher than 15.85% at 12th (HR: 3.105, P < 0.002) months after liver resection were independent predictors of RFS. Conclusion: Postoperative RDW values seem to be predictive of tumor recurrence in HCC patients. RDW levels at the 6th and 12th months postoperatively were independent predictors of recurrence after LRx.

Validation of the ISGLS classification of bile leakage after pancreatic surgery: A rare but severe complication.

INTRODUCTION: Hepaticoenterostomy is an important step of reconstruction during hepatopancreatobiliary (HPB) surgery with a subsequent bile leakage rate of up to 5%. The International Study Group of Liver Surgery (ISGLS) proposed a severity grading system for defining bile leakage after HPB surgery, which has not been validated after pancreatic surgery in a large patient cohort. The present study aimed to validate the ISGLS definition for bile leakage in pancreatic surgery and to investigate the postoperative outcomes of bile leakage after pancreatic resections. MATERIALS AND METHODS: Data from the prospectively maintained database for pancreas surgery were extracted for any type of pancreatectomy with hepaticoenterostomy between 2006 and 2019. The severity of bile leakage was graded according to the ISGLS definition. The influence of our standardized hepaticoenterostomy technique and of the complexity of the surgical procedure on the rate of clinically relevant bile leakages (B and C) were assessed in three different timeframes. RESULTS: Bile leakage was detected in 152 of 5,300 patients (2.9%). Clinically relevant bile leakages included seventy patients with grade B and eighty-two patients with grade C bile leakages (46.1% and 53.9%, respectively). During the study period, the overall rate of bile leakage showed to be stable (from 3.5% to 2.4%). Patients with grade C bile leakage had a higher rate of postoperative wound infection (P < 0.001) and longer ICU stays and hospital stays compared to patients with grade B bile leakage (P = 0.03 and P < 0.001 respectively). These parameters were significantly higher in patients with late grade C bile leakage but were similar between patients with grade B bile leakage and early grade C bile leakage (<5th day POD). In the whole patients' cohort, the 90-day mortality rate was 3.2% (174/5,300), with a rate of 25% in patients with bile leakage (38/152). CONCLUSION: The ISGLS classification is a valid method for classifying postoperative bile leak after pancreas surgery. Standardization of our hepaticoenterostomy technique resulted in a stable rate of bile leakage. Although rare, bile leakage following pancreas surgery is a severe complication that has a major impact on patient outcomes and contributes significantly to morbidity and mortality, even in the absence of POPF.

Spleen transient elastography predicts actuarial survival after liver transplantation.

Background: Splenic transient elastography (TE) correlates with increased portal pressure. Little data are available in the post liver transplantation (LTx) setting. Methods: Three months after LTx, we performed splenic TE in 125 LTx recipients. Results: Mean splenic TE values were 29.4 (±6.3; range, 21.6-49.2) kPa. Splenic TE correlated with reduced time to development until persistent ascites (30 events, OR =1.082, 95% CI: 1.034-1.133; P=0.001), hepatorenal syndrome (8 events, OR =1.109, 95% CI: 1.015-1.211; P=0.022) and hepatic encephalopathy (16 events, OR =1.136, 95% CI: 1.066-1.211; P=0.000). In Cox univariate analysis, splenic TE served as a predictor of actuarial survival free of liver (OR =1.114, 95% CI: 1.050-1.182; P<0.001) and remained an independent risk factor associated with reduced actuarial survival free of LTx in multivariate analysis (OR =1.103, 95% CI: 1.026-1.186; P=0.008). Conclusions: Splenic TE measurement at 3 months after LTx serves as a robust predictor of survival in LTx recipients.

Clinical effects and safety of different transarterial chemoembolization methods for bridging and palliative treatments in hepatocellular carcinoma.

PURPOSE: We assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting. METHODS: In our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE. RESULTS: The cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance. CONCLUSIONS: The clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA.

We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

Prophylactic Peritoneal Fenestration during Kidney Transplantation Can Reduce the Type C Lymphocele Formation.

Lymphocele is a common complication following kidney transplantation (KTx). We aimed to evaluate the preventive effect of peritoneal fenestration during KTx in reducing lymphocele. From January 2001, the data of all KTx were prospectively gathered in our digital data bank. From 2008, preventive peritoneal fenestration was performed as a routine procedure for all patients with KTx. Between 2001 and 2008, 579 KTx were performed without preventive peritoneal fenestration. To compare the results between with and without peritoneal fenestration, the same number of patients after 2008 (579 patients) was included in this study. The pre-, intra-, and postoperative data of the patients in these two groups were analyzed and compared, especially regarding the postoperative different types of lymphocele formation. The mean recipient age was 52.6 ± 13.8, and 33.7% of the patients were female. Type C lymphocele was significantly lower in the group with preventive fenestration (5.3% vs. 8.8%, p = 0.014 for 31/579 vs. 51/579). Peritoneal dialysis and implantation of the kidney in the left fossa were independently associated with a higher rate of type C lymphocele (OR 2.842, 95% CI 1.354-5.967, p = 0.006 and OR 3.614, 95% CI 1.215-10.747, p = 0.021, respectively). The results of this study showed that intraoperative preventive peritoneal fenestration could significantly reduce type C lymphocele.

Validating Consensus-Defined Severity Grading of Lymphatic Complications after Kidney Transplant.

Lymphatic complications after kidney transplantation (KTx) are associated with morbidities such as impaired wound healing, thrombosis, and organ failure. Recently, a consensus regarding the definition and severity grading of lymphoceles has been suggested. The aim of the present study was to validate this classification method. All adult patients who underwent KTx between December 2011 and September 2016 in our department were evaluated regarding lymphoceles that were diagnosed within 6 months after KTx based on the recent definition. Patients with lymphoceles were categorized according to the classification criteria, and clinical outcomes were compared between the groups. In our department, a total of 587 patients underwent KTx between 2011 and 2016. Lymphoceles were detected after KTx in 90 patients (15.3%). Among these patients, 24 (26.6%) had grade A lymphoceles, 14 (15.6%) had grade B, and 52 (57.8%) had grade C. The median duration times of intermediate care (IMC) and hospital stay were significantly higher among patients with grade C lymphoceles than they were among patients with grade A and B lymphoceles. Significantly more patients with grade C lymphoceles were readmitted to the hospital for treatment. The recently published definition and severity grading of lymphoceles after KTx is an easy-to-use and valid classification system, which may facilitate the comparison of results from different studies on lymphoceles after KTx.

Gastric venous reconstruction to reduce gastric venous congestion after total pancreatectomy: study protocol of a single-centre prospective non-randomised observational study (IDEAL Phase 2A) - GENDER study (Gastric vENous DrainagE Reconstruction).

INTRODUCTION: Total pancreatoduodenectomy (TP) is the standard surgical approach for treating extended pancreas tumours. If TP is performed with splenectomy, the left gastric vein (LGV) sometimes needs to be sacrificed for oncological or technical reasons, which can result in gastric venous congestion (GVC). GVC can lead to gastric venous infarction, which in turn causes gastric perforation with abdominal sepsis. To avoid gastric venous infarction, partial or total gastrectomy is usually performed if GVC occurs after TP. However, gastrectomy can be avoided by reconstructing the gastric venous outflow to overcome GVC and avoid gastric venous infarction. The current study aims to assess the role of gastric venous outflow reconstruction to prevent GVC after TP and avoid gastrectomy. METHODS AND ANALYSIS: In the current single-centre observational pilot study, 20 patients will be assigned to study after intraoperative evaluation of gastric venous drainage after LGV resection during TP. During surgery, on-site evaluation by the surgeon, endoscopic examination, indocyanine green, gastric venous drainage flowmetry and spectral analysis will be performed. Postoperatively, patients will receive standard post-TP care and treatment. During hospitalisation, endoscopic examination with indocyanine green will be performed on the 1st, 3rd and 7th postoperative day to evaluate gastric ischaemia. Ischaemia markers will be evaluated daily after surgery. After discharge, patients will be followed-up for 90 days, during which mortality and morbidities will be recorded. The main endpoints of the study will include, rate of GVC, rate of gastric ischaemia, rate of postpancreatectomy gastrectomy, rate of reoperation, morbidity and mortality. ETHICS AND DISSEMINATION: The study protocol has been reviewed and approved by the Ethics Committee of the University of Heidelberg. The results will be actively disseminated through peer-reviewed journals and conference presentations, and are expected in 2022. TRIAL REGISTRATION NUMBER: NCT04850430.

Prognostic role of the Donor Risk Index, the Eurotransplant Donor Risk Index, and the Balance of Risk score on graft loss after liver transplantation.

This study aimed to identify cutoff values for donor risk index (DRI), Eurotransplant (ET)-DRI, and balance of risk (BAR) scores that predict the risk of liver graft loss. MEDLINE and Web of Science databases were searched systematically and unrestrictedly. Graft loss odds ratios and 95% confidence intervals were assessed by meta-analyses using Mantel-Haenszel tests with a random-effects model. Cutoff values for predicting graft loss at 3 months, 1 year, and 3 years were analyzed for each of the scores. Measures of calibration and discrimination used in studies validating the DRI and the ET-DRI were summarized. DRI ≥ 1.4 (six studies, n = 35 580 patients) and ET-DRI ≥ 1.4 (four studies, n = 11 666 patients) were associated with the highest risk of graft loss at all time points. BAR > 18 was associated with the highest risk of 3-month and 1-year graft loss (n = 6499 patients). A DRI cutoff of 1.8 and an ET-DRI cutoff of 1.7 were estimated using a summary receiver operator characteristic curve, but the sensitivity and specificity of these cutoff values were low. A DRI and ET-DRI score ≥ 1.4 and a BAR score > 18 have a negative influence on graft survival, but these cutoff values are not well suited for predicting graft loss.

HBV-infection rate and long-term outcome after liver-transplantation of anti-HBc-positive liver-grafts to HBV-naïve recipients: A retrospective study.

BACKGROUND: Anti-HBc only positive liver grafts may be suitable for HBV-naive recipients insofar as an appropriate infection prophylaxis is performed. Therefore, we investigated the effect of prophylactic regimens on HBV infection prevention and long-term outcome of anti-HBc-positive graft recipients. PATIENTS AND METHODS: This retrospective monocenter study consisted of a cohort of 1912 patients who underwent deceased donor liver transplantation at our transplant center between June 1987 and July 2019. 81 HBV-naïve patients after reception of an anti-HBc-positive liver-graft and consecutive HBV prophylaxis were selected for further examination. HBV infection rate and host- and graft-survival rates were compared to a matched control group consisting of 162 HBV-naïve patients after reception of anti-HBc-negative grafts. Pharmaceutical HBV prophylaxis included: only HBIG, only NUCs, or combined HBIG and NUCs. RESULTS: Compared to control cases of HBV-naïve anti-HBc-negative graft recipients, no differences in host- and graft-survival rate were determined.13 of 81 anti-HBc-positive graft recipients (16%) developed HBV-infection after liver transplantation. No patient suffered from HBV infection after receiving modern NUCs. Survival analysis showed no statistical differences between patients with and without infection concerning host- and graft-survival. CONCLUSION: Especially in times of organ shortage, anti-HBc-positive liver grafts may be useful for liver transplantation in HBV-naïve recipients. Efficient prophylactic regimens can prevent HBV-infection.