Survival After Adrenalectomy for Metastatic Hepatocellular Carcinoma: A 25-year Institutional Experience.

BACKGROUND: Extrahepatic manifestation of hepatocellular carcinoma (HCC) is rare and primarily affects lung, lymph nodes and bone. Metastases to the adrenal glands are relatively infrequent. This 25-year institutional experience aimed for an analysis of factors influencing survival in patients undergoing surgery for HCC adrenal metastasis. METHODS: A retrospective analysis of the institutional database of the Clinic for General-, Visceral- and Transplantation Surgery of the University Medical Center Mainz, Germany, was performed. Patients who underwent surgery for HCC adrenal metastases from January 1995 to June 2020 were included. Pre-, peri- and postoperative factors with potential influence on survival were assessed. RESULTS: In 16 patients (14 males, two females), one bilateral and 15 unilateral adrenalectomies were performed (13 metachronous, three synchronous). Thirteen operations were carried out via laparotomy, and three adrenalectomies were minimally invasive (two laparoscopic, one retroperitoneoscopic). Median overall survival (after HCC diagnosis) was 35 months, range: 5-198. Median post-resection survival (after adrenalectomy) was 15 months, range: 0-75. Overall survival was longer in patients with the primary HCC treatment being liver transplantation (median 66 months) or liver resection (median 51 months), compared to only palliative intended treatment of the primary with chemotherapy (median 35 months) or local ablation (median 23 months). CONCLUSIONS: Surgery is a feasible treatment option for patients with adrenal metastases originating from HCC. In patients who underwent adrenalectomy for HCC adrenal metastasis, overall survival was superior, if primary HCC treatment was potentially curative (liver transplantation or resection).

Hepatitis E Is a Rare Finding in Liver Transplant Patients With Chronic Elevated Liver Enzymes and Biopsy-Proven Acute Rejection.

BACKGROUND: In past decades, liver transplant (LT) patients were not routinely screened for hepatitis E virus (HEV) infection, and thus it might have been misdiagnosed as an acute rejection episode. Our aim was to analyze a real-world cohort of LT patients who presented with at least 1 episode of biopsy-proven acute rejection (BPAR) and suffered from persistent elevated transaminases, to evaluate the frequency of HEV infection misdiagnosed as a rejection episode. METHODS: Data from 306 patients transplanted between 1997 and 2017, including 565 liver biopsies, were analyzed. Biopsies from patients suffering from hepatitis C (n = 79; 25.8%) and from patients who presented with a Rejection Activity Index <5 (n = 134; 43.8%) were excluded. A subgroup of 74 patients (with 134 BPAR) with persistently elevated liver enzymes was chosen for further HEV testing. RESULTS: Positive HEV IgG was detectable in 18 of 73 patients (24.7%). Positive HEV RNA was diagnosed in 3 of 73 patients with BPAR (4.1%). Patients with HEV infection showed no difference in etiology of the liver disease, type of immunosuppression, or median Rejection Activity Index. CONCLUSION: Few HEV infections were misdiagnosed as acute rejection episodes in this real-world cohort. Thus, HEV infection is an infrequent diagnosis in cases with persistent elevated liver enzymes and BPAR after LT.

[Surgical treatment of hepatic tumors-liver resection and transplantation]. / Chirurgische Therapie bei Lebertumoren ­ Leberresektion und -transplantation.

The most frequent primary hepatic malignancies are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (intrahepatic cholangiocellular adenocarcinoma [iCCA]). For HCC in cirrhosis, liver transplantation offers the advantage of a complete hepatectomy radically removing all tumorous tissue along with the surrounding cirrhotic parenchyma, which is otherwise associated with a very high risk of recurrence. For HCC in non-cirrhotic livers and iCCA, liver resection is the treatment of choice. Nowadays, even extended resections can be performed with low mortality in experienced centers. Surgical therapy is more and more embedded into multimodal treatment concepts and decision making should be interdisciplinary as for other gastrointestinal tumors.

[Indications for transplantation and bridging procedures for primary hepatobiliary malignancies]. / Transplantationsindikation und Bridging-Verfahren bei primären hepatobiliären Malignomen.

Primary hepatobiliary malignancies are hepatocellular carcinoma, cholangiocarcinoma and the rare hepatocellular cholangiocarcinoma (mixed tumor). The indications for liver transplantation and the oncological prognosis differ considerably between these tumor entities. Treatment and decision making for these tumors are often complicated by an underlying chronic liver disease. The aim of this review is to delineate the indications for transplantation and bridging therapies for each cancer entity as well as to highlight some aspects pertinent to transplantation, such as the principles of organ allocation.

Randomized clinical trial comparing liver resection with and without perioperative assessment of liver function.

BACKGROUND: Liver function tests may help to predict outcomes after liver surgery. The aim of this study was to evaluate the clinical impact on postoperative outcome and patient management of perioperative liver function testing using the LiMAx® test. METHODS: A multicentre RCT was conducted in six academic liver centres. Patients with intrahepatic tumours scheduled for open liver resection of at least one segment were eligible. Patients were randomized to undergo additional perioperative liver function tests (LiMAx® group) or standard care (control group). Patients in the intervention arm received two perioperative LiMAx® tests, one before the operation for surgical planning and another after surgery for postoperative management. The primary endpoint was the proportion of patients transferred directly to a general ward. Secondary endpoints were severe complications, length of hospital stay (LOS) and length of intermediate care/ICU (LOI) stay. RESULTS: Some 148 patients were randomized. Thirty-six of 58 patients (62 per cent) in the LiMAx® group were transferred directly to a general ward, compared with one of 60 (2 per cent) in the control group (P < 0·001). The rate of severe complications was significantly lower in the LiMAx® group (14 per cent versus 28 per cent in the control group; P = 0·022). LOS and LOI were significantly shorter in the LiMAx® group (LOS: 10·6 versus 13·3 days respectively, P = 0·012; LOI: 0·8 versus 3·0 days, P < 0·001). CONCLUSION: Perioperative use of the LiMAx® test improves postoperative management and reduces the incidence of severe complications after liver surgery. Registration number: NCT01785082 ( https://clinicaltrials.gov).

[Technical aspects of laparoscopic liver surgery : Transfer from open to laparoscopic liver surgery]. / Technische Aspekte der laparoskopischen Leberchirurgie : Transfer von der offenen zur laparoskopischen Leberchirurgie.

BACKGROUND: Laparoscopic surgery has become the standard for most visceral surgery procedures in many hospitals. Now, liver resections are also being increasingly carried out laparoscopically. The advantages of the laparoscopic technique have been demonstrated in numerous case series and in a recent randomized controlled trial. AIMS: The aim of this review article is to present the available techniques for laparoscopic liver surgery (LLS). METHODS: The technical variations reported in the literature as well as the own experience with LLS are reported. RESULTS: Optimal patient and trocar positions are crucial for successful LLS and they are chosen according to the planned type of liver surgery: the literature offers several options in particular for surgery of the cranial and dorsal liver segments. As for open liver surgery, a restrictive volume management and the application of the Pringle maneuver are helpful to reduce intraoperative blood loss in LLS. In addition, several dissection techniques have been adopted from open liver surgery. The Cavitron Ultrasound Surgical Aspirator (CUSA™) is particularly suitable for parenchymal dissection close to major vascular structures, since it guarantees a meticulous parenchymal dissection with minimal vascular injuries. CONCLUSION: The developments of minimally invasive surgery nowadays allow complex liver resections, which can mostly be performed comparable to open liver surgery. Hopefully, minimally invasive liver surgery will further develop in Germany in the near future, since it offers several advantages over open liver surgery.

Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation.

BACKGROUND: Cardiovascular disease is a serious problem of liver transplant (LT) recipients because of increased cardiovascular risk due to immunosuppressive therapy, higher age, intraoperative risk and comorbidities (such as diabetes and nicotine abuse). Reported frequency of cardiovascular events after LT shows a high variability between different LT cohorts. Our aim was to analyze a cohort of LT recipients from a single center in Germany to evaluate frequency of the cardiovascular endpoints (CVE) myocardial infarction and/or cardiac death after LT and to investigate correlations of CVE post LT with pretransplant patient characteristics. PATIENTS: In total, data from 352 LT patients were analyzed. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports. RESULTS: During the median follow-up of 4.0 (0-13) years, 10 cases of CVE were documented (six myocardial infarctions and four coronary deaths). The frequency of CVE did not differ according to classic cardiovascular risk factors such as body mass index (p=0.071), total cholesterol (p=0.533), hypertension (p=0.747), smoking (p=1.000) and pretransplant diabetes mellitus (p=0.146). In patients with pretransplant coronary heart disease (n=24; 6.8%) CVE were found more frequently (p=0.024). CONCLUSION: In summary, we found a rate of 2.8% CVE after LT in a German transplant cohort. Pretransplant CHD was the only risk factor for CVE, but showed no significant impact on overall survival.

[Vascular reconstruction in hepatic surgery]. / Gefäßrekonstruktionen in der Leberchirurgie.

BACKGROUND: Due to their size or location liver tumors can infiltrate important vascular structures, which are essential for postoperative liver function. OBJECTIVE: To present the technical possibilities and results of current concepts of vascular resection and reconstruction in liver surgery. MATERIAL AND METHODS: A literature search of the Medline and Cochrane databases was performed regarding currently available studies on vascular resection and reconstruction in liver surgery. RESULTS: Portal vein resections are routinely performed by many institutions and can be performed as an end-to-end anastomosis or graft interposition. This is the basis of the en bloc resection concept, especially for Klatskin tumors. Reconstruction of the inferior vena cava as well as the hepatic arteries is technically feasible and is increasingly being reported in smaller series. In particular, the resection of tumors near the hepatic veins may require total vascular exclusion for complete interruption of liver perfusion, which enables resection in the non-perfused liver and by this reduced blood loss. Furthermore, in situ cooling, ante situm and ex situ resections increase both technical resectability and the ischemic tolerance of the liver to more than 60 min. The majority of vascular reconstructions can be performed without a significant increase in morbidity; however, vascular tumor infiltration is associated with impaired long-term survival. CONCLUSION: Based on the experience of transplantation surgery concepts for vascular reconstruction can be safely applied to liver surgery. These concepts contribute to increasing the resectability of liver tumors. Due to the often impaired prognosis of vascular tumor infiltration, the use of these concepts should be individually assessed by weighing the prognosis against the morbidity.

New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor.

BACKGROUND: The influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients. METHODS: Data from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included. RESULTS: NODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(±1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (±2.67) years). CONCLUSION: NODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor.

Preoperative left ventricular hypertrophy is associated with reduced patient survival after liver transplantation.

UNLABELLED: Left ventricular hypertrophy (LVH) has been described in the context of cirrhotic cardiomyopathy. The influence of LVH on survival of liver transplant (LT) recipients has not been clarified. Therefore, we evaluated the effect of LVH on survival in LT recipients. In total, data from 352 LT patients were analyzed. LVH was diagnosed by echocardiographic measurement of left ventricular wall thickness before LT. Patients were followed up for a mean of 4.2 yr. LVH was diagnosed in 135 (38.4%) patients. Patients with LVH had significantly more frequently male gender (p = 0.046), diastolic dysfunction (p < 0.001), and hepatocellular carcinoma (HCC; p = 0.004). Furthermore, LVH patients were older (p < 0.001) and had a higher body mass index (BMI; p = 0.001). There was no difference in frequency of arterial hypertension, pre-transplant diabetes mellitus, or etiology of liver cirrhosis. Patients without LVH had a better survival (log rank: p = 0.05) compared with LVH patients. In a multivariate Cox regression LVH (p = 0.031), end-stage renal disease (ESRD; p = 0.003) and lack of arterial hypertension (p = 0.004) but not MELD score (p = 0.885) were associated with poorer survival. CONCLUSION: LVH is frequently diagnosed in patients on the waiting list and influences survival after LT.

[Expanding the liver donor pool through extended-criteria donation]. / Ausweitung des Spenderpools unter Verwendung marginaler Organe.

Due to the great shortage of donor organs in liver transplantation, the utilization of liver allografts from extended-criteria donors is gaining importance. An accepted precise definition of extended-criteria donors remains elusive. The most frequent criteria include high donor age, graft steatosis, and prolonged ICU stay. The influence of using extended-criteria donors on post-transplant outcome has yet to be defined. Its possibly higher rates of graft dysfunction and impaired graft and recipient survival are countered by a proven reduction in waiting-list mortality. Moreover, recipient factors of particular risk such as high MELD (model for endstage liver disease) score and underlying hepatitis C infection have to be defined and taken into consideration.

Adult living donor liver transplantation: living donation of the right liver lobe.

BACKGROUND: Adult living donor liver transplantation (LDLT) has become a routine treatment option for patients waiting for liver transplantation. In European and North American countries, LDLT for adult recipients is mainly performed with right lobe grafts. Indications, when compared to deceased donor liver transplantation, are controversial. MATERIALS AND METHODS: In our institution, patients suffering from hepatocellular carcinoma in cirrhosis, non-resectable hilar cholangiocarcinoma, viral hepatitis associated cirrhosis, as well as cholestatic liver and biliary disease are considered good candidates for LDLT. RESULTS: In this overview, donor evaluation, graft selection, and the donor operation with special regard to operative techniques and strategies are discussed. For visualization, a 5-min video sequence of the standard donor operation as performed in our institution is attached. CONCLUSION: Given the ongoing shortage of donor organs, adult LDLT has become a routine treatment option for patients waiting for liver transplantation. The associated inevitable risk for the healthy donor, however, remains ethically controversial.

Transabdominal ligation of the thoracic duct as treatment of choice for postoperative chylothorax after esophagectomy.

Postoperative chylothorax after injury of the thoracic duct during esophagectomy is a rare but severe complication which may lead to serious problems such as loss of fat and proteins, and immunodeficiency. Without treatment mortality can rise to over 50%. From 1988 to 2005, we treated 10 patients with postoperative chylothorax after 409 resections of the esophagus (2.4%). Of these 10 patients nine underwent transthoracic esophagectomy with gastric pull-up to enable an intrathoracic (n = 7) or cervical (n = 2) anastomosis and one patient received a transhiatal esophagectomy with gastric pull-up and cervical anastomosis. The average amount of postoperative chylus was 2205 mL (200-4500 mL) per day. After a median postoperative interval of 10 days, relaparotomy and transhiatal double ligation of the thoracic duct was performed in nine out of 10 patients. One patient could be managed conservatively. The average amount of chylus was reduced to 151 mL per day (90.5%). Seven patients had no complications, and three suffered from postoperative pneumonia. Two of the patients with pneumonia recovered, and one died. Discharge from hospital, after ligation of the thoracic duct, was possible after a median time of 18 days (11-52). Ligation of the thoracic duct via relaparotomy appeared to be a simple and safe method to treat postoperative chylothorax.

Improved long-term graft survival after HO-1 induction in brain-dead donors.

Brain death (BD) of the donor, a risk factor uniquely relevant for organs derived from cadaver donors, influences organ quality by induction of various inflammatory events. Consequently ischemia/reperfusion injury is deteriorated and acute and chronic rejections accelerated. Donor treatment might be an approach to improve the quality of the graft. The induction of heme oxygenase 1 (HO-1) has been shown to exert beneficial effects in living-donor transplantation models. Therefore, we examined the impact of donor treatment with the selective inducer of HO-1, cobalt protoporphyrin (CoPP), on organ quality and transplant outcome in a standardized BD model in a F344-->LEW kidney transplant rat model. Immediately after BD induction, donor animals were administered a single dose of CoPP (5 mg/kg) and in control groups, HO-1 activity was blocked with zinc protoporphyrin (ZnPP, 20 mg/kg). Recipients of organs from brain-dead donors treated with CoPP survived significantly better than those from untreated brain-dead donors (p < 0.05) and intra-graft analysis showed improved histology (p < 0.05). Blockade of HO-1 with ZnPP decreased the survival rates (p < 0.05) comparable to untreated brain-dead donors. Our results demonstrate that HO-1 induction by one single treatment of CoPP in brain-dead donors leads to enhanced allograft survival.

Effect of drug efficacy and the eclipse phase of the viral life cycle on estimates of HIV viral dynamic parameters.

Fits of mathematic models to the decline in HIV-1 RNA after antiretroviral therapies have yielded estimates for the life span of productively infected cells of 1 to 2 days. In a previous report, we described the mathematic properties of an extended model that accounts for imperfect viral suppression and the eclipse phase of the viral life cycle (the intracellular delay between initial infection and release of progeny virions). In this article, we fit this extended model to detailed data on the decline of plasma HIV-1 RNA after treatment with the protease inhibitor ritonavir. Because the therapy in this study was most likely not completely suppressive, we allowed the drug efficacy parameter to vary from 70% to 100%. Estimates for the clearance rate of free virus, c, increased with the addition of the intracellular delay (as reported previously) but were not appreciably affected by changes in the drug efficacy parameter. By contrast, the estimated death rate of virus-producing cells, delta, increased from an average of 0.49 day-1 to 0.90 day-1 (an increase of 84%) because the drug efficacy parameter was reduced from 100% to 70%. Neglecting the intracellular delay, the comparable increase in delta was only about 55%. The inferred increases in delta doubled when the model was extended to account for possible increases in target cell densities after treatment initiation. This work suggests that estimates for delta may be greater than previously reported and that the half-life of a cell in vivo that is producing virus, on average, may be 1 day.

Health insurance expansion through states in a pluralistic system.

The United States continues to stand almost alone among developed nations in its lack of universal health care coverage. In this essay, we argue that even though the debate over whether the federal government or states should lead the effort to expand health care coverage under the federal system is relevant in strategizing how to cover the uninsured; the more critical issues stem from the challenge of the mixed and fragmented mode of public-private financing of our pluralistic health care system. We base this argument on (1) an in-depth review of Oregon's and Tennessee's five years of experience with broad coverage reform in the context of the United States health care system and on (2) a more abbreviated review of other state experiences in providing health care coverage. We conclude from our review that when the will exists, states can substantially expand coverage. However, as one moves up the income scale, political support and resources are harder to come by. Further, concerns grow about the interface of public and private coverage, with issues of "crowd out" and other distributional questions dominating the discussion of coverage expansion as policy makers focus less on how to cover people than on how to make sure one kind of coverage doesn't preempt another. Concern for crowd out can then lead to policies that keep out some of the very people policy makers may want to cover. In this context the question whether states or the federal government is more likely to succeed in expanding coverage is eclipsed by the more fundamental challenges raised by pluralism. Neither federal nor state government is likely to be fully successful without first identifying ways of better coordinating public and private activities and resources to provide continuous and affordable coverage.

Initiation of therapy during primary HIV type 1 infection results in a continuous decay of proviral DNA and a highly restricted viral evolution.

A latent pool of HIV-1 is established early in memory CD4+ T lymphocytes and persists during antiretroviral therapy. Also, viral replication may continue in subjects despite undetectable viremia. However, it remains unclear whether this residual replication results in any significant sequence evolution. We were therefore interested in studying the viral evolution and HIV-1 DNA dynamics in subjects with primary infection receiving or not receiving early potent antiretroviral therapy. In 16 subjects, HIV-1 DNA load was monitored from 1 to 23 days, up to 1253 days, after onset of symptoms. Extensive sequential cloning and sequence analysis of the V3 region was performed in four subjects. In the treated subjects a continuous decline in the proviral load was found, corresponding to a half-life of about 6 months. As expected in newly infected individuals the founder virus populations showed high intrasubject sequence similarity. Also, a limited increase in the viral divergence was detected during the first 6 months in three treated subjects. Thereafter, no significant sequence changes were found despite analysis of a large number of clones. Our data thus suggest that early and successful therapy in compliant subjects with primary HIV-1 infection results in a highly restricted viral evolution and a decline in the proviral load close to the decay rate of human memory T lymphocytes.

Short-term measures of relative efficacy predict longer-term reductions in human immunodeficiency virus type 1 RNA levels following nelfinavir monotherapy.

We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir. Relative efficacies based on the rate of decline of HIV-1 RNA levels in plasma over the first 14 to 21 days correlated with drug dose and viral load reduction by day 56. Calculation of relative treatment efficacies over the first 2 to 3 weeks of treatment can allow rapid assessment of new antiretroviral agents and dosing regimens, reducing the need to keep subjects in clinical trials on monotherapy for prolonged periods of time. Relative efficacy may also serve as a measure of treatment efficacy in patients in initiating established therapies.

Viral dynamics in primary HIV-1 infection. Karolinska Institutet Primary HIV Infection Study Group.

OBJECTIVES: To study the natural course of viremia during primary HIV infection (PHI). METHOD: Eight patients were followed from a median of 5 days from the onset of PHI illness. Plasma HIV-1 RNA levels were measured frequently and the results were fitted to mathematical models. HIV-1 RNA levels were also monitored in nine patients given two reverse transcriptase inhibitors and a protease inhibitor after a median of 7 days from the onset of PHI illness. RESULTS: HIV-1 RNA appeared in the blood during the week preceding onset of PHI illness and increased rapidly during the first viremic phase, reaching a peak at a mean of 7 days after onset of illness. This was followed by a phase of rapidly decreasing levels of HIV-1 RNA to an average of 21 days after onset. Viral density continued to decline thereafter but at a 5- to 50-fold lower rate; a steady-state level was reached at a median of 2 months after onset of PHI. Peak viral density levels correlated significantly with levels measured between days 50 and 600. Initiation of antiretroviral treatment during PHI resulted in rapidly declining levels to below 50 copies/mL. CONCLUSIONS: This study demonstrates the kinetic phases of viremia during PHI and indicates two new contributions to the natural history of HIV-1 infection: PHI peak levels correlate with steady-state levels and HIV-1 RNA declines biphasically; an initial rapid decay is usually followed by a slow decay, which is similar to the initial changes seen with antiviral treatment.