Successful implementation of preventive measures leads to low relevance of SARS‐CoV‐2 in liver transplant patients: Observations from a German outpatient department

Background: Immunosuppressed liver transplant (LT) patients are considered to be at high risk for any kind of infection. What the outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) means for the transplant cohort is a question that, as of now, cannot easily be answered. Data on prevalence, relevance of the novel virus, and clinical course of the infection in stable LT patients are limited. Methods: Nasopharyngeal swabs were performed in our outpatient department during the shutdown between March and April 2020 in Germany. Results: The prevalence of SARS-CoV-2 was 3%. Three out of a cohort of 101 LT patients were asymptomatic for respiratory diseases. Respiratory complaints were common and not associated with SARS-CoV-2 infection. The overall monthly mortality rate was 0.22% and did not show alterations during the shutdown in Germany. Conclusions: If preventive measures are applied, LT patients do not seem to be at a higher risk for SARS-CoV-2 infection. Telemedicine in the outpatient setting may help to maintain distance and to reduce direct patient contact. However, standard of care must be guaranteed for patients with relevant comorbidities in spite of pandemics, because complications may arise from preexisting conditions

How to Estimate the Probability of Tolerance Long-Term in Liver Transplant Recipients

Background: Operational tolerance as the ability to accept the liver transplant without pharmacological immunosuppression is a common phenomenon in the long-term course. However, it is currently underutilized due to a lack of simple diagnostic support and fear of rejection despite its recognized benefits. In the present work, we present a simple score based on clinical parameters to estimate the probability of tolerance. Patients and methods: In order to estimate the probability of tolerance, clinical parameters from 82 patients after LT who underwent weaning from the IS for various reasons at our transplant center were extracted from a prospectively organized database and analyzed retrospectively. Univariate testing as well as multivariable logistic regression analysis were performed to assess the association of clinical variables with tolerance in the real-world setting. Results: The most important factors associated with tolerance after multivariable logistic regression were IS monotherapy, male sex, history of hepatocellular carcinoma pretransplant, time since LT, and lack of rejection. These five predictors were retained in an approximate model that could be presented as a simple scoring system to estimate the clinical probability of tolerance or IS dispensability with good predictive performance (AUC = 0.89). Conclusion: In parallel with the existence of a tremendous need for further research on tolerance mechanisms, the presented score, after validation in a larger collective preferably in a multicenter setting, could be easily and safely applied in the real world and already now address all three levels of prevention in LT patients over the long-term course

Characteristics of inflammation and resolution in anatomical compartments of the spinal cord after induction of sterile inflammation

Andauernde Inflammation im Myelon nach Rückenmarkverletzung (spinal cord injury - SCI) trägt einen relevanten Anteil am Sekundärschaden des Gewebes jenseits des ursprünglichen Schadens. Experimentelle Studien beschrieben ein sog. Resolutionsdefizit nach SCI. Für die hieraus resultierenden Schadensprozesse sind zudem innerhalb des Rückenmarks entsprechend den in Vaskularisierung und Metabolismus verschiedenen anatomischen Kompartimenten unterschiedliche Verläufe anzunehmen. Darüber hinaus ist mit dem SCI-induced- Immune Deficiency Syndrom (SCI-IDS) ein Mechanismus der läsionshöhenabhängigen Auswirkung der SCI auf systemische und lokale inflammatorische Prozesse beschrieben worden. Erwachsene Lewis Ratten wurden auf Wirbelkörper Th9 oder Th3 einer Laminektomie über ein Segment unterzogen. Stereotaktisch erfolgte dann die kalibrierte Injektion einer Zymosan A – Lösung über eine Mikropipette zur Inflammationsinduktion in entweder die weiße (AL) oder die graue Substanz (GR). Zu definierten Zeitpunkten, von 24 Stunden bis 12 Wochen nach der Injektion, erfolgte die Tötung und Gewebeentnahme zur histologischen Aufarbeitung. Neben einer Vermessung der Läsion wurden zur Analyse der wichtigsten Zellpopulationen der Inflammation immunhistochemische MPO, CD68, CD43, CD3 und GFAP – Färbungen an transversalen Schnitten durchgeführt und die Zellen quantitativ zur statistischen Analyse und der Berechnung von Resolutionsindices erfasst. Insgesamt wurden n=146 Tiere eingeschlossen. Ein Unterschied in der Läsionsgröße zwischen den Gruppen war nicht festzustellen. Auf Höhe Th9 und Th3 zeigte sich kein Unterschied der Kinetik der MPO+ Zellen. Für die CD68+ Zellen auf Höhe Th9 zeigte sich im Vergleich zwischen den Gruppen GR und AL ein signifikanter Unterschied 24h nach Injektion mit höheren Zellzahlen in der GR-Gruppe und zwölf Wochen nach der Injektion mit signifikant niedrigen Zahlen in der GR bei stark unterschiedlichen Resolutionsplateaus (AL: RP=58,9% / GR: RP=20,9%). CD43+ Zellen sowie CD3+ zeigten zwischen den Gruppen keine Unterschiede. GFAP+ Zellen waren sieben Tage und 12 Wochen nach der Injektion in der GR- gegenüber der AL-Gruppe signifikant erhöht. Der Vergleich der Kinetiken zwischen Th9 und Th3 war aufgrund methodischer Einschränkungen nur unzureichend durchführbar. Diskussion Zwischen grauer und weißer Substanz gibt es für Makrophagen/Mikroglia, und Astrozyten unterschiedliche Inflammations- bzw. Resolutionskinetiken mit deutlich effektiverer Resolution in der GR für Makrophagen. Dies könnte mit Unterschieden in der Dichte der Vaskularisation, Zellinflux über den Zentralkanal und Charakteristika der Blut-Rückenmark- Schranke zu erklären sein. Astrozyten könnten in diesem Zusammenhang möglicherweise neuroprotektive Funktion besitzen. Neben einer sorgfältigen Aufschlüsselung der Inflammation im Zeitverlauf lässt sich aus der vorliegenden Arbeit ein Hinweis auf eine Differenzierung von Inflammation und Resolution in Abhängigkeit von anatomischen Kompartimenten sehen. Zellspezifische Subgruppen sollten identifiziert und das Resolutionsdefizit auf klinische Relevanz überprüft werden.Ongoing Inflammation within the myelon after Spinal Cord Injury (SCI) contributes to secondary damage beyond inital injury. Experimental data suggest a resolution deficit of spinal cord inflammation, that may contribute to sustained injury progression and impede recovery. Additionally, different kinetics in secondary damage processes regarding anatomical locations have been described. Furthermore, the SCI-induced-Immune Deficiency Syndrom (SCI- IDS) suggests impact on inflammatory processes dependant on lesion height. Adult Lewis rats underwent single-level laminectomy and subsequently stereotactic intraspinal injection of zymosan via glass micropipettes into either white (AL) or grey (GR) matter at level th9 or th3. At pre-specified timepoints ranging from 24 hours to 12 weeks after injections, animals were sacrificed and spinal cords were fixed and embedded. Lesion diameter in serial coronar slices was identified and immunohistological staining of MPO, CD68, CD43, CD3 und GFAP representing dominant inflammatory cell populations was conducted. Statistical analysis was performed and calculation of indices of resolution was calculated assuming half-life kinetics. n=146 animals were included in this study. Lesion size did not differ between groups. Kinetics of MPO+ cells did not show major differences between AL and GR-groups at either th9 or th3. CD68+ cells at level th9 showed significant differences in cell count at 24h post injection with higher numbers in GR-group and with significant lower numbers twelve weeks post injection, resulting in highly different resolution plateaus (AL: RP=58,9% / GR: RP=20,9%). No differences were observed in CD43+ and CD3+ cells. GFAP+ cells were significantly higher in GR lesions compared to AL at both seven days and twelve weeks post injection. Comparison between th9 and th3 proved to be difficult as included numbers at level th3 were low. Differences between white and grey matter lesions regarding inflammation and resolution were observed for macrophages/microglia and astrocytes. The grey matter showed to resolve macrophages/microglia more effectively. Neuroanatomical properties like density of vascular structures, cell migration via the central canal, and differences in blood-spinal-cord barrier may contribute. Probably, also astrocytes might be associated with faster resolution. Subtle differences between th9 and th3 might as well be explained by the arterial watershed of the upper thoracic spine and BSCB-permeability. Conclusion This study suggests, that precise understanding of inflammation and resolution might not only be necessary regarding time course, but also regarding its anatomical compartments. Still, subgroups of inflammatory cells need to be identified and the impact of the specific resolution deficit on clinical outcome should be measured

Clinical and Histological Long-Term Follow-Up of De Novo HBV-Infection after Liver Transplantation

Background and Objectives: Development of hepatitis-B is considered a serious complication after liver transplantation. HBV de novo infection is a rather rare phenomenon, however it deserves attention in the era of donor organ shortage. The aim of the present analysis was to examine its course in liver transplant patients. Materials and Methods: Prevalence of de novo HBV-infections was extracted from our local transplant data base. Analysis focused on the moment of HBV-detection and on the long-term follow-up in terms of biochemical and histological changes over 30 years. Results: 46 patients were identified with the diagnosis of de novo hepatitis B. Median time from liver transplantation to diagnosis was 397 days (7–5505). 39 patients received antiviral therapy. No fibrosis progression could be detected, whereas the grade of inflammation significantly lessened from the moment of HBV detection to the end of histological follow-up over a median of 4344 days (range 123–9490). Patients with a poor virological control demonstrated a significantly poorer overall survival. Conclusions: De novo hepatitis B in liver transplant patients is a condition that can be controlled very well without significant fibrosis progression or graft loss if recognized on time within a regular transplant follow-up schedule

Discontinuation of Passive Immunization Is Safe after Liver Transplantation for Combined HBV/HDV Infection

Patients after LT due to combined HBV/HDV infection are considered to be high-risk patients for recurrence of hepatitis B and D. To date, life-long prophylaxis with hepatitis B immunoglobulin (HBIG) and replication control with nucleos(t)ide analogs (NA) remains standard. We examined the course of 36 patients that underwent liver transplantation from 1989 to 2020 for combined HBV/HDV-associated end-stage liver disease in this retrospective study. Seventeen patients eventually discontinued HBIG therapy for various reasons. Their graft function, histopathological findings from routine liver biopsies and overall survival were compared with those that received an unaltered NA-based standard regimen combined with HBIG. The median follow-up was 204 and 227 months, respectively. The recurrence of HBV was 25% and did not differ between the groups of standard reinfection prophylaxis NA/HBIG (21.1%) and HBIG discontinuation (29.4%); (p = 0.56). No significant differences were found regarding the clinical course or histopathological aspects of liver tissue damage (inflammation, fibrosis, steatosis) between these two groups. Overall, and adjusted survival did not differ between the groups. Discontinuation of HBIG in stable patients after LT for combined HBV/HDV did not lead to impaired overall survival or higher recurrence rate of HBV/HDV infection in this long-term follow-up. Therefore, the recommendation of the duration of HBG administration must be questioned. The earliest time of discontinuation remains unclear

Textbook Outcome after Gastrectomy for Gastric Cancer Is Associated with Improved Overall and Disease-Free Survival.

(1) Background: The complexity of the perioperative outcome for patients with gastric cancer is not well reflected by single quality metrics. To study the effect of the surgical outcome on survival, we have evaluated the relationship between textbook outcome (TO)-a new composite parameter-and oncological outcome. (2) Methods: All patients undergoing total gastrectomy or trans-hiatal extended gastrectomy for gastric cancer with curative intent between 2017 and 2021 at our institution were included. TO was defined by negative resection margins (R0); collection of ≥25 lymph nodes; the absence of major perioperative complications (Clavien-Dindo ≥ 3); the absence of any reintervention; absence of unplanned ICU re-admission; length of hospital stay 4 (p = 0.034, OR 2.844, CI 1.079-7.493) were significant factors affecting DFS upon univariate analysis. In multivariate analysis, CCI > 4 (p = 0.035, OR 2.605, CI 0.983-6.905) was significantly associated with DFS. (4) Conclusions: We identified patient- and procedure-related factors influencing TO. Importantly, achieving TO is strongly associated with improved long-term survival in gastric cancer patients and merits further focus on surgical quality improvement efforts

Minimization of Immunosuppressive Therapy Is Associated with Improved Survival of Liver Transplant Patients with Recurrent Hepatocellular Carcinoma

Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful

A Reduction of Calcineurin Inhibitors May Improve Survival in Patients with De Novo Colorectal Cancer after Liver Transplantation

Background and Objectives: After liver transplantation (LT), long-term immunosuppression (IS) is essential. IS is associated with de novo malignancies, and the incidence of colorectal cancer (CRC) is increased in LT patients. We assessed course of disease in patients with de novo CRC after LT with focus of IS and impact on survival in a retrospective, single-center study. Materials and Methods: All patients diagnosed with CRC after LT between 1988 and 2019 were included. The management of IS regimen following diagnosis and the oncological treatment approach were analyzed: Kaplan–Meier analysis as well as univariate and multivariate analysis were performed. Results: A total of 33 out of 2744 patients were diagnosed with CRC after LT. Two groups were identified: patients with restrictive IS management undergoing dose reduction (RIM group, n = 20) and those with unaltered regimen (maintenance group, n = 13). The groups did not differ in clinical and oncological characteristics. Statistically significant improved survival was found in Kaplan–Meier analysis for patients in the RIM group with 83.46 (8.4–193.1) months in RIM and 24.8 (0.5–298.9) months in the maintenance group (log rank = 0.02) and showed a trend in multivariate cox regression (p = 0.054, HR = 14.3, CI = 0.96–213.67). Conclusions: Immunosuppressive therapy should be reduced further in patients suffering from CRC after LT in an individualized manner to enable optimal oncological therapy and enable improved survival

Minimization of Immunosuppressive Therapy Is Associated with Improved Survival of Liver Transplant Patients with Recurrent Hepatocellular Carcinoma

Simple Summary: Liver transplantation is a curative treatment option for a subset of patients with hepatocellular carcinoma (HCC). However, about twenty percent of patients develop recurrence in the graft or at extrahepatic sites, which is associated with limited therapeutic options and poor survival. To date, management of the immunosuppressive regimen after recurrence and its impact on survival are unknown. In this retrospective study, we analyzed a cohort of liver recipients with HCC recurrence. Our findings indicate that reduction of immunosuppressive therapy after diagnosis of recurrence has a beneficial impact on patient survival. Therefore, we propose further investigation into the management of immunosuppressive therapy following recurrence. Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charite Universitatsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0-203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3-228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful

The Role of Immunosuppression for Recurrent Cholangiocellular Carcinoma after Liver Transplantation

Liver transplantation (LT) for cholangiocarcinoma (CCA), or biliary tract cancer (BTC), remains controversial regarding high recurrence rates and poor prognosis. Oncological follow-up may benefit from tumor-inhibiting properties of mTOR inhibitors (mTORI), shown with improved survival for recurrent hepatocellular carcinoma (HCC) patients after LT. The aim of this study was to investigate the recurrence and survival in relation to tumor type and type of immunosuppression (IS). LT patients with CCA or mixed HCC/CCA (mHCC/CCA) (n = 67) were retrospectively analyzed. Endpoints were the time from LT to recurrence (n = 44) and survival after recurrence. Statistically significant impairment in survival for recurrent CCA (rCCA) was shown in patients not eligible for surgical resection (HR 2.46 (CI: 1.2&ndash;5.1; p = 0.02). Histological proven grading &gt;1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03&ndash;0.58); p &lt; 0.01 and HR 3.4 (CI: 1.0&ndash;11.65); p = 0.05). Reduced IS after tumor recurrence improved survival (HR 4.2/CI: 1.3&ndash;13.6; p = 0.02). MTORI initiation before recurrence or after had no significant impact on survival. Our data thereby indicate, similar to findings in recurrent HCC after LT, that patients with rCCA after LT benefit from a reduction in IS upon recurrence