Detrimental impact of immunosuppressive burden on clinical course in patients with Cytomegalovirus infection after liver transplantation.

INTRODUCTION: Cytomegalovirus (CMV)-infection and reactivation remain a relevant complication after liver transplantation (LT). The recipient and donor serum CMV-IgG-status has been established for risk stratification when choosing various pharmaceutical regimens for CMV-prophylaxis in the last two decades. However, factors influencing course of CMV-infection in LT remain largely unknown. In this study, the impact of immunosuppressive regimen was examined in a large cohort of patients. METHODS: All patients that underwent primary LT between 2006 and 2018 at the Charité-Universitaetsmedizin, Berlin, were included. Clinical course as well as histological and laboratory findings of patients were analyzed our prospectively maintained database. Univariate and multivariate regression analysis for impact of variables on CMV-occurrence was conducted, and survival was examined using Kaplan-Meier analysis. RESULTS: Overall, 867 patients were included in the final analysis. CMV-infection was diagnosed in 325 (37.5%) patients after transplantation. Significantly improved overall survival was observed in these patients (Log rank = 0.03). As shown by correlation and regression tree classification and regression tree analysis, the recipient/donor CMV-IgG-status with either positivity had the largest influence on CMV-occurrence. Analysis of immunosuppressive burden did not reveal statistical impact on CMV-infection, but statistically significant inverse correlation of cumulative tacrolimus trough levels and survival was found (Log rank < .001). Multivariate analysis confirmed these findings (p = .02). DISCUSSION: CMV-infection remains of clinical importance after LT. Undergone CMV-infection of either recipient or donor requires prophylactic treatment. Additionally, we found a highly significant, dosage-dependent impact of immunosuppression (IS) on long-term outcomes for these patients, underlying the importance of minimization of IS in liver transplant recipients.

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.

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 < 21 days; absence of 30-day readmission and 30-day mortality. We evaluated factors affecting TO by multivariate logistic regression. The correlation between TO and long-term survival was assessed using a multivariate cox proportional-hazards model. (3) Results: Of the patients included in this study, 52 (52.5 %) achieved all TO metrics. Open surgery (p = 0.010; OR 3.715, CI 1.334-10.351) and incomplete neoadjuvant chemotherapy (p = 0.020, OR 4.278, CI 1.176-15.553) were associated with failure to achieve TO on multivariate analysis. The achievement of TO significantly affected overall survival (p = 0.015). TO (p = 0.037, OD 0.448, CI 0.211-0.954) and CCI > 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.

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.

Current status of robotic surgery for hepato-pancreato-biliary malignancies.

INTRODUCTION: Robotic surgery is an emerging aspect of gastrointestinal surgery. Hepato-pancreato-biliary surgery is currently being explored for a broad spectrum of indications, entities, and postoperative outcomes. Noninferiority and financial aspects are the focus of studies. In this review, the impact on oncological therapies is assessed. AREAS COVERED: An extensive literature review was conducted, and relevant studies and articles and reviews for robotic surgery in the field of hepato-pancreato-biliary surgery were examined. Special attention was given to the oncological aspects of robotic surgery and its possible impact on the therapy of malignant neoplasms. EXPERT OPINION: Robotic-assisted surgery for oncological indications is promising, in part, an established technique that has already shown its advantages in the last decade, although high-quality studies are missing. Upcoming experience must consider the oncological benefit and putative new indications in a rapidly changing field of anti-neoplastic regimens. Also, robotic surgery may possess the ability to accelerate digitalization and AI-based augmentation in this context.

Reducing Immunosuppression in Patients with De Novo Lung Carcinoma after Liver Transplantation Could Significantly Prolong Survival.

(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution's register of liver allograft recipients (Charité-Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7-27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0-196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS 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: 1.2−5.1; p = 0.02). Histological proven grading >1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03−0.58); p < 0.01 and HR 3.4 (CI: 1.0−11.65); p = 0.05). Reduced IS after tumor recurrence improved survival (HR 4.2/CI: 1.3−13.6; 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.

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.

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.

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.

Lymph node upstaging for non-small cell lung cancer after uniportal video-assisted thoracoscopy.

BACKGROUND: Radical lymph node dissection (LND) plays a major role in the treatment of non-small cell lung cancer (NSCLC). This study presents the analysis of the results after uniportal video-assisted thoracoscopy (VATS) lymphadenectomy during anatomical lung resections for NSCLC, focusing on pathological nodal upstaging. Any possible risk factor affecting nodal upstaging was also investigated. METHODS: The prospectively collected clinical data of 136 patients undergone uniportal VATS anatomical lung resections, from June 2012 to September 2017, were reviewed. In particular, all details inherent the clinical and pathological node stage and any possible risk factor affecting nodal upstaging were analyzed. RESULTS: The patient population consisted of 90 males and 46 females; their mean age was 67.42±10.64 years. The mean number of lymph nodes retrieved during uniportal VATS lymphadenectomy was 20.14±10.73 (7.27±5.90 and 12.60±7.96 in N1 and N2 stations, respectively). The incidence of nodal upstaging was 13.3% (18 cases). In particular there was a N0-1 upstaging in 10 cases (7.4%), a N1-2 upstaging in 3 (2.2%) and a N0-2 in 4 (3%). The ROC analysis showed that the resection of 18 lymph nodes was the best predictor of a general upstaging with an AUC-ROC of 0.595, while the resection of 7 hilar lymph nodes was the best predictor of N1 upstaging (AUC-ROC: 0.554) and 11 mediastinal nodes was the best predictor of N2 upstaging (AUC-ROC: 0.671). The number of positive lymph nodes of stations 5-6 (OR: 2.035, 95% CI: 1.082-3.826, P=0.027) and stations 2-3-4 (OR: 6.198, 95% CI: 1.580-24.321, P=0.009) were confirmed to be the only independent risk factors for N2 upstaging by multivariate analysis. CONCLUSIONS: According to our experience, uniportal VATS allows a safe and effective radical lymphadenectomy, with a satisfactory pathological nodal upstaging, comparable to other minimally invasive techniques.

Uniportal video-assisted thoracoscopy major lung resections after neoadjuvant chemotherapy.

BACKGROUND: The combination of neoadjuvant chemotherapy and surgery in lung cancer therapy is well established. The role of uniportal video assisted thoracoscopy (VATS) is still not described in literature. This study presents the preliminary short-term results of uniportal VATS after neoadjuvant therapy in our series. METHODS: The prospectively collected data of 154 patients after uniportal VATS anatomical lung resection (18 patients after neoadjuvant chemotherapy and 136 surgeries alone) were retrospectively reviewed. The perioperative results and follow-up of patients after neoadjuvant therapy were analyzed and compared to those after surgery alone. RESULTS: The mean age of population was 67.51±10.63 years. The mean operative time was overlapping in both groups: 248.97±118.17 min in surgery group and 287.17±94.13 min in chemotherapy + surgery group (P=0.190), with no difference in terms of types of anatomical lung resections performed and number of lymph nodes retrieved. The intraoperative mortality was null in both groups. The incidence of all complications was the same in both groups and no correlations was found with any possible risk factor evaluated (age, gender, comorbidities, type of resection, histology, etc.). Among minor complications, the incidence of parenchymal fistula was significantly higher in the 18 patients underwent chemotherapy (22.2% vs. 5.1% respectively, P=0.013). The overall survival of the series was 93% at 1 year follow-up and 88% at 5-year. The 1- and 2-year survival in only surgery group was 94% and 89% respectively vs. 85% and 85% in Chemotherapy + surgery, without any significant difference (P=0.324). CONCLUSIONS: According to our experience, uniportal VATS after neoadjuvant therapy is feasible and quite safe. The oncological results and postoperative complications are comparable to those of other techniques. Uniportal VATS can be performed even for complicated cases in experienced centers.

Uniportal video-assisted thoracic surgery in the treatment of pleural empyema.

BACKGROUND: The efficacy of video-assisted thoracic surgery (VATS) in the treatment of pleural empyema has recently been proven. Till today, very few works evaluated the role of uniportal-VATS (U-VATS) approach in the treatment of pleural empyema even if it currently represents the most innovative and less invasive thoracoscopic approach. We report our experience with U-VATS in the treatment of pleural empyema. METHODS: A retrospective bicentric analysis of 35 consecutive patients who underwent surgical treatment of stage II and stage III pleural empyema was performed, from January 2015 to May 2017. RESULTS: The mean age of patients was 57.26±18.29 years and 54.3% of them were males. In 85.7% of the cases, empyema was related to a complicated parapneumonic effusion; in only 5 cases it was a post-surgical consequence. All patients were treated with broad-spectrum antibiotics and subsequent target therapy for 14.62±21.76 days prior to operation and 23 patients needed the placement of a chest tube. Twenty patients (57.1%) presented with stage III, 11 patients (31.4%) stage II and 4 patients (11.4%) stage I empyema. Complete debridement and decortication were obtained in all patients through U-VATS approach and no conversion or further access was needed for any reason. No major complication was recorded. Only 2 cases of trapped lung were not responsive to surgical treatment. At a mean follow-up of 247.42±306.29 days, 33 patients (94.3%) were alive with no recurrence, 2 patients died for causes unrelated to the operation. CONCLUSIONS: According to our experience, we consider U-VATS as an adequate procedure in the treatment of "stages II and III" empyemas when the necessary surgical expertise has been achieved. Indeed, U-VATS permits an easier performance and complete debridement and decortication, with a very low risk for conversion and excellent postoperative outcomes in terms of less pain, fast recovery and cosmetic results.

Uniportal vs. triportal video-assisted thoracic surgery in the treatment of primary pneumothorax-a propensity matched bicentric study.

BACKGROUND: The role of triportal video-assisted thoracoscopic surgery (VATS) is widely recognized for the treatment of primary spontaneous pneumothorax (PSP). The aim of this study was to assess the effectiveness and the potential advantages of uniportal VATS (U-VATS) for the treatment of PSP compared with triportal VATS. METHODS: A total of 104 triportal (n=39) and uniportal (n=65) VATS procedures where performed for the treatment of PSP in two University hospitals. The prospectively collected data of postoperative outcomes were retrospectively reviewed and a 1:1 propensity score matching analysis was performed to compare the two VATS approaches. RESULTS: No major adverse events occurred after operation. Compared with triportal-VATS, Uniportal-VATS showed the same effectiveness in terms of risk of recurrence (null in both groups), post-operative complications (P=1.000) and operating time (66.04±16.92 vs. 74.57±21.38 min, P=0.141). However, there was a statistically significant difference in favor of uniportal-VATS in terms of necessity of further access [0 vs. 7 (30.4%), P=0.004], chest tube duration (4.39±1.41 vs. 6.32±0.94 days, P<<0.001), postoperative hospital stay (4.78±1.31 vs. 6.61±1.67 days, P<<0.001), visual analogue pain score (VAS) at 24 hours (3.45±1.41 vs. 6.44±2.45, P<<0.001), number of patients who had pain after chest drain removal [1 (4.3%) vs. 16 (69.6%), P<<0.001], VAS after drainage removal (0.11±0.47 vs. 2.74±2.25, P<<0.001), postoperative pain duration (2.50±1.20 vs. 14.82±37.41 days, P<<0.001), pain killers intake (0.75±1.06 vs. 7.53±3.96 days, P=0.001), chronic paresthesia (level scale: 0 to 2; 0 vs. 0.52±0.66, P<<0.001), chronic neuralgia (0 vs. 0.43±0.59, P<<0.001) and cosmetic results (level scale: 0 to 3; 2.91±0.28 vs. 2.00±0.77, P<<0.001). CONCLUSIONS: U-VATS is feasible and safe and may be a less invasive alternative to triportal VATS for the treatment of PSP because of its effectiveness in reducing postoperative pain, paresthesia, hospital stay and in improving cosmetic results.