Influence of Lymphatic, Microvascular and Perineural Invasion on Oncological Outcome in Patients with Neuroendocrine Tumors of the Small Intestine.

For the histopathological work-up of resected neuroendocrine tumors of the small intestine (siNET), the determination of lymphatic (LI), microvascular (VI) and perineural (PnI) invasion is recommended. Their association with poorer prognosis has already been demonstrated in many tumor entities. However, the influence of LI, VI and PnI in siNET has not been sufficiently described yet. A retrospective analysis of all patients treated for siNET at the ENETS Center of Excellence Charité-Universitätsmedizin Berlin, from 2010 to 2020 was performed (n = 510). Patients who did not undergo primary resection or had G3 tumors were excluded. In the entire cohort (n = 161), patients with LI, VI and PnI status had more distant metastases (48.0% vs. 71.4%, p = 0.005; 47.1% vs. 84.4%, p < 0.001; 34.2% vs. 84.7%, p < 0.001) and had lower rates of curative surgery (58.0% vs. 21.0%, p < 0.001; 48.3% vs. 16.7%, p < 0.001; 68.4% vs. 14.3%, p < 0.001). Progression-free survival was significantly reduced in patients with LI, VI or PnI compared to patients without. This was also demonstrated in patients who underwent curative surgery. Lymphatic, vascular and perineural invasion were associated with disease progression and recurrence in patients with siNET, and these should therefore be included in postoperative treatment considerations.

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.

Prognostic differences in grading and metastatic lymph node pattern in patients with small bowel neuroendocrine tumors.

PURPOSE: Neuroendocrine tumors of the small intestine (si-NET) describe a heterogenous group of neoplasms. Based on the Ki67 proliferation index si-NET are divided into G1 (Ki67 < 2%), G2 (Ki67 3-20%) and rarely G3 (Ki67 > 20%) tumors. However, few studies evaluate the impact of tumor grading on prognosis in si-NET. Moreover, si-NET can form distinct lymphatic spread patterns to the mesenteric root, aortocaval lymph nodes, and distant organs. This study aims to identify prognostic factors within the lymphatic spread patterns and grading. METHODS: Demographic, pathological, and surgical data of 208 (90 male, 118 female) individuals with si-NETs treated at Charité University Medicine Berlin between 2010 and 2020 were analyzed retrospectively. RESULTS: A total of 113 (54.5%) specimens were defined as G1 and 93 (44.7%) as G2 tumors. Interestingly, splitting the G2 group in two subgroups: G2 low (Ki67 3-9%) and G2 high (Ki67 10-20%), displayed significant differences in overall survival (OS) (p = 0.008) and progression free survival (PFS) (p = 0.004) between these subgroups. Remission after surgery was less often achieved in patients with higher Ki67 index (> 10%). Lymph node metastases (N +) were present in 174 (83.6%) patients. Patients with isolated locoregional disease showed better PFS and OS in comparison to patients with additional aortocaval and distant lymph node metastases. CONCLUSION: Lymphatic spread pattern influences patient outcome. In G2 tumors, low and high grading shows heterogenous outcome in OS and PFS. Differentiation within this group might impact follow-up, adjuvant treatment, and surgical strategy.

Surgical Approach to Liver Metastases in GEP-NET in a Tertiary Reference Center.

Indications for liver resection in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) vary from liver resection with curative intent to tumor debulking or tissue sampling for histopathological characterization. With increasing expertise, the number of minimally invasive liver surgeries (MILS) in GEP-NET patients has increased. However, the influence on the oncological outcome has hardly been described. The clinicopathological data of patients who underwent liver resection for hepatic metastases of GEP-NET at the Department of Surgery, Charité-Universitätsmedizin Berlin, were analyzed. Propensity score matching (PSM) was performed to compare MILS with open liver surgery (OLS). In total, 22 patients underwent liver surgery with curative intent, and 30 debulking surgeries were analyzed. Disease-free survival (DFS) was longer than progression-free survival (PFS) (10 vs. 24 months), whereas overall survival (OS) did not differ significantly (p = 0.588). Thirty-nine (75%) liver resections were performed as OLS, and thirteen (25%) as MILS. After PSM, a shorter length of hospital stay was found for the MILS group (14 vs. 10 d, p = 0.034), while neither DFS/PFS nor OS differed significantly. Both curative intended and cytoreductive resection of hepatic GEP-NET metastases achieved excellent outcomes. MILS led to a reduced length of hospital, while preserving a good oncological outcome.

The Learning Curve for Hand-Assisted Laparoscopic Total Gastrectomy in Gastric Cancer Patients.

(1) Background: Hand-assisted laparoscopic total gastrectomy (LTG) for patients with gastric cancer (GC) has been established as the standard surgical treatment at our center. This study aims to quantify the learning curve for surgeons performing minimally invasive total gastrectomy at a high-volume single center. (2) Methods: One hundred and eighteen consecutive patients who underwent minimally invasive total gastrectomy between January 2014 and December 2020 at a single high-volume center were included and reviewed retrospectively. Risk-adjusted cumulative sum analysis (RA-CUSUM) was used to monitor the surgical outcomes for patients with different risks of postoperative mortality using varying-coefficient logistic regression models. Patients were ordered by the sequential number of the procedure performed and divided into two groups according to the degree of surgeon proficiency as determined by RA-CUSUM analysis (group A: 45; group B: 73 patients). Age, gender, body mass index (BMI), tumor location, pathology, and comorbidities were compared while primary endpoints comprised surgical parameters, postoperative course, and survival outcomes. (3) Results: Forty-four cases were required for the completion of the learning curve. During this time, the mean operating time decreased. Hand-assisted laparoscopic total gastrectomy performed after a learning curve was associated with a shorter median operating time (OT) (360 min vs. 289 min, <0.001), and a reduced length of stay (A = 18.0 vs. B = 14.0 days) (p = 0.154), while there was a trend toward less major complications (Clavien−Dindo (CD) 3−5 within 90 days (12 (26.67%) vs. 10 (13.70%) p = 0.079). Our results showed no difference in anastomotic leakage between the two groups (group A vs. group B, 3 (6.67%) vs. 4 (5.48%) p = 0.99). Similarly, 30-day (0 (0%) vs. 1 (1.7%), p = 0.365) and 90-day mortality (1 (2.08%) vs. 2 (3.39%), p = 0.684) were comparable. Following multivariate analysis, the level of surgical proficiency was not a significant prognostic factor for overall survival. (4) Conclusions: A minimum of 44 cases are required for experienced laparoscopic surgeons to achieve technical competence for performing LTG. While operation time decreased after completion of the learning curve, quality criteria such as achievement of R0 resection, anastomotic leakage, and perioperative mortality remained unaltered. Of note, the level of surgical training showed no significant impact on the 2 year OS or DFS.

Comorbidities rather than older age define outcome in adult patients with tumors of the Ewing sarcoma family.

BACKGROUND: Ewing family of tumors (EFT) is rarely diagnosed in patients (pts) over the age of 18 years (years), and data on the clinical course and the outcome of adult EFT pts is sparse. METHODS: In this retrospective analysis, we summarize our experience with adult EFT pts. From 2002 to 2020, we identified 71 pts of whom 58 were evaluable for the final analysis. RESULTS: Median age was 31 years (18-90 years). Pts presented with skeletal (n = 26), and extra-skeletal primary disease (n =32). Tumor size was ≥8 cm in 20 pts and 19 pts were metastasized at first diagnosis. Between the age groups (≤25 vs. 26-40 vs. ≥41 years) we observed differences of Charlson comorbidity index (CCI), tumor origin, as well as type and number of therapy cycles. Overall, median overall survival (OS) was 79 months (95% confidence interval, CI; 28.5-131.4 months), and median progression-free survival (PFS) 34 months (95% CI; 21.4-45.8 months). We observed a poorer outcome (OS, PFS) in older pts. This could be in part due to differences in treatment intensity and the CCI (<3 vs. ≥3; hazard ratio, HR 0.334, 95% CI 0.15-0.72, p = 0.006). In addition, tumor stage had a significant impact on PFS (localized vs. metastasized stage: HR 0.403, 95% CI 0.18-0.87, p = 0.021). CONCLUSIONS: Our data confirms the feasibility of intensive treatment regimens in adult EFT pts. While in our cohort outcome was influenced by age, due to differences in treatment intensity, CCI, and tumor stage, larger studies are warranted to further explore optimized treatment protocols in adult EFT pts.

Hyperkalemia Following Parathyroidectomy in Patients with Renal Hyperparathyroidism-New Thresholds for Urgent Perioperative Dialysis.

Parathyroidectomy (PTX) is a mainstay of treating secondary hyperparathyroidism (SHPT) in patients with kidney failure in order to reduce the incidence of cardiovascular events (CVE), increase overall survival and improve quality of life. Perioperative hyperkalemia may lead to devastating cardiac complications. Distinct preoperative thresholds for serum potassium levels (SPL) were defined, but neither their usefulness nor consecutive risks are understood. This study compared the results and efficacy of different clinical procedures in preventing or treating perioperative hyperkalemia, including postoperative urgent hemodialysis (UHD). Methods: Patients from Charité-Universitätsmedizin Berlin and Rheinland Klinikum Lukaskrankenhaus, Neuss, undergoing PTX due to SHPT between 2008 and 2018 were analyzed retrospectively with regard to demographic parameters, surgery specific conditions and perioperative laboratory results. Comparisons of patient values from both centers with focus on perioperative hyperkalemia and the need for UHD were performed. Results: A total of 251 patients undergoing PTX for SHPT were included (Neuss: n = 121 (48%); Berlin: n = 130 (52%)). Perioperative hyperkalemia (SPL ≥ 5.5 mmol/L) was noted in 134 patients (53%). UHD on the day of surgery was performed especially in patients with intraoperative hyperkalemia, in females (n = 40 (16%) vs. n = 27 (11%); p = 0.023), in obese patients (n = 27 (40%) vs. n = 50 (28%), p = 0.040) and more often in patients treated in Neuss (n = 42 (35%) vs. 25 (19%); p = 0.006). For patients treated in Neuss, the intraoperative hyperkalemia cut-off level above 5.75 mmol/L was the most predictive factor for UHD (n = 30 (71%) vs. n = 8 (10%); p < 0.001). Concerning secondary effects of hyperkalemia or UHD, no patient died within the postoperative period, and only three patients suffered from acute CVE, with SPL > 5.5 mmol/L measured in only one patient. Conclusion: Perioperative values could not predict postoperative hyperkalemia with the need for UHD. Previously defined cut-off levels for SPL should be reconsidered, especially for patients undergoing PTX. Early postoperative dialysis in patients with postoperative hyperkalemia can be performed with a low risk for complications and may be indicated for all patients with increased perioperative SPL.

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.

Self-limited HBV infection of the recipient does not reactivate after liver transplantation: Observations from a 30-year liver transplant program.

BACKGROUND: A self-limited hepatitis B infection can reactivate in patients under immunosuppression or chemotherapy (reappearance of hepatitis B surface antigen (HBsAg) or HBV-DNA). Exact circumstances of HBV reactivation in patients undergoing liver transplantation (LT) for end-stage liver diseases (ESLD) unrelated to HBV are unknown, and recommendations on HBV prophylaxis remain unclear. PATIENTS AND METHODS: Among 1273 liver transplants, 168 patients with a self-limited HBV hepatitis B infection prior to LT were identified from our prospective liver transplant database. Patients with underlying chronic HBV infection and recipients of an anti-HBc-positive liver were not included in the analysis. Demographic, laboratory, serological, and virological data were analyzed retrospectively. Appearance of HBsAg or HBV-DNA was defined as reactivation. RESULTS: The median follow-up after LT was 12.0 years (0.6-30.7 years). The rate of HBV reactivation was 0% independent of antiviral prophylaxis (n = 7; 4.2%), the etiology of ESLD, hepatitis C treatment, or the anti-HBs concentration. The overall patient survival with a history of a self-limited HBV infection before LT did not significantly differ from the rest of the cohort. CONCLUSION: Antiviral treatment with nucleos(t)ide analogues post-liver transplantation in order to prevent HBV reactivation in patients with a resolved self-limited hepatitis B infection prior to LT seems to be omittable since the main viral reservoir is removed by the hepatectomy. These findings may clarify the current uncertainty in the recommendations regarding the risk of HBV reactivation in patients with self-limited hepatitis B prior to LT.

Long-term Outcome of Orthotopic Liver Transplantation in Patients With Hemochromatosis: A Summary of a 30-year Transplant Program.

Hemochromatosis (HC) is an autosomal recessive disease characterized by impaired iron metabolism and a rare indication for orthotopic liver transplantation (LT). Data about iron reaccumulation and remodeling of the liver graft after LT are limited. Therefore, we performed an evaluation of the histopathologic changes during long-term follow-up in patients with HC. METHODS: A retrospective analysis of patients undergoing LT at our center between 1990 and 2016 identified 29 patients with HC. End points were the evaluation of post-LT iron reaccumulation and the stage of fibrosis as well as the degree of inflammation of the liver graft. Secondary end points were patient survival and postoperative complications. RESULTS: The median age was 52.7 y, and there were more male (82.8%) than female patients (17.2%). Post-LT serum ferritin values (>1000 µg/L) were only temporarily elevated in 2 patients. The median estimated survival after LT was 45.5 mo (0.1-285.9 mo). Twenty patients (69%) died during follow-up of 10 y. The survival of patients with HC was significantly worse (P = 0.001) when compared with the overall cohort of patients undergoing LT because of to other causes. CONCLUSIONS: There was no significant iron overload detected in patients with HC after LT, and only minimal iron deposits were described in liver biopsies. Nevertheless, patients suffering from HC show a lower post-LT survival when compared with patients without iron storage disease but mostly because of extrahepatic causes.

Ischemic-Type Biliary Lesions After Liver Transplant: Factors Causing Early-Onset Versus Late-Onset Disease.

OBJECTIVES: Biliary complications such as an ischemic-type biliary lesion can increase morbidity and mortality after liver transplant. Former studies have investigated several risk factors, but the underlying pathomechanism remains unclear. The focus of this study was to investigate factors causing early-onset (< 12 mo after liver transplant) versus late-onset ischemic-type biliary lesions (> 12 mo after liver transplant). MATERIALS AND METHODS: This retrospective study included 641 patients. Patients were grouped to those who developed ischemic-type biliary lesion and those who did not. Patients developing ischemic-type biliary lesions were further subgrouped into those diagnosed early (< 12 mo) and late (> 12 mo) after liver transplant. We analyzed demographic data, characteristics, and comorbidities of the recipients and donors, operative variables, and postoperative course, as well as laboratory values. RESULTS: The incidence of ischemic-type biliary lesions was 4.9%. Retransplant was performed more frequently in patients developing ischemic-type biliary lesions. The number of transfusions of blood products was higher in ischemic-type biliary lesion patients, especially in the early-onset ischemic-type biliary lesion group. Bilirubin levels were higher in patients with ischemic-type biliary lesions starting from day 7 after the operation, particularly in the early-onset group. Survival tended to be best in the late-onset ischemic-type biliary lesion group; however, this difference was not significant. CONCLUSIONS: This study serves as a supplement to current data and the understanding of ischemic-type biliary lesions with emphasis on the relevance of disease onset and causes. We could in fact determine transfusion of blood products as a determinant of an early onset of ischemic-type biliary lesion. Bilirubin could be a surrogate marker for ischemic-type biliary lesions, especially in its early-onset form.

Hepatitis B Immunoglobulin discontinuation in long-term liver transplant patients.

BACKGROUND: Hepatitis B immunoglobulin (HBIG)-as a monotherapy or combined with nucleos(t)ide analogs (NUCs)-has effectively lowered Hepatitis B virus (HBV) reinfection after liver transplantation. However, it is associated with high costs and viral resistance. HBIG-free prophylaxis with novel NUCs (tenofovir, entecavir) composes a viable alternative. We evaluated reinfection rate, histological changes, and outcome associated with HBIG discontinuation. METHODS: A retrospective analysis was performed of patients undergoing liver transplantation due to HBV-induced liver disease at our center since 1988. A controlled HBIG discontinuation was conducted between 2015 and 2017 in 65 patients. Recurrent infection was determined by HbsAg values. Fibrosis and inflammation were evaluated by routine biopsy. The survival of patients after HBIG discontinuation was compared to a control population on HBIG for prophylaxis. RESULTS: From 1988 to 2013, 352 patients underwent liver transplantation due to HBV-induced liver disease. 169 patients could be included for analysis. 104 (51.5%) patients continued a prophylaxis containing HBIG. HBIG was discontinued in 65 (38.5%) patients in a controlled manner, maintaining an oral NUC. None of those patients showed HBV reinfection or graft dysfunction. No significant changes of inflammation grades (P = .067) or fibrosis stages (P = .051) were detected. The survival of patients after HBIG discontinuation was comparable to the control (P = .95). CONCLUSION: HBIG withdrawal under continuation of oral NUC therapy is safe and not related to graft dysfunction, based on blood tests and histology. HBIG-free prophylaxis is not associated with a worse outcome and displays a financial relief as well as a logistic simplification during long-term follow-up.