OBJECTIVE:Optimal treatment strategies for small (≤2 cm) nonfunctioning pancreatic neuroendocrine neoplasms are still subject to discussion. The aim of this study was to analyze real-world data of patients with pancreatic neuroendocrine neoplasms ≤2 cm regarding the indications for surgery and long-term postresection survival. METHODS:All patients undergoing surgery for nonfunctioning pancreatic neuroendocrine neoplasms ≤2 cm between 2003 and 2023 were analyzed. Indications for surgery, clinicopathologic parameters, and long-term survival were assessed. Differences between pancreatic neuroendocrine neoplasms <1 cm and 1-2 cm were evaluated. RESULTS:Of a total of 806 resected pancreatic neuroendocrine neoplasms, 237 patients had a lesion ≤2 cm (29.4%), 85 of which were smaller than 1 cm. The 3 most common indications for surgery for pancreatic neuroendocrine neoplasms ≤2 cm were either suspicion of a non-neuroendocrine neoplasm malignancy (55.2%), suspicion of neuroendocrine tumor (25.9%), or obstruction of the pancreatic duct (9.4%). Tumor differentiation was 84% G1, 15% G2, and 1.3% G3. Noticeably, 5.1% of pancreatic neuroendocrine neoplasms ≤2 cm had lymph node metastasis (pN1). Five patients with a small pancreatic neuroendocrine neoplasm developed distant metastasis (pM1). The 10-year overall survival was 86.9% for <1 cm and 84.5% for 1-2 cm (P = .964). 10-year disease-free survival was 83.1% in patients with a pancreatic neuroendocrine neoplasms <1 cm and 81.1% for pancreatic neuroendocrine neoplasms 1-2 cm (P = .784). CONCLUSION:Surgical treatment of small (≤2 cm) pancreatic neuroendocrine neoplasms provides excellent long-term survival. Since even small pancreatic neuroendocrine neoplasms can develop lymph node and distant metastases, treatment decisions should not be determined on the basis of tumor size alone.

Recurrent amplification and overexpression of FRS2 in STS.

Background: The impact of lymph node metastasis on survival in pancreatic neuroendocrine neoplasms as well as their best surgical treatment is controversial. We aimed to determine the frequency and prognostic impact of lymph node involvement in pancreatic neuroendocrine neoplasms. Methods: Patients undergoing pancreatic resections for pancreatic neuroendocrine neoplasms between 2001 and 2019 were retrospectively analyzed based on a prospective database. Clinicopathological pa-rameters and perioperative outcome were assessed. Overall and disease-free survival was analyzed. Subgroup analysis was performed for sporadic, nonfunctional pancreatic neuroendocrine neoplasms without distant metastases and >= 4 analyzed lymph nodes. Results: Of 605 surgically resected pancreatic neuroendocrine neoplasms, 55% were G1, 36% were G2, and 9% were G3 differentiated. At the time of resection, 34% of patients had lymph node metastasis, and 16% had distant metastases. For subgroup analysis, 314 patients were analyzed. Lymph node metastases occurred in 36% of patients and were most frequent in G3 patients (67%). An increase in tumor size and advancement was associated with higher rates of lymph node metastasis, and disease-free survival was significantly impaired. Significant differences in disease-free survival were observed between 1 and 3 (5-year disease-free survival 52%) and >= 4 positive lymph nodes (5-year disease-free survival 28%), as well as when G3 tumors were excluded. In multivariable analysis, grading, tumor stage, and especially lymph node metastases as well as the proposed pN1 and pN2 categories were confirmed as independent predictors of recurrence. Conclusion: The presence and extent of lymph node involvement has considerable prognostic impact in pancreatic neuroendocrine neoplasms. This study, for the first time, validated the proposed pN2 stage for well-differentiated pancreatic neuroendocrine neoplasms. (c) 2022 Elsevier Inc. All rights reserved.

MEN1, which encodes menin protein, is the most frequently mutated gene in pancreatic neuroendocrine neoplasms (pNEN). Pleiotrophin (PTN) has been reported as a downstream factor of menin that promotes metastasis in different tumor entities. In this study, the effect of menin and its link to PTN were assessed using features of pNEN cells and the outcome of patients with pNEN. The expression levels of menin and PTN in tissues from patients with pNEN were examined using qRT-PCR and western blot and compared with their metastasis status. Functional assays, including transwell migration/invasion and scratch wound-healing assays, were performed on specifically designed CRISPR/Cas9-mediated MEN1-knockout (MEN1-KO) pNEN cell lines (BON1MEN1-KO and QGP1MEN1-KO ) to study the metastasis of pNEN. Among 30 patients with menin-negative pNEN, 21 revealed a strong protein expression of PTN. This combination was associated with metastasis and shorter disease-free survival. Accordingly, in BON1MEN1-KO and QGP1MEN1-KO cells, PTN protein expression was positively associated with enhanced cell migration and invasion, which could be reversed using PTN silencing. PTN is a predicting factor of metastatic behavior of menin-deficient-pNEN. In vitro, menin is able to both promote and suppress the metastasis of pNEN by regulating PTN expression depending on the tumoral origin of pNEN cells.

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1–2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel’s C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78–88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70–0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1–2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.

The extent of surgical resection in the treatment of pancreatic neuroendocrine neoplasms (pNEN) is still controversial. This study aimed to evaluate the outcomes of enucleation for well-differentiated non-functional (nf) pNEN. Patients undergoing enucleation (2001–2020) were analyzed. Clinicopathological parameters, perioperative outcomes and survival were assessed. The analysis was performed as a nested case-control study and matched-pair analysis with formal resection. Sixty-one patients undergoing enucleation were identified. Compared to patients undergoing formal resection, enucleation was associated with a significantly shorter median length of operative time (128 (IQR 95–170) versus 263 (172–337) minutes, p < 0.0001) and a significantly lower rate of postoperative diabetes (2% versus 21%, p = 0.0020). There was no significant difference in postoperative pancreatic fistula rate (18% versus 16% type B/C, p = 1.0), Clavien−Dindo ≥ III complications (20% versus 26%, p = 0.5189), readmission rate (12% versus 15%, p = 0.6022) or length of hospital stay (8 (7–11) versus 10 (8–17) days, p = 0.0652). There was no 30-day mortality after enucleation compared to 1.6% (n = 1) after formal resection. 10-year overall survival (OS) and disease-free survival (DFS) was similar between the two groups (OS: 89% versus 77%, p = 0.2756; DFS: 98% versus 91%, p = 0.0873). Enucleation presents a safe surgical approach for well-differentiated nf-pNEN with good long-term outcomes for selected patients.

Pankreatische neuroendokrine Neoplasien (pNEN) werden mit zunehmender Inzidenz verzeichnet und vermehrt in frühen (resektablen) Stadien diagnostiziert. Aufgrund der Seltenheit dieser Neoplasien beruhen die Empfehlungen der verfügbaren Leitlinien vor allem auf retrospektiven Daten. Die onkologische und chirurgische Therapie dieser seltenen Erkrankung sollte spezialisierten Zentren vorbehalten sein. Bei resektablem Befund ohne Hinweis auf diffuse Filialisierung ist die kurativ intendierte vollständige Entfernung anzustreben. Alternativ zur chirurgischen Resektion wurde bei kleinen nichtfunktionellen Tumoren < 2 cm die Watch-and-wait-Strategie empfohlen, neuere Daten zeigen jedoch ein längeres Überleben nach Resektion von Neoplasien in der Größe zwischen 1 und 2 cm. Für benigne Insulinome und nichtfunktionelle gut differenzierte kleine pNEN stehen parenchymsparende Verfahren wie die Enukleation oder die Segmentresektion zur Verfügung. Die Frage des Einflusses von Lymphknotenmetastasen auf das langfristige tumorfreie und Gesamtüberleben und damit der Stellenwert der systematischen Lymphadenektomie ist nicht abschließend geklärt. Bei Neoplasien > 2 cm ist eine formelle Resektion mit Lymphadenektomie anzustreben. Minimal-invasive und robotisch assistierte Verfahren haben einen zunehmenden Stellenwert auch bei formellen Resektionen.

Introduction: Local recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS. Methods: Patients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients. Results: 201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p < 0.001), second (p = 0.001), and third recurrences (p < 0.001) was an independent prognostic factor for poor OS. Conclusion: Development of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences. (C) 2021 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Introduction: Hepatocellular carcinoma (HCC) is by far the leading malignant indication for liver transplantation (LT). Few other malignancies, including cholangiocellular carcinoma (CCC), metastases from neuroendocrine tumors (NET), and sarcomas of the liver (LSAR), also are commonly accepted indications for LT. However, there is limited information on their outcome after LT. Methods: Graft and patient survival in 14,623 LTs performed in patients with hepatocellular carcinoma, CCC, NET, and LSAR from 1988 to 2017 and reported to the Collaborative Transplant Study were analyzed. Results: The study group consisted of 13,862 patients who had HCC (94.8%), 498 (3.4%) who had CCC, 100 (0.7%) who had NET, and 163 (1.1%) who had LSAR. CCC patients showed a 5-year graft survival rate of 32.1%, strikingly lower than the 63.2% rate in HCC, 51.6% rate in NET, and 64.5% rate in LSAR patients (P < 0.001 for all vs. CCC). Multivariable Cox regression analysis revealed a significantly higher risk of graft loss and death due to cancer during the first five post-transplant years in CCC vs. HCC patients (HR 1.77 and 2.56; P < 0.001 for both). The same risks were increased also in NET and LSAR patients but did not reach statistical significance. Conclusion: Among patients with rare malignant indications for LT, CCC patients showed significantly impaired graft as well as patient survival compared to HCC patients. The observed differences might challenge traditional decision-making processes for LT indication and palliative treatment in specific hepatic malignancies.

Pancreatic neuroendocrine neoplasms (pNEN) are highly variable in their postresection survival. Determination of preoperative risk factors is essential for treatment strategies. C-reactive protein (CRP) has been implicated in the pathogenesis of pNEN and shown to be associated with survival in different tumour entities. Patients undergoing surgery for pNEN were retrospectively analysed. Patients were divided into three subgroups according to preoperative CRP serum levels. Clinicopathological features, overall and disease-free survival were assessed. Uni- and multivariable survival analyses were performed. 517 surgically resected pNEN patients were analysed. CRP levels were significantly associated with relevant clinicopathological parameters and prognosis and were able to stratify subgroups with significant and clinically relevant differences in overall and disease-free survival. In univariable sensitivity analyses CRP was confirmed as a prognostic factor for overall survival in subgroups with G2 differentiation, T1/T2 and T3/T4 tumour stages, patients with node positive disease and with and without distant metastases. By multivariable analysis, preoperative CRP was confirmed as an independent predictor of postresection survival together with patient age and the established postoperative pathological predictors grading, T-stage and metastases. Preoperative serum CRP is a strong predictive biomarker for both overall and disease free survival of surgically resected pNEN. CRP is associated with prognosis independently of grading and tumour stage and may be of additional use for treatment decisions.

Sporadische neuroendokrine Neoplasien der Bauchspeicheldrüse (pNEN) sind seltene Tumoren. Nicht-funktionelle (NF)-pNEN sind in frühen Stadien zunächst asymptomatisch und werden klinisch erst auffällig, wenn sie durch ihre Größe Symptome verursachen. Im Rahmen des Staging kommen bildgebende Verfahren wie das CT oder auch MRT zum Einsatz und können durch das PET-CT ergänzt werden. Neben Chromogranin A als Tumormarker kann zusätzlich ein NETest im Sinne einer „liquid biopsy“ erfolgen. Die chirurgische Resektion ist die Therapie der Wahl für jede pNEN in einem resektablen Stadium, wobei eine R0-Situation erreicht werden sollte. Therapiealternativen bilden unter anderem Somatostatinanaloga, die Chemotherapie oder Peptidradiorezeptortherapie. Eine Nachsorge sollte über bildgebende Verlaufskontrollen bei allen NEN im Intervall von 6–12 Monaten erfolgen.

Introduction: For pathological diagnosis of pancreatic neuroendocrine neoplasms (pNENs) the routinely used immunohistochemical markers are chromogranin A (CgA) and synaptophysin (Syn). Their ability as prognostic markers is not well established. A splice variant of actinin-4 (Actn-4sv) was recently found to be an excellent biomarker of neuroendocrine neoplasms of the lung. We aimed to investigate the expression of Actn-4sv in pNENs and evaluate its quality as a biomarker of pNENs. Methods: Paraffin-embedded and frozen tissues specimens from 122 pNENs were analyzed. Western blots were performed to prove and compare the relative amount of Actn-4sv expression in pNENs tissue homogenates. For comparison pancreatic ductal adenocarcinoma (PDAC) and normal pancreatic tissues were analyzed in parallel. Immunohistochemistry (IHC) of paraffin sections of pNENs for Actn-4sv were performed and compared to the classic neuroendocrine markers CgA and Syn. Correlations were calculated between the staining intensity and distribution of Actn-4sv and staging, grading and afflicted lymph nodes respectively. Results: Actn-4sv was expressed in 88.5% (108/122) of pNENs, but not in normal pancreatic tissues (0/14) or PDAC (0/14). Compared to CgA and Syn, Actn-4sv was not detectable in islet cells of the normal pancreas. Staining intensity of Actn-4sv on pNENs negatively correlated to the histological grading (Spearman r=-0.4990, p<0.0001) and staging (r = -0.2581, p = 0.0041) but no correlation to afflicted lymph nodes was found. A significantly better overall survival was observed for pNEN patients with higher expression of Actn-4sv (hazard ratio 2.7; log-rank test p= 0.0349). Conclusions: The expression of Actn-4sv may be an important prognostic factor for patients with pNENs. Its expression correlates with the grading and staging of the tumors.

BACKGROUND:Preoperative α-blockade in phaeochromocytoma surgery is recommended by all guidelines to prevent intraoperative cardiocirculatory events. The aim of this meta-analysis was to assess the benefit of such preoperative treatment compared with no treatment before adrenalectomy for phaeochromocytoma.METHODS:A systematic literature search was undertaken in MEDLINE, Web of Science and CENTRAL without language restrictions. Randomized and non-randomized comparative studies investigating preoperative α-blockade in phaeochromocytoma surgery were included. Data on perioperative safety, effectiveness and outcomes were extracted. Pooled results were calculated as an odds ratio or mean difference with 95 per cent confidence interval.RESULTS:A total of four retrospective comparative studies were included investigating 603 patients undergoing phaeochromocytoma surgery. Mortality, cardiovascular complications, mean maximal intraoperative systolic and diastolic BP, and mean maximal intraoperative heart rate did not differ between patients with or without α-blockade. The certainty of the evidence was very low owing to the inferior quality of studies.CONCLUSION:This meta-analysis has shown a lack of evidence for preoperative α-blockade in surgery for phaeochromocytoma. RCTs are needed to evaluate whether preoperative α-blockade can be abandoned.

BACKGROUND:Clinical management of duodenal neuroendocrine neoplasms (dNEN) is controversial. The aim of this study was to assess the outcome of surgical management and to identify risk factors for metastatic disease. METHODS:Patients undergoing surgery for dNEN were retrospectively analysed. Clinicopathologic features, perioperative outcome and survival were assessed. A literature review with focus on risk factors for metastatic disease was additionally performed. RESULTS:24 patients were identified. Out of 22 patients presenting with their primary tumour, 20 patients underwent curative resection and 18 patients received curative resection with systematic lymphadenectomy. 17 patients underwent formal oncological resection. Surgical mortality was 1 out of 24 patients. The 5-year overall survival rate was 67% in the entire cohort, 71% in patients undergoing resection for their primary tumour, 72% for patients undergoing curative resection with systematic lymphadenectomy, 75% for pN0 and 70% for pN1 tumours. Lymph node metastases were identified in 15 patients undergoing systematic lymphadenectomy, including 9 of 14 patients with tumours smaller than 2 cm, and 6 of 10 patients with G1 tumours. Literature review confirmed a high risk of metastases in small (58%) or G1 (24%) tumours. Tumour grade and angioinvasion were significantly associated with overall and disease-free survival. CONCLUSION:Even well differentiated or small dNEN harbour a considerable risk of metastases. These data challenge the concepts of surveillance, local resection and endoscopic management for dNEN based on size and grading. Angioinvasion was identified as a strong negative predictor of overall and disease-free survival in dNEN.

Incidentally discovered adrenal alterations should be separated into those without any clinical importance and adrenal diseases that have to be surgically or conservatively treated. Before operative treatment, in addition to the possible different functional activity of tumors, a differentiation must be made between sporadically arising singular or multiple adrenal tumors or nodular adrenal hyperplasia, adrenal tumors as part of a familial syndrome and metastases of other primary malignant tumors into the adrenal glands. Benign hormonally active adrenal tumors as well as questionable malignant tumors of the adrenal cortex are resected by minimally invasive techniques. For large malignant tumors infiltrating into surrounding tissues and tumors with proven lymph node metastases, the primarily open approach is indicated. Patients with adrenal diseases should always undergo an interdisciplinary assessment and in cases with clear indications for surgery, sometimes transferred to a center with experience in surgery and postoperative management of these patients.

Zufällig entdeckte Nebennierenveränderungen ohne Krankheitswert sind gegenüber den operativ oder konservativ zu behandelnden Nebennierenerkrankungen abzugrenzen. Vor einer operativen Therapie ist neben den möglichen unterschiedlichen funktionellen Aktivitäten der Tumoren zwischen sporadisch entstandenen singulären und multiplen Nebennierentumoren oder einer knotigen Nebennierenhyperplasie, Nebennierentumoren im Rahmen vererbter Syndromerkrankungen und Metastasen von malignen Tumoren anderen Ursprungs in der Nebenniere zu unterscheiden. Benigne, hormonaktive Tumoren werden minimal-invasiv reseziert, ebenso fraglich maligne Tumoren der Nebennierenrinde. Für große maligne Tumoren mit Infiltration von Umgebungsstrukturen und für Tumoren mit nachgewiesener Lymphknotenmetastasierung ist das primär offene Vorgehen indiziert. Patienten mit Nebennierenerkrankungen sollten immer interdisziplinär beurteilt und bei eindeutiger Operationsindikation ggf. in einem Zentrum mit Erfahrung in der Operation wie auch der postoperativen Betreuung von Nebennierenpatienten behandelt werden.

The optimal surgical strategy for pancreatic neuroendocrine tumors (PNETs) is unknown. However, current guidelines recommend a watch-and-wait strategy for small nonfunctional PNETs (NF-PNETs). The aim of this study is to investigate the risk stratification and prognostic significance of lymph node metastasis (LNM) of PNETs to guide decision-making for lymphadenectomy. The MEDLINE and Web of Science databases were systematically searched for studies reporting either risk factors of LNM in resected PNETs or survival of patients with LNM. The weighted average incidence of LNM was calculated according to tumor characteristics. Random-effects metaanalyses were performed, and pooled hazard ratios (HR) and their 95% confidence intervals (CI) were calculated to determine the impact of LNM on overall survival (OS). In subgroup analyses, NF-PNETs were assessed. From a total of 5883 articles, 98 retrospective studies with 13,374 patients undergoing resection for PNET were included. In all PNETs, the weighted median rates of LNM were 11.5% for small (≤ 2 cm) PNETs and 15.8% for G1 PNETs. In NF-PNETs, the rates were 11.2% for small PNETs and 10.3% for G1 PNETs. LNM of all PNETs (HR 3.87, 95% CI 3.00–4.99, P < 0.001) and NF-PNETs (HR 4.98, 95% CI 2.81–8.83, P < 0.001) was associated with worse OS. LNM is potentially prevalent even in small and well-differentiated PNETs and is associated with worse prognosis. A watch-and-wait strategy for small NF-PNETs should be reappraised, and oncologic resection with lymphadenectomy can be considered. Prospective and controlled studies are needed in the future.

BACKGROUND/AIMS:Many aspects of the biology of pancreatic neuroendocrine tumors (PanNETs), including determinants of proliferative, invasive, and metastatic potential, remain poorly understood. Placenta-specific 8 (PLAC8), a gene with unknown molecular function, has been reported to have tumor-promoting roles in different human malignancies, including exocrine pancreatic cancer. Since preliminary data suggested deregulation of PLAC8 expression in PanNET, we have performed detailed analyses of PLAC8 expression and function in human PanNET.METHODS:Primary tissue from PanNET patients was immunohistochemically stained for PLAC8, and expression was correlated with clinicopathological data. In vitro, PLAC8 expression was inhibited by siRNA transfection in PanNET cell lines and effects were analyzed by qRT-PCR, Western blot, and proliferation assays.RESULTS:We report that PLAC8 is expressed in the majority of well-differentiated human PanNETs, predominantly in early-stage and low-grade tumors. SiRNA-mediated knockdown of PLAC8 in PanNET cells resulted in decreased proliferation and viability, while apoptosis was not induced. Mechanistically, these effects were mediated by attenuation of cell cycle progression, as Western blot analyses demonstrated upregulation of the tumor suppressor p21/CDKN2A and downregulation of the cell cycle regulator Cyclin D1 as well as reduced levels of phosphorylated ribosomal protein s6 and retinoblastoma protein.CONCLUSION:Our findings establish PLAC8 as a central mediator of cell growth in a subset of human PanNET, providing evidence for the existence of distinct molecular subtypes within this class of tumors.