The link between menin and pleiotrophin in the tumor biology of pancreatic neuroendocrine neoplasms.

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.

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors.

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.

Systematic Review and Metaanalysis of Lymph Node Metastases of Resected Pancreatic Neuroendocrine Tumors.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas.

BACKGROUND/OBJECTIVES: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management. METHODS: Patients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed. RESULTS: Of 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients. CONCLUSIONS: MiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.

Placenta-Specific 8 Is Overexpressed and Regulates Cell Proliferation in Low-Grade Human Pancreatic Neuroendocrine Tumors.

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.

Differential nuclear ATRX expression in sarcomas.

AIM: Nuclear α-thalassemia/mental retardation X-linked (ATRX) loss and alternative lengthening of telomeres (ALT) are linked in distinct malignancies. We therefore aimed to determine the nuclear ATRX expression correlated with ALT in a comprehensive series of sarcomas. METHODS AND RESULTS: A total of 573 formalin-fixed paraffin-embedded sarcomas comprising 28 entities were investigated for nuclear ATRX expression by immunohistochemistry. Telomere-specific fluorescence in-situ hybridization (FISH) was used to determine the ALT phenotype in 50 sarcomas with complete or heterogeneous ATRX loss. Complete nuclear ATRX loss was detected in 58 of 573 sarcomas, all high-grade, with the highest prevalence in undifferentiated pleomorphic sarcomas (38%) and pleomorphic liposarcomas (38%), followed by dedifferentiated liposarcomas (24%), osteosarcomas (21%), leiomyosarcomas (17%), myxofibrosarcomas (11%) and malignant peripheral nerve sheath tumours (4%). Interestingly, a further 20 sarcomas, all belonging to the aforementioned entities with complete ATRX loss, presented with a heterogeneous ATRX expression pattern. ALT was observed in 41 of 42 sarcomas with complete ATRX loss, but only in two of eight sarcomas with heterogeneous expression. CONCLUSION: Nuclear ATRX loss, either complete or heterogeneous, is encountered in a considerable number of high-grade sarcomas with non-specific genetic alterations. A causal relationship with ALT might be indicated at least in cases with a complete nuclear ATRX loss.

Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling.

Chromosome 1p35-36, which encodes tumor suppressors and mitotic checkpoint control genes, is commonly altered in human malignancies. One gene at this locus, stathmin 1 (STMN1), is involved in cell cycle progression and metastasis. We hypothesized that increased STMN1 expression may play a role in pancreatic neuroendocrine neoplasm (pNEN) malignancy. We investigated stathmin copy number variation, mRNA, and protein expression using PCR-Taqman Copy Number Assays, Q-PCR, Western blot, and immunohistochemistry. A mechanistic role for stathmin in proliferation was assessed in the BON cell line under growth-restrictive conditions and siRNA silencing. Furthermore, its role in PI3K signaling pathway activation was evaluated using pharmacological inhibitors. mRNA (p = 0.0001) and protein (p < 0.05) were overexpressed in pNENs. Expression was associated with pNEN tumor extension (p < 0.05), size (p < 0.01), and Ki67 expression (p < 0.01). Serum depletion decreased Ki67 expression (p < 0.01) as well as Ser38 phosphorylation (p < 0.05) in BON cells. STMN1 knockdown (siRNA) decreased proliferation (p < 0.05), and PI3K inhibitors directly inhibited proliferation via stathmin inactivation (dephosphorylation p < 0.01). We identified that stathmin was overexpressed and associated with pathological parameters in pancreatic NENs. We postulate that STMN1 overexpression and phosphorylation result in a loss of cell cycle mitotic checkpoint control and may render tumors amenable to PI3K inhibitory therapy.

Autotransplantation of parathyroid grafts into the tibialis anterior muscle after parathyroidectomy: a novel autotransplantation site.

BACKGROUND: Surgical management of renal secondary hyperparathyroidism (sHPT) is varying. Total parathyroidectomy with heterotopic autotransplantation (TPTX + AT) is one of the standard surgical procedures in sHPT, but there is no consensus about the optimal site for graft insertion. At the surgical department of the University Hospital of Heidelberg we prefer the autotransplantation into the tibialis anterior muscle. The aim of this study was to assess the long-term function of the auto-transplanted parathyroid tissue in this type of surgical procedure. METHODS: The function of the autograft of 42 patients was assessed 8.2 ± 2.5 years after surgery, using a modified Casanova-test of the leg bearing the parathyroid tissue. Ischemic blockage was induced by tourniquet and the levels of parathyroid hormone (PTH) were assessed during the test. RESULTS: At the point of assessment, the ischemic blockage led to a significant reduction in the concentration of PTH (≥50% of the baseline value) in 19 patients (45%) indicating well-functioning autografts. In 11 patients (26%), ischemic blockage did not cause any change in the concentration of PTH (≤20% of the baseline value), indicating functioning residual parathyroid tissue from another site. The source of PTH production was classified as unidentifiable in five patients (12%). Two patients had developed graft-dependent recurrent HPT (5%) without therapeutic consequences and three patients suffered from persistent symptomatic hypoparathyroidism (7%). CONCLUSIONS: These results indicate that TPTX + AT into the tibialis anterior muscle is a successful surgical treatment for renal HPT and that the modified Casanova-test is a suitable diagnostic tool for autografts function.

Duodenal stump fistula managed with percutaneous drainage, percutaneous transcholecystic biliary diversion and transduodenal glue embolization - A case report.

Duodenal stump insufficiency is an infrequent but potentially devastating complication of upper gastrointestinal surgery. In the era of image-guided interventions, duodenal stump insufficiency is usually treated rather conservatively or with percutaneous interventions than with surgery. Herein, we present a case of a postsurgical duodenal stump fistula successfully treated in a step-by-step manner with percutaneous drainage of a periduodenal abscess-fistula complex, percutaneous transcholecystic biliary drainage for partial biliary diversion and percutaneous transcatheter fistula embolization via the duodenum with n-butyl-cyanoacrylate.

Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors.

Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT7 receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT7 receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, AKT and ERK). IGF-1 synthesis/secretion was evaluated using QPCR and ELISA. IGF-1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF-1 production and 5-HT7 expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT7 receptor. 5-HT activated cAMP/PKA activity, pCREB (130-205%, P < 0.05) and pERK/pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT7 receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC50: 7-70 pg/mL) and could be reversed by the small molecule inhibitor BMS-754807. IGF-1 and 5-HT were elevated (40-300×) in peri-tumoral hepatic tissue in nude mice, while 5-HT7 was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT7 receptor, which, at elevated 5-HT concentrations that occur in liver metastases, signals via CREB/AKT and is linked to IGF-1 synthesis and secretion. Because IGF-1 regulates NEN proliferation, identification of a role for 5-HT7 in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors.

The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) exhibit widely divergent behavior, limited biologic information (apart from Ki-67) is available to characterize malignancy. Therefore, the identification of alternative biomarkers is a key unmet need. Given the role of internexin alpha (INA) in neuronal development, the authors assessed its function in neuroendocrine cell systems and the clinical implications of its expression as a GEP-NEN biomarker. METHODS: Functional assays were undertaken to investigate the mechanistic role of INA in the pancreatic BON cell line. Expression levels of INA were investigated in 50 pancreatic NENs (43 primaries, 7 metastases), 43 small intestinal NENs (25 primaries, 18 metastases), normal pancreas (n = 10), small intestinal mucosa (n = 16), normal enterochromaffin (EC) cells (n = 9), mouse xenografts (n = 4) and NEN cell lines (n = 6) using quantitative polymerase chain reaction, Western blot, and immunostaining analyses. RESULTS: In BON cells, decreased levels of INA messenger RNA and protein were associated with the inhibition of both proliferation and mitogen-activated protein kinase (MAPK) signaling. INA was not expressed in normal neuroendocrine cells but was overexpressed (from 2-fold to 42-fold) in NEN cell lines and murine xenografts. In pancreatic NENs, INA was overexpressed compared with pancreatic adenocarcinomas and normal pancreas (27-fold [P = .0001], and 9-fold [P = .02], respectively). INA transcripts were correlated positively with Ki-67 (correlation coefficient [r] = 0.5; P < .0001) and chromogranin A (r = 0.59; P < .0001). INA distinguished between primary tumors and metastases (P = .02), and its expression was correlated with tumor size, infiltration, and grade (P < .05). CONCLUSIONS: INA is a novel NEN biomarker, and its expression was associated with MAPK signaling and proliferation. In clinical samples, elevated INA was correlated with Ki-67 and identified malignancy. INA may provide additional biologic information relevant to delineation of both pancreatic NEN tumor phenotypes and clinical behavior.

Enucleation Is a Feasible Procedure for Well-Differentiated pNEN-A Matched Pair Analysis.

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.

Lymph node metastases and recurrence in pancreatic neuroendocrine neoplasms.

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 parameters 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.

Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.

BACKGROUND & AIMS: Chronic pancreatitis is characterized by alternating phases of acute inflammation and quiescent disease. Involvement of T-cell responses has been suggested, but pancreatitis-specific T cells have not been described. METHODS: We characterized T-cell responses against pancreatitis, pancreatic carcinoma-associated antigens, and tetanus toxoid in the bone marrow, blood, and/or pancreatitis lesions of patients with pancreatitis, pancreatic cancer, and healthy individuals. T cells were functionally characterized by antigen-dependent secretion of interferon (IFN)-gamma, interleukin (Il)-4, and IL-10, which indicate type 1, type 2, or regulatory T-cell responses, respectively. Regulatory T cells were characterized by multicolor flow cytometry. Isolated regulatory T cells were tested for their capacity to recognize pancreatitis-associated antigens and to suppress conventional T cells in an antigen-dependent manner. T cell-derived cytokines in tissue lesions were quantified by enzyme-linked immunosorbent assay. RESULTS: Chronic pancreatitis patients showed similar to pancreatic cancer patients and healthy individuals type 1 T-cell responses against tetanus toxoid; however, they exhibited strong IL-10-based T-cell responses against pancreatitis-associated but not pancreatic carcinoma-associated antigens. T cells from pancreatic cancer patients responded to pancreatic cancer-associated but not pancreatitis-associated antigens with IFN-gamma secretion. Pancreatitis-specific IL-10 responses were mediated by IL-10(+)IFN-gamma(-)FoxP3(+) regulatory T cells, which were expanded in the blood, bone marrow, and pancreatitis lesions and possessed the potential to suppress the proliferation of autologous conventional T cells in an antigen-specific manner. Pancreatitis lesions, in comparison with pancreatic carcinomas, contained increased concentrations of IL-10 and reduced levels of IFN-gamma, suggesting pancreatitis-specific activity of regulatory T cells in situ. CONCLUSIONS: Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.

The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Recent data demonstrate that the incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased exponentially (overall ~500%) over the last three decades, thus refuting the erroneous concept of rarity. GEP-NETs comprise 2% of all malignancies and in terms of prevalence, are the second commonest gastrointestinal malignancy after colorectal cancer. Diagnosis is usually late since there is no biochemical screening test and symptoms are protean and overlooked. As a consequence, 60-80% exhibit metastases with a consequent suboptimal outcome. DISCUSSION: The gastrointestinal tract and pancreas exhibit ~17 different neuroendocrine cell types, but neither the cell of origin nor the biological basis of GEP-NETs is understood. This review examines GEP-NETs from the cellular and molecular perspective and addresses the distinct patterns of functional tumor biology pertinent to clinicians. Although grouped as a neoplastic entity (NETs), each lesion is derived from distinct cell precursors, produces specific bioactive products, exhibits distinct chromosomal abnormalities and somatic mutation events and has uniquely dissimilar clinical presentations. GEP-NETs demonstrate very different survival rates reflecting the intrinsic differences in malignant potential and variations in proliferative regulation. Apart from the identification of the inhibitory role of the somatostatin receptors, there is limited biological knowledge of the key regulators of proliferation and hence a paucity of successful targeted therapeutic agents. IGF-I, TGFß and a variety of tyrosine kinases have been postulated as key regulatory elements; rigorous data is still required to define predictably effective and rational therapeutic strategy in an individual tumor. A critical issue in the clinical management of GEP-NETs is the need to appreciate both the neuroendocrine commonalities of the disease as well as the unique characteristics of each tumor. The further acquisition of a detailed biological and molecular appreciation of GEP-NETs is vital to the development of effective management strategy.

The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant.

BACKGROUND: Neuroendocrine neoplasms (NENs) are increasing in incidence and prevalence. This reflects greater clinical awareness, effective imaging, and increasing pathological diagnostic recognition. Although the identification and treatment of clinical neuroendocrine syndromes are established, there is confusion when a NEN has no discernible clinical symptoms. DISCUSSION: Nonfunctional tumors are usually diagnosed incidentally and at a later stage largely because either they do not secrete a bioactive product or do so, but in a form that is either inactive or in quantities that have no discernible effect. Nevertheless, the histopathology is indistinguishable from functional NENs, and tumors exhibit somatostatin receptor expression, and positive immunohistochemistry for neuroendocrine cell markers (CgA, NSE/synaptophysin). Similarly, their rates of growth and metastatic behavior are, like other NENs, predictably based on staging and grading (mitotic rate and Ki67 expression). Both types are diagnosed biochemically (CgA) and by imaging in an identical fashion with computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, and endoscopic ultrasound. NENs, irrespective of function or bioactive secretory profile, respond with equal efficacy to the same regimen of surgery or antitumor drugs (e.g., somatostatin analogs with or without tyrosine kinase inhibitors/antiangiogenics or cytotoxics) depending on grade. Given the efficacy of somatostatin analogs in increasing progression free survival, nonfunctional NENs should be managed identically to symptomatic NENs. The consideration of NENs as functional or nonfunctional is an archaic clinical concept that should be discarded since the tumors are indistinguishable at a cellular, biological, and morphological level. All current evidences indicate that their diagnosis and treatment should follow the same common principles.

Quality of life is not influenced by the extent of surgery in patients with benign goiter.

INTRODUCTION: The surgical approach to benign goiter is becoming increasingly radical due to the risk of recurrent goiter. The aim of this prospective study was to evaluate the impact of surgery on health-related quality of life (HRQoL) of patients with benign goiter. MATERIAL AND METHODS: HRQoL data from 115 patients with benign goiter were analyzed. Thirty-three patients (group 1) had a hemithyroidectomy. Sixty-five patients (group 2) had a so-called Dunhill operation (hemithyroidectomy + near-total thyroidectomy of the opposite side), and in 17 patients, a total resection of the goiter was performed. The validated HRQoL instrument, the EuroQol-5D, was applied to measure the health-related quality of life. RESULTS: With an overall complication rate of 10% and no permanent recurrent laryngeal nerve palsy, it was shown that surgery for benign goiter is safe. In the validated HRQoL questionnaire (EQ-5D), no significant variance could be found between different surgical procedures such as thyroidectomy, hemithyroidectomy, or Dunhill procedure. Further, no significant differences in QoL were found in EQ-5D questionnaire compared to normal population. CONCLUSION: Thyroid surgery can be done safely and without impairment of life quality, regardless of the extent of the operation.

Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report.

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.

C-reactive protein independently predicts survival in pancreatic neuroendocrine neoplasms.

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.

Outcome after surgical resection of multiple recurrent retroperitoneal soft tissue sarcoma.

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.