Hepatic resection for metastatic gastrointestinal and pancreatic neuroendocrine tumours: outcome and prognostic predictors.
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ABSTRACT: BACKGROUND: Treatment modalities for hepatic metastases from neuroendocrine tumours (NETs) include surgery, somatostatin analogues and arterial embolization. The aims of this study were to evaluate the outcome of patients following surgery and to identify prognostic predictors of recurrent disease. PATIENTS AND METHODS: This was a retrospective clinico-pathological analysis of patients managed with hepatic NET metastases over a 13-year period (January 1994 to December 2006). RESULTS: Eighteen patients with hepatic metastases from NET were identified with a median age of 53 years (range 31-75). The localization of the primary tumour was the terminal ileum (n=8), pancreas (n=7), appendix (n=2) or duodenum (n=1). Twelve patients had synchronous disease and six patients developed metachronous hepatic tumours over a median period of 20 months (range 6-144). Presenting symptoms included abdominal pain (n =13), recurrent diarrhoea (n=7) and flushing (n=7). Fifteen patients underwent surgery with complete cytoreduction and three patients had partial cytoreduction. The overall 2- and 5-year actuarial survival rates were 94% and 86%, respectively. The 2- and 5-year disease-free rates following hepatic resection with complete cytoreduction were both 66%. Partial or complete control of endocrine-related symptoms was achieved in all patients with functioning tumours following surgery. Recurrent disease occurred in four patients following complete cytoreductive surgery. Resection margin involvement was associated with developing recurrent disease (p=0.041). CONCLUSION: Surgical resection for hepatic NET metastases results in good long-term survival in selected patients and resection margin involvement was associated with recurrent disease.
Project description:BackgroundGastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST.MethodsThis retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated.ResultsThe total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262).ConclusionPatients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.
Project description:Neuroendocrine tumours are increasing in incidence and cause a variety of symptoms. The mammalian target of rapamycin (mTOR) pathway plays a key role in neuroendocrine tumour (NET) pathogenesis, leading to increased lipid synthesis, protein synthesis and cellular growth. Upregulation of this pathway is noted in both hereditary and sporadic NETs. This understanding has led to investigations of mTOR inhibitors as therapy for metastatic NETs. After promising preclinical findings, everolimus, an mTOR inhibitor, was trialled in the RADIANT-1-4 studies on patients with advanced, well differentiated NETs. RADIANT-3 and RADIANT-4 established the efficacy of everolimus in improving progression-free survival (PFS) for metastatic NET of pancreatic, lung and gastrointestinal origin, leading to the US Food and Drug Administration (FDA) approval for its use in tumour control in those settings. Everolimus treatment is generally well tolerated; common adverse events include stomatitis, diarrhoea, rash and hyperglycaemia. Although discontinuation rates are low, many patients may require dose modification to successfully continue therapy. The combination of everolimus with somatostatin analogues (SSAs) (such as octreotide or pasireotide) or other targeted agents such as bevacizumab has not produced additional incremental benefit, and dual biologic therapy is not used widely. Ongoing trials are investigating everolimus compared with chemotherapy, optimal sequencing of therapy and combination of everolimus with radiotherapy. Future research should concentrate on identification of predictive biomarkers for benefit from mTOR therapy and include quality of life as a measure.
Project description:Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor (VEGF), basic-fibroblastic growth factor, transforming growth factor (TGF-α and -β), platelet derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit (stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing.
Project description:BackgroundPalliative resection of the primary tumor for metastatic pancreatic neuroendocrine carcinoma (pNEC) patients is not recommended because of the poor prognosis compared to that of patients with well-differentiated, lower grade tumors. However, the published data supporting this recommendation regarding pNEC are limited. In the present study, we assessed whether palliative primary tumor resection in stage IV pNEC patients affects survival and identified other factors that affect survival in these patients.MethodsWe collected data from stage IV pNEC patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2014. Univariate and multivariate Cox regression analysis were used to compare overall survival (OS) and cancer-specific survival (CSS) of patients who did or did not undergo primary tumor resection.ResultsWe identified 350 patients with metastatic, poorly differentiated, and undifferentiated pNEC. A total of 14.3% (50/350) of patients underwent primary tumor resection. Multivariate Cox regression analysis showed that primary tumor resection provided a significant benefit for both OS and CSS in stage IV pNEC patients. Additionally, chemotherapy and the presence of the primary tumor in the pancreatic tail were independent positive prognostic factors for metastatic pNEC patients in the multivariate Cox regression analysis.ConclusionsThe present study suggests that chemotherapy, location of the primary tumor in the pancreatic tail, and, most importantly, surgical removal of the primary tumor are associated with prolonged survival in stage IV pNEC patients.
Project description:BackgroundA novel multidimensional inflammatory and nutritional assessment system named the Naples prognostic score could serve as an independent prognostic indicator. However, its significance in patients with high- and intermediate-risk gastrointestinal stromal tumours remains unclear.MethodsWe performed this retrospective cohort study based on a prospectively collected database of gastrointestinal stromal tumours (GISTs) between March 2010 and December 2019. The Kaplan-Meier method and log-rank test were used for survival analyses. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analysis was used for univariate and multivariate analyses. Time-dependent receiver operating characteristic curves were generated to evaluate the discriminatory ability of the prognostic scoring systems. Differences in the areas under the curve were further compared.ResultsA total of 405 patients with regular follow-up were included and analysed in this study. Significant differences in progression-free survival and overall survival were observed between the groups (P < 0.001). Multivariate analysis demonstrated that the NPS was a significant predictor of poor progression-free survival (1 vs 0, HR = 4.622, P = 0.001; 2 vs 0, HR = 12.770, P < 0.001) and overall survival (2 vs 0, HR = 5.535, P = 0.002). Furthermore, time-dependent AUC analyses showed that the NPS was more accurate than other haematologic prognostic systems.ConclusionsThe present study demonstrates that the NPS could independently predict disease progression and survival among patients with high- and intermediate-risk GISTs. The NPS might be regarded and applied as one of the most convenient and effective preoperative risk stratification tools in the future, which should be validated by large-scale multicentre prospective cohort studies.
Project description:BackgroundSmall-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis.AimWe aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs.MethodA PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019.ResultsThe search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44-100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs.ConclusionSI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.
Project description:Preclinical trials of cancer drugs in animal models are important for drug development. The Rip1Tag2 (RT2) transgenic mouse, a model of pancreatic neuroendocrine tumours (PNET), has provided immense knowledge about PNET biology, although tumour progression occurs in a location inaccessible for real-time monitoring. To overcome this hurdle we have developed a novel platform for intravital 3D imaging of RT2 tumours to facilitate real-time studies of cancer progression. Pre-oncogenic islets retrieved from RT2 mice were implanted into the anterior chamber of the eye (ACE) of host mice, where they engrafted on the iris, recruited blood vessels and showed continuous growth. Noninvasive confocal and two-photon laser-scanning microscopy through the transparent cornea facilitated high-resolution imaging of tumour growth and angiogenesis. RT2 tumours in the ACE expanded up to 8-fold in size and shared hallmarks with tumours developing in situ in the pancreas. Genetically encoded fluorescent reporters enabled high-resolution imaging of stromal cells and tumour cell migration. Sunitinib treatment impaired RT2 tumour angiogenesis and growth, while overexpression of the vascular endothelial growth factor (VEGF)-B increased tumour angiogenesis though tumour growth was impaired. In conclusion, we present a novel platform for intravital high-resolution and 3D imaging of PNET biology and cancer drug assessment.