Gastroenteropancreatic Neuroendocrine Tumors Patients Research Articles

Circulating Chromogranin A as Surveillance Biomarker in Patients with Carcinoids - The CASPAR Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value > 100 ng/mL in the following CgA concentration was considered positive. 153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%-95·5%, p < 0·001), sensitivity 34·4% (25·6%-44·3%), positive predictive value 57·9% (45·0-69·8), negative predictive value (NPV) 84·3% (80·5-87·6), and area under the curve 0·73 (0·67-0·79). Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.

To Perform, or Not to Perform Interim PET: Questioning the Impact of Midtherapy Evaluation During PRRT in GEP-NET Patients.

This study aimed to analyze the impact of interim evaluation on the continuation of 177Lu-based peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to survey its usage across German university hospitals. In 119 GEP-NET patients who underwent PRRT, we retrospectively assessed the results and therapeutic impact of restaging performed after 2 cycles using MRI/CT/somatostatin receptor imaging. Therapeutic decisions based on interim PET results were made in multidisciplinary tumor board meetings. Additionally, an online survey was conducted among 37 German university hospitals regarding their interim evaluation practices, focusing on the change in management. Of 119 patients, 83 completed 4 PRRT cycles; 36 stopped after 2: 27 showed PD, 3 had PR leading to surgery, 5 experienced toxicity, and 1 died. Those completing 4 cycles showed a median PFS of 38.0 months (95% confidence interval, 32.2-43.8). Seventeen of 37 surveyed hospitals routinely used interim evaluation. In a survey among 37 German university hospitals, 62% reported offering PRRT for GEP-NET patients, with 74% of these performing a routinely interim evaluation after 2 cycles of PRRT, primarily using PET/CT imaging techniques. Interim PET after 2 PRRT cycles helps to identify early progression in GEP-NET patients. Standardizing interim evaluation practices could enhance the comparability of clinical outcomes and optimize patient management.

Quantitative SPECT/CT Metrics in Early Prediction of [177Lu]Lu-DOTATATE Treatment Response in Gastroenteropancreatic Neuroendocrine Tumor Patients.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [177Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [177Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (ΔTBS) and changes in normalized peak count (ΔnPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in ΔTBSsecond-first, ΔTBSthird-first, and ΔTBSfourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [177Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. -0.049, 0.08 vs. -0.116, and 0.109 vs. -0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). ΔnPCsecond-first showed significant group differences (mean, -0.107 vs. -0.282; P = 0.033); ΔnPCthird-first and ΔnPCfourth-first did not reach statistical significance (mean, -0.122 vs. -0.312 and -0.183 vs. -0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, ΔTBSfourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. ΔTBSsecond-first and ΔTBSthird-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. ΔnPCsecond-first, ΔnPCthird-first, and ΔnPCfourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: ΔTBS and ΔnPC can predict [177Lu]Lu-DOTATATE response by the second treatment session.

Interest of Integrated Whole-Body PET/MR Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms: A Retro-Prospective Study.

Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI and is a tool for the assessment of gastroenteropancreatic neuroendocrine neoplasms (G-NENs). However, it remains poorly evaluated with no clear recommendations in current guidelines. Thus, we evaluated the prognostic impact of PET-MRI in G-NEN patients. From June 2017 to December 2021, 71 G-NEN patients underwent whole-body PET-MRI for staging and/or follow-up purposes. A whole-body emission scan with 18F-6-fluoro-L-dihydroxyphenylalanine (18FDOPA, n = 30), 18F-fluoro-2-deoxy-D-glucose (18FDG, n = 21), or 68Ga-(DOTA(0)-Phe(1)-Tyr(3))-octreotide (68Ga-DOTATOC, n = 20) with the simultaneous acquisition of a T1-Dixon sequence and diffusion-weighed imaging (DWI), followed by a dedicated step of MRI sequences with a Gadolinium contrast was performed. The patients underwent PET-MRI every 6-12 months during the follow-up period until death. Over this period, 50 patients with two or more PET-MRI were evaluated. The mean age was 61 [extremes, 31-92] years. At the baseline, PET-MRI provided new information in 12 cases (17%) as compared to conventional imaging: there were more metastases in eight, an undescribed location (myocardia) in two, and an unknown primary location in two cases. G grading at the baseline influenced overall survival. During the follow-up (7-381 months, mean 194), clinical and therapy managements were influenced by PET-MRI in three (6%) patients due to new metastases findings when neither overall, nor disease-free survivals in these two subgroups (n = 12 vs. n = 59), were different. Our study suggests that using PET/MRI with the appropriate radiotracer improves the diagnostic performance with no benefit on survival. Further studies are warranted to evaluate the cost-effectiveness of this procedure.

Defining the optimal segmentation method for measuring somatostatin receptor expressing tumor volume on 68 Ga-DOTATATE positron emission tomography/computed tomography to predict prognosis in patients with gastroenteropancreatic neuroendocrine tumors.

We aimed to compare different segmentation methods used to calculate prognostically valuable volumetric parameters, somatostatin receptor expressing tumor volume (SRETV), and total lesion somatostatin receptor expression (TLSRE), measured by 68 Ga-DOTATATE PET/CT and to find the optimal segmentation method to predict prognosis. Images of 34 patients diagnosed with gastroenteropancreatic neuroendocrine tumor (GEPNET) who underwent 68 Ga-DOTATATE PET/CT imaging were reanalyzed. Four different threshold-based methods (fixed relative threshold method, normal liver background threshold method, fixed absolute standardized uptake value (SUV) threshold method, and adaptive threshold method) were used to calculate SRETV and TLSRE values. SRETV of all lesions of a patient was summarized as whole body SRETV (WB-SRETV) and TLSRE of all lesions of a patient was computed as whole body TLSRE (WB-TLSRE). WB-SRETVs calculated with all segmentation methods were statistically significantly associated with progression-free survival except WB-SRETV at which was calculated using adaptive threshold method. The fixed relative threshold methods calculated by using 45% (WB-SRETV 45% ) and 60% (WB-SRETV 60% ) of the SUV value as threshold respectively, were found to have statistically significant highest prognostic value (C-index = 0.704, CI = 0.622-0.786, P = 0.007). Among WB-TLSRE parameters, WB-TLSRE 35% , WB-TLSRE 40% , and WB-TLSRE 50% had the highest prognostic value (C-index = 0.689, CI = 0.604-0.774, P = 0.008). The fixed relative threshold method was found to be the most effective and easily applicable method to measure SRETV on pretreatment 68 Ga-DOTATATE PET/CT to predict prognosis in GEPNET patients. WB-SRETV 45% (cutoff value of 11.8 cm 3 ) and WB-SRETV 60% (cutoff value of 6.3 cm 3 ) were found to be the strongest predictors of prognosis in GEPNET patients.

Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients’ clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

Risk factors, prognostic factors, and nomograms for distant metastases in patients with gastroenteropancreatic neuroendocrine tumors: a population-based study.

Patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor prognosis for distant metastasis. Currently, there are no studies on predictive models for the risk of distant metastasis in GEP-NETs. In this study, risk factors associated with metastasis in patients with GEP-NETs in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed by univariate and multivariate logistic regression, and a nomogram model for metastasis risk prediction was constructed. Prognostic factors associated with distant metastasis in patients with GEP-NETs were analyzed by univariate and multivariate Cox, and a nomogram model for prognostic prediction was constructed. Finally, the performance of the nomogram model predictions is validated by internal validation set and external validation set. A total of 9145 patients with GEP-NETs were enrolled in this study. Univariate and multivariate logistic analysis demonstrated that T stage, N stage, tumor size, primary site, and histologic types independent risk factors associated with distant metastasis in GEP-NETs patients (p value < 0.05). Univariate and multivariate Cox analyses demonstrated that age, histologic type, tumor size, N stage, and primary site surgery were independent factors associated with the prognosis of patients with GEP-NETs (p value < 0.05). The nomogram model constructed based on metastasis risk factors and prognostic factors can predict the occurrence of metastasis and patient prognosis of GEP-NETs very effectively in the internal training and validation sets as well as in the external validation set. In conclusion, we constructed a new distant metastasis risk nomogram model and a new prognostic nomogram model for GEP-NETs patients, which provides a decision-making reference for individualized treatment of clinical patients.

Epidemiological, Clinical and Biological Hemogram Features in a Cohort of Neuroendocrine Tumor Patients.

We conducted a retrospective study based on 55 patients diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs)-gastric (G-NET), small bowel (SB-NET) and colonic (C-NET), hospitalized and evaluated within the Surgical, Gastroenterology and Internal Medicine Clinics, in The Clinical Emergency County Hospital Craiova, between May 2016 and April 2024. We aimed in this study to analyze the epidemiological aspects and clinical characteristics of patients with GEP-NETs. In our study group, the patients' ages were between 39-82 years, with a mean of 66.40 (±12.46) years. The incidence of GEP-NETs cases in young patients was insignificant low-1 case. 45.46% of all patients lived in urban areas. 16.36% were G-NET, 14,54 were SB-NET and 69.09% were C-NET. The GEP-NETs diagnosis was established by immunohistochemistry features. Also, we observed that the most frequency localization was on the ascending colon, while the rarest on the colon it is located on the transverse colon and the rarest is on the small bowel, in spite of the generally literature data. From the C-NET group, 49.09% have been presented arterial hypertension probable explained by serotonin and dopamine secretion an inflammatory through phenotype expression and just one patient has been presented an erythematous psoriasis, which could be also explained by the same neurotransmitter's involvement as a possible purposed mechanism. The results obtained in our study demonstrate that could be a common profile of GEP-NETs patients through epidemiological general information and clinical characteristics. Also, we demonstrate that, in the last years, the incidence increased for the GEP-NETs.

Initial validation of the clinical significance of the NETest in Japanese gastroenteropancreatic neuroendocrine tumor patients.

As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49-66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.

Circulating Regulatory T Cells: A Novel Marker Associated with Liver Metastasis and the Treatment Response of Transarterial Embolization in Gastroenteropancreatic Neuroendocrine Tumors

Introduction: The aim of this study was to investigate the role of circulating regulatory T cells (Tregs) as a novel marker associated with liver metastases and treatment response to transarterial embolization (TAE) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Circulating Tregs, defined as the CD4+CD25+CD127low/− population, were examined by flow cytometry in peripheral blood mononuclear cells from patients with GEP-NETs. Clinicopathological parameters, radiologic response, and hepatic progression-free survival (hPFS) data were collected. Results: The association between circulating Tregs and clinicopathological parameters was analyzed in 139 GEP-NET patients. Higher Treg levels were significantly associated with more progressive clinical features, including a higher WHO grade, more advanced TNM stage, and the presence of liver metastases. A Treg level ≥8.015% distinguished between patients with and without liver metastases. Among a cohort of 51 GEP-NET patients who were subjected to TAE for reducing liver metastasis burden, patients with higher Treg levels depicted unfavorable responses and significantly reduced hPFS after TAE treatment. We also revealed that patients with Treghigh (≥8.975%) displayed significantly shorter median hPFS than patients with Treglow (<8.975%). Additionally, after adjusting for other confounding clinical parameters, the association between Tregs and treatment response as well as hPFS remained significant, suggesting that Tregs may have a strong and independent prognostic impact in GEP-NETs. Conclusion: Our data suggest that circulating Tregs are a novel immunological marker associated with liver metastases and treatment response to TAE in patients with GEP-NETs.

Impact of primary tumor resection and metastasectomy among gastroentero-pancreatic neuroendocrine tumors with liver metastases only on survival

BackgroundDespite recommendations for primary tumor resection (PTR) with or without liver resection (LR) in the patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and isolated liver metastases, there are conflicting data for their impact on overall survival (OS). Methods2320 patients with GEP-NETs and isolated liver metastases were identified from NCDB. Multiple imputations were used to accommodate missing data, and inverse probability of treatment weighting (IPTW) was conducted to minimize bias. ResultsPatients with PTR had a greater OS than those without PTR (3-year rate of 88.6% vs. 69.9%, P < 0.001), which was preserved in the adjusted analysis (IPTW-adjusted HR = 0.387, 95% CI: 0.264–0.567; P < 0.001). Patients with LR had a greater OS than those without LR (3-year rate 87.7% vs. 75.2%, P = 0.003), which was also preserved in adjusted analysis (IPTW-adjusted HR = 0.450, 95% CI: 0.229–0.885; P = 0.021). Patients undergoing both PTR and LR had the greatest survival advantage than those with other surgical interventions (P < 0.001). ConclusionsEither PTR or LR is associated with improved survival for GEP-NET patients with isolated liver metastases. However, there remains significant selection bias in the current study, and caution should be exercised when selecting patients for resection.

Radiofrequency and microwave ablation controls hepatic oligoprogression of advanced gastroenteropancreatic neuroendocrine tumors.

In progression of multifocal liver metastases of gastroenteropancreatic neuroendocrine tumors (GEP-NET) escalation of systemic therapy is indicated. The aim of this retrospective study was to investigate the potential of local thermal ablation in hepatic oligoprogression and otherwise stable disease in GEP-NET. Patients with hepatic oligoprogression and otherwise stable disease, who underwent radiofrequency ablation (RFA) or microwave ablation (MWA) for local control, were included in the study. Thermal ablation was performed while maintaining the ongoing systemic therapy or without addition of a systemic therapy. The effectiveness of this therapeutic approach was evaluated by determination of local treatment success, improvement of progression-free survival (PFS) and the safety. Seventeen thermal ablation procedures were performed in 13 patients with well differentiated NET including seven ileum NET, four pancreatic NET, one appendix NET and one rectum NET. RFA and MWA of liver metastases were well tolerated without major complications. Thermal ablation resulted in an estimated median PFS of 62.6 weeks (mean 50.5 weeks; range 10.1-78.9 weeks) per procedure. In four patients, two ablation procedures were performed throughout the course of their disease resulting in an estimated median PFS of 69.1 weeks (mean 71.6 weeks; range 10.1-123.1 weeks) per patient. Start or change of systemic therapy could be delayed up to 123.1 weeks by using thermal ablations for isolated progression of single liver metastases. 88% of thermal ablations prolonged PFS. Thermal ablation of liver metastases in a non-curative intent has the potential to provide focal growth control and to prolong PFS in GEP-NET patients with hepatic oligoprogression.

The impact of surgery and survival prediction in patients with gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

This study aimed at assessing the impact of surgical treatments in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A propensity score-matched analysis based on data in the Surveillance, Epidemiology, and End Results database was used to assess the efficacy of surgical treatment in patients with GEP-NETs. A total of 7515 patients diagnosed with GEP-NETs from 2004 to 2015 were evaluated from the Surveillance, Epidemiology, and End Results database. There were 1483 patients in the surgery group and 6032 patients in the nonsurgery group. Compared with patients in the surgery group, patients in the nonsurgery group were inclined to receive chemotherapy (50.8 vs. 16.7%) and radiation (12.9 vs. 3.7%) as treatment options. Multivariate Cox regression analysis revealed higher rates of overall survival (OS) outcomes for GEP-NETs patients who had been subjected to surgery (hazard ratio=0.483, 95% CI=0.439-0.533, P <0.001). Then, to reduce the impact of bias, a 1:1 propensity score-matched analysis was performed for the two groups of patients. A total of 1760 patients were assessed and each subgroup included 880 patients. In the matched population, the patients exhibited the ability to significantly benefit from surgery (hazard ratio=0.455, 95% CI=0.439-0.533, P <0.001). The OS outcomes for radiation or chemotherapy patients who had been treated with surgery were better than those of patients who had not been treated with surgery ( P <0.001). In addition, it was found that the OS of patients was not significant after rectum and small intestine surgery, whereas there was a significant difference in OS after colon, pancreas, and stomach surgery on the patients. Patients who had been subjected to surgery in the rectum and small intestines exhibited better therapeutic benefits. Patients with GEP-NETs who are treated with surgery have better OS outcomes. Therefore, surgery is recommended for specified selected patients with metastatic GEP-NETs.

Chromogranin A as surveillance biomarker in patients with carcinoids: CASPAR.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of &gt;100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p &lt; 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p &lt; 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

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.

Diagnostic role and prognostic value of tumor markers in high-grade gastro-enteropancreatic neuroendocrine neoplasms

ObjectivesHigh-grade gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors of two different types: well differentiated neuroendocrine tumors grade 3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). This study aimed to explore the value of eight common preoperative markers in differentiating NETs G3 from NECs and the prognosis prediction of high-grade GEP-NENs. MethodsSeventy-two patients diagnosed with high-grade GEP-NENs who underwent surgery at our institution were recruited for this study. Demographic and clinicopathological characteristics, preoperative serum tumor markers, and survival data were collected and analyzed. Kaplan–Meier methods were used to analyze survival rates, and a Cox regression model was used to perform multivariate analyses. ResultsSerum carcinoembryonic antigen (CEA) was dramatically higher in NECs than in NETs G3 (P = 0.025). After follow-up, 57 of the 72 patients remained for survival analysis. Elevated serum carbohydrate antigen 19-9 (CA19-9), CEA, cancer antigen 125 and sialic acid (SA) levels indicated poorer survival of high-grade GEP-NEN patients. Only CA19-9 (HR: 6.901, 95% CI: 1.843 to 25.837, P = 0.004) was regarded as an independent risk factor for overall survival. Serum CA19-9 (HR: 4.689, 95% CI: 1.127 to 19.506, P = 0.034) was also regarded as an independent factor for overall survival in NECs. ConclusionsSerum CEA levels can be used to distinguish NETs G3 from NECs. Preoperative CA19-9, CEA, cancer antigen 125 and SA levels have predictive value in the prognosis of high-grade GEP-NENs. Preoperative CA19-9, neuron-specific enolase, and SA levels can predict the prognosis of NECs.

Ga-68-Edotreotide Positron Emission Tomography/Computed Tomography Somatostatin Receptors Tumor Volume Predicts Outcome in Patients With Primary Gastroenteropancreatic Neuroendocrine Tumors.

We retrospectively aimed to assess the prognostic significance of somatostatin receptor (SSTR) standardized uptake value (SUVmaxsstr), SSTR representative tumor volume (RTVsstr) and total lesion SSTR expression (TLsstr) obtained by [68Ga]Ga-edotreotide PET/CT ([68Ga]Ga-SSTR PET/CT) in patients with primary gastroenteropancreatic neuroendocrine tumors (GEP-NET) before surgery. We analyzed patients who underwent [68Ga]Ga-SSTR PET/CT 3-6weeks before surgery from February 2020 to April 2022. The mean SUVmaxsstr value, the RTVsstr (cm3; 42% threshold) and the TLsstr (g) were registered. Thereafter the patients were followed up 10.3 months (range 3-27). The PET/CT results were compared to the event free survival (EFS). Forty-two patients (61 ± 13years) have been enrolled. At multivariate analysis only RTVsstr values were predictive. The Kaplan-Meier survival analysis for RTVsstr showed a significant better EFS in patients presenting lower values as compared to those having greater (P = .003, log-rank test). SUVmaxsstr was not suitable for predicting EFS, TLsstr mildly. RTVsstr represents a valuable volumetric parameter able to predict the outcome in GEP-NET patients who underwent surgery. The magnitude of the SSTR representative tumor burden holds a predominant value for determining the response to therapy in GEP-NET patients before surgery, rather than the maximal SSTR representation at single voxel.

CD44v6 expression in gastroenteropancreatic neuroendocrine neoplasms: Clinicopathological correlation and prognosis.

Clinical course of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) patients are determined by complicated and multifaceted factors. Ki-67 has been used to predict the behavior of NEN with statistically significant high probability. Immunohistochemical prognostic markers other than Ki-67 have been reported, but due to insufficient validation, they have not been used routinely. CD44 and its isoform variants showed significant inverse correlation with lymph node status, distant metastasis, and mortality in pancreatic neuroendocrine neoplasm (Pan-NEN). The aim of this study is to determine the prognostic value of CD44v6 expression among GEP-NENs. Immunohistochemical staining (IHC) of CD44v6 was studied in 26 formalin-fixed-paraffin-embedded (FFPE) specimens from GEP-NENs patients in the Srinagarind Hospital, Khon Kaen University, Thailand, between 2013 and 2018. Demographic data were collected. IHC staining result was interpreted based on H-score and correlated with neuroendocrine IHC markers, proliferation index, lymph nodes status, metastasis, and patients' survival. All cases showed variable staining for CD44v6 without statistically significant correlation with age, gender, histological grading, lymph node metastasis, distant metastasis, Ki-67 proliferative index, or neuroendocrine marker expression. Survival analysis showed association of higher CD44v6 expression with better prognosis (p=0.033). Hazard ratio of CD44v6 low expression patients with age ≥49 was 12.736 (p=0.028, 1.318-123.073), presence of lymph node metastasis was 8.267 (p=0.036, 1.142-59.841), presence of distant metastasis 12.736 (p=0.028, 1.318-123.073). Higher expression of CD44v6 IHC is significantly associated with better overall survival, histological grading, and Ki-67 index of GEP-NENs patients. CD44v6 IHC can be used as an additional prognostic immunohistochemical marker related to the metastatic status.

Impact of Change in Body Composition during Follow-Up on the Survival of GEP-NET.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous rare diseases causing malnutrition and cachexia in which the study of body composition may have an impact in prognosis. Aim: Evaluation of muscle and fat tissues by computed tomography (CT) at the level of the third lumbar (L3 level) at diagnosis and at the end of follow-up in GET-NET patients and their relationships with clinical and biochemical variables as predictors of survival. Methodology: Ninety-eight GEP-NET patients were included. Clinical and biochemical parameters were evaluated. Total body, subcutaneous, visceral and total fat areas and very low-density, low-density, normal density, high-density, very high-density and total muscle areas were obtained from CT images. Results: Body composition measures and overall mortality correlated with age, ECOG (Eastern Cooperative Oncology Group performance status) metastases, lactate dehydrogenase (LDH), albumin and urea levels. Although there was no relationship between body composition variables at diagnosis and overall and specific mortality, an increase in low-density muscle and a decrease in normal-density muscle during follow-up were independently correlated to overall (p <0.05) and tumor-cause mortality (p < 0.05). Conclusion: Although body composition measures obtained by CT at diagnosis did not impact survival of GEP-NET patients, a loss of good quality muscle during follow-up was associated with an increased overall and tumor-related mortality. Nutritional status should therefore be supervised by nutrition specialists and an increase in good quality muscle could improve prognosis.

Peptide Receptor Radionuclide Therapy.

The concept of using a targeting molecule labeled with a diagnostic radionuclide for using positron emission tomography or single photon emission computed tomography imaging with the potential to demonstrate that tumoricidal radiation can be delivered to tumoral sites by administration of the same or a similar targeting molecule labeled with a therapeutic radionuclide termed "theranostics." Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (SSAs) is a well-established second/third-line theranostic treatment for somatostatin receptor-positive well-differentiated (neuro-)endocrine neoplasms (NENs). PRRT with 177Lu-DOTATATE was approved by the regulatory authorities in 2017 and 2018 for selected patients with low-grade well-differentiated gastroenteropancreatic (GEP) NENs. It improves progression-free survival as well as quality of life of GEP NEN patients. Favorable symptomatic and biochemical responses using PRRT with 177Lu-DOTATATE have also been reported in patients with functioning metastatic GEP NENs like metastatic insulinomas, Verner Morrison syndromes (VIPomas), glucagonomas, and gastrinomas and patients with carcinoid syndrome. This therapy might also become a valuable therapeutic option for inoperable low-grade bronchopulmonary NENs, inoperable or progressive pheochromocytomas and paragangliomas, and medullary thyroid carcinomas. First-line PRRT with 177Lu-DOTATATE and combinations of this therapy with cytotoxic drugs are currently under investigation. New radiolabeled somatostatin receptor ligands include SSAs coupled with alpha radiation emitting radionuclides and somatostatin receptor antagonists coupled with radionuclides.