Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection.
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ABSTRACT:
SUBMITTER: Laskaratos FM
PROVIDER: S-EPMC7392928 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection.
Laskaratos Faidon-Marios FM Liu Man M Malczewska Anna A Ogunbiyi Olagunju O Watkins Jennifer J Luong Tu Vinh TV Mandair Dalvinder D Caplin Martyn M Toumpanakis Christos C
Endocrine 20200414 2
<h4>Purpose</h4>Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue.<h4>Methods</h4>We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINEN ...[more]
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Project description:PurposePeptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction.MethodsThree independent 177Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics.ResultsOne hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS).ConclusionsPPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.
| S-EPMC7515632 | biostudies-literature
Project description:ImportanceThe number of patients with small nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is increasing. However, the role of surgery for small NF-PanNETs remains unclear.ObjectiveTo evaluate the association between surgical resection for NF-PanNETs measuring 2 cm or smaller and survival.Design, setting, and participantsThis cohort study used data from the National Cancer Database and included patients with NF-pancreatic neuroendocrine neoplasms who were diagnosed between January 1, 2004, and December 31, 2017. Patients with small NF-PanNETs were divided into 2 groups: group 1a (tumor size, ≤1 cm) and group 1b (tumor size, 1.1-2.0 cm). Patients without information on tumor size, overall survival, and surgical resection were excluded. Data analysis was performed in June 2022.ExposuresPatients with vs without surgical resection.Main outcomes and measuresThe primary outcome was overall survival of patients in group 1a or group 1b who underwent surgical resection compared with those who did not, which was evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Interactions between preoperative factors and surgical resection were analyzed with a multivariable Cox proportional hazards regression model.ResultsOf the 10 504 patients with localized NF-PanNETs identified, 4641 were analyzed. These patients had a mean (SD) age of 60.5 (12.7) years and included 2338 males (50.4%). The median (IQR) follow-up time was 47.1 (28.2-71.6) months. In total, 1278 patients were in group 1a and 3363 patients were in group 1b. The surgical resection rates were 82.0% in group 1a and 87.0% in group 1b. After adjustment for preoperative factors, surgical resection was associated with longer survival for patients in group 1b (hazard ratio [HR], 0.58; 95% CI, 0.42-0.80; P < .001) but not for patients in group 1a (HR, 0.68; 95% CI, 0.41-1.11; P = .12). In group 1b, interaction analysis found that age of 64 years or younger, absence of comorbidities, treatment at academic institutions, and distal pancreatic tumors were factors associated with increased survival after surgical resection.Conclusions and relevanceFindings of this study support an association between surgical resection and increased survival in select patients with NF-PanNETs measuring 1.1 to 2.0 cm who were younger than 65 years, had no comorbidities, received treatment at academic institutions, and had tumors of the distal pancreas. Future investigations of surgical resection for small NF-PanNETs that include the Ki-67 index are warranted to validate these findings.
| S-EPMC10051047 | biostudies-literature
Project description:Although small bowel resection is generally considered a low risk gastrointestinal procedure, this might not be true for small bowel neuroendocrine neoplasms (SB-NEN) as a result of potential central mesenteric involvement. We aimed to determine the reported morbidity and mortality after resection of SB-NEN in the literature and assess the effect of hospital volume on postoperative morbidity and mortality. A systematic review was performed by searching MEDLINE and Embase in March 2021. All studies reporting morbidity and/or mortality after SB-NEN resection were included. Pooled proportions of overall morbidity (Clavien-Dindo I-IV), severe morbidity (Clavien-Dindo III-IV), 30-day mortality, 90-day mortality and in-hospital mortality were calculated, as well as the association with hospital volume (high volume defined as the fourth quartile). Thirteen studies were included, with a total of 1087 patients. Pooled proportions revealed an overall morbidity of 13% (95% confidence interval [CI] = 7%-24%, I2 = 90%), severe morbidity of 7% (95% CI = 4%-14%, I2 = 70%), 30-day mortality of 2% (95% CI = 1%-3%, I2 = 0%), 90-day mortality of2% (95% CI = 2%-4%, I2 = 35%) and in-hospital mortality of 1% (95% CI = 0%-2%, I2 = 0%). An annual hospital volume of nine or more resections was associated with lower overall and severe morbidity compared to lower volume: 10% vs 15% and 4% vs 9%, respectively. Thirty-day mortality was similar (2% vs 1%) and 90-day mortality was higher in high-volume hospitals: 4% vs 1%. This systematic review with meta-analyses showed severe morbidity of 7% and low mortality rates after resection of SB-NEN. The currently available literature suggests a certain impact of hospital volume on postoperative outcomes, although heterogeneity among the included studies constrains interpretation.
| S-EPMC8459236 | biostudies-literature
Project description:We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.
| S-EPMC4420277 | biostudies-other
Project description:The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.
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Project description:ImportancePrimary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV small intestinal neuroendocrine tumors (SI-NETs) are controversial.ObjectiveTo determine the association of locoregional surgery (LRS) performed at diagnosis with outcomes in patients with asymptomatic SI-NETs and distant metastases.Design, setting, and participantsThis cohort study included asymptomatic patients with stage IV SI-NETs diagnosed from January 1, 1985, through December 31, 2015, and identified using the prospective database of SI-NETs from Uppsala University Hospital, Uppsala, Sweden. Patients included were treated at a tertiary referral center and followed up until May 31, 2016, with data from the Swedish National Patient Register. The 363 patients with stage IV SI-NETs without abdominal symptoms were divided between those who underwent prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment (hereafter referred to as LRS group [n?=?161]) and those who underwent nonsurgical treatment or delayed surgery as needed combined with oncologic treatment (hereafer referred to as delayed LRS group [n?=?202]).ExposuresProphylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment vs nonsurgical treatment or delayed surgery as needed combined with oncologic treatment.Main outcomes and measuresOverall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality, and reoperation rates measured from baseline. Propensity score matching was performed between the 2 groups.ResultsThe 363 patients included 173 women (47.7%) and 190 men (52.3%), with a mean (SD) age at diagnosis of 62.4 (11.1) years. Two isonumerical groups with 91 patients in each resulted after propensity score matching. The LRS and delayed LRS groups were comparable in median OS (7.9 years [range, 5.1-10.7 years] vs 7.6 years [range, 5.8-9.5 years]; hazard ratio [HR], 0.98; 95% CI, 0.70-1.37; log-rank P?=?.93) and cancer-specific survival (7.7 years [range, 4.5-10.8 years] vs 7.6 years [range, 5.6-9.7 years]; HR, 0.99; 95% CI, 0.71-1.40; log-rank P?=?.99). No difference was found in 30-day mortality (0 patients in both matched groups) or postoperative morbidity (2 [2.2%] vs 1 [1.1%]; P?>?.99), median LOS (73 days [range, 2-270 days] vs 76 days [range, 0-339 days]; P?=?.64) or LOS due to local tumor-related symptoms (7.0 days [range, 0-90 days] vs 11.5 days [range, 0-69 days]; P?=?.81), or incisional hernia repairs (4 patients [4.4%] in both groups; P?>?.99). Patients in the LRS group underwent more reoperative procedures (13 [14.3%]) compared with those in the delayed LRS group (3 [3.3%]) owing to intestinal obstruction (P?<?.001).Conclusions and relevanceProphylactic up-front LRS conferred no survival advantage in asymptomatic patients with stage IV SI-NETs. Delayed surgery as needed was comparable in all examined outcomes and was associated with fewer reoperations for intestinal obstruction. The value of a priori LRS in the presence of distant metastases is challenged and needs to be elucidated in a randomized clinical study.
| S-EPMC5838704 | biostudies-literature
Project description:Single-cell profiling of circulating tumor cells (CTCs) as part of a minimally invasive liquid biopsy presents an opportunity to characterize and monitor tumor heterogeneity and evolution in individual patients. In this study, we aimed to compare single-cell copy number variation (CNV) data with tissue and define the degree of intra- and inter-patient genomic heterogeneity. We performed next-generation sequencing (NGS) whole-genome CNV analysis of 125 single CTCs derived from seven patients with neuroendocrine neoplasms (NEN) alongside matched white blood cells (WBC), formalin-fixed paraffin-embedded (FFPE), and fresh frozen (FF) samples. CTC CNV profiling demonstrated recurrent chromosomal alterations in previously reported NEN copy number hotspots, including the prognostically relevant loss of chromosome 18. Unsupervised hierarchical clustering revealed CTCs with distinct clonal lineages as well as significant intra- and inter-patient genomic heterogeneity, including subclonal alterations not detectable by bulk analysis and previously unreported in NEN. Notably, we also demonstrated the presence of genomically distinct CTCs according to the enrichment strategy utilized (EpCAM-dependent vs size-based). This work has significant implications for the identification of therapeutic targets, tracking of evolutionary change, and the implementation of CTC-biomarkers in cancer.
| S-EPMC8428071 | biostudies-literature
Project description:Small intestinal neuroendocrine tumors (SiNETs) without distant metastasis typically behave in an indolent manner, but there can be heterogeneity. We aimed to define the survival outcomes and impacts of surgical intervention.A retrospective cohort study was conducted by using data from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were analyzed in 4407 patients between 2000 and 2012. The cancer specific survival (CSS) was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors.The adjusted incidence of early SiNETs is 1.3/100,000. Tumors are most commonly located in the ileum and are small (? 2 cm). The 5-year and 10-year CSS rates were 95.0% and 88.5%, respectively. Age > 50 years, large tumor size (> 2cm), poor differentiation, advanced T classification, and absence of surgical treatment were independent predictors of poor survival. Stratified analysis indicated that surgery significantly improved survival in patients that were white (HR, 0.45), > 50 years old (HR, 0.61), had duodenal tumors (HR, 0.43), large tumors (> 2cm) (HR, 0.32), advanced T classification (T3: HR, 0.29; T4: HR, 0.18) or well differentiation (HR, 0.55). There was no significant survival difference between local resection and radical resection (P =0.884).Early SiNETs have a favorable prognosis. Surgical resection may improve outcomes, particularly in older patients and those with large tumors. More aggressive resections couldn't improve outcomes.
| S-EPMC5354882 | biostudies-other
Project description:BackgroundChromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs.MethodsIn the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA1-439) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs.ResultsPatients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25th-75th-percentiles); total-CgA: 1.85 nM (1.01-4.28) vs 0.75 nM (0.52-0.89), p = 0.004; VS-1: 2.76 nM (1.09-7.10) vs 0.29 nM (0.26-0.32), p<0.001, respectively], but not of CgA1-439 or CgA1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p<0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1.ConclusionThese findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA.
| S-EPMC5933774 | biostudies-literature
Project description:The goal of this study was to gain insights into the transcriptomes, mutations and copy number variants present in small intestinal neuroendocrine tumors. The present dataset contains RNA-sequencing performed on seven such tumors.
| EGAS00001003358 | EGA