Watchful waiting for small non-functional pancreatic neuroendocrine tumours: nationwide prospective cohort study (PANDORA).
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ABSTRACT:
SUBMITTER: Heidsma CM
PROVIDER: S-EPMC10364894 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Watchful waiting for small non-functional pancreatic neuroendocrine tumours: nationwide prospective cohort study (PANDORA).
Heidsma C M CM Engelsman A F AF van Dieren S S Stommel M W J MWJ de Hingh I I Vriens M M Hol L L Festen S S Mekenkamp L L Hoogwater F J H FJH Daams F F Klümpen H-J HJ Besselink M G MG van Eijck C H CH Nieveen van Dijkum E J EJ
The British journal of surgery 20210801 8
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Project description:IntroductionGiven that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX.MethodA real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH.ResultAmong 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. Median CLD [DZX, 15 days (6-27) vs. WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than the WW group [62.5 days (9-198) vs. 16 days (6-27), P < 0.001].ConclusionCLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS.
| S-EPMC10332304 | biostudies-literature
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.
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Project description:BackgroundInfiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers.Materials and methodsPopulation-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival.ResultsA total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5-7.2) in region A compared with 14.4 years (95% CI 10.4-18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001).ConclusionIn parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.
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Project description:BackgroundRadical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.MethodsBetween 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.ResultsDuring 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04).ConclusionsExtended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.).
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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.
| S-EPMC6787246 | biostudies-literature
Project description:Background/aimsSmall intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response.MethodsTumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs.ResultsMelatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038).ConclusionImmunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.
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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.
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Project description:Improved surgical resection and oncological treatment, or an earlier diagnosis may increase survival in small intestinal neuroendocrine tumours (SI-NETs), but only few studies have examined survival trends. We aimed to examine the trend in overall survival and associated factors in SI-NET patients. All patients with SI-NETs at a regional hospital from June 2005 to December 2021 (n = 242) were identified, and the cohort was divided in half, constituting a first period (until November 2012) and a second period (from November 2012). Disease and treatment characteristics, including European Neuroendocrine Tumour Society (ENETS) stage, surgery, oncological treatment and survival, were recorded. The majority (n = 205 (84.7%)) were treated surgically and surgery was considered curative in 137 (66.8%) patients. Median survival was longer in the second period (9.0 years 95% CI 6.4-11.7 in the first period vs. median not reached in the second period, p = 0.014), with 5-year survival rates of 63.5% and 83.5%, respectively. ENETS stage and oncological treatment did not differ between the periods, but factors associated with surgical quality, such as lymph node harvest and resection of multiple SI-NETs, were significantly higher in the second period. Age, ENETS stage, time period and tumour resection were independently associated with survival in a multivariate analysis.
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Project description:Pancreatic neuroendocrine tumours (PanNETs) significantly impact life expectancy in multiple endocrine neoplasia type 1 (MEN1). Both solid and cystic pancreatic lesions are observed in MEN1, yet limited research has been focused on cystic lesions in MEN1. While solid PanNETs are generally considered to have an indolent course, the natural course of cystic lesions remains unclear. This study aims to provide more insights into the natural course of cystic PanNETs in MEN1. Patients with MEN1 and radiologically suspected PanNETs, treated at UMC Utrecht and Radboudumc between 2010 and 2023, were included. In the first part, we examined the characteristics of patients with tumours visible on imaging scans. In the second part, we investigated outcomes of pathological examinations, following resection of these lesions. A total of 136 patients were included, comprising 60 men and 76 women. The median follow-up was 5.1 years. [68Ga]Ga-DOTATOC PET/CT scans showed that both cystic and solid lesions demonstrated [68Ga]Ga-DOTATOC PET/CT uptake. The median growth of cystic and solid PanNETs was similar. Pathological examination of 38 resected tumours confirmed that cystic lesions identified on imaging were indeed PanNETs. Cystic lesions had a median diameter of 26 mm at the time of resection, compared to 18 mm for solid lesions, with comparable Ki-67 indices and mitotic counts. We conclude that cystic and solid PanNETs in MEN1 patients appear to be morphological variations of the same entity, suggesting that similar management approaches should be considered.
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