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Frontiers in Endocrinology 2024Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic,... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs.
METHODS
A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25 of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package.
RESULTS
Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was , with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in , , , , , , and/or ) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The point mutations/indels were distributed throughout . Overall, (16%, 37/225) and -variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. mutations occurred more frequently in PNETs with mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways.
DISCUSSION
The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).
Topics: Humans; Pancreatic Neoplasms; Neuroendocrine Tumors; Sequence Analysis, DNA; Mutation
PubMed: 38868744
DOI: 10.3389/fendo.2024.1351624 -
Endocrine Nov 2023Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome that combines endocrine and non-endocrine tumors. Thymic neuroendocrine tumors are uncommon components that...
BACKGROUND
Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome that combines endocrine and non-endocrine tumors. Thymic neuroendocrine tumors are uncommon components that predict poor prognosis in patients with MEN1. We aimed to summarize the clinical characteristics of thymoma in MEN1 by reviewing the current reports from the literature.
METHODS
A patient with multiple endocrine neoplasia type 1 (parathyroid hyperplasia, pituitary adenoma, and insulinoma) was found to have a 2 × 1.5 cm thymic mass during long-term follow-up. Thoracoscope surgery was performed, and a histopathology examination revealed WHO Type B3 thymoma. A pathogenic mutation of c.783 + 1G > A in the MEN1 gene was identified. We further searched PubMed and EMBASE for thymoma in association with MEN1.
RESULTS
A comprehensive overview of the literature concerning characteristics of MEN1-related thymoma was summarized. Clinical characteristics and differences between thymoma and thymic carcinoid are highlighted.
CONCLUSIONS
Besides carcinoid, other tumors, including thymoma, need to be identified for thymic space-occupying lesions in MEN1 patients. The impact of thymoma on the long-term prognosis of MEN1 patients needs further investigation.
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Thymoma; Thymus Neoplasms; Carcinoid Tumor; Pancreatic Neoplasms
PubMed: 37668926
DOI: 10.1007/s12020-023-03440-5 -
Frontiers in Endocrinology 2023Surgical resection is the standard of care for the treatment of pancreatic neuro-endocrine tumors (pNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1)....
Precision radiotherapy using MR-linac for pancreatic neuroendocrine tumors in MEN1 patients (PRIME): a protocol for a phase I-II trial, and systematic review on available evidence for radiotherapy of pNETs.
BACKGROUND
Surgical resection is the standard of care for the treatment of pancreatic neuro-endocrine tumors (pNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1). However, surgery can cause significant short- and long-term morbidity. Magnetic resonance-guided radiotherapy (MRgRT) is a potential effective treatment with little side effects. With traditional radiotherapy techniques, irradiation of pancreatic tumors to high dose levels was hampered by poor visibility of the tumor during treatment. MRgRT uses onboard MRI to guide the treatment, thereby enabling delivery of ablative irradiation doses to the tumor, while sparing surrounding tissues. In this study, we describe results from a systematic review assessing efficacy of radiotherapy in pNET and present the protocol of the PRIME study.
METHODS
PubMed, Embase and Cochrane Library were searched for articles assessing efficacy and side effects of radiotherapy for the treatment of pNETs. Risk of bias was assessed using the ROBINS-I Risk of Bias Tool for observational studies. Descriptive statistics were used to describe results of included trials.
RESULTS
Four studies comprising of 33 patients treated by conventional radiotherapy were included. Despite the heterogeneity of studies, radiotherapy appeared to be effective for the treatment of pNETs with most patients responding (45.5%) or stabilizing (42.4%) in tumor size.
CONCLUSION AND TRIAL DESIGN
Due to the limited literature available and concerns about damage to surrounding tissue, conventional radiotherapy is currently little used for pNETs. The PRIME study is a phase I-II trial with a single arm prospective cohort study design, investigating the efficacy of MRgRT in MEN1 patients with pNET. MEN1 patients with growing pNETs with a size between 1.0 and 3.0 cm without malignant features are eligible for inclusion. Patients are treated with 40 Gy in 5 fractions on the pNET, using online adaptive MRgRT on a 1.5T MR-linac. The primary endpoint is the change in tumor size at MRI 12 months follow-up. Secondary endpoints include radiotoxicity, quality of life, endocrine and exocrine pancreas function, resection rate, metastatic free and overall survival. When MRgRT is found effective with low radiotoxicity, it could reduce the need for surgery for pNET and preserve quality of life.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO https://clinicaltrials.gov/, (CRD42022325542).
Topics: Humans; Clinical Trial Protocols as Topic; Drug-Related Side Effects and Adverse Reactions; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Prospective Studies; Quality of Life; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic
PubMed: 37305036
DOI: 10.3389/fendo.2023.994370 -
Annales D'endocrinologie Aug 2023
Topics: Humans; Astrocytoma; Brain Neoplasms; Magnetic Resonance Imaging; Pituitary Gland; Multiple Endocrine Neoplasia Type 1; Male; Adolescent
PubMed: 37169283
DOI: 10.1016/j.ando.2023.04.004 -
World Journal of Surgery Nov 2022
Meta-Analysis
Topics: Humans; Hyperparathyroidism, Primary; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2a; Neoplasm Recurrence, Local; Parathyroid Glands; Parathyroidectomy
PubMed: 36042033
DOI: 10.1007/s00268-022-06707-6 -
World Journal of Surgery Nov 2022Multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) is classically associated with an asymmetric and asynchronous parathyroid... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) is classically associated with an asymmetric and asynchronous parathyroid involvement. Subtotal parathyroidectomy (STP), which is currently the recommended surgical treatment, carries a high risk of permanent hypoparathyroidism. The results of less than subtotal parathyroidectomy (LSTP) are conflicting, and its place in this setting is still a matter of debate. The aim of this study was to identify the place of LSTP in the surgical management of patients with MEN-associated pHPT.
METHODS
A systematic literature review was conducted in accordance with PRISMA and MOOSE guidelines, for studies comparing STP and LSTP for MEN1-associated pHPT. The results of the two techniques, regarding permanent hypoparathyroidism, persistent hyperparathyroidism and recurrent hyperparathyroidism were computed using pairwise random-effect meta-analysis.
RESULTS
Twenty-five studies comparing STP and LSTP qualified for inclusion in the quantitative synthesis. In total, 947 patients with MEN1-associated pHPT were allocated to STP (n = 569) or LSTP (n = 378). LSTP reduces the risk of permanent hypoparathyroidism [odds ratio (OR) 0.29, confidence interval (CI) 95% 0.17-0.49)], but exposes to higher rates of persistent hyperparathyroidism [OR 4.60, 95% CI 2.66-7.97]. Rates of recurrent hyperparathyroidism were not significantly different between the two groups [OR 1.26, CI 95% 0.83-1.91].
CONCLUSIONS
LSTP should not be abandoned and should be considered as a suitable surgical option for selected patients with MEN1-associated pHPT. The increased risk of persistent hyperparathyroidism could improve with the emergence of more efficient preoperative localization imaging techniques and a more adequate patients selection.
Topics: Humans; Hyperparathyroidism, Primary; Hypoparathyroidism; Multiple Endocrine Neoplasia Type 1; Parathyroid Glands; Parathyroidectomy
PubMed: 35767091
DOI: 10.1007/s00268-022-06633-7 -
Pharmaceuticals (Basel, Switzerland) Oct 2021Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1... (Review)
Review
Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1 (MEN1) where patients display a 70% lifelong risk of developing a pancreatic NENs (pNENs). To date, specific personalized treatment for pNENs in patients with MEN1 are lacking. The aim of this study was to systematically analyze the efficacy and safety of somatostatin analogue (SSA) treatment in patients affected by MEN1-related pNENs. We performed a systematic review of the literature, searching for peer-reviewed articles on SSA (octreotide or lanreotide) treatment in MEN1 associated with pNENs. We selected 20 studies with a pooled population of 105 MEN1 patients with pNENs. Females were 58.5%, median age was 44 years (18-73). TNM stage at diagnosis was stage I-II in 84.8% and stage IV in 15.2%. The overall response rate (SD+PR+CR) was achieved in 88.3% of cases, with stable disease in 75.6% and objective response in 12.7% of patients. The safety profile was favorable with both SSA agents. SSAs appear to be an effective and safe treatment option for MEN1-related pNEN, either at localized or advanced stages.
PubMed: 34681263
DOI: 10.3390/ph14101039 -
Advances in Therapy Feb 2021Somatostatin analogs (SSAs) are used to treat neuroendocrine tumors (NETs) and acromegaly. Two first-generation SSAs, octreotide long-acting release (OCT LAR) and... (Review)
Review
Patient and Healthcare Provider Perspectives of First-Generation Somatostatin Analogs in the Management of Neuroendocrine Tumors and Acromegaly: A Systematic Literature Review.
INTRODUCTION
Somatostatin analogs (SSAs) are used to treat neuroendocrine tumors (NETs) and acromegaly. Two first-generation SSAs, octreotide long-acting release (OCT LAR) and lanreotide autogel/depot (LAN), are available. A systematic literature review (SLR) was conducted to investigate which characteristics beyond efficacy are most important in patient and healthcare practitioner (HCP) experience of LAN and OCT when used to treat acromegaly and NETs.
METHODS
MEDLINE, Embase, the Cochrane Library, and Database of Abstracts of Reviews of Effect were searched from database inception to January 2019 with terms for first-generation SSAs, NETs, acromegaly, preferences, decision-making, and human factors. Key congresses in 2016-2018 and SLR bibliographies were hand-searched. Two independent reviewers screened articles at title/abstract and full-text stage. Publications fulfilling pre-specified inclusion criteria reported patient or HCP perspectives of LAN or OCT, or any factors affecting treatment perspectives for NETs or acromegaly.
RESULTS
A total of 1110 unique records were screened, of which 21 studies were included, reporting from the perspectives of patients (n = 18) and/or HCPs (n = 9). Perspectives were collected using shared decision-making frameworks, questionnaires, informal patient opinion, and a Delphi panel. Where patient preference was specifically reported, LAN was preferred in 4/5 studies and OCT LAR in 1/5. Common factors underlying treatment experience included technical problems with injections and associated pain, emotional quality/anxiety of injections, time and convenience of treatment administration, and independence. Immediate aspects of injections appeared most important to patients, though the possibilities of extended dosing intervals and self-/partner-injection with LAN were also notable factors.
CONCLUSIONS
Study outcomes favored LAN in this SLR, with factors surrounding injection administration most influential in treatment experience. The findings of this SLR provide a basis that could inform development of decision-making criteria, with patient and HCP treatment perspectives considered. Future studies should utilize a common method to report preference and associated drivers.
Topics: Acromegaly; Health Personnel; Humans; Neuroendocrine Tumors; Octreotide; Somatostatin
PubMed: 33432541
DOI: 10.1007/s12325-020-01600-x -
JAMA Otolaryngology-- Head & Neck... Feb 2021Intraoperative parathyroid hormone (ioPTH) is a surgical adjunct that has been increasingly used during minimally invasive parathyroidectomy (MIP). Despite its growing... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Intraoperative parathyroid hormone (ioPTH) is a surgical adjunct that has been increasingly used during minimally invasive parathyroidectomy (MIP). Despite its growing popularity, to our knowledge a meta-analysis comparing MIP with ioPTH vs MIP without ioPTH has not yet been conducted.
OBJECTIVE
To evaluate the safety and efficacy of MIP with ioPTH for treatment of primary hyperparathyroidism.
DATA SOURCES
A systematic search of the databases PubMed, Embase, Scopus, Web of Science, and Cochrane Collaboration was performed to identify studies that compared MIP with and without ioPTH. Data were analyzed between August and September 2019.
STUDY SELECTION
Inclusion criteria consisted of randomized clinical trials and observational studies with a retrospective/prospective design, comparing MIP using ioPTH vs MIP not using ioPTH for treatment of primary hyperparathyroidism. Eligible studies had to present odds ratio (OR), risk ratio, or hazard ratio estimates (with 95% CI), standard errors, or number of events necessary to calculate these for the outcome of interest rate. Studies involving patients with secondary or tertiary hyperparathyroidism or those with multiple endocrine neoplasia syndrome were excluded.
DATA EXTRACTION
Two reviewers independently reviewed the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Dichotomous variables were pooled as ORs while continuous variables were compared using weighted mean differences. Quality assessment was performed using the Newcastle-Ottawa Scale.
MAIN OUTCOMES AND MEASURES
The primary outcome was rate of cure. Secondary outcomes included need for reoperation, need for bilateral neck exploration, morbidity, and length of surgery.
RESULTS
A total of 12 studies, involving 2290 patients with primary hyperparathyroidism, were eligible for inclusion. The median (SD) age of participants was 60.1 (11.8) years and 77.3% of participants were women. The median Newcastle-Ottawa score was 7. Patients who underwent MIP with ioPTH had higher cure rates (OR, 3.88; 95% CI, 2.12-7.10; P < .001). There was a greater need for reoperation in the group of patients who had surgery without ioPTH (OR, 0.40; 95% CI, 0.19-0.86; P = .02). There was a trend toward longer operating times/increased duration of surgery in the ioPTH group; however, this did not reach statistical significance (weighted mean difference, 21.62 minutes; 95% CI, -0.93 to 44.17 minutes; P = .06). The use of ioPTH was associated with higher rates of bilateral neck exploration (OR, 3.55; 95% CI, 1.27-9.92; P = .02).
CONCLUSIONS AND RELEVANCE
Use of ioPTH is associated with higher cure rates for patients with primary hyperparathyroidism undergoing MIP. Minimally invasive parathyroidectomy performed without ioPTH is associated with less conversion to bilateral neck exploration at initial surgery but with lower cure rates and an increased risk for reoperation.
TRIAL REGISTRATION
PROSPERO identifier: CRD42020148588.
Topics: Humans; Hyperparathyroidism, Primary; Intraoperative Care; Minimally Invasive Surgical Procedures; Parathyroid Hormone; Parathyroidectomy
PubMed: 33211086
DOI: 10.1001/jamaoto.2020.4021 -
Surgery Feb 2021Hyperparathyroidism is an almost universal feature of multiple endocrine neoplasia type 1 syndrome. We present a systematic review and meta-analysis of the postoperative... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hyperparathyroidism is an almost universal feature of multiple endocrine neoplasia type 1 syndrome. We present a systematic review and meta-analysis of the postoperative outcomes of patients undergoing initial operative treatment of primary hyperparathyroidism complicating multiple endocrine neoplasia 1.
METHODS
A comprehensive literature search was performed with a priori defined exclusion criteria for studies comparing total parathyroidectomy, subtotal parathyroidectomy, and less than subtotal parathyroidectomy.
RESULTS
Twenty-one studies incorporating 1,131 patients (272 undergoing total parathyroidectomy, 510 subtotal parathyroidectomy, and 349 less than subtotal parathyroidectomy) were identified. Pooled results revealed increased risk for long-term hypoparathyroidism in total parathyroidectomy patients (relative risk 1.61; 95% confidence interval, 1.12-2.31; P = .009) versus those undergoing subtotal parathyroidectomy. In the less than subtotal parathyroidectomy or subtotal parathyroidectomy comparison group, a greater risk for recurrence of hyperparathyroidism (relative risk 1.37; 95% confidence interval, 1.05-1.79; P = .02), persistence of hyperparathyroidism (relative risk 2.26; 95% confidence interval, 1.49-3.41; P = .0001), and reoperation for hyperparathyroidism (relative risk 2.48; 95% confidence interval, 1.65-3.73; P < .0001) was noted for less than subtotal parathyroidectomy patients, albeit with lesser risk for long-term for hypoparathyroidism (relative risk 0.47; 95% confidence interval, 0.29-0.75; P = .002).
CONCLUSION
Subtotal parathyroidectomy compares favorably to total parathyroidectomy, exhibiting similar recurrence and persistence rates with a decreased propensity for long-term postoperative hypoparathyroidism. The benefit of the decreased risk of hypoparathyroidism in less than subtotal parathyroidectomy is negated by the increase in the risk for recurrence, persistence, and reoperation. Future studies evaluating the performance of less than subtotal parathyroidectomy in specific multiple endocrine neoplasia 1 phenotypes should be pursued in an effort to delineate a patient-tailored, operative approach that optimizes long-term outcomes.
Topics: Humans; Hyperparathyroidism, Primary; Hypoparathyroidism; Multiple Endocrine Neoplasia Type 1; Parathyroid Glands; Parathyroidectomy; Postoperative Complications; Recurrence; Reoperation; Treatment Outcome
PubMed: 33008613
DOI: 10.1016/j.surg.2020.08.021