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- Krauss, Tobias, et al.
(författare)
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Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors
- 2018
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Ingår i: Endocrine-Related Cancer. - : BIOSCIENTIFICA LTD. - 1351-0088 .- 1479-6821. ; 25:9, s. 783-793
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were >= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off >= 2.8 cm, 44% and 91% for TVDT cut-off of <= 24 months). In 117 of 273 patients, PanNETs > 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs < 2.8 cm vs >= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.
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| 2. |
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| 3. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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| 4. |
- Herrera, Miguel F., et al.
(författare)
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AACE/ACE DISEASE STATE CLINICAL REVIEW : PANCREATIC NEUROENDOCRINE INCIDENTALOMAS
- 2015
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Ingår i: Endocrine Practice. - 1530-891X .- 1934-2403. ; 21:5, s. 546-553
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Forskningsöversikt (refereegranskat)abstract
- Incidental detection of pancreatic neuroendocrine tumors (PNETs) has substantially increased over the last decade due to widespread use of advanced imaging studies. Reliable initial imaging-based characterization is crucial for the differential diagnosis from other exocrine neoplasms and to determine the appropriate management plan. Measurements of chromogranin A, pancreatic polypeptide, and calcitonin are recommended for the biochemical evaluation. A thorough medical history needs to be performed to rule out multiple endocrine neoplasia (MEN) type 1. The European Neuroendocrine Tumor Society (ENETS)/Tumor Node Metastasis (TNM) staging system together with a grading based on the Ki-67 proliferation index and mitotic counts has proven to give more appropriate prognostic information than the World Health Organization (WHO)/American Joint Committee on Cancer (AJCC) TNM staging but may still fail to safely differentiate benign from malignant lesions. Poorly differentiated PNETs generally present with metastases and are rarely amenable for resection. Well-or intermediately differentiated tumors >= 2 cm with imaging evidence of malignancy or with a Ki-67 > 2% should be resected. It has been suggested that non-MEN related, nonfunctioning, and asymptomatic PNETs < 2 cm with a Ki-67 index >= 2% carry a low risk of metastasis and may be observed in the absence of clinical or radiologic criteria of malignancy or progression, especially in older patients. However, because metastases may occur with long delay with smaller PNETS, physicians should consider patient age, lesion location, and the risks of operation, and patients not undergoing surgery need to be closely followed closely.
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