| 1. |
- Crona, Joakim, et al.
(författare)
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Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids
- 2013
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 98:2, s. 151-155
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with tennozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11(52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxcities grade 3-4 were noted in 4 patients, thrombocytopenia (n =3) and leukopenia (n = 1). Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining tennozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients. Copyright (C) 2013 S. Karger AG, Basel
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| 2. |
- Crona, Joakim, et al.
(författare)
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Metastases from Neuroendocrine Tumors to the Breast Are More Common than Previously Thought. A Diagnostic Pitfall?
- 2013
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 37:7, s. 1701-1706
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Tidskriftsartikel (refereegranskat)abstract
- Metastases from neuroendocrine tumors (NETs) to the breast have been described as a rare phenomenon. Presentation, imaging results, and cytopathologic findings of these tumours may closely mimic those of a mammary carcinoma. This study was a retrospective review of 661 patients with metastatic NETs, of whom 280 were females, treated at Uppsala University Hospital, Uppsala, Sweden. Patients with pathological breast lesions were identified. Histopathological slides from available NET breast lesions were analyzed for mammary carcinoma and neuroendocrine markers. We have identified 20 female patients with NET metastases to the breast, 11/235 with small intestinal NETs, 8/55 with lung NETs, and 1/6 with thymic NETs. There were no male patients with NET metastatic to the breast. Four patients had their breast lesion initially diagnosed as mammary carcinoma. Retrospectively, these lesions showed negative staining for mammary carcinoma markers. Metastases to the breast from neuroendocrine tumors may be more common than previously thought. Patients with a lesion to the breast and symptoms typical for NET may benefit from additional histopathological investigation, because NET metastases and mammary carcinoma have different immunohistochemical profiles.
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| 3. |
- Crona, Joakim, et al.
(författare)
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Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma
- 2013
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Ingår i: Endocrine Connections. - 2049-3614. ; 2:2, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Recent findings have shown that up to 60% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are caused by germline or somatic mutations in one of the 11 hitherto known susceptibility genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A (EPAS1), RET, NF1, TMEM127 and MAX. This list of genes is constantly growing and the 11 genes together consist of 144 exons. A genetic screening test is extensively time consuming and expensive. Hence, we introduce next-generation sequencing (NGS) as a time-efficient and cost-effective alternative.METHODS:Tumour lesions from three patients with apparently sporadic PCC were subjected to whole exome sequencing utilizing Agilent Sureselect target enrichment system and Illumina Hi seq platform. Bioinformatics analysis was performed in-house using commercially available software. Variants in PCC and PGL susceptibility genes were identified.RESULTS:We have identified 16 unique genetic variants in PCC susceptibility loci in three different PCC, spending less than a 30-min hands-on, in-house time. Two patients had one unique variant each that was classified as probably and possibly pathogenic: NF1 Arg304Ter and RET Tyr791Phe. The RET variant was verified by Sanger sequencing.CONCLUSIONS:NGS can serve as a fast and cost-effective method in the clinical genetic screening of PCC. The bioinformatics analysis may be performed without expert skills. We identified process optimization, characterization of unknown variants and determination of additive effects of multiple variants as key issues to be addressed by future studies.
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| 4. |
- Crona, Joakim, et al.
(författare)
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Somatic Mutations in H-RAS in Sporadic Pheochromocytoma and Paraganglioma Identified by Exome Sequencing
- 2013
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:7, s. E1266-E1271
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Tidskriftsartikel (refereegranskat)abstract
- Context: Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL. Objectives: The aim of this study was to identify novel disease causing genes in PCC and PGL tumors. Design, setting, and participants: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions. Results: Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007). Conclusions: We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.
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| 5. |
- Crona, Joakim, et al.
(författare)
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Treatment, prognostic markers and survival in thymic neuroendocrine tumours : A study from a single tertiary referral centre
- 2013
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 79:3, s. 289-293
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Tidskriftsartikel (refereegranskat)abstract
- Thymic neuroendocrine tumours (TNETs) are uncommon but malignant neoplasms, usually associated with a poor prognosis. The number of cases reported is limited to a few hundreds and there are few prognostic factors available. All 28 patients (22 male, 6 female; median age 46.5 years) with thymic neuroendocrine tumour, treated at the Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden between 1985 and 2011 were studied. The overall 3, 5 and 10-year survival was 89%, 79% and 41% respectively. Ki67<10% (p=0.018) as well as surgical resection (p=0.001) and macroscopically radical primary surgery (p=0.034) was associated with increased survival. Staging & grading according to Masaoka and ENETS systems did not correlate with survival. However, a modified ENETS grading showed a positive correlation (p=0.015). Median time to progression was 20.5 months with Temozolomide and 18 months with platinum based therapy. Partial responses were noted in three patients (38%) treated with platinum based therapy and in two patients (20%) treated with Temozolomide based therapy. High proliferative rate, measured by Ki67 index, and absence of macroscopically radical primary resection as well as no surgical resection are three negative prognostic factors in patients with TNETs. Temozolomide or Platinum based chemotherapy should be considered as first-line medical therapy in patients with metastatic or non-resectable tumours.
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