| 1. |
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| 2. |
- Bülow, Birgitta, et al.
(författare)
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Adrenal incidentaloma - follow-up results from a Swedish prospective study
- 2006
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 154:3, s. 419-23
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas. DESIGN: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3-108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results. METHODS: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3-6 months, 15-18 months and 27-30 months, as well as hormonal evaluation at baseline and after 27-30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour. RESULTS: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28-84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1-8 cm). During the follow-up period, an increase in incidentaloma size of > or =0.5 cm was reported in 17 (7.4%) and of > or =1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing's syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed. CONCLUSIONS: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.
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| 3. |
- Johanson, Viktor, 1958, et al.
(författare)
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A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis
- 2007
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 14:2, s. 433-444
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
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| 4. |
- Abrahamsson, Gun, 1947, et al.
(författare)
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Ovarian cyst formation in women of reproductive age receiving mitotane as part of the treatment of adrenocortical carcinoma: Clinical and experimental observations
- 2020
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Ingår i: Acta Obstetricia Et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 99:10, s. 1297-1302
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Mitotane is an adrenolytic drug that is used as an adjuvant to treat adrenocortical carcinoma. This study aimed to evaluate the clinical course and pathogenetic mechanisms underlying ovarian cyst formation in women of reproductive age diagnosed with adrenocortical carcinoma and being treated with mitotane as an adjuvant to surgery. Material and methods Five women presented with stage III-IV adrenocortical carcinoma and ovarian cyst formation during mitotane treatment. The clinical course of the disease was followed during and after treatment. The effects of mitotane on progesterone production and cell proliferation were studied in cultured human ovarian granulosa cells. Results Computed tomography and vaginal ultrasonography during mitotane treatment repeatedly demonstrated ovarian cysts of varying size without solid intralocular structures. Two women became amenorrheic during the treatment period. After mitotane cessation, the ovarian cysts disappeared and normal menstrual cycles resumed. One woman had an uncomplicated pregnancy two years after mitotane treatment. In one woman, who underwent salpingo-oophorectomy, histological analysis demonstrated benign ovarian cysts. Mitotane impeded the synthesis of progesterone, reduced the stimulatory effect of gonadotropins on progesterone formation, and reduced labeling with [H-3]thymidine in cultured granulosa cells. Conclusions Therapeutic concentrations of mitotane are associated with the formation of benign ovarian cysts and amenorrhea. Mitotane-induced suppression of ovarian steroidogenesis and impediment of the proliferative capacity of steroid-producing cells are suggested potential pathogenetic mechanisms underlying mitotane-induced ovarian dysfunction and cyst development. Mitotane treatment does not compromise future ovarian function.
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| 5. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Adrenocortical carcinoma--diagnostic and therapeutical implications.
- 1993
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Ingår i: The European journal of surgery = Acta chirurgica. - 1102-4151. ; 159:3, s. 149-58
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the results of treatment of a consecutive series of patients with adrenocortical carcinoma who presented during the six year period 1985 to 1991.
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| 6. |
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| 7. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Aspects on diagnosis and treatment of the foregut carcinoid syndrome.
- 1992
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Ingår i: Scandinavian journal of gastroenterology. - 0036-5521. ; 27:6, s. 459-71
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Tidskriftsartikel (refereegranskat)abstract
- Eight patients with the foregut carcinoid syndrome (two gastric and six bronchial primary tumors) are reported. The patients presented with complex clinical symptoms including ectopic production of adrenocorticotrophic hormone and growth hormone-releasing factors. The most alarming symptoms were facial flush and edema, accompanied by severe bronchoconstriction, which easily was misinterpreted as asthmatic attacks. Conventional bronchodilatory drugs may be potentially dangerous in these patients, in whom combined blockade of histamine receptors and treatment with cortisone and octreotide are recommended. Owing to the patients' age and general condition individualized long-term therapy was instituted. Surgical therapy under optimal protection by drugs can be of substantial value also in patients with advanced disease. One patient with life-threatening hormonal symptoms underwent hyperthermic perfusion of the liver with cytotoxic drugs, resulting in good palliation.
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| 8. |
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| 9. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Clinical efficacy of octreotide scintigraphy in patients with midgut carcinoid tumours and evaluation of intraoperative scintillation detection.
- 1994
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Ingår i: The British journal of surgery. - 0007-1323. ; 81:8, s. 1144-9
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Tidskriftsartikel (refereegranskat)abstract
- 111In-diethylenetriamine penta-acetate-D-Phe1-octreotide scintigraphy was evaluated in a group of 27 patients with disseminated midgut carcinoid tumour. Additional information gained by the intraoperative use of a scintillation detector was studied in five patients with midgut carcinoid tumours and in two with endocrine pancreatic tumours. In 19 patients tumours not recognized by non-invasive radiological methods were visualized in 27 locations, most commonly in liver and para-aortic lymph nodes. Three false-negative tumour locations were noted (ovarian and peritoneal). With guidance from scintigraphic findings, nine patients underwent surgical tumour reduction, leading to complete remission in three. Clinically suspect tumour lesions were measured by the detector in situ, and ex vivo after excision. After excision the tissue:blood activity concentration ratios were calculated. In situ measurements were helpful in the localization of tumours and in the control of adequate clearance of tumour tissue. High tissue:blood activity concentration ratios at 1, 2 and 5 days in the five patients with midgut carcinoid tumour indicate a potential role for radiation therapy with radiolabelled octreotide in patients with somatostatin receptor-positive tumours.
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| 10. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Clinical management of gastric carcinoid tumors.
- 1994
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Ingår i: Digestion. - 0012-2823. ; 55 Suppl 3, s. 77-85
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Tidskriftsartikel (refereegranskat)abstract
- Four types of gastric carcinoids have been identified: (1) multiple small body-fundus carcinoids associated with chronic atrophic gastritis type A (A-CAG); (2) sporadic solitary lesions without specific pathogenetic background (non-A-CAG); (3) carcinoidosis associated with Zollinger-Ellison/MEN 1 syndrome, and (4) rare tumors, e.g. gastrin cell tumors, neuroendocrine carcinomas and mixed endocrine-exocrine tumors. In a retrospective study of 15 patients with gastric carcinoids (11 A-CAG, 3 non-A-CAG and 1 gastrin cell tumor) over a 10-year period, the histopathological and clinical features were assessed. The A-CAG-type carcinoids were clinically silent with lymph node metastases in 2/11 cases but no hepatic metastases. The non-A-CAG-type carcinoids were malignant with disseminated disease, hormonal symptoms and increased urinary excretion of the main histamine metabolite, MeImAA. Five patients with A-CAG tumors were subjected to antrectomy to remove hypergastrinemia, which is thought to be of pathogenetic importance for these tumors. During the observation period (1.5-8 years) 1 patient developed recurrent tumors, while the other 4 showed persistent argyrophil cell hyperplasia. A prospective treatment protocol of these tumors is suggested with endoscopic removal of less numerous, small lesions as first-step therapy, followed by antrectomy at recurrence. Larger lesions should be excised in combination with antrectomy. Gastrectomy is reserved for the rare cases of invasive tumors with lymph node metastases. As evident from the outcome of patients with non-A-CAG tumors radical surgery should be performed whenever practicable.
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| 11. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Cytotoxic treatment of adrenocortical carcinoma.
- 2001
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Ingår i: World journal of surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 25:7, s. 927-33
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Tidskriftsartikel (refereegranskat)abstract
- Adrenocortical carcinoma (ACC) is a rare, aggressive tumor that is often detected in an advanced stage. Medical treatment with the adrenotoxic drug mitotane has been used for decades, but critical prospective trials on its role in residual disease or as an adjuvant agent after surgical resection are still lacking. The concept of a critical threshold plasma level of the drug must be confirmed in controlled studies. Because individual responsiveness cannot be predicted, the use mitotane is still advised for nonresectable disease. In case of cortisol or other steroid overproduction, several drugs (e.g., ketoconazole or aminoglutethimide) may be used. Chemotherapy with single agents (e.g., doxorubicin or cisplatin) have been disappointing, with low response rates (< 30%) and a short response duration. Part of this refractoriness may be explained by the fact that ACC tumors express the multidrug-resistance gene MDR-1. Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. The best results were achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane, achieving a response rate of 54%, including individual complete responses. To be able to make progress in treating advanced ACC disease, adjuvant multicenter trials must be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.
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| 12. |
- Ahlman, Håkan, 1947, et al.
(författare)
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En "ny" tumörmarkör.
- 1996
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Ingår i: Klinisk Kemi i Norden, 8.. - Göteborg. ; , s. 45-52
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 13. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Growth regulation in carcinoid tumors.
- 1993
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Ingår i: Endocrinology and metabolism clinics of North America. - 0889-8529. ; 22:4, s. 889-915
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Forskningsöversikt (refereegranskat)abstract
- In hormone-producing tumors such as the carcinoids, overproduction of certain hormones may activate proto-oncogenes. Hormones, or growth factors, thus can be of importance for growth regulation. Information is presented on some growth factors and their receptors in this respect and on the involvement of gastrin and its receptor on tumor development in the experimental Mastomys model. The relevance of differential expression of cell adhesion molecules in endocrine tumors is discussed also.
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| 14. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Interventional treatment of gastrointestinal neuroendocrine tumours.
- 2000
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Ingår i: Digestion. - 0012-2823. ; 62 Suppl 1, s. 59-68
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine (NE) tumours of the gastrointestinal tract (carcinoids and endocrine pancreatic tumours) are rare diseases. In the presence of liver metastases these patients may suffer from disabling symptoms due to hormone overproduction. Patients with localized disease can be resected for cure and also patients with liver metastases can undergo potentially curative tumour resection. However, long-term follow-up of the latter cases indicates frequent recurrence of tumour. Using close biochemical monitoring of tumour markers combined with newer techniques for tumour visualization, these recurrences can often be diagnosed at an early stage so that repeat surgical procedures can be performed. During the last years very active surgery has been recommended for NE tumours, many of which have a relatively slow growth. Even in patients not amenable to curative liver surgery, debulking can be considered if the main tumour burden can be safely excised. The primary aim of this type of treatment is palliation of hormonal symptoms. An important question is whether the aggressive treatment actually prolongs survival. No prospective studies have been performed. Such studies are hampered by the lack of strict surgical programs running over long periods and the relative rarity of NE tumours. Liver transplantation may be another treatment modality in selected cases.
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| 15. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Liver transplantation for treatment of metastatic neuroendocrine tumors
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - 0077-8923. ; 1014, s. 265-9
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Tidskriftsartikel (refereegranskat)abstract
- Liver transplantation can be considered a therapeutic option for patients with neuroendocrine tumors only metastatic to the liver. Important selection criteria are well-differentiated tumors and a low proliferation rate (Ki67 <10%). In this series, orthopic liver transplantation offered good relief of symptoms and long disease-free intervals with initial survival of grafts and patients as in benign disease. The experience with multivisceral transplantation is still limited.
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| 16. |
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| 17. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Management of disseminated midgut carcinoid tumours.
- 1991
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Ingår i: Digestion. - 0012-2823. ; 49:2, s. 78-96
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Tidskriftsartikel (refereegranskat)abstract
- Forty-one patients with disseminated midgut carcinoid tumours were treated over a 6-year period according to a strict programme including primary surgical treatment. In 10 patients, a total remission of the disease was obtained. Patients with bilobar hepatic disease had ischaemic treatment of their liver metastases by hepatic arterial embolisation after primary surgical and medical treatment (low dose octreotide). Thus, by combining surgical, radiological and medical treatment modalities, we wanted to offer these patients optimal palliation. This treatment programme resulted in good symptomatic relief in all patients accompanied by a marked reduction in 5-hydroxyindoleacetic acid (5-HIAA) levels. At recurrence of symptoms in combination with rising 5-HIAA levels, embolisation was repeated. Ten of the treated patients have deceased during the observation period, but only 5 from their carcinoid disease.
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| 18. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Neuroendocrine insights from the laboratory to the clinic.
- 1996
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Ingår i: American journal of surgery. - 0002-9610. ; 172:1, s. 61-7
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Tidskriftsartikel (refereegranskat)abstract
- The interaction between adrenergic nerves and enterochromaffin (EC) cells was studied in health and disease using animal models and patients with the midgut carcinoid syndrome.
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| 19. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Sjukdomar i endokrina organ.
- 2003
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Ingår i: Kirurgi för sjuksköterskor. eds:Jeppssen B, Bengmark S. - Lund, Sverige : Studentlitteratur. - 9144074050
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Bokkapitel (refereegranskat)
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| 20. |
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| 21. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Somatostatin receptors on neuroendocrine tumors--a way to intraoperative diagnosis and localization.
- 1994
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Ingår i: The Yale journal of biology and medicine. - 0044-0086. ; 67:3-4, s. 215-21
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Tidskriftsartikel (refereegranskat)abstract
- Intraoperative radionuclide detection using 111In-DTPA-D-Phe1-octreotide was evaluated in five patients with midgut carcinoids and in three patients with recurrent medullary thyroid carcinoma. Three different time intervals (24, 48 and 120 hr) from injection of the radiopharmaceutical to surgery were used. At surgery, suspect tumors were measured by probe in situ and ex vivo after excision. All tissue specimens and blood samples withdrawn during surgery were measured for 111In activity, and tissue/blood activity concentration ratios were calculated. In situ measurements were valuable especially in neck surgery, where the probe was helpful not only in localization of tumors but also in the control of tumor clearance. Ex vivo measurements were helpful in diagnosing tumor tissue. All five patients with midgut carcinoids were somatostatin receptor-positive, while only three out of seven patients with medullary thyroid carcinoma were receptor-positive. The tissue/blood activity concentration ratios and probe measurement ratios were in general higher in patients with midgut carcinoid than in patients with medullary thyroid carcinoma. Of particular interest were the high tissue/blood concentration ratios in all receptor-positive patients at all time intervals studied. This fact suggests a potential role for radiolabelled octreotide in radiotherapy of these tumor types.
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| 22. |
- Ahlman, Håkan, 1947, et al.
(författare)
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The relevance of somatostatin receptors in thyroid neoplasia.
- 1997
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Ingår i: The Yale journal of biology and medicine. - 0044-0086. ; 70:5-6, s. 523-33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 111In-octreotide scintigraphy in patients with persistent medullary thyroid carcinoma (MTC) visualized tumors in about half of the surgically explored sites. Tumor visualization correlated with rapid tumor growth and large tumor volume as judged from calcitonin levels. The 111In concentration ratio between tumor (T) and blood (B) in surgically excised lymph node metastases of MTC showed a large variation, with low values for microscopic and high values for macroscopic metastases in individual patients. Three cases of MTC, Hürthle cell adenoma and papillary thyroid cancer are reported with preoperative scintigraphy, T/B ratios and Northern analyses of the surgical biopsies. Visualization of tumors was possible in the absence of sstr2 (the high affinity receptor for octreotide) with the exception of microscopic tumor growth. T/B values in the patient with Hürthle cell adenoma were similar to those found in the contralateral thyroid lobe with goitre. The relatively high uptake of 111In in benign thyroid conditions probably limits the use of octreotide scintigraphy in the diagnosis of primary tumors. The technique has certain advantages over radioiodine scintigraphy after the surgical treatment of thyroid tumors: no need for withdrawal of thyroxin substitution; a possibility to diagnose metastases of tumors that do not concentrate radioiodine (MTC, Hürthle cell cancer); and complementary information about metastatic sites of non-medullary thyroid cancer (papillary and follicular tumors).
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| 23. |
- Ahlman, Håkan, 1947, et al.
(författare)
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Treatment of liver metastases of carcinoid tumors.
- 1996
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Ingår i: World journal of surgery. - 0364-2313. ; 20:2, s. 196-202
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Tidskriftsartikel (refereegranskat)abstract
- Liver metastases imply a major problem in patients with carcinoid tumors. Patients with localized disease should always undergo resection for cure. Patients with distant metastatic disease can also undergo resection for potential cure or symptom palliation because of the slow growth rate of many carcinoid tumors. In patients with the midgut carcinoid syndrome and bilobar hepatic disease we have performed primary surgery to relieve such symptoms as intestinal obstruction and ischemia, followed by successive embolizations of the hepatic arteries to reduce functional tumor burden in the liver. For optimal palliation, all patients with residual tumor were treated by octreotide. In a consecutive series of 64 patients with the midgut carcinoid syndrome we thus attained a 5-year survival rate of 70%. Fourteen of the patients underwent intentionally curative surgery (e.g., primary surgery followed by liver surgery). Of these patients, none died from their tumor disease during the period of study. The value of adjunctive interferon therapy is currently under evaluation.
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| 24. |
- Amiri-Mosavi, A, et al.
(författare)
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Expression of cholecystokinin-B/gastrin receptors in medullary thyroid cancer.
- 1999
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Ingår i: The European journal of surgery = Acta chirurgica. - : Oxford University Press (OUP). - 1102-4151. ; 165:7, s. 628-31
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Tidskriftsartikel (refereegranskat)abstract
- To characterise the cholecystokinin (CCK) receptor subtypes in medullary thyroid cancer by measuring the expression of CCK-A and CCK-B/gastrin receptor mRNA.
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| 25. |
- Andersson, Ellinor, et al.
(författare)
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Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.
- 2016
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 29:6, s. 616-629
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Tidskriftsartikel (refereegranskat)abstract
- We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients.
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| 26. |
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| 27. |
- Andersson, P, et al.
(författare)
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Internalization of indium-111 into human neuroendocrine tumor cells after incubation with indium-111-DTPA-D-Phe1-octreotide.
- 1996
-
Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 37:12, s. 2002-6
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumor cells frequently overexpress somatostatin receptors at their cell surfaces. To evaluate the possibility of using the somatostatin analog 111In-DTPA-D-Phe1-octreotide for radiation therapy, we studied the binding and subsequent internalization of 111In into three types of cultured human neuroendocrine tumor cells.
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| 28. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells.
- 2016
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 1423-0194 .- 0028-3835. ; 103:5, s. 578-591
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Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class-I and class-IIa HDACs, on neuroendocrine tumour (NET) cell growth.
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| 29. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival
- 2018
-
Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 31, s. 1302-1317
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Tidskriftsartikel (refereegranskat)abstract
- © 2018, United States & Canadian Academy of Pathology. The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR-488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of β-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker.
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| 30. |
- Basson, M D, et al.
(författare)
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Biology and management of the midgut carcinoid.
- 1993
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Ingår i: American journal of surgery. - 0002-9610. ; 165:2, s. 288-97
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Forskningsöversikt (refereegranskat)abstract
- Midgut carcinoid tumors derive from gut entoderm. These tumors may cause a complex of symptoms comprising the carcinoid syndrome by secreting a wide variety of bioactive agents in addition to serotonin. Such symptoms generally follow metastases to the liver but may also occur in primary ovarian or retroperitoneal tumors. After localization and biochemical characterization, the bioactivity of these tumors should be blocked by octreotide, sometimes in combination with other pharmacologic antagonists, so that primary resection may be performed safely. If curative resection is impossible, then a cytoreductive management scheme should be employed that includes surgical debulking and hepatic arterial embolization, followed by palliation with octreotide.
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| 31. |
- Benjegård, S A, et al.
(författare)
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Evaluation of three gamma detectors for intraoperative detection of tumors using 111In-labeled radiopharmaceuticals.
- 1999
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 40:12, s. 2094-101
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Tidskriftsartikel (refereegranskat)abstract
- Attempts to detect tumors with intraoperative scintillation using tumor-binding radiopharmaceuticals have intensified recently. In some cases previously unknown lesions were found, but in most cases no additional lesions were detected. In this study the physical characteristics of three detector systems and their ability to detect tumors through accumulation of an 111In-labeled radiopharmaceutical were investigated. The first was a sodium iodide (NaI[TI]) detector; the second, a cesium iodide (CsI[TI]) detector; and the third, a cadmium telluride (CdTe) detector.
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| 32. |
- Benjegård, S A, et al.
(författare)
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Intraoperative tumour detection using 111In-DTPA-D-Phe1-octreotide and a scintillation detector.
- 2001
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Ingår i: European journal of nuclear medicine. - : Springer Science and Business Media LLC. - 0340-6997 .- 1619-7070 .- 1619-7089. ; 28:10, s. 1456-62
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Tidskriftsartikel (refereegranskat)abstract
- Intraoperative tumour detection has been used in many applications. The examined tumour forms have varied and different detector systems and radiopharmaceuticals have also been used. The aim of this study was to evaluate and compare the ability of an NaI(T1) scintillation detector to detect primary tumours and metastases in patients with different endocrine tumour types (e.g. carcinoid tumours, endocrine pancreatic tumours and thyroid tumours) and in patients with breast carcinoma or benign thyroid lesions, on the basis of their somatostatin receptor expression after i.v. injection of 111In-DTPA-D-Phe1-octreotide. Thirty patients were injected with 111In-DTPA-D-Phe1-octreotide intravenously. Scintigraphic images were taken 1 day after injection of the radiopharmaceutical, and surgery was performed 1-7 days post injection. An NaI(T1) scintillation detector was used for intraoperative tumour detection. Tissue samples were collected during surgery for determination of 111In activity concentration and histopathological examination. The scintigraphic images were positive in 29 out of 30 patients. Intraoperative tumour detection was successful in 43 of 66 collected biopsies: 10 out of 11 for carcinoid tumours, 7 out of 10 for medullary thyroid carcinoma (MTC) and 14 out of 22 for breast cancer. On the basis of our findings we conclude that intraoperative tumour detection with 111In-DTPA-D-Phe1-octreotide using this NaI(T1) detector can be successful especially for carcinoid tumours and endocrine pancreatic tumours, due to the relatively high activity concentrations in these tumour types, but is less successful in other forms of thyroid cancer, including MTC, and breast cancer. For successful intraoperative detection, the detector characteristics are also very important, and further improvement of the detector systems is required to increase the sensitivity and specificity.
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| 33. |
- Bergman, B, et al.
(författare)
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Transfer of terbutaline across the human placenta in late pregnancy.
- 1984
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Ingår i: European journal of respiratory diseases. Supplement. - 0106-4347. ; 134, s. 81-6
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Tidskriftsartikel (refereegranskat)abstract
- Placental transfer of terbutaline was studied in 22 women in late pregnancy who were delivered by elective Caesarian section. A single i.v. dose of terbutaline (0.25 or 0.5 mg) was given at various times (13-295 min) before delivery. Immediately after delivery, one blood sample was drawn from the placental side of the umbilical vein and one from the mother's antecubital vein. By use of gas chromatography plus mass spectrometry terbutaline was assayed in maternal plasma and in plasma and whole blood from the umbilical vein. Plasma concentrations in the mothers (Cmv) were initially 7 micrograms/L, while the highest umbilical venous level ( Cuv ) recorded was 3.5 micrograms/L. The ratio Cuv /Cmv increased continuously during the time interval studied and approached unity after 2-3 h. The blood:plasma concentration ratio in venous umbilical blood was initially low. It reached unity after about 60 min, but increased steadily to about 1.5 during the time of study. Thus there was a continuous uptake of terbutaline from plasma into the erythrocytes. The slow in vivo equilibration of terbutaline between plasma and erythrocytes is probably due to the low lipophilicity of the drug. However, the latter characteristic did not seem to impede its diffusion across the placenta to any great degree.
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| 34. |
- Bümming, Per, 1965, et al.
(författare)
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Can the early reduction of tumour markers predict outcome in surgically treated sporadic medullary thyroid carcinoma?
- 2008
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Ingår i: Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie. - : Springer Science and Business Media LLC. - 1435-2443. ; 393:5, s. 699-703
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Patients with sporadic medullary thyroid carcinoma (MTC) have a variable clinical course. Our aim was to analyse the reduction of tumour markers after thyroidectomy with meticulous dissection and relate it to clinical outcome. MATERIALS AND METHODS: Twenty consecutive patients with palpable sporadic MTC underwent thyroidectomy with central and uni- or bilateral modified radical neck dissection; three were subjected to mediastinal dissection. Basal (b-) and stimulated (s-) calcitonin (CT) and carcinoembryonic antigen (CEA)-levels were measured before and 6-8 weeks after primary surgery, and the reduction of these tumour markers was determined. RESULTS: Median CT (b- and s-) were markedly reduced after surgery (98.5% and 99.1%, respectively), and CEA decreased 11 times. CT (b-) fell >99% in seven patients after surgery; in these and four additional patients, CT (s-) showed a similar reduction. During follow-up (median 52.5 months), two patients (stages IV B and C) died of MTC; they had <95% reduction of CT. Four patients (stage IV A) are alive with verified metastases. Eight patients (one stage III, seven stage IV A) are alive with hypercalcitoninemia. Five stages I-III patients and one stage IV A patient are disease-free. CONCLUSIONS: Thyroidectomy and meticulous dissection caused a pronounced reduction of tumour markers. A postoperative reduction of CT (s-) >/=97% seems to be associated with less aggressive clinical course, while CEA had lower predictive value.
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| 35. |
- Bümming, Per, 1965, et al.
(författare)
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Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients.
- 2003
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 89:3, s. 460-4
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Tidskriftsartikel (refereegranskat)abstract
- Malignant gastrointestinal stromal tumours (GIST) have a poor prognosis. Since these tumours are resistant to conventional radiation and chemotherapy, surgery has been the mainstay of treatment. However, surgery is usually inadequate for the treatment of malignant GIST. Imatinib, a KIT tyrosine kinase inhibitor, has recently been found to have a dramatic antitumour effect on GIST. In this centre-based study of 17 consecutive patients with high-risk or overtly malignant GIST, imatinib was used in three different settings - palliatively, adjuvantly, and neoadjuvantly. The treatment was found to be safe and particularly effective in tumours with activating mutations of exon 11 of the KIT gene. Clinical response to imatinib treatment correlated morphologically to tumour necrosis, hyalinisation, and reduced proliferative activity. The value of neoadjuvant imatinib treatment was illustrated in one case.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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| 40. |
- Elf, Anna-Karin, et al.
(författare)
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Evaluation of sstr2 expression in si-nets and relation to overall survival after prrt
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- (1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 41. |
- Elf, Anna-Karin, et al.
(författare)
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NAMPT inhibitor GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment of neuroendocrine tumors.
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 288-292
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumors (NETs) can be treated by peptide receptor radionuclide therapy using radiolabeled somatostatin analogs. However, the efficacy of such treatment is low and needs to be optimized.To evaluate the potential radiosensitizing effects of NAMPT inhibition on (177)Lu-DOTATATE treatment in a NET model.Nude mice xenografted with the human NET cell line GOT1 were treated with semi-efficient doses of (177)Lu-DOTATATE (7,5 MBq, i.v.) and/or GMX1778 (100 mg/kg/week, p.o.).Median time to tumor progression (tumor volume larger than at day 0) was 3 days for controls, 7 days for single dose GMX1778, 28 days for single dose (177)Lu-DOTATATE and 35 days for 3 weekly doses of GMX1778. Combined treatment with (177)Lu-DOTATATE and GMX1778 x1 resulted in a median time to progression of 98 days. After (177)Lu-DOTATATE and 3 weekly doses of GMX1778 none of the tumors progressed within 120 days.The NAMPT inhibitor GMX1778 enhances the efficacy of (177)Lu-DOTATATE treatment and induces a prolonged antitumor response. Combinations of radiolabeled somatostatin analogs and radiosensitizing drugs should be further evaluated to optimize the efficacy of peptide receptor radionuclide therapy in NETs.
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| 42. |
- Elf, Anna-Karin, et al.
(författare)
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Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial.
- 2018
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 42:2, s. 506-513
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Tidskriftsartikel (refereegranskat)abstract
- Radioembolization (RE) with intra-arterial administration of 90Y microspheres is a promising technique for the treatment of liver metastases from small intestinal neuroendocrine tumors (SI-NET) not amenable to surgery or local ablation. However, studies comparing RE to other loco-regional therapies are lacking. The aim of this randomized study was to compare the therapeutic response and safety after RE and bland hepatic arterial embolization (HAE), and to investigate early therapy-induced changes with diffusion-weighted MRI (DWI-MRI).Eleven patients were included in a prospective randomized controlled pilot study, six assigned to RE and five to HAE. Response according to RECIST 1.1 using MRI or CT at 3 and 6months post-treatment was recorded as well as changes in DWI-MRI parameters after 1month. Data on biochemical tumor response, toxicity, and side effects were also collected.Three months after treatment, all patients in the HAE group showed partial response according to RECIST while none in the RE group did (p=0.0022). After 6months, the response rates were 4/5 (80%) and 2/6 (33%) in the HAE and RE groups, respectively (NS). DWI-MRI metrics could not predict RECIST response, but lower pretreatment ADC(120-800) and larger ADC(0-800) increase at 1month were related to larger decrease in tumor diameter when all tumors were counted.HAE resulted in significantly higher RECIST response after 3months, but no difference compared to RE remained after 6months. These preliminary findings indicate that HAE remains a safe option for the treatment of liver metastases from SI-NET, and further studies are needed to establish the role of RE and the predictive value of MR-DWI.
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| 43. |
- Fjälling, M, et al.
(författare)
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Systemic radionuclide therapy using indium-111-DTPA-D-Phe1-octreotide in midgut carcinoid syndrome.
- 1996
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 37:9, s. 1519-21
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Tidskriftsartikel (refereegranskat)abstract
- A 55-yr-old woman with a midgut carcinoid syndrome due to metastatic spread of an ileal tumor to the liver, paraortic and mediastinal lymph nodes and to the skeleton was given systemic radionuclide therapy with 111In-DTPA-D-Phe1-octreotide. Before therapy, dosimetric calculations were performed on whole-body scintigraphs and 111In retention was shown to be long-lasting. Excretion was mainly seen during the first 24 hr after injection; thereafter whole-body retention remained stationary at 30%. Indium-111 activity in tumor biopsies and blood was measured using a gamma counter. Very high tumor-to-blood ratios were obtained: 150 for the primary tumor and 400-650 for liver metastases, which further justified radiation therapy. Indium-111-DTPA-D-Phe1-octreotide treatment was given on three separate occasions (3.0, 3.5 and 3.1 GBq) 8 and 4 wk apart. After each therapy, the patient experienced facial flush and pain over the skeletal lesions followed by symptomatic relief, even though no objective tumor regression was found radiologically after 5 mo. After initiation of octreotide treatment, there was a 14% reduction of the main tumor marker, urinary 5-HIAA. After three subsequent radionuclide therapies, there was a further 31% reduction of 5-HIAA levels. No adverse reactions, other than a slight decrease in leukocyte counts, were seen. The mean absorbed radiation dose after the three treatments was estimated to be about 10-12 Gy in liver metastases and 3-6 Gy in other tumors, depending on the size and location of the metastases. Assuming internalization of 111In into tumor cells and a radiobiological effect from short range Auger and conversion electrons, there might be a therapeutic effect on the tumor.
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| 44. |
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| 45. |
- Forssell-Aronsson, Eva, 1961, et al.
(författare)
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Aspects on radionuclide therapy in malignant pheochromocytomas.
- 2006
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1073, s. 498-504
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pheochromocytomas/paragangliomas (PCs/PGs) often have distant metastases to the skeleton, liver, and lungs. Radionuclide therapy is valuable for treatment of disseminated tumor disease and could be used as adjuvant therapy after surgery. Patients with local and/or distant metastases of PC/PG should be investigated preoperatively by scintigraphy using both 123I-MIBG and 111In-DTPA-D-Phe1-octreotide, to evaluate the possibilities for radionuclide therapy (i.e., a dosimetric estimation of radiation dose to the tumor tissue versus critical normal tissues). Individual patient dose-planning should be performed. For patients in whom positive therapeutic effects are anticipated radionuclide therapy can be applied. Therapy with both 131I-MIBG and 177Lu-octreotate might be favorable in individual patients with lesions visualized by both metaiodobenzylguanidine (MIBG) and octreotide scintigraphy with enhanced therapeutic effects and reduced side effects.
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| 46. |
- Forssell-Aronsson, Eva, 1961, et al.
(författare)
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Biodistribution data from 100 patients i.v. injected with 111In-DTPA-D-Phe1-octreotide
- 2004
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 43:5, s. 436-42
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to obtain accurate data on the biodistribution of 111In-DTPA-D-Phe1-octreotide in tumour and normal tissues to facilitate dosimetric evaluations. Patients with carcinoid tumours, medullary thyroid carcinoma (MTC), differentiated thyroid tumours, endocrine pancreatic tumour (EPT), breast carcinoma, and various other tumour types were i.v. injected with 111In-DTPA-D-Phe-1-octreotide. Tumour and normal tissue samples were collected during surgery 1-35 days later, and the 111In activity concentration determined. Results showed large inter- and intra-individual variations. The 111In concentration was in general higher in carcinoids and some EPT (range 0.33-77% IA/kg) than in MTC and other tumours (0.017-7.8% IA/kg). Tumour-to-blood ratios (T/B) higher than 100 were found in most patients with carcinoids, EPT, renal carcinoma, and neuroendocrine carcinoma (max value 1500), while T/B was below 80 in most other tumours. Normal-tissue-to-blood ratios were in general < or = 10 but higher values were found in liver, kidneys, and spleen. The results presented are important for dosimetric calculations, when radiolabelled octreotide is used for diagnostic or therapeutic purposes.
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| 47. |
- Forssell-Aronsson, Eva, 1961, et al.
(författare)
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Indium-111 activity concentration in tissue samples after intravenous injection of indium-111-DTPA-D-Phe-1-octreotide.
- 1995
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 36:1, s. 7-12
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Tidskriftsartikel (refereegranskat)abstract
- Indium-111 activity concentrations in human tumor and normal tissue samples were determined at 24, 48 and 120 hr after i.v. injection of 111In-DTPA-D-Phe-1-octreotide. Fourteen patients were included in the study. Seven patients had medullary thyroid carcinoma, four had midgut carcinoid tumors, two had endocrine pancreatic tumors and one had chronic pancreatitis.
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| 48. |
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| 49. |
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| 50. |
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