| 1. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
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Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
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| 2. |
- Forsberg, Elin, et al.
(författare)
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HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy-Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
- 2019
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Ingår i: Cancer Research. - 0008-5472. ; 79:5, s. 899-904
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Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
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| 3. |
- Hofving, Tobias, 1989, et al.
(författare)
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The Microenvironment of Small Intestinal Neuroendocrine Tumours Contains Lymphocytes Capable of Recognition and Activation after Expansion
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:17
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The body's immune system can recognize tumors because they often contain proteins that are either different from or more abundant than in normal cells. Here, we characterised the immune cells of a rare tumor type called small-intestinal neuroendocrine tumors (SINET). We find that so called tumour-infiltrating lymphocytes (TILs) can be grown in the laboratory and activated by challenging them with digested tumor. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET. Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
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| 4. |
- Sjölund, Katarina, et al.
(författare)
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Downsizing treatment with tyrosine kinase inhibitors in patients with advanced gastrointestinal stromal tumors improved resectability.
- 2010
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Ingår i: World journal of surgery. - : Springer Science and Business Media LLC. - 1432-2323 .- 0364-2313. ; 34:9, s. 2090-2097
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT. Most GISTs have mutations in the KIT or PDGFRA gene, causing activation of tyrosine kinase. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line palliative treatment for advanced GISTs. Sunitinib was introduced for patients with mutations not responsive to imatinib. The aim was to compare the survival of patients with high-risk resected GISTs treated with TKI prior to surgery with historical controls and to determine if organ-preserving surgery was facilitated. METHODS: Ten high-risk GIST-patients had downsizing/adjuvant TKI treatment: nine with imatinib and one with sunitinib. The patients were matched with historical controls (n = 89) treated with surgery alone, from our population-based series (n = 259). Mutational analysis of KIT and PDGFRA was performed in all cases. The progression-free survival was calculated. RESULTS: The primary tumors decreased in mean diameter from 20.4 cm to 10.5 cm on downsizing imatinib. Four patients with R0 resection and a period of adjuvant imatinib had no recurrences versus 67% in the historical control group. Four patients with residual liver metastases have stable disease on continuous imatinib treatment after surgery. One patient has undergone reoperation with liver resection. The downsizing treatment led to organ-preserving surgery in nine patients and improved preoperative nutritional status in one patient. CONCLUSIONS: Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning.
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| 5. |
- 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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| 6. |
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| 7. |
- Arne, Gabriella, et al.
(författare)
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Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location, and poor prognosis.
- 2011
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 129:5, s. 1149-1161
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Tidskriftsartikel (refereegranskat)abstract
- In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by meta-analysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n=180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio=2.23, P=0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, NIH risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis.
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| 8. |
- Arne, Gabriella, et al.
(författare)
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Gastrointestinal stromal tumors (GISTs) express somatostatin receptors and bind radiolabeled somatostatin analogs.
- 2013
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Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X .- 0284-186X. ; 52:4, s. 783-792
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Tidskriftsartikel (refereegranskat)abstract
- Background. Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT). Material and methods. Expression profiling of SSTR1-5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ((111)In-octreotide) and measurement of (111)In activity in tumor specimens was performed in seven patients. Uptake and internalization of (177)Lu- octreotate was studied in primary cell cultures from two patients. Results. Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3-5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3-5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using (111)In-octreotide, demonstrated tumor uptake of (111)In in three of six GIST patients. Measurement of (111)In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized (177)Lu when incubated with the therapeutic compound (177)Lu-octreotate for 4-48 hours (p < 0.05). Conclusion. Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.
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| 9. |
- 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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| 10. |
- Bümming, Per, 1965, et al.
(författare)
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Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype.
- 2007
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Ingår i: Endocrine-related cancer. - 1351-0088. ; 14:3, s. 853-63
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST.
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| 11. |
- Bümming, Per, 1965, et al.
(författare)
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Use of 2-tracer PET to diagnose gastrointestinal stromal tumour and pheochromocytoma in patients with Carney triad and neurofibromatosis type 1
- 2006
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 41:5, s. 626-30
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Tidskriftsartikel (refereegranskat)abstract
- There is rapid evolution in the functional imaging of tumours. In two patients with concomitant pheochromocytoma and gastrointestinal stromal tumour (GIST), previously unrecognized tumours were visualized by combined 2-tracer positron emission tomography (PET), which also provided precise information about tumour type. PET imaging led to radical resection and the diagnoses were histopathologically confirmed. GISTs from the Carney patient and the patient with neurofibromatosis type 1 (NF1) both lacked KIT mutations.
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| 12. |
- Ekeblad, Sara, et al.
(författare)
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Gastrointestinal stromal tumors express the orexigen ghrelin
- 2006
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Ingår i: Endocrine-related cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 13:3, s. 963-70
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the neuroendocrine marker synaptic vesicle protein 2 (SV2) has been reported in a few cases of gastrointestinal stromal tumors (GISTs). The goal of the present study was to assess the relevance of this finding and identify a possible hormone production in these tumors. We chose to study the orexigen ghrelin and its receptor, since these patients are seldom cachexic, even in advanced disease stages. We investigated ghrelin expression by means of immunohistochemistry on frozen or paraffin-embedded sections from 22 GISTs from a well-characterized patient material. Expression of the growth hormone secretagogue receptor, the ghrelin receptor, was investigated in a subset of lesions. In six tumors, mRNA levels of ghrelin, the ghrelin receptor, and SV2 were analyzed by real-time quantitative PCR. Totally 17 out of 22 tumors showed immunoreactivity for ghrelin. Five out of ten tumors were immunoreactive for the ghrelin receptor, and all of these co-expressed ghrelin. All tumors expressed ghrelin, ghrelin receptor, and SV2 mRNA. GISTs frequently express SV2, ghrelin, and its receptor, indicating the presence of autocrine/paracrine loops.
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| 13. |
- Hedenström, Per, et al.
(författare)
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High clinical impact and diagnostic accuracy of EUS-guided biopsy sampling of subepithelial lesions: a prospective, comparative study.
- 2018
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Ingår i: Surgical endoscopy. - : Springer Science and Business Media LLC. - 1432-2218 .- 0930-2794. ; 32:3, s. 1304-1313
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Tidskriftsartikel (refereegranskat)abstract
- In a tertiary center setting we aimed to study the diagnostic accuracy and clinical impact of EUS-guided biopsy sampling (EUS-FNB) with a reverse bevel needle compared with that of fine needle aspiration (EUS-FNA) in the work-up of subepithelial lesions (SEL).All patients presenting with SELs referred for EUS-guided sampling were prospectively included in 2012-2015. After randomization of the first pass modality, dual sampling with both EUS-FNB and EUS-FNA was performed in each lesion. Outcome measures in an intention-to-diagnose analysis were the diagnostic accuracy, technical failures, and adverse events. The clinical impact was measured as the performance of additional diagnostic procedures post-EUS and the rate of unwarranted resections compared with a reference cohort of SELs sampled in the same institution 2006-2011.In 70 dual sampling procedures of unique lesions (size: 6-220mm) the diagnostic sensitivity for malignancy and the overall accuracy of EUS-FNB was superior to EUS-FNA compared head-to-head (90 vs 52%, and 83 vs 49%, both p<0.001). The adverse event rate of EUS-FNB was low (1.2%). EUS-FNB in 2012-2015 had a positive clinical impact in comparison with the reference cohort demonstrated by less cases referred for an additional diagnostic procedure, 12/83 (14%) vs 39/73 (53%), p<0.001, and fewer unwarranted resections in cases subjected to surgery, 3/48 (6%) vs 12/35 (34%), p=0.001.EUS-FNB with a reverse bevel needle is safe and superior to EUS-FNA in providing a conclusive diagnosis of subepithelial lesions. This biopsy sampling approach facilitates a rational clinical management and accurate treatment.
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| 14. |
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| 15. |
- Janson, Per-Olof, 1940, et al.
(författare)
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Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6.
- 1998
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Ingår i: Clinical endocrinology. - 0300-0664. ; 48:2, s. 243-50
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Tidskriftsartikel (refereegranskat)abstract
- A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500-1800 nmol/l) without diurnal variation. Plasma ACTH levels (200-250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600-1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80-90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.
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| 16. |
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| 17. |
- Khorram-Manesh, Amir, 1958, et al.
(författare)
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Long-term outcome of a large series of patients surgically treated for pheochromocytoma
- 2005
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Ingår i: Journal of internal medicine. - 0954-6820. ; 258:1, s. 55-66
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To analyse the morbidity, mortality and long-term outcome in a consecutive series of surgically treated patients with pheochromocytoma (PC), or paraganglioma (PG), from the western region of Sweden between 1950 and 1997. PATIENTS: All patients (n = 121) who had been hospitalized and treated for PC/PG over 47 years. DESIGN: Retrospective review of patients with PC/PG regarding presenting symptoms, tumour characteristics, clinical management and long-term outcome after treatment. SETTING: One referral centre for all patients from the western region of Sweden. RESULTS: During an observation of 15 +/- 6 years, 42 patients died vs. 23.6 expected in the general population (P < 0.001). There was no intra- or post-operative mortality. Four patients with sporadic disease died of malignant PC and six with hereditary disease of associated neuroectodermal tumours. Five patients died of other malignancies, 20 of cardiovascular disease and seven of other causes. Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed risk factor for death (P = 0.02). At diagnosis 85% of the patients were hypertensive; one year after surgery more than half were still hypertensive. However, pre- and post-operative hypertension did not influence the risk for death versus controls. CONCLUSION: Pheochromocytoma/PG can be safely treated by surgery. Death of malignant PC/PG was unusual, but the patients as a group had an increased risk of death. We recommend life-long follow-up of patients treated for PC/PG with screening for recurrent tumour in sporadic cases and for associated tumours in hereditary cases. This strategy would also be helpful in diagnosing cardiovascular disease at an early stage.
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| 18. |
- Lindskog, Stefan, et al.
(författare)
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Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618
- 2004
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 91:6, s. 713-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Multiple endocrine neoplasia type 2A (MEN2A) is caused by missense mutations in the RET proto-oncogene on chromosome 10. This paper reports the phenotypic expression of a family with MEN2A, in which serine substitutes for cysteine at codon 618 in exon 10 of the RET gene. It was first claimed that medullary thyroid cancer (MTC) with this rare mutation led to mild disease; this has recently been updated to intermediate-high risk, based on stratified genetic information. METHODS: The family was mapped over six generations. In 1971 family members were invited to join a screening programme. Genetic testing was started in 1994. RESULTS: Twenty-two individuals with MTC were identified, 16 by the screening programme. One screened patient had a phaeochromocytoma and four had hyperparathyroidism. At surgery for MTC 12 patients had local tumour metastases and two young patients also had liver metastases. No screened patient died from MTC during a mean observation time of 19 years. Six other family members were diagnosed with MTC by signs and symptoms, five of whom died from MTC. CONCLUSION: Because of the great interindividual differences in tumour aggressiveness within the family it is impossible to predict whether an individual gene carrier will have an aggressive MTC or not. This unpredictability is an additional argument, besides those obtained in stratified genetic studies, for operating on gene carriers at young age.
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| 19. |
- Lönnroth, Christina, 1946, et al.
(författare)
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Survival and erythropoietin receptor protein in tumours from patients randomly treated with rhEPO for palliative care.
- 2008
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Ingår i: Medical oncology (Northwood, London, England). - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 25:1, s. 22-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recombinant erythropoietin (rhEPOalpha) corrects anaemia, improves physical functioning and quality of life in cancer patients. However, published reports have suggested risks for tumour stimulation by provision EPO to patients with remaining tumour cells perhaps related to the presence of EPO receptor protein in tumour tissue. Therefore, the aim of the present study was to exclude a possibility that cancer patients who respond favourably to EPO treatment have mainly tumours with low EPO receptor protein expression. METHODS: Tumour tissue was evaluated in 87 patients out of 108 randomly allocated for treatment with rhEPOalpha (n = 50) versus controls (n = 58). Tumour cell proliferation (Ki-67 index) and EPO receptor protein expression were evaluated by immunohistochemistry. RESULTS: EPO treatment varied between 2 and 35 months, in doses between 10,000 and 40,000 Units/week. Ki-67 index did not differ between study and control patients before EPO treatment. Tumour tissue erythropoietin receptor protein was also similar between treated and untreated patients. Around 40% of tumour cells contained EPO receptors. Survival did not differ among EPO treated and control patients analysed as intention to treat, while survival was significantly improved in EPO treated patients per protocol treatment (P < 0.05). Ki-67 index and tumour tissue erythropoietin receptor protein did not predict survival, which systemic inflammation (ESR) did (P < 0.02). CONCLUSIONS: Our results support that reported risk to accelerate disease progression by EPO treatment in palliative care is not justified in patients with solid, gastrointestinal cancer despite tumour presence of EPO receptor protein.
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| 20. |
- Nilsson, Bengt E, 1949, et al.
(författare)
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Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST)
- 2007
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 96:11, s. 1656-8
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Tidskriftsartikel (refereegranskat)abstract
- Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.
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| 21. |
- Nilsson, Bengt E, 1949, et al.
(författare)
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Treatment of gastrointestinal stromal tumours: imatinib, sunitinib -- and then?
- 2009
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Ingår i: Expert opinion on investigational drugs. - : Informa Healthcare. - 1744-7658 .- 1354-3784. ; 18:4, s. 457-68
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Tidskriftsartikel (refereegranskat)abstract
- With the discovery of gain-of-function mutations of KIT in a majority of gastrointestinal stromal tumours (GIST) and access to the tailored tyrosine kinase inhibitor (TKI) imatinib, a new era in cancer therapy started. The drug caused marked tumour responses in most patients with advanced GISTs, but could also be used in an adjuvant setting after radical surgery or as downstaging treatment before intentionally curative surgery. With prolonged treatment imatinib resistance can develop, most likely due to secondary KIT mutations. In this situation the second-line TKI sunitinib is well suited to patients with KIT exon 9 mutations, or for patients without KIT/PDGFRA mutations (wild-type GIST). New treatment is required to treat imatinib or sunitinib resistance. New-generation TKIs have broader target profiles and increased activity against certain targets; but also new principles have been proposed, for example dose escalation, inhibition of downstream signalling molecules, HSP90 chaperon inhibition, transcriptional repression, combination with chemotherapy or receptor-mediated therapy of highly expressed cell surface receptors. Targeting of cancer stem cells may be another option.
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| 22. |
- Nyberg, Jenny, 1976, et al.
(författare)
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Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation.
- 2005
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - : Society for Neuroscience. - 1529-2401. ; 25:7, s. 1816-25
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal dentate gyrus (DG) is an area of active proliferation and neurogenesis within the adult brain. The molecular events controlling adult cell genesis in the hippocampus essentially remain unknown. It has been reported previously that adult male and female rats from the strains Sprague Dawley (SD) and spontaneously hypertensive (SHR) have a marked difference in proliferation rates of cells in the hippocampal DG. To exploit this natural variability and identify potential regulators of cell genesis in the hippocampus, hippocampal gene expression from male SHR as well as male and female SD rats was analyzed using a cDNA array strategy. Hippocampal expression of the gene-encoding glucose-dependent insulinotropic polypeptide (GIP) varied strongly in parallel with cell-proliferation rates in the adult rat DG. Moreover, robust GIP immunoreactivity could be detected in the DG. The GIP receptor is expressed by cultured adult hippocampal progenitors and throughout the granule cell layer of the DG, including progenitor cells. Thus, these cells have the ability to respond to GIP. Indeed, exogenously delivered GIP induced proliferation of adult-derived hippocampal progenitors in vivo as well as in vitro, and adult GIP receptor knock-out mice exhibit a significantly lower number of newborn cells in the hippocampal DG compared with wild-type mice. This investigation demonstrates the presence of GIP in the brain for the first time and provides evidence for a regulatory function for GIP in progenitor cell proliferation.
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| 23. |
- Størsrud, Stine, 1972, et al.
(författare)
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Adult coeliac patients do tolerate large amounts of oats.
- 2003
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Ingår i: European journal of clinical nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 57:1, s. 163-9
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate whether adult patients with coeliac disease in remission could include large amounts of oats in their daily gluten-free diet for an extended period of time without adverse effects. DESIGN, SUBJECTS AND METHODS: Twenty adult coeliac patients in remission included large amounts of uncontaminated rolled oats in their daily diet for a prolonged period. The examinations, performed four times during the study period, included small bowel endoscopy with biopsies, blood samples (nutritional status, serological analysis), height and body weight, gastrointestinal symptoms and dietary records. Gastrointestinal symptoms and diet were also investigated through unannounced telephone interviews once a month during the study period.
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| 24. |
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| 25. |
- Wängberg, Bo, 1953, et al.
(författare)
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The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane.
- 2010
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Ingår i: Endocrine-related cancer. - 1479-6821. ; 17:1, s. 265-72
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Tidskriftsartikel (refereegranskat)abstract
- Adrenocortical carcinoma (ACC) is a rare tumour disease with sinister prognosis also after attempts to radical surgery; better prognosis is seen for low-stage tumours. Adjuvant treatment with the adrenolytic drug mitotane has been attempted, but not proven to prevent from recurrence. The drug may offer survival advantage in case of recurrence. The aim of this single-centre study (1979-2007) of 43 consecutive patients was to evaluate the long-term survival after active surgical treatment combined with monitored mitotane (to reduce side effects of the drug). The series is unique, since all patients were offered a period of mitotane as adjuvant or palliative treatment; six patients refused mitotane. Despite a high proportion of high-stage tumours (67%), the complete resection rate was high (77%). The disease-specific 5-year survival was high (64.1%); very high for patients with low-stage tumours without evident relation to mitotane levels. Patients with high-stage tumours had a clear survival advantage with mitotane levels above a threshold of 14 mg/l in serum. The hazard ratio for patients with high mitotane levels versus all patients indicates a significant effect of the drug. The results indicate that adjuvant mitotane may be the standard of care for patients with high-stage ACC after complete resection.
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