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2.
  • Aljabery, Firas, et al. (författare)
  • M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer
  • 2018
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 36:4
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundTumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer(UBC) is controversial.MethodsWe prospectively studied 103 patients with stage pT1–T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome.ResultsThe mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02).ConclusionsM2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact.
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3.
  • Aljabery, Firas, et al. (författare)
  • Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer : a prospective clinical study.
  • 2017
  • Ingår i: BJU International. - : Wiley-Blackwell Publishing Inc.. - 1464-4096 .- 1464-410X. ; 120:3, s. 329-336
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.
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4.
  • Aljabery, Firas (författare)
  • Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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5.
  • Aljabery, Firas, et al. (författare)
  • The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer
  • 2018
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 36:12, s. 530.e7-530.e18
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy.Materials and methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival.Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03).Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.
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6.
  • Anlauf, Martin, et al. (författare)
  • Primary lymph node Gastrinoma or occult duodenal microgastrinoma with lymph node Metastases in a MEN1 patient - The need for a systematic search for the primary tumor
  • 2008
  • Ingår i: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 32:7, s. 1101-1105
  • Tidskriftsartikel (refereegranskat)abstract
    • Gastrinoma tissue has been found frequently in lymph nodes located near the duodenum without a known primary tumor. Therefore, it has been suggested that a primary lymph node gastrinoma exists. We report on a 38-year-old woman suffering from multiple endocrine neoplasia type 1 (MEN 1) confirmed by menin gene mutation analysis. MEN1 disease started with primary hyperparathyroidism followed by Cushing disease, the detection of tumors of the pituitary, adrenal cortex, and the pancreas and also an elevated serum gastrin level. An octreotide scan revealed 4 tumors in the upper abdomen. A selective arterial calcium stimulation test located the source of the hypergastrinemia to the area of the gastroduodenal and the superior mesenteric arteries. Total pancreatoduodenectomy was performed and conventional histopathologic examination revealed a well-differentiated cystic neuroendocrine tumor of the pancreas expressing glucagon and accompanied by several microadenomas. In addition, 3 suprapancreatic lymph nodes with gastrin-positive endocrine tissue were found. None of the pancreatic microadenomas expressed gastrin and no duodenal endocrine tumor was found despite careful macroscopic examination. Only after complete embedding of the duodenal and pancreatic tissue in 65 paraffin blocks, 2 microgastrinomas (0.45 and 0.8 mm in diameter) were identified in the duodenum. It is concluded that duodenal gastrinomas that give rise to lymph node metastases may be so tiny that they are easily overlooked in a routine examination and that systematic tissue monitoring is required to identify them.
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7.
  • Anlauf, Martin, et al. (författare)
  • Sporadic versus hereditary gastrinomas of the duodenum and pancreas : distinct clinico-pathological and epidemiological features.
  • 2006
  • Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 12:34, s. 5440-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.
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8.
  • Arnesen, Thomas, et al. (författare)
  • Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway
  • 2013
  • Ingår i: Langenbeck's archives of surgery (Print). - : Springer Verlag (Germany). - 1435-2443 .- 1435-2451. ; 398:6, s. 869-874
  • Tidskriftsartikel (refereegranskat)abstract
    • Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway. less thanbrgreater than less thanbrgreater thanTwenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status. less thanbrgreater than less thanbrgreater thanTen out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type. less thanbrgreater than less thanbrgreater thanKCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).
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9.
  • Bausch, Birke, et al. (författare)
  • Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
  • 2017
  • Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 3:9, s. 1204-1212
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.
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10.
  • Bausch, Birke, et al. (författare)
  • Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
  • 2007
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2784-92
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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11.
  • Beka, Ervin, et al. (författare)
  • Hemithyroidectomy, does the indication influence the outcome?
  • 2024
  • Ingår i: Langenbeck's archives of surgery (Print). - : SPRINGER. - 1435-2443 .- 1435-2451. ; 409:1
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeHemithyroidectomies are mainly performed for two indications, either therapeutically to relieve compression symptoms or diagnostically for suspicious nodule(s). In case of the latter, one could consider the approach to be rather extensive since the majority of patients have no symptoms and will have benign disease. The aim of this study is to investigate the complication rates of diagnostic hemithyroidectomy and to compare it with the complication rates of compressive symptoms hemithyroidectomy.MethodsData from patients who had undergone hemithyroidectomy either for compression symptoms or for excluding malignancy were extracted from a well-established Scandinavian quality register (SQRTPA). The following complications were analyzed: bleedings, wound infections, and paresis of the recurrent laryngeal nerve (RLN). Risk factors for these complications were examined by univariable and multivariable logistic regression.ResultsA total of 9677 patients were included, 3871 (40%) underwent surgery to exclude malignancy and 5806 (60%) due to compression symptoms. In the multivariable analysis, the totally excised thyroid weight was an independent risk factor for bleeding. Permanent (6-12 months after the operation) RLN paresis were less common in the excluding malignancy group (p = 0.03).ConclusionA range of factors interfere and contribute to bleeding, wound infections, and RLN paresis after hemithyroidectomy. In this observational study based on a Scandinavian quality register, the indication "excluding malignancy" for hemithyroidectomy is associated with less permanent RLN paresis than the indication "compression symptoms." Thus, patients undergoing diagnostic hemithyroidectomy can be reassured that this procedure is a safe surgical procedure and does not entail an unjustified risk.
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12.
  • Beka, Ervin, et al. (författare)
  • Patient Experiences of Symptoms and Coping Strategies in the Early Postoperative Phase Following Hemithyroidectomy: A Qualitative Interview Study
  • 2024
  • Ingår i: JOURNAL OF PATIENT EXPERIENCE. - : SAGE PUBLICATIONS INC. - 2374-3743. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to explore patients' early experiences of symptoms after hemithyroidectomy and how these symptoms influenced their daily lives. An inductive explorative qualitative research design was performed. Sixteen patients from two hospitals were interviewed between two-three weeks after the surgery. All the patients experienced compression symptoms before the surgery. The study was analyzed with conventional manifest content analysis. The inductive analysis yielded two main categories and one subcategory. The two main categories were: Early postoperative symptoms that caused disadvantage in daily life and Early postoperative symptoms and coping strategies. The subcategory was: Early postoperative experiences of concerns about the future. Key points: 1. Patients experienced early postoperative symptoms that affected their lives in multiple levels, making them develop coping strategies and awaking concerns about remaining symptoms in the future. 2. The effect of hemithyroidectomy influenced patients' daily life in the early postoperative phase considerably. 3. The study shows that tailored preoperative patient information is important. The findings may guide professionals to tailored preoperative information to optimize the care for this patient group.
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13.
  • Beka, Ervin, et al. (författare)
  • Voice Changes Without Laryngeal Nerve Alterations After Thyroidectomy: The Need For Prospective Trials - A Review Study
  • 2024
  • Ingår i: Journal of Voice. - : MOSBY-ELSEVIER. - 0892-1997 .- 1873-4588. ; 38:1, s. 231-238
  • Forskningsöversikt (refereegranskat)abstract
    • Background. Thyroidectomy is a commonly performed surgical procedure that is offered for different thyroid pathologies. The most frequent complication after total thyroidectomy is transient or permanent hypoparathyroidism followed by transient or permanent recurrent laryngeal nerve palsy. Patients may experience voice impairment despite intact laryngeal nerve function. These patients are of special interest because they experience subjective symptoms which are difficult to measure and therefore to treat. Summary. The Voice Handicap Index (VHI) and VHI-10 are the most commonly used subjective questionnaires. Their results correlate with objective findings. Female sex, in particular after menopause, is a dominant factor for developing voice impairment after thyroidectomy. The extent of neck surgery and the weight and volume of the removed thyroid correlates directly with both objective and subjective voice impairment after surgery. Videolaryngostroboscopy should be considered to examine vocal cord pathologies in this patient group. Surprisingly, there are no studies showing that speech and voice therapy are beneficial for patients with voice alterations but with intact laryngeal nerves. Conclusions. While recurrent laryngeal nerve (RLN) paralysis can be evaluated by objective exams postoperatively, we are still left with the issue of possible partial or complete external branch of superior laryngeal nerve (EBSLN) injury. It is therefore quite difficult to segregate neural (RLN and EBSLN) and non -neural voice change populations, regardless of the method of literature evaluation. Perhaps patients' perspectives on how they experience voice functionality should play a superior role in deciding which patients should be investigated further with laryngoscopy, acoustic or perceptual analysis, and which patients should be offered treatment.
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14.
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15.
  • Bengtsson, Daniel, 1975- (författare)
  • Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD. Main conclusions of the thesis:Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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16.
  • Benn, Diana E, et al. (författare)
  • Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.
  • 2006
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:3, s. 827-36
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.
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17.
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18.
  • Brauckhoff, M., et al. (författare)
  • Limitations of intraoperative adrenal remnant volume measurement in patients undergoing subtotal adrenalectomy
  • 2008
  • Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 32:5, s. 863-872
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Recent studies have shown that a minimum of approximately one-third of one normal adrenal gland is required for sufficient adrenocortical stress capacity. Correlation between intraoperative measurement, determination of remnant size by computed tomography (CT), and adrenocortical stress capacity has not been examined so far. Methods: Twenty-two patients with familial pheochromocytoma (n = 13), sporadic pheochromocytoma (n = 3), and adrenocortical tumors (n = 6) who underwent unilateral or bilateral subtotal adrenalectomy (STAE, 28 adrenal remnants) were prospectively studied. Patients were examined in a multi-slice CT to determine residual adrenal tissue and by ACTH test 4 days and 3 months postoperatively. Results: There was a slight significant correlation between intraoperative and CT calculated volumes (r = 0.77, p < 0.001). However, volumes assessed by CT were almost doubled compared with intraoperative determination (p < 0.001). Although recovery of adrenal function could be observed, no significant changes of remnant volumes could be detected within 3 months. In patients with familial pheochromocytoma, there was a significant correlation between residual adrenal volume and stimulated cortisol levels (P < 0.001). A distinct minimum of adrenal volume for intact adrenocortical stress capacity could not be exactly determined, however, in one patient with only 10% residual adrenal tissue intact stress capacity was found. Conclusions: Residual adrenal tissue of approximately 10-15% offers intact stress capacity. However, an exact determination of the size of an adrenal remnant after STAE has limitations. CT gives larger volumes compared with intraoperative determination. For calculation of a volume-function correlation of residual adrenal tissue, in clinical practice, the determination of relative adrenal residual volume is acceptable. © 2008 Société Internationale de Chirurgie.
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19.
  • Brauckhoff, Michael, et al. (författare)
  • Long-term results and functional outcome after cervical evisceration in patients with thyroid cancer.
  • 2006
  • Ingår i: Surgery. - : Elsevier BV. - 0039-6060 .- 1532-7361. ; 140:6, s. 953-9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Surgical strategy in patients with thyroid cancer (TC) infiltrating the aerodigestive system is controversial. This study was undertaken to examine the long-term results of cervical evisceration (CE).PATIENTS AND METHODS: Since 1995, 14 consecutive patients with advanced TC underwent total laryngectomy (LE, n = 6) or esophagolaryngectomy (ELR, n = 8). Patients with unusual thyroid neoplasms or metastases to the thyroid (n = 3) were excluded. For esophageal reconstruction, free jejunal grafts (n = 6) and gastric tubes (n = 2) were used.RESULTS: Procedure-related morbidity and mortality were 42% and 14%, respectively. ELR was associated with a significant higher frequency of complications and reoperations compared with LE. Twelve-month and 30-month survival rates were 73% and 55%, respectively; 85% of the patients were satisfied with the surgical results. There were no long-term problems concerning food intake in the ELR patients. Two ELR patients were able to learn a substitutive voice.CONCLUSIONS: Cervical evisceration in patients with TC is associated with significant perioperative morbidity and mortality requiring careful patient selection. Regarding long-term survival, local tumor control, and patient's satisfaction, however, CE should be taken into account in suitable patients with advanced TC.
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20.
  • Brauckhoff, Michael, et al. (författare)
  • Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B : An exploratory analysis
  • 2008
  • Ingår i: SURGERY. - : Elsevier BV. - 0039-6060. ; 144:6, s. 1044-1050
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene. DNA-based screening for RET germline mutations is rarely useful for early diagnosis, which thus is contingent on the clinical ascertainment of MEN 2B-specifitc symptoms as soon as they emerge. Little information exists about the presence of these symptoms in infancy.Methods. Detailed information was gathered regarding the development of MEN 2B-associated symptoms from the parents of 25 M918T RET carriers and 50 age- and sex-matched, controls with the use of a disease-specific questionnaire.Results. Until the end of the study, at a median age of 16 2 (range, 0.5-34.9 years), all 25 M918T RET carriers had developed medullary thyroid cancer. By that time, 96%, 91%, 71%, 75%, and 28% Of carriers displayed oral manifestations, ocular abnormalities, intestinal symptoms, musculoskeletal malformations, and pheochromocytoma, respectively. During the first year of life, fewer than 20% of carriers were found to express the typical MEN 2B phenotype, whereas 86% and 61% of these children, but none of the controls, were noted for their inability to cry tears and for constipation.Conclusion. Because the classic MEW 2B phenotype is rare during the first year of life, more emphasis should be placed on the more subtle features of the syndrome. Additional studies are needed to validate the usefulness of the symptoms "inability to cry" and "constipation" for earlier diagnosis of MEAT 2B.
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21.
  • Carlander, Johan, 1971- (författare)
  • Energy based surgical instruments : With particular focus on collateral thermal injury
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Iatrogenic post-operative nerve dysfunction is a significant problem in many areas of surgery and can be caused by collateral thermal injury from activation of energy based surgical devices (EBD).The aims of this thesis were to: create an animal model in order to compare mono- and bipolar electrosurgery (ES) and an ultrasonic dissection (UD) with regard to collateral thermal nerve injury, and with data of a national multicenter register to study the use of EBD and their potential effects on operation time and complication rates in thyroid surgery.urgical devices (EBD).Material and Methods: The biceps femoris muscle of 104 anesthetized rats was cut in a standard manner adjacent to the sciatic nerve using clinical relevant settings of mono- and bipolar ES and UD. The sciatic nerve was stimulated supramaximally and the electromyographic (EMG) potential recorded before and after each experiment. Nerve dysfunction was defined as > 10% reduction of the evoked EMG potential. In Paper II and III temperature was measured before, during and after instrument activation. The sciatic nerves were coded and examined blinded with light (LM) and electron microscopy (EM). Advanced temperature measurements were conducted in Paper II and III. In Paper IV, the use of EBD was specifically registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) during one year and 1297 patients were included. Operation time, recurrent laryngeal nerve (RLN) injury, post-operative hypoparathyroidism and the use of topical haemostatic agents were compared between bipolar ES, electric vessel sealing (EVS) and UD. Clamp and Tie technique (C-A-T) being without thermal risk constituted the control group.Results: In Paper I the EMG potential was significantly more frequent reduced in the monopolar and bipolar ES group compared to the UD group and LM showed significantly less nerve damage in the UD group. In Paper II exact temperature measurements was possible with thermoelectric micros sensors and the thermal dose was significantly less and with less variation for the UD compared to the bipolar ES. Similar to the Paper I the EMG potential was significantly more frequent reduced in the ES group. Moderate and severe morphological damage was significantly less common in the UD group compared to monopolar ES. We found no statistical correlation between the highest temperatures/doses and the degree of morphological damage or functional loss. In Paper III the temperature increase was significantly less and with shorter duration in the UD group, compared to bipolar ES. LM and EM demonstrated loss of density in the myelin sheet only in a small number of nerves in all groups after instrument activation 1 mm from the nerve.In Paper IV, operation time was significantly shorter in the UD group and significantly longer in the EVS and bipolar ES group, compared to C-A-T. Postoperative hypoparathyroidism with need for Calcium treatment at discharge and at 6 weeks was significantly higher with ES instruments compared to UD. The incidence of reported RLN injury was 2.5% at 6 weeks postoperatively without statistical differences between the groups. Topical haemostatic agents were more frequently used in the EBD groups compared to C-A-T.Conclusion: The experimental Papers (I-III) demonstrated a lower risk of adverse collateral thermal nerve injury with activation of the mechanical UD technique compared to ES techniques. In the nationwide multicenter register Paper (IV), the use of UD shortened end EVS increased operation time compared to the low cost C-A-T. The UD instruments had a lower risk of hypoparathyroidism than electrosurgery.
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22.
  • Carlander, Johan, et al. (författare)
  • Heat Production, Nerve Function, and Morphology following Nerve Close Dissection with Surgical Instruments
  • 2012
  • Ingår i: World Journal of Surgery. - : Springer Verlag (Germany). - 0364-2313 .- 1432-2323. ; 36:6, s. 1361-1367
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the present study was to compare an ultrasonically activated instrument (US), monopolar electrosurgery, and bipolar electrosurgery (ES) with respect to heat production, nerve function, and nerve morphology following in vivo application. less thanbrgreater than less thanbrgreater thanThe biceps femoris muscle of anesthetized rats was cut in a standardized manner longitudinally 1 mm adjacent to the sciatic nerve using US shears, a monopolar ES knife, or a bipolar ES scissors. Activation time and temperature were recorded continuously within 1-4 mm of the activation site ipsilateral and contralateral to the nerve with two thermoelectric microsensors. Temperature rise and time delay of reaching the temperature maximum, as an expression of heat spread within tissue, maximum temperature, and thermal dose (equivalent time of exposure at 43A degrees C) were measured and calculated. A total of 49 functional experiments were conducted. The electromyographic (EMG) potential was recorded distally. Nerve dysfunction was defined as more than 10% loss of the evoked EMG amplitude. Forty-eight nerves were coded and submitted to blind histopathological examination, and morphological damage was graded on a 4-grade scale. less thanbrgreater than less thanbrgreater thanThe maximum temperature elevation and the thermal dose were significantly higher for the bipolar ES compared with the US instrument ( = 0.024, = 0.049), and with much less variation of results for the US instrument. The monopolar ES maximum temperature and thermal dose were lower, but a very large variation occurred, probably as a result of more random electrical spread to the ground electrode and muscle motion artifacts. Functional loss was least common in the US group-without being significant-compared to bipolar and monopolar ES. Moderate and severe morphological damage was significantly less common in the US group than in the monopolar ES group ( = 0.041). We found no statistically significant correlation between the highest temperatures and the degree of morphological damage or functional loss less thanbrgreater than less thanbrgreater thanThe temperature elevation depends strongly on the distance to the activated instrument. The bipolar ES scissors generates a higher maximum temperature and thermal dose with a greater variation in than the US. Functional loss and severe morphological damage were uncommon in all groups.
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23.
  • Carlander, Johan, et al. (författare)
  • Risk of Complications with Energy-Based Surgical Devices in Thyroid Surgery : A National Multicenter Register Study
  • 2016
  • Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 40:1, s. 117-123
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundEnergy-based surgical devices (EBD) combining cutting and coagulation are increasingly used in thyroid surgery. However, there is a lack of information about potential benefits and risk of complications outside controlled trials. The aims of this national multicenter register study were to describe the use of EDB, their potential effect on complication rates, and on operation time.Materials and methodsThe Scandinavian Quality Register for Thyroid and Parathyroid surgery includes 35 surgical units in Sweden and covered 88 % of the thyroid procedures performed during 2008–2009. The use of the EBD was specifically registered for 12 months, and 1297 patients were included. Surgically related complications and operation time were evaluated. The clamp-and-tie group (C-A-T) constituted the control group for comparison with procedures where EBD was used.ResultsThe thyroid procedures performed included C-A-T (16.6 %), bipolar electrosurgery (ES: 56.5 %), electronic vessel sealing (EVS: 12.2 %), and ultrasonic dissection (UD: 14.5 %). Mean operative time was longer with EVS (p < 0.001) and shorter with UD (p < 0.05) than in the other groups. The bipolar ES group and the EVS group had higher incidence of calcium treatment at discharge and after 6 weeks than the UD group. No significant difference in nerve injury was found between the groups. There was a significant more frequent use of topical hemostatic agents in the EBD group compared to C-A-T.ConclusionIn this national multicenter study, the use of UD shortened and EVS increased operating time. There was a higher risk of calcium treatment at discharge and after 6 weeks after use of EVS and bipolar ES than after UD use. There was a significant more frequent use of topical hemostatic agents in the EBD groups compared to C-A-T.
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24.
  • Christofer Juhlin, C., et al. (författare)
  • Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
  • 2015
  • Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
  • Tidskriftsartikel (refereegranskat)abstract
    • As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
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25.
  • Dammann, R., et al. (författare)
  • Frequent promoter methylation of tumor-related genes in sporadic and men2-associated pheochromocytomas
  • 2005
  • Ingår i: Experimental and clinical endocrinology & diabetes. - : Georg Thieme Verlag KG. - 0947-7349 .- 1439-3646. ; 113:1, s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypermethylation of CpG island promoters is associated with transcriptional inactivation of tumor suppressor genes in neoplasia. Inactivation of p16 and Pten was related to the development of pheochromocytomas. In this report, we investigated the methylation status of the p16INK4a cell cycle inhibitor gene and other prominent tumor-related genes ( PTEN, RASSF1 A, CDH1, MSH2, MLH1, VHL, and TIMP3) in sporadic and multiple endocrine neoplasia type 2 (MEN2) pheochromocytomas by methylation-specific PCR. Hypermethylation was detected in 48 % of pheochromocytomas for RASSF1 A, 24 % for p16, 36 % for MSH2, 16 % for CDH1, and 8 % for PTEN. No VHL, MLH1, and TIMP3 methylation was observed. Interestingly, the frequency of p16 inactivation in familial tumors was higher (5 out of 12, 42 %) than in sporadic tumors (1 out of 13, 8 %; p = 0.047) and RASSF1 A inactivation was more common in the hereditary tumors (58 %) compared to the sporadic tumors (38 %). Combined methylation of RASSF1 A and p16 was found only in MEN2-related pheochromocytomas. Thus, a subset of hereditary pheochromocytomas displays preferential methylation of p16 and RASSF1 A.
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26.
  • Dutta, Ravi Kumar, et al. (författare)
  • A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma
  • 2019
  • Ingår i: European Journal of Endocrinology. - : BIOSCIENTIFICA LTD. - 0804-4643 .- 1479-683X. ; 181:5, s. K37-K41
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs). Description: Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (CIC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured. Conclusion: In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.
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27.
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28.
  • Dutta, Ravi Kumar, 1983- (författare)
  • Genetic and molecular alterations in aldosterone producing adenomas
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Aldosterone producing tumors (APA, also known as Conn tumors) are adrenal tumors that overproduce aldosterone, a hormone that regulates the sodium levels in blood and contributes to blood pressure (BP) regulation. Excessive production of aldosterone causes hypertension and approximately 5-15% of hypertensive patients have hyperaldosteronism, known as primary aldosteronism (PA). Major causes of PA are bilateral adrenal hyperplasia (BAH) or aldosterone producing adenoma (APA) and about 30% of PA patients have APAs. In most cases, the disease is unilateral, in rare case bilateral. Patients with APA are often detected when they have elevated blood pressure (BP>160/100mmHg) or when BP cannot be controlled with drugs. Surgery dramatically normalizes or lowers BP in patients with APA.In this thesis, we first explored the mutation frequency in susceptibility genes in sporadic APAs. About 60% of APAs displayed complementary mutations in the KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNAID and CLCN2 genes (Paper I, II & III). Copy number variation analysis of 35 APAs identified amplification of chromosome 10q24.31 in two tumors, where CALHM1-3- genes encoding for potential calcium ion channels are located. Only CALHM2 is expressed in adrenals and sequencing of CALHM2 revealed three different heterozygous sequence variants; c.341_42delCT (CALHM2P114Rfs*12), c.286G>A (CALHM2A96T) and c.580G>A (CALHM2V194M) in 5 APAs. CALHM2 is expressed in the mitochondrial membranes and Ca2+ imaging revealed that CALHM2 has selection of another ion rather than Ca2+. The genetic variant CALHM2V194M converts CALHM2 into a non-selective channel and results in higher Ca2+ conductance in mitochondria. We further found that loss of CALHM2 function upregulates REELIN/LRP8 signaling activating β-catenin dependent transcription of target genes (Paper II). In Paper IV, we investigated Scandinavian APA cases (n=35) and Swedish controls (n=60) for GWAS and discovered a susceptibility locus on chromosome Xq13.3 in a 4 Mb region to be significantly associated with APAs. Significance level was still same after genotyping the sentinel SNP rs2224095 in a replication cohort of APAs (n=52) and controls (n=740). Sequencing of an adjacent gene of the sentinel SNP, MAGEE1, identified a rare variant in one APA, which is complementary to other mutations in our primary cohort. In Summary, our studies have increased the knowledge of molecular genetic events in APAs. The results may contribute to find future non-surgical treatments for APAs.  
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29.
  • Dutta, Ravi Kumar, et al. (författare)
  • Genetics of primary hyperaldosteronism
  • 2016
  • Ingår i: Endocrine-Related Cancer. - : BIOSCIENTIFICA LTD. - 1351-0088 .- 1479-6821. ; 23:10, s. R437-R454
  • Forskningsöversikt (refereegranskat)abstract
    • Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.
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30.
  • Dutta, Ravi Kumar, et al. (författare)
  • X-chromosome variants are associated with aldosterone producing adenomas
  • 2021
  • Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n=35) and Swedish controls (n=60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR=7.9, 95% CI=2.8-22.4, P=1x10(-7)) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n=83) and a control group (n=740) revealed persistently strong significance (OR=6.1, 95% CI=3.5-10.6, p<0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.
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31.
  • Eneholm, Johan, et al. (författare)
  • A retrospective study comparing minimally invasive versus open surgical resection of small intestinal neuroendocrine neoplasms at a tertiary referral center
  • 2024
  • Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 50:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Neuroendocrine neoplasms (SI-NEN) are the commonest malignancies of the small intestine. Traditionally, surgical treatment for SI-NEN has been open surgery.Purpose: The purpose of this study was to compare minimally invasive surgery (MIS) with the traditional open surgery approach for treating SI-NEN in a Swedish population.Methods: Patients with histopathological confirmed SI-NEN who underwent open surgery or MIS resection within 2009-2021 were extracted from the hospital's medical records.Results: 65 patients were included in this study, with 35 (54 %) undergoing MIS and 30 (46 %) undergoing open surgery. We found no statistically significant difference (p = 0.173) in the frequency of R0 resections (MIS group n = 34 (97 %), open surgery group n = 26 (87 %)). Nor was there a significant difference (p = 0.101) when comparing the median number of resected lymph nodes (MIS group n = 13.5, open surgery group n = 10). A post-operative paralytic ileus was more often reported (p = 0.052) in the MIS group (n = 9, 26 %) compared to the open surgery group (n = 2, 7 %). In light of this, the days of hospital stay did not differ significantly (MIS group median = 6, IQR (5-8), open surgery group median = 6, IQR (5-9)). The Kaplan-Meier analysis did not reveal differences concerning cancer-related deaths (p = 0.109).Conclusion: The results from this study support that a MIS approach for the treatment of SI-NEN may not be inferior to open surgery. The higher number of resected lymph nodes and R0 resections may even speak in favor for a MIS approach. More studies with a longer time of observation are needed to further support this conclusion.
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32.
  • Franz, F, et al. (författare)
  • The Transcriptional Regulation of FOXO Genes in Thyrocytes.
  • 2016
  • Ingår i: Hormone and Metabolic Research. - Stuttgart : Georg Thieme Verlag. - 0018-5043 .- 1439-4286. ; 48:9, s. 601-6
  • Tidskriftsartikel (refereegranskat)abstract
    • FOXO transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO isoforms in thyroid epithelial cells. mRNA expression of FOXO isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally, mRNA expression levels of FOXO isoforms were determined in human epithelial thyroid tumours. Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3 mRNA levels were significantly downregulated in papillary thyroid carcinoma when compared to normal tissues. In contrast, follicular thyroid carcinomas showed significant upregulation of FOXO4 mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced thyroid cancers.
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33.
  • Georgitsi, Marianthi, et al. (författare)
  • Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.
  • 2007
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:8, s. 3321-5
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.SETTING: The study was conducted at nonprofit academic research and medical centers.PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.
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34.
  • Gill, Anthony J, et al. (författare)
  • Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias.
  • 2006
  • Ingår i: American Journal of Surgical Pathology. - : Ovid Technologies (Wolters Kluwer Health). - 0147-5185 .- 1532-0979. ; 30:9, s. 1140-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Parathyroid carcinoma is notoriously difficult to diagnose with confidence in borderline cases. Commonly there is a long lag time between diagnosis and clinical evidence of malignant behavior even in histopathologically straightforward lesions. There is therefore a need for a novel adjunctive marker to assist in the diagnosis of carcinoma. Parafibromin is the protein encoded by the putative tumor suppressor gene HRPT2. Mutations predicted to inactivate parafibromin were first detected in the germline of patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Subsequently, somatic mutations have been identified in the majority of sporadic carcinomas. We performed immunohistochemistry for parafibromin on 115 parathyroid tissues comprising 4 HPT-JT-related tumors (3 adenomas and 1 carcinoma), 11 sporadic parathyroid carcinomas, 79 sporadic adenomas, 3 multiple endocrine neoplasia 2A-related adenomas, 2 sporadic primary hyperplasias, 2 multiple endocrine neoplasia (MEN)-1-related hyperplasias, 6 secondary hyperplasias, 4 tertiary hyperplasias, and 4 normal parathyroid glands. There was complete absence of nuclear staining in 3 of 4 (75%) HPT-JT-related tumors and 8 of 11 (73%) sporadic parathyroid carcinomas and focal weak staining in 1 of 4 HPT-JT tumors and 2 of 11 sporadic parathyroid carcinomas. Only 1 parathyroid carcinoma exhibited diffuse strong nuclear expression of parafibromin. In contrast, 98 of 100 non-HPT-JT-related benign parathyroids showed diffuse strong nuclear positivity and 2 of 100 showed weak positive staining. We conclude that, in the correct clinical and pathologic context, complete absence of nuclear staining for parafibromin is diagnostic of parathyroid carcinoma or an HPT-JT-related tumor.
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35.
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36.
  • Gimm, Oliver, et al. (författare)
  • Challenges of training in adrenal surgery
  • 2019
  • Ingår i: Gland surgery. - : AME PUBL CO. - 2227-684X .- 2227-8575. ; 8, s. S3-S9
  • Forskningsöversikt (refereegranskat)abstract
    • While adrenal tumors are common, adrenalectomy is rather uncommon. This is one reason for the many challenges regarding the training of adrenal surgery. Here we focus on issues that are most pertinent regarding training of the young surgeons performing adrenalectomy. Due to the very limited literature, what is presented is mainly based on personal experience and/or from the literature published for other surgical operations and subspecialties. The discussed challenges include indications for surgery, surgical approaches and extent, and intraoperative complications. With advances in adrenal surgery, we expect some old challenges to be resolved, and some new challenges to arise. These challenges will be faced in order to continue to help our younger trainee acquire the knowledge and skills to best care for our patients with adrenal diseases.
  •  
37.
  • Gimm, Oliver, et al. (författare)
  • Distinct expression of galectin-3 in pheochromocytomas.
  • 2006
  • Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1073, s. 571-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Unless distant metastases or local invasion are present, the diagnosis of malignant pheochromocytoma is challenging. Hence, biological markers are sought after and we thought to examine galectin-3 in such a role. Four malignant and 24 benign (10 sporadic, 14 hereditary) pheochromocytomas were analyzed for the expression of galectin-3. One malignant pheochromocytoma with distant metastases showed strong and one malignant undifferentiated pheochromocytoma with local invasion showed partly strong cytoplasmic staining. Nine of 10 sporadic and all hereditary benign pheochromocytomas had absent/weak staining. One benign sporadic pheochromocytoma had moderate cytoplasmic staining. The distinct expression in various types of pheochromocytomas is intriguing and requires further investigation.
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38.
  • Gimm, Oliver, et al. (författare)
  • Dual-Energy Computed Tomography Localizes Ectopic Parathyroid Adenoma
  • 2010
  • Ingår i: The Journal of Clinical Endocrinology & Metabolism. - Chevy Chase, MD, United States : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:7, s. 3092-3093
  • Tidskriftsartikel (refereegranskat)abstract
    • Dual-energy computed tomography (DECT) can acquire two datasets showing different attenuation levels allowing collectionof additional information about the elementary chemical compositionof the scanned material. Color can then be assigned accordingto the 80- and 140-kV computed tomography (CT) values to obtaina color-mapped, dual-energy image. DECT has been used extensivelyin our department in postmortem CT with excellent results (1).One of the advantages of DECT is that iodine contrast uptakein soft tissue can be quantified. We were wondering about itsability to localize parathyroid adenomas (PAs).
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39.
  • Gimm, Oliver, et al. (författare)
  • Increased diagnostic sensitivity of palpation-guided thyroid nodule fine-needle aspiration cytology by BRAF V600E-mutation analysis
  • 2021
  • Ingår i: The journal of pathology. Clinical research. - : Wiley-Blackwell. - 2056-4538. ; 7:6, s. 556-564
  • Tidskriftsartikel (refereegranskat)abstract
    • Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and its incidence is increasing. Preoperative diagnosis is warranted in order to avoid two-stage procedures that are associated with additional costs and higher radioactive iodine remnant uptake. In the setting of thyroid cancer, somatic BRAF V600E-mutations are highly specific for PTC and can be analyzed in aspirates from fine-needle aspiration cytology (FNAC). The gold standard to perform FNAC is ultrasound guidance. Here, we analyze whether adding BRAF V600E-mutation analysis could be of value in palpation-guided FNACs. A total of 430 consecutive patients were included. Ultrasound-guided FNACs were performed in 251 patients and 179 patients underwent palpation-guided FNACs. BRAF V600E-mutation analysis was performed using two methods, an allele-specific polymerase chain reaction (PCR) analyzed by capillary gel electrophoresis (PCR/Qiaxcel), and a droplet digital PCR (ddPCR) assay. A total of 80 patients underwent surgery, and histology revealed 25 patients to have PTC. Of the 25 PTCs, 23 (92%) showed a BRAF V600E-mutation. Both mutation analysis methods (PCR/Qiaxcel and ddPCR) produced concordant results. In the ultrasound-guided group, the preoperative diagnostic sensitivity of FNAC using the Bethesda classification alone was very high and additional BRAF V600E-mutation analysis added little to the preoperative diagnostic sensitivity. By contrast, in the palpation-guided group, by adding BRAF V600E-mutation analysis, eight instead of four patients were diagnosed of having PTC. This increase in the diagnostic sensitivity was statistically significant (p < 0.05). The costs per sample were as low as 62 USD (PCR/Qiaxcel and ddPCR) and 35 USD (PCR/Qiaxcel only). Ultrasound-guided FNAC should be aimed for when dealing with thyroid nodules. However, if palpation-guided FNAC cannot be avoided or may be required due to resource utilization, adding BRAF V600E-mutation analysis using the methods described in this study might significantly increase the proportion of preoperatively diagnosed PTCs. The additional costs can be considered very reasonable.
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40.
  • Gimm, Oliver, et al. (författare)
  • Intra-operative quick insulin assay to confirm complete resection of insulinomas guided by selective arterial calcium injection (SACI).
  • 2007
  • Ingår i: Langenbeck's archives of surgery (Print). - : Springer Science and Business Media LLC. - 1435-2443 .- 1435-2451. ; 392:6, s. 679-84
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND AIMS: Insulinomas are rare endocrine disorders. Pre-operatively, conventional imaging techniques often fail to localise the tumor. In addition, due to the lack of quick insulin assays, intra-operative confirmation of complete resection was impossible until recently.MATERIALS AND METHODS: Six patients with biochemical evidence of an insulinoma underwent pre-operative localisation studies and selective arterial calcium injection (SACI). In addition, insulin was measured before surgery and every 10-15 min after resection of the tumor using a quick insulin assay.RESULTS: Pre-operative localisation studies identified the tumor correctly as follows: endosonography: three of four, magnetic resonance imaging: two of four and SACI: six of six. Tumors in the head and body were enucleated while those in the tail were resected (n = 2, each). Those three patients, in whom magnetic resonance imaging and/or endosonography could localise the tumors pre-operatively, underwent laparoscopic surgery while the remaining three patients underwent open surgery. Intra-operatively, insulin dropped to normal levels within 20 min in all cases. After a follow-up of 0.8-3 years, all patients remained biochemically cured.CONCLUSIONS: Pre-operatively, SACI appears to be a very sensitive localisation technique and may be most helpful in guiding the surgeon if conventional imaging techniques fail to localise the tumor. Complete removal of an insulinoma can be reliably predicted using a quick insulin assay.
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41.
  • Gimm, Oliver, et al. (författare)
  • Malignant pheochromocytomas and paragangliomas: a diagnostic challenge
  • 2012
  • Ingår i: Langenbeck's archives of surgery (Print). - : Springer Verlag (Germany). - 1435-2443 .- 1435-2451. ; 397:2, s. 155-177
  • Forskningsöversikt (refereegranskat)abstract
    • Introduction Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively. less thanbrgreater than less thanbrgreater thanMethods This review summarizes our current knowledge on how benign and malignant tumors can be distinguished. less thanbrgreater than less thanbrgreater thanConclusion Due to the rarity of malignant PCCs/PGLs and the obvious difficulties in distinguishing benign and malignant PCCs/PGLs, any patient with a PCC/PGL should be treated in a specialized center where a multidisciplinary setting with specialized teams consisting of radiologists, endocrinologist, oncologists, pathologists and surgeons is available. This would also facilitate future studies to address the existing diagnostic and/or therapeutic obstacles.
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42.
  • Gimm, Oliver (författare)
  • Medullary thyroid carcinoma - Characteristics, diagnostics, therapy and follow-up [Medulläres Schilddrüsenkarzinom - Besonderheiten, Diagnostik, Therapie und Nachsorge]
  • 2012
  • Ingår i: Klinikarzt. - : Georg Thieme Verlag. - 0341-2350. ; 41:10, s. 476-480
  • Tidskriftsartikel (refereegranskat)abstract
    • Medullary thyroid carcinoma (MTC) is a rare malignant tumor of the thyroid gland, it probably accounts for about 3 - 8% of all thyroids cancers. In contrast to the majority of thyroid cancers that develop from thyreocytes, MTC has its origins in parafollicular C cells. Among others, these cells synthesize calcitonin which thus represents a very sensitive tumor marker. MTC is not responsive to the usually employed conventional radio-iodine therapy because C cells, in contrast to threocytes, do not take up iodine. This fact places additional demands on surgical treatment. The management of MTCs that are not suitable for operative treatment because of their inoperable nature or, respectively, due to the presence of distant disseminated metastases is a hot topic of current intensive research. © Georg Thieme Verlag KG · Stuttgart · New York.
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43.
  • Gimm, Oliver (författare)
  • Pheochromocytoma-associated syndromes : genes, proteins and functions of RET, VHL and SDHx
  • 2005
  • Ingår i: Familial Cancer. - : Kluwer Academic Publishers. - 1389-9600 .- 1573-7292. ; 4:1, s. 17-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Pheochromocytoma are tumors derived from chromaffin cells that secrete catecholamines. These catecholamines may lead to increased blood pressure and even death. Historically, pheochromocytoma have been described as 10 tumor, i.e. about 10 were believed to be malignant, 10 were found to be extra-adrenal, and 10 were meant to be bilateral. Also, about 10 were considered to be hereditary. In these instances, they were most often part of either the multiple endocrine neoplasia type 2 (MEN 2) syndrome or the von Hippel-Lindau (VHL) disease. The genes (RET and VHL) involved have been known for several years and their function is the subject of ongoing investigation. Very recently, several genes (SDHD, SDHB, and SDHC) that belong to the mitochondrial complex II have been identified to be involved in the so-called pheochromocytoma-paraganglioma syndrome. Only SDHD and SDHB have so far been implicated in the pathogenesis of pheochromocytoma.
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44.
  • Gimm, Oliver, et al. (författare)
  • Prognostic significance of disseminated tumor cells in the connective tissue of patients with medullary thyroid carcinoma.
  • 2006
  • Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 30:5, s. 847-52
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Disseminated tumor cells in the connective tissue (CT-DTCs) do not have any connection to a primary tumor or the lymph nodes. They are identified quite often in patients with medullary thyroid carcinoma (MTC), but nothing is known regarding their prognostic significance.METHODS: Among 450 patients with MTC, 69 (15%) were identified as having CT-DTCs. A case-control group of patients without CT-DTCs was selected. The two groups were matched concerning TNM classification, age, heredity, and sex. Because many patients with CT-DTCs had extrathyroidal tumor extension (pT4 category), distant metastases (M1 category), or both, only 35 matched pairs could be identified. The TNM classification in both groups was as follows: pT1, n = 8; pT2, n = 15; pT3, n = 4; pT4, n = 8; pN0, n = 4; pN1, n = 31; M0, n = 30; M1, n = 5. The mean age was 46.8 +/- 17.0 years in the CT-DTC group and 44.4 +/- 15.0 years in the case-control group (NS).RESULTS: In both groups, 23 patients had sporadic MTC, and 12 patients had hereditary MTC. Neither mean basal preoperative nor postoperative calcitonin levels differed significantly between the two groups. In contrast, none of the patients with CT-DTCs was biochemically cured (normal calcitonin level after pentagastrin stimulation) compared to eight patients without CT-DTCs (P < 0.005). The two groups did not differ concerning other parameters (basal calcitonin level > 3000 pg/ml, more than 10 lymph node metastases, more than two involved locoregional lymph node compartments, mediastinal lymph node metastases) that have been reported to correlate with the lack of or almost (< 10%) lack of biochemical cure.CONCLUSIONS: In patients with MTC, disseminated tumor cells in the connective tissue correlate with advanced tumor stages and appear to be of prognostic significance.
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45.
  • Gimm, Oliver, et al. (författare)
  • Super-selective venous sampling in conjunction with quickPTH for patients with persistent primary hyperparathyroidism: report of five cases
  • 2012
  • Ingår i: Surgery today (Print). - : Springer Verlag (Germany). - 0941-1291 .- 1436-2813. ; 42:6, s. 570-576
  • Tidskriftsartikel (refereegranskat)abstract
    • Selective venous sampling (SVS) helps to interpret imaging results in patients with persistent primary hyperparathyroidism (pHPT). However, one of the drawbacks of conventional SVS may be low "spatial resolution", depending on the sample size. We modified SVS in the following way: first, patients underwent conventional SVS with up to 11 parathyroid hormone (PTH) samples taken. The quickPTH assay was used to measure PTH levels. The patients subsequently underwent super-selective venous sampling (super-SVS) in the region with the highest quickPTH level in the same session. The subjects were five consecutive patients with persistent pHPT investigated by various imaging techniques, none of which was considered conclusive. Therefore, all five patients underwent super-SVS, which was done successfully in four. Re-evaluation of the imaging results of these four patients resulted in localization of the parathyroid adenoma. Curative surgery was performed successfully in all four patients during the study period. Super-SVS increases the "spatial resolution" of conventional SVS and may have advantages when imaging results of patients with persistent pHPT are interpreted. Its true value must be analyzed in larger studies.
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46.
  • Gimm, Oliver, et al. (författare)
  • Training in endocrine surgery
  • 2019
  • Ingår i: Langenbeck's archives of surgery (Print). - : SPRINGER. - 1435-2443 .- 1435-2451. ; 404, s. 929-944
  • Forskningsöversikt (refereegranskat)abstract
    • Background/purpose In Europe, the Division of Endocrine Surgery (DES) determines the number of operations (thyroid, neck dissection, parathyroids, adrenals, neuroendocrine tumors of the gastro-entero-pancreatic tract (GEP-NETs)) to be required for the European Board of Surgery Qualification in (neck) endocrine surgery. However, it is the national surgical boards that determine how surgical training is delivered in their respective countries. There is a lack of knowledge on the current situation concerning the training of surgical residents and fellows with regard to (neck) endocrine surgery in Europe. Methods A survey was sent out to all 28 current national delegates of the DES. One questionnaire was addressing the training of surgical residents while the other was addressing the training of fellows in endocrine surgery. Particular focus was put on the numbers of operations considered appropriate. Results For most of the operations, the overall number as defined by national surgical boards matched quite well the views of the national delegates even though differences exist between countries. In addition, the current numbers required for the EBSQ exam are well within this range for thyroid and parathyroid procedures but below for neck dissections as well as operations on the adrenals and GEP-NETs. Conclusions Training in endocrine surgery should be performed in units that perform a minimum of 100 thyroid, 50 parathyroid, 15 adrenal, and/or 10 GEP-NET operations yearly. Fellows should be expected to have been the performing surgeon of a minimum of 50 thyroid operations, 10 (central or lateral) lymph node dissections, 15 parathyroid, 5 adrenal, and 5 GEP-NET operations.
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47.
  • Hahn, Michael A, et al. (författare)
  • CDC73/HRPT2 CpG island hypermethylation and mutation of 5 -untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors
  • 2010
  • Ingår i: ENDOCRINE-RELATED CANCER. - 1351-0088. ; 17:1, s. 273-282
  • Tidskriftsartikel (refereegranskat)abstract
    • The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in similar to 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5-untranslated region (5-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.
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48.
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49.
  •  
50.
  • Haj-Hosseini, Neda, 1980-, et al. (författare)
  • Optiska metoder för identifiering av bisköldkörtel och sköldkörtel
  • 2017
  • Konferensbidrag (refereegranskat)abstract
    • Identifiering av bisköldkörtlar är viktigt vid sköldkörtel- och bisköldkörtelkirurgi och kan vara svårt då de liknar omgivande vävnad såsom fett och lymfkörtlar. Peroperativ detektering av dessa vävnader kan förbättra möjligheten att bota patienter med hyperparathyroidism och minska risken för bisköldkörtelskador vid thyroideakirurgi. Optiska metoder är potentiella tekniker för att möjliggöra detta. Optiska tekniker utvärderades på vävnadsprover från patienter vid bisköldkörtel- och sköldkörteloperation. Teknikerna bestod av nära infraröd fluorescens (NIR) spektroskopi och optisk koherenstomografi (OCT) som ger en bild av vävnadens mikrostruktur liknande till ultraljud med högre upplösning (10 μm).
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