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Hellman, Per
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Publications (10 of 173) Show all publications
Hellman, P., Björklund, P. & Åkerström, T. (2019). Aldosterone-Producing Adenomas. In: Litwack, Gerald (Ed.), ALDOSTERONE: (pp. 407-431). ELSEVIER ACADEMIC PRESS INC
Open this publication in new window or tab >>Aldosterone-Producing Adenomas
2019 (English)In: ALDOSTERONE / [ed] Litwack, Gerald, ELSEVIER ACADEMIC PRESS INC , 2019, p. 407-431Chapter in book (Refereed)
Abstract [en]

Aldosterone-producing adenomas (APA) are more common than initially anticipated. APA cause primary aldosteronism (PA), which affect 3-10% of the hypertensive population. Research during recent years has led to an increased knowledge of the background dysregulation of the increased aldosterone release, where mutation in the gene encoding the potassium channel GIRK4-KCNJ5-is the most common. Moreover, the discovery of aldosterone-producing cell clusters in apparently normal adenomas has also led to increased understanding of the development of PA, and presumably also APA. A continuum ranging from low-renin hypertension to APA and overt PA is reasoned, and the secondary effects of aldosterone on especially the cardiovascular system have also become more evident. Diagnostics of PA and APA is important in order to reduce cardiovascular morbidity and mortality, but the diagnostic methods are somewhat unspecific and insensitive, indicating the need for novel methods.

Place, publisher, year, edition, pages
ELSEVIER ACADEMIC PRESS INC, 2019
Series
Vitamins and Hormones, ISSN 0083-6729 ; 109
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-401949 (URN)10.1016/bs.vh.2018.10.007 (DOI)000500344300018 ()30678866 (PubMedID)978-0-12-817782-2 (ISBN)
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Daskalakis, K., Norlén, O., Hellman, P. & Stålberg, P. (2019). Applying the use of novel biomarkers for neuroendocrine tumors in the clinic: where are we now?. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY, 6(1), Article ID IJE14.
Open this publication in new window or tab >>Applying the use of novel biomarkers for neuroendocrine tumors in the clinic: where are we now?
2019 (English)In: INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY, ISSN 2045-0869, Vol. 6, no 1, article id IJE14Article in journal, Editorial material (Other academic) Published
Keywords
biomarkers, neuroendocrine tumors, prognosis, targeted therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-399971 (URN)10.2217/ije-2017-0012 (DOI)000498810800003 ()
Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-18Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Hellman, P. & Sundin, A. (2019). C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma. Cancers, 11(6), Article ID 847.
Open this publication in new window or tab >>C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 6, article id 847Article in journal (Refereed) Published
Abstract [en]

Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
pheochromocytoma, paraganglioma, PET-CT, C-11-hydroxy-ephedrine, adrenal incidentaloma
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-390633 (URN)10.3390/cancers11060847 (DOI)000475351200111 ()31248124 (PubMedID)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-09-10Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Granberg, D., Garske-Román, U., Sandström, M., . . . Sundin, A. (2019). Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.. Cancers, 11(7), Article ID 909.
Open this publication in new window or tab >>Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 909Article in journal (Refereed) Published
Abstract [en]

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

Keywords
pheochromocytoma, paraganglioma, Lu-177-DOTATATE, peptide receptor radiotherapy, PRRT, neuroendocrine tumor, NET, PCC, PGL
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392835 (URN)10.3390/cancers11070909 (DOI)000479322800020 ()31261748 (PubMedID)
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-10-30Bibliographically approved
Botling, J., Lamarca, A., Bajic, D., Norlén, O., Lönngren, V., Kjaer, J., . . . Crona, J. (2019). High-grade progression confers poor survival in pancreatic neuroendocrine tumors.. Neuroendocrinology
Open this publication in new window or tab >>High-grade progression confers poor survival in pancreatic neuroendocrine tumors.
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2019 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194Article in journal (Refereed) Epub ahead of print
Abstract [en]

INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).

PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.

RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).

CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-399943 (URN)10.1159/000504392 (DOI)31658459 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-01-08
Söderbäck, H., Gunnarsson, U., Martling, A., Hellman, P. & Sandblom, G. (2019). Incidence of wound dehiscence after colorectal cancer surgery: results from a national population-based register for colorectal cancer. International Journal of Colorectal Disease, 34(10), 1757-1762
Open this publication in new window or tab >>Incidence of wound dehiscence after colorectal cancer surgery: results from a national population-based register for colorectal cancer
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2019 (English)In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 34, no 10, p. 1757-1762Article in journal (Refereed) Published
Abstract [en]

Background

Patient-related risk factors for wound dehiscence after colorectal surgery remain obscure.

Methods

All open abdominal procedures for colorectal cancer registered in the Swedish Colorectal Cancer Registry (SCRCR, 5) 2007–2013 were identified. Potential risk factors for wound dehiscence were identified by cross-matching between the SCRCR and the National Patient Register (NPR). The endpoint in this study was reoperation for wound dehiscence registered in either the SCRCR or NPR and patients not reoperated were considered controls.

Results

A total of 30,050 patients were included in the study. In a multivariable regression analysis, age > 70 years, male gender, BMI > 30, history of chronic obstructive pulmonary disease, history of generalised inflammatory disease, and duration of surgery less than 180 min were independently and significantly associated with increased risk for wound dehiscence. A history of diabetes, chronic renal disease, liver cirrhosis, and distant metastases was not associated with wound dehiscence. The hazard ratio for postoperative death was 1.24 for patients who underwent reoperation for wound dehiscence compared with that for controls.

Discussion

Patients reoperated for wound dehiscence face a significantly higher postoperative mortality than those without. Risk factors include male gender, age > 70 years, obesity, history of chronic obstructive pulmonary disease, and history of generalised inflammatory disease. Patients at high risk for developing wound dehiscence may, if identified preoperatively, benefit from active prevention measures implemented in routine surgical practice.

Keywords
Wound dehiscence, Colorectal cancer, Surgery
National Category
Gastroenterology and Hepatology Surgery
Identifiers
urn:nbn:se:uu:diva-395788 (URN)10.1007/s00384-019-03390-3 (DOI)000487143200015 ()31501927 (PubMedID)
Funder
The Karolinska Institutet's Research Foundation
Available from: 2019-10-28 Created: 2019-10-28 Last updated: 2019-10-28Bibliographically approved
Barazeghi, E., Hellman, P., Westin, G. & Stålberg, P. (2019). PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors. Endocrine Connections, 8(8), 1126-1135
Open this publication in new window or tab >>PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors
2019 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 8, no 8, p. 1126-1135Article in journal (Refereed) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTP mu (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2'deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD, 2019
Keywords
DNA methylation, neuroendocrine tumors, epigenetic, SI-NETs, PTPRM
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-393899 (URN)10.1530/EC-19-0279 (DOI)000483142900007 ()31349215 (PubMedID)
Funder
Swedish Cancer SocietyErik, Karin och Gösta Selanders Foundation
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved
Backman, S., Åkerström, T., Maharjan, R., Cupisti, K., Willenberg, H. S., Hellman, P. & Björklund, P. (2019). RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas. Scientific Reports, 9, Article ID 6269.
Open this publication in new window or tab >>RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6269Article in journal (Refereed) Published
Abstract [en]

Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383193 (URN)10.1038/s41598-019-41525-2 (DOI)000465001600023 ()31000732 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-07-24 Created: 2019-07-24 Last updated: 2019-07-24Bibliographically approved
Backman, S., Bajic, D., Crona, J., Hellman, P., Skogseid, B. & Stålberg, P. (2019). Whole genome sequencing of apparently mutation-negative MEN1 patients. European Journal of Endocrinology, 182(1), 35-45
Open this publication in new window or tab >>Whole genome sequencing of apparently mutation-negative MEN1 patients
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2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 1, p. 35-45Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-401244 (URN)10.1530/eje-19-0522 (DOI)
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-10Bibliographically approved
Daskalakis, K., Karakatsanis, A., Hessman, O., Stuart, H. C., Welin, S., Tiensuu Janson, E., . . . Stålberg, P. (2018). Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.. JAMA Oncology, 4(2), 183-189
Open this publication in new window or tab >>Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.
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2018 (English)In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, no 2, p. 183-189Article in journal (Refereed) Published
Abstract [en]

Importance: Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV Small Intestinal Neuroendocrine Tumors (SI-NETs) is controversial.

Objective:  To determine whether locoregional surgery performed at diagnosis in asymptomatic SI-NETs patients with distant metastases affects overall survival (OS), morbidity and mortality, length of hospital stay (LOS) and re-operation rates.

Design: This investigation was a cohort study of asymptomatic patients with stage IV SI-NET, diagnosed between 1985 and 2015, using the prospective Uppsala database of SI-NETs and the Swedish National Patient Register. Patients included were followed until May 2016 and divided to a first group, which underwent Prophylactic Upfront Surgery within six months from diagnosis Combined with Oncological treatment (PUSCO group) and a second group, which was either treated non-surgically or operated later (Delayed Surgery As Needed Combined with Oncological treatment [DSANCO group]).

Setting: A tertiary referral center with follow-up data from the Swedish National Patient Register.

Participants: We included 363 stage IV SI-NET patients without any abdominal symptoms within 6 months from diagnosis, treated either with PUSCO (n=161) or DSANCO (n=202).

Exposure: PUSCO vs DSANCO.

Main Outcomes and Measures: Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality and re-operation rates measured from baseline. Propensity score match was performed between the two groups.

Results: Two isonumerical groups (n=91) occurred after propensity score matching. There was no difference between groups in OS (PUSCO median 7.9 vs DSANCO 7.6 years; [hazard ratio] HR, 0.98; [95% CI, 0.70-1.37]; log-rank P=.93) and cancer-specific survival (median 7.7 vs 7.6 years, HR, 0.99; [95%CI, 0.71-1.40]; log-rank P=.99). There was no difference in 30-day mortality (0% in both matched groups) or postoperative morbidity (2% vs 1%; P>.99), LOS (median 73 vs 76 days; P=.64), LOS due to local tumor-related symptoms (median 7 vs 11.5 days; P=.81) or incisional hernia repairs (4% in both groups; P>.99).  Patients from the PUSCO group underwent more re-operative procedures (14%) compared to the DSANCO group (3%) due to intestinal obstruction (P< .001).

Conclusion: Prophylactic upfront locoregional surgery confers no survival advantage in asymptomatic stage IV SI-NET patients. Delayed surgery as needed seems to be comparable in all examined outcomes, whilst offering the advantage of less re-operations for intestinal obstruction.  The value of a priori locoregional surgery in the presence of distant metastases is challenged and needs to be elucidated in a randomized controlled study.

 

Keywords
Small Intestinal NETs, prophylactic loco-regional surgery, stage IV
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-330702 (URN)10.1001/jamaoncol.2017.3326 (DOI)000424778600010 ()29049611 (PubMedID)
Funder
Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Cancer Society
Available from: 2017-10-21 Created: 2017-10-03 Last updated: 2018-04-16Bibliographically approved
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