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Welin, Staffan
Publications (10 of 33) Show all publications
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.

 

Keyword
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
Garske, U., Sandström, M., Fröss-Baron, K., Lundin, L., Hellman, P., Welin, S., . . . Granberg, D. (2018). Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.. European Journal of Nuclear Medicine and Molecular Imaging, 45(6)
Open this publication in new window or tab >>Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no 6Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

METHODS: Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%).

RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

CONCLUSIONS: Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Keyword
177Lu-DOTA-octreotate, Dosimetry, Neuroendocrine tumour, Outcome, PRRT, Toxicity
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346995 (URN)10.1007/s00259-018-3945-z (DOI)29497803 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-04-27Bibliographically approved
Fust, K., Maschio, M., Pastor, M., Kohli, M., Weinstein, M. C., Singh, S., . . . Feuilly, M. (2017). A Budget Impact Model Of The Addition Of Telotristat Ethyl Treatment In Patients With Uncontrolled Carcinoid Syndrome. Value in Health, 20(9), A548-A549
Open this publication in new window or tab >>A Budget Impact Model Of The Addition Of Telotristat Ethyl Treatment In Patients With Uncontrolled Carcinoid Syndrome
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2017 (English)In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 9, p. A548-A549Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345694 (URN)000413599901196 ()
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Dumanski, J. P., Rasi, C., Björklund, P., Davies, H., Ali, A. S., Grönberg, M., . . . Tiensuu Janson, E. (2017). A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocrine-Related Cancer, 24(8), 427-443
Open this publication in new window or tab >>A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
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2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 8, p. 427-443Article in journal (Refereed) Published
Abstract [en]

The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

Keyword
DNA excision-repair pathway, cancer predisposition, familial cancer, oxidative stress, small intestinal carcinoid
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-328686 (URN)10.1530/ERC-17-0196 (DOI)000406493000011 ()28634180 (PubMedID)
Available from: 2017-08-29 Created: 2017-08-29 Last updated: 2017-11-06Bibliographically approved
Öberg, K., Couvelard, A., Delle Fave, G., Gross, D., Grossman, A., Jensen, R. T., . . . Ferone, D. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 105(3), 201-211
Open this publication in new window or tab >>ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 201-211Article in journal (Refereed) Published
Abstract [en]

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called "general tumor markers." The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by highperformance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA anal ysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now.

Keyword
Biomarkers, Chromogranin A, Urinary 5-hydroxyindoleacetic acid, Neuroendocrine tumor test
National Category
Endocrinology and Diabetes Neurology
Identifiers
urn:nbn:se:uu:diva-336660 (URN)10.1159/000472254 (DOI)000411501200003 ()28391265 (PubMedID)
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-01-04Bibliographically approved
Perren, A., Couvelard, A., Scoazec, J.-Y., Costa, F., Borbath, I., Delle Fave, G., . . . Welin, S. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pathology-Diagnosis and Prognostic Stratification. Neuroendocrinology, 105(3), 196-200
Open this publication in new window or tab >>ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pathology-Diagnosis and Prognostic Stratification
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 196-200Article in journal (Refereed) Published
Abstract [en]

The European Neuroendocrine Tumor Society (ENETS) proposed standard of care guidelines for pathology in 2009. Since then, profound changes in the classification have been made, dividing neuroendocrine neoplasia (NEN) into well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) in the 2010 WHO classification. The 7th edition of the TNM classification (2009) included NEN for the first time, widely adapting ENETS proposals but with some differences for NEC and for NET of the pancreas and the appendix. Therapy guidelines for gastroenteropancreatic NET were updated in 2016. The need for an update of the standards of care prompted the ENETS to organize a consensus conference which was held in Antibes in 2015; a working group was designated to propose pathological standards of care.

Keyword
Classification, Immunohistochemistry, Neuroendocrine tumor, Grading, Differentiation
National Category
Neurosciences Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-336659 (URN)10.1159/000457956 (DOI)000411501200002 ()28190015 (PubMedID)
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-01-13Bibliographically approved
Ali, A. S., Grönberg, M., Federspiel, B., Scoazec, J.-Y., Hjortland, G. O., Gronbaek, H., . . . Tiensuu Janson, E. (2017). Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma. PLoS ONE, 12(11), Article ID e0187667.
Open this publication in new window or tab >>Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed) Published
Abstract [en]

Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-341933 (URN)10.1371/journal.pone.0187667 (DOI)000414572100031 ()29112960 (PubMedID)
Funder
Swedish Cancer Society, CAN558/2014
Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-02-16Bibliographically approved
Anthony, L., Kulke, M. H., Hoersch, D., Bergsland, E., Öberg, K., Welin, S., . . . Pavel, M. (2017). Impact of Concomitant Medication on Efficacy of Telotristat Ethyl - A Post Hoc Subgroup Analysis of the Phase 3 TELESTAR Study in Carcinoid Syndrome. Paper presented at 14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN. Neuroendocrinology, 105, 212-212
Open this publication in new window or tab >>Impact of Concomitant Medication on Efficacy of Telotristat Ethyl - A Post Hoc Subgroup Analysis of the Phase 3 TELESTAR Study in Carcinoid Syndrome
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 212-212Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
KARGER, 2017
Keyword
serotonin, diarrhea
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346591 (URN)000413957900213 ()
Conference
14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN
Note

Meeting Abstract: L2

Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2018-03-20Bibliographically approved
Crona, J., Norlén, O., Antonodimitrakis, P., Welin, S., Stålberg, P. & Eriksson, B. (2017). Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumors. Pancreas, 46(3), 441-441
Open this publication in new window or tab >>Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumors
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2017 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 3, p. 441-441Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321065 (URN)10.1097/MPA.0000000000000812 (DOI)000394448600077 ()
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2017-05-11Bibliographically approved
Kjellman, M., Knigge, U., Welin, S., Gronbaek, H., This-Evensen, E., Sorbye, H., . . . Belusa, R. (2017). Plasma Protein Fingerprinting for the Diagnosis of Small Intestinal Neuroendocrine Tumors (siNETs). Paper presented at 14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN. Neuroendocrinology, 105, 148-148
Open this publication in new window or tab >>Plasma Protein Fingerprinting for the Diagnosis of Small Intestinal Neuroendocrine Tumors (siNETs)
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 148-148Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
KARGER, 2017
Keyword
net biomarker diagnosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346589 (URN)000413957900149 ()
Conference
14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN
Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2018-03-20Bibliographically approved
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