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Welin, Staffan
Publications (10 of 39) 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.

 

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
Ali, A. A., Grönberg, M., Hjortland, G. O., Grønbæk, H., Ladekarl, M., Langer, S. W., . . . Tiensuu Janson, E. (2018). Intravenous versus Oral Etoposide: Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3). Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 184-184
Open this publication in new window or tab >>Intravenous versus Oral Etoposide: Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 184-184Article in journal, Meeting abstract (Other academic) Published
Keywords
chemotherapy, neuroendocrine neoplasms, intravenous, oral, survival
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-355844 (URN)10.1159/000487699 (DOI)000427285300182 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: H01

Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2018-07-13Bibliographically approved
Ali, A. S., Grönberg, M., Langer, S. W., Ladekarl, M., Hjortland, G. O., Vestermark, L. W., . . . Janson, E. T. (2018). Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Medical Oncology, 35(4), Article ID 47.
Open this publication in new window or tab >>Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)
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2018 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, no 4, article id 47Article in journal (Refereed) Published
Abstract [en]

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Chemotherapy, Intravenous, Oral, Etoposide, Neuroendocrine neoplasms, WHO G3
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351690 (URN)10.1007/s12032-018-1103-x (DOI)000428784500004 ()29511910 (PubMedID)
Funder
Swedish Cancer Society, CAN558/2014
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-06-04Bibliographically approved
Kjellman, M., Knigge, U., Welin, S., Grønbæk, H., Thiis-Evensen, E., Sørbye, H., . . . Belusa, R. (2018). Plasma Protein Kallikrein-14 Strongly Predicts Pronounced Chromogranin A (CgA) Response in Small Intestinal Neuroendocrine Tumor (NET) Patients after Somatostatin Analog (SSA) Treatment: The Nordic EXPLAIN Biomarker Study. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 155-155
Open this publication in new window or tab >>Plasma Protein Kallikrein-14 Strongly Predicts Pronounced Chromogranin A (CgA) Response in Small Intestinal Neuroendocrine Tumor (NET) Patients after Somatostatin Analog (SSA) Treatment: The Nordic EXPLAIN Biomarker Study
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 155-155Article in journal, Meeting abstract (Other academic) Published
Keywords
plasma protein biomarker
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-355841 (URN)10.1159/000487699 (DOI)000427285300153 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: F08

Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2018-07-13Bibliographically 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), 970-988
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 6, p. 970-988Article 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.

Keywords
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)000430832400010 ()29497803 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-08-02Bibliographically approved
Dillon, J., Kulke, M., Warner, R., Bergsland, E., Welin, S., O'Dorisio, T., . . . Pavel, M. (2018). Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 224-224
Open this publication in new window or tab >>Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 224-224Article in journal, Meeting abstract (Other academic) Published
Keywords
telotristat ethyl, somatostatin analogs, carcinoid syndrome
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354379 (URN)10.1159/000487699 (DOI)000427285300222 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: J06

Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Dillon, J. S., Kulke, M. H., Pavel, M., Horsch, D., Anthony, L. B., Warner, R. R. P., . . . Lapuerta, P. (2018). Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl: Analysis of the Phase 3 TELESTAR Study. Paper presented at The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.. Pancreas, 47(3), 337-338
Open this publication in new window or tab >>Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl: Analysis of the Phase 3 TELESTAR Study
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2018 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 337-338Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351592 (URN)10.1097/MPA.0000000000000997 (DOI)000426086300038 ()
Conference
The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Weickert, M. O., Kaltsas, G., Hörsch, D., Lapuerta, P., Pavel, M., Valle, J. W., . . . Kulke, M. H. (2018). Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome. Paper presented at The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.. Pancreas, 47(3), 357-358
Open this publication in new window or tab >>Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome
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2018 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 357-358Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351595 (URN)10.1097/MPA.0000000000000997 (DOI)000426086300110 ()
Conference
The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically 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.

Keywords
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: 2018-07-13Bibliographically approved
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