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Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Small Intestinal Neuroendocrine Tumours (SI-NET) are considered to be generally resistant to systemic treatment. To date predictive markers for drug activity are lacking.

Patients and Methods: Tumour samples from 27 patients with SI-NET were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer, and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinico-pathological variables and pre-treatment biomarkers.

Results: For standard cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinums, gemcitabine and doxorubicin compared with CRC. For targeted kinase inhibitors, SI-NET was among the most sensitive diagnoses. CLL and ovarian cancer were generally the most sensitive diagnoses to both cytotoxic drugs and protein kinase inhibitors. The mTOR inhibitor sirolimus exhibited modest cytotoxic activity.

Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors.

Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo.

Conclusions: SI-NETs exhibit variable but generally intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinico-pathological factors and currently used biomarkers were not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NETs. The great variability in drug sensitivity calls for individualized selection of therapy.

Keyword [en]
Small Intestinal NETs, Ex vivo sensitivity, cytotoxic drugs, targeted agents
National Category
Cancer and Oncology Surgery
Research subject
Oncology; Surgery
Identifiers
URN: urn:nbn:se:uu:diva-330700OAI: oai:DiVA.org:uu-330700DiVA: diva2:1146549
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-24Bibliographically approved
In thesis
1. Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
Open this publication in new window or tab >>Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small Intestinal Neuroendocrine Tumors (SI-NETs) are indolent neoplasms with an increasing annual incidence of approximately 1/100 000 people. They are often diagnosed at a late stage, restricting treatment efficacy. The aim of this thesis was to investigate clinical aspects of patients with advanced and/or disseminated disease with regard to clinical signs and management of abdominal fibrosis, the role of locoregional surgery and liver transplantation, as well as the ex vivo sensitivity of tumor samples to cytotoxic and targeted agents. Additionally, novel serum biomarkers for the diagnosis and prognosis of SI-NETs were investigated. In Paper I, abdominal fibrosis induced by serotonin and other cytokines from tumor cells, was associated with clinically significant symptoms of intestinal ischemia and/or obstructive uropathy, and was linked to advanced disease. Prompt recognition and minimally invasive intervention with superior mesenteric vein stenting and/or percutaneous nephrostomy and J stent treatment were effective in disease palliation. Paper II challenged the role of prophylactic, upfront locoregional surgery in Stage IV, which conferred no survival advantage in asymptomatic SI-NET patients. The option of delayed surgery as needed seemed to be comparable in all the outcomes examined, whilst also offering the advantage of fewer re-operations for intestinal obstruction in patients with already disseminated disease. Paper III confirmed that most young patients (<65 years) with SI-NET and liver metastases had a favorable survival with standardized multimodality treatment and that survival figures reported after liver transplantation for NETs do not surpass these figures. In Paper IV, 145 biomarkers were analyzed in blood serum using two different multiplex proximity assays. Subsequent ELISA and immunohistochemical analyses identified DcR3, TFF3 and midkine as novel serum biomarkers for SI-NETs. In Paper V, SI-NET samples were profiled with respect to sensitivity ex vivo to a panel of standard chemotherapeutics and targeted agents using a short-term total cell kill assay. SI-NETs exhibited variable but generally intermediate sensitivity ex vivo compared with other cancer diagnoses, calling for individualized selection of therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 84 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1386
Keyword
SI-NET, fibrosis, locoregional surgery, liver transplantation, biomarkers, ex vivo sensitivity.
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-330554 (URN)978-91-513-0113-6 (ISBN)
Public defence
2017-12-08, Rosénsalen, Akademiska sjukhuset, ing 95-96, Uppsala, 09:00 (Swedish)
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Supervisors
Available from: 2017-11-16 Created: 2017-10-02 Last updated: 2017-11-16
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Daskalakis, KosmasNorlén, OlovKarakatsanis, AndreasHellman, PerLarsson, RolfNygren, PeterStålberg, Peter

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