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Small Intestinal Neuroendocrine Tumors: Clinical Studies, Novel Serum Biomarkers and Sensitivity to Cytotoxic and Targeted Agents
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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. , p. 84
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1386
Keyword [en]
SI-NET, fibrosis, locoregional surgery, liver transplantation, biomarkers, ex vivo sensitivity.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-330554ISBN: 978-91-513-0113-6 (print)OAI: oai:DiVA.org:uu-330554DiVA, id: diva2:1146351
Public defence
2017-12-08, Rosénsalen, Akademiska sjukhuset, ing 95-96, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-11-16 Created: 2017-10-02 Last updated: 2018-03-07
List of papers
1. Clinical signs of fibrosis in small intestinal neuroendocrine tumours.
Open this publication in new window or tab >>Clinical signs of fibrosis in small intestinal neuroendocrine tumours.
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2016 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 1, p. 69-75Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In patients with small intestinal neuroendocrine tumours (SI-NETs), serotonin and other cytokines released from tumour cells may induce fibrosis, leading to carcinoid heart disease and abdominal fibrotic reactions. The aim of this study was to assess the prevalence, clinical complications and management of this reaction in the abdomen.

METHODS: This was a retrospective cohort study of patients with SI-NETs diagnosed between 1985 and 2015. Clinical data, outcomes, radiological findings, and surgical and radiological interventions were reviewed.

RESULTS: A total of 824 patients were diagnosed with SI-NETs in the study interval. Clinically significant abdominal signs and symptoms of fibrosis occurred in 36 patients. Of these, 20 had critically symptomatic central mesenteric fibrosis causing obstruction of mesenteric vessels, and 16 had retroperitoneal fibrosis causing obstructive uropathy with hydronephrosis. Extensive fibrosis causing mesenteric vessel obstruction and/or obstructive uropathy was more often associated with symptomatic and advanced disease encompassing lymph node metastases in the mesenteric root, para-aortic lymph node metastases, as well as liver metastases and peritoneal carcinomatosis. Palliative intervention in terms of superior mesenteric vein stenting or resection of central mesenteric metastases and/or percutaneous nephrostomy and J stent treatment was beneficial in the majority of the patients.

CONCLUSION: Extensive abdominal fibrosis associated with clinically significant symptoms of intestinal ischaemia and/or obstructive uropathy was linked to advanced disease in patients with SI-NETs. Prompt recognition and minimally invasive intervention was effective in disease palliation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-307778 (URN)10.1002/bjs.10333 (DOI)000393594900010 ()27861745 (PubMedID)
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2018-02-20Bibliographically approved
2. Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.
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
3. Indication for Liver Transplantation in Young Patients with Small Intestinal NETs Is Rare?
Open this publication in new window or tab >>Indication for Liver Transplantation in Young Patients with Small Intestinal NETs Is Rare?
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2014 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 38, no 3, p. 742-747Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

A majority of patients with small intestinal neuroendocrine tumors (SI-NETs) present with or develop liver metastases (LM). A number of treatments for LM are used clinically, including liver transplantation (LTx). Indications for LTx are under debate; young age (<65 years), absence of extrahepatic disease, resected primary tumor and limited extent of LM have been suggested as inclusion criteria for LTx with the aim to optimize outcome.

MATERIALS AND METHODS:

From our series of 672 patients with SI-NET treated at the University Hospital in Uppsala between 1985 and 2012, we identified 78 patients according to the following criteria: <65 years of age, locoregional surgery (LRS) of the primary tumor and mesenteric metastases successfully performed, LM present but no extrahepatic disease. Baseline was chosen as the first date the following points were met: First visit to our center, LRS performed, LM present. The patients underwent treatment according to the standard clinical protocols at our center, and during this time period we did not perform or refer any SI-NET patients for LTx. Kaplan-Meier survival analyses were performed in three different groups based on hypothetical criteria for LTx.

RESULTS:

Five-year overall survival rates for patients <65 years (n = 78) and <55 years (n = 36) of age were 84 ± 8 and 92 ± 9 %, respectively. For patients fulfilling the Milan criteria (n = 33) the 5-year survival was 97 ± 6 %.

CONCLUSIONS:

Most young patients (<65 years) with SI-NET and LM have a favorable survival with standardized multimodality treatment. Indeed, most survival figures reported after LTx of NET do not surpass these figures.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-212143 (URN)10.1007/s00268-013-2331-z (DOI)000333151700032 ()24233660 (PubMedID)
Available from: 2013-12-06 Created: 2013-12-06 Last updated: 2018-02-20Bibliographically approved
4. DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
Open this publication in new window or tab >>DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 2, p. 170-181Article in journal (Refereed) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-307769 (URN)10.1159/000452891 (DOI)000407672700008 ()27829249 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2018-02-20Bibliographically approved
5. Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETs
Open this publication in new window or tab >>Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETs
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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
Small Intestinal NETs, Ex vivo sensitivity, cytotoxic drugs, targeted agents
National Category
Cancer and Oncology Surgery
Research subject
Oncology; Surgery
Identifiers
urn:nbn:se:uu:diva-330700 (URN)
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-02-20Bibliographically approved

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