uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3: Biological and Clinical Aspects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. (Endocrine Oncology)ORCID iD: 0000-0001-9881-769x
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate biological and clinical aspects of G3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs).

In our first study, the expression of the tumor suppressor p53 was investigated. In a cohort of G3 GEP-NENs we found the expression of p53 protein to be present in 39% of 124 cases. Expression of p53 correlated to poorer progression-free survival (PFS) and overall survival (OS) for patients with G3 GEP-NENs originating from colon or rectum. In the next study, we aimed to demonstrate the prevalence of PD-L1 expression in G3 GEP-NENs and its possible clinical importance. Ten per cent of 136 tumor specimens were immunoreactive for PD-L1 in either tumor cells or immune cells. In contrast to p53 expression that could be correlated to PFS and OS in a subgroup of patients the expression of PD-L1 did not correlate to any clinicopathological variables and conclusively, PD-L1 may not have a vital role for the pathogenesis of G3 GEP-NENs. In a further study, we sought to identify new potential biomarkers and a panel of immuno-oncological proteins were measured in serum collected from pancreatic G3 NENs and healthy controls. Out of 87 proteins, 62% were significantly lower in serum concentration in healthy controls compared to patients. One protein, FasL, was present in significantly higher levels in healthy controls compared to patients. FasL may have a protective role in its ability to activate T cells in the immune system. Other proteins of interest were chemokine (c-c motif) ligand and interleukin 8 that both correlated to poorer prognosis in G3 pancreatic NEN patients. More studies are needed for further understanding of the roles and clinical relevance of immuno-oncological proteins in G3 pancreatic NENs.

Finally, we evaluated whether intravenous or oral administration of etoposide differed with regards to PFS and OS in patients with G3 GEP-NENs. There was no significant difference in PFS nor OS between patients receiving oral compared to intravenous etoposide; demonstrating that an oral option of etoposide is not inferior in its efficacy as compared to the more used intravenous formulation. These results suggest that considering oral options of etoposide is important since they are more often preferred by patients, increase the quality of life for the patients and reduce hospital costs.

This thesis has contributed to an understanding of the distribution and clinical relevance of p53 and PD-L1 in GEP-NENs. A potential role of FasL, chemokine and interleukin 8 as prognostic and/or diagnostic factors in pancreatic G3 NENs has been identified and should be further investigated. The thesis also gave some insight into the role of oral etoposide as an alternative option to intravenous formulation with regards to efficacy. Oral formulations are preferred by many patients and improve quality of life while decreasing hospital-related costs. Further studies are needed to compare the tolerability of oral formulation compared to the intravenous formulation. 

 

 

 

Place, publisher, year, edition, pages
Uppsala University: Acta Universitatis Upsaliensis, 2019. , p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1576
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-382061ISBN: 978-91-513-0663-6 (print)OAI: oai:DiVA.org:uu-382061DiVA, id: diva2:1305970
Public defence
2019-06-13, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2019-05-20 Created: 2019-04-21 Last updated: 2019-06-17
List of papers
1. Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
Open this publication in new window or tab >>Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
Show others...
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: 2019-04-21Bibliographically approved
2. PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
Open this publication in new window or tab >>PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
(English)Manuscript (preprint) (Other academic)
Abstract [en]

G3 Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare but highly aggressive tumors and traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers making them escape the immune system and hence progress making them excellent targets for treatment. Our aim was investigate the immunohistochemical expression of PD-L1 protein in G3 GEP-NEN (Ki67 >20%) and to evaluate the frequency and location of expression and its correlation to clinical parameters.

   In a cohort of 136 patients, 14 tumor samples (10%) had PD-L1 immunoreactive cells; in four (3%) patient’s expression was seen in the tumor cells and in 10 (7%) expression was seen in immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival.    We conclude that PD-L1 expression is present only in a subset of G3 GEP-NENs. Further studies are needed to fully understand the role of PD-L1 in patients with G3 GEP-NEN, and to assess the potential treatment with immune checkpoint inhibitors.

Keywords
PD-L1, immune check inhibitors, G3 GEP-NEN, immunohistochemistry
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-382058 (URN)
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-21
3. Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
Open this publication in new window or tab >>Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Pancreatic G3 neuroendocrine neoplasms (NENs) are rare, aggressive and poorly understood tumors that compose 1-2% of all pancreatic tumors. Generally treated with chemotherapy with poor progression free survival according to their WHO 2010 classification, these tumors are heterogeneous and new diagnostic and prognostic biomarkers are needed to fully understand their biology, sub-categorize them and effectively treat them.

Materials and methods: Serum from 42 patients and 42 healthy controls were screened for the presence of 96 different proteins with an immune-oncology panel using the proximity extension assay provided by Olink Biosciences. Immunohistochemical staining was performed on 16 patient tumor specimens with a commercial antibody versus FasL.

Results: Fifty-four out of 87 evaluable proteins differed significantly in concentration between serum from patients and serum from healthy controls. FasL concentration in serum was significantly lower in patients compared to controls. Furthermore, chemokine (c-c motif) ligand 4 (CCL4) and interleukin 8 (IL8) were present in significantly higher serum concentration in patients who had progressive disease.  Five of 15 evaluable specimens showed FasL immunoreactivity in the tumor cells and 10 showed immunoreactivity in immune cells.

Conclusion: FasL concentration in serum was significantly lower in patients with pancreatic G3 NENs compared to controls, and the expression in tumor tissue was variable. CCL4 and IL8 correlated to worse prognosis. However, further studies in larger cohorts are needed for evaluation of the true clinical value of these proteins for patients with pancreatic G3 NENs.

Keywords
PEA, FasL, CCL4, IL8, pancreatic neuroendocrine neoplasm, immunohistochemistry
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-382060 (URN)
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-21
4. Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)
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)
Show others...
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: 2019-04-21Bibliographically approved

Open Access in DiVA

fulltext(1120 kB)81 downloads
File information
File name FULLTEXT01.pdfFile size 1120 kBChecksum SHA-512
434172dbd9b47ec7c98c70de99fefcafbfb20ac1b7cd69d1793e3a9859874c284b7679b5db84f540663c01281b4a5d8638e597ee5df8fbc58bc8097730621dcd
Type fulltextMimetype application/pdf
Buy this publication >>

Authority records BETA

Ali, Abir Salwa

Search in DiVA

By author/editor
Ali, Abir Salwa
By organisation
Endocrine Oncology
Clinical Medicine

Search outside of DiVA

GoogleGoogle Scholar
Total: 81 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 192 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf