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  • 1.
    Ali, Abir A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Hjortland, G. O.
    Univ Oslo, Dept Oncol, Oslo, Norway.
    Grønbæk, H.
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Ladekarl, M.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Langer, S. W.
    Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Vestermark, L. W.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Österlund, P.
    Tampere Helsinki Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Helsinki Univ, Tampere, Finland.
    Knigge, U.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark; Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.
    Sørbye, H.
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway; Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Intravenous versus Oral Etoposide: Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)2018Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, nr Supplement: 1, s. 184-184Artikkel i tidsskrift (Annet vitenskapelig)
  • 2.
    Ali, Abir Salwa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3: Biological and Clinical Aspects2019Doktoravhandling, med artikler (Annet vitenskapelig)
    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. 

     

     

     

    Delarbeid
    1. Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
    Åpne denne publikasjonen i ny fane eller vindu >>Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
    Vise andre…
    2017 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikkel-id e0187667Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-341933 (URN)10.1371/journal.pone.0187667 (DOI)000414572100031 ()29112960 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society, CAN558/2014
    Tilgjengelig fra: 2018-02-16 Laget: 2018-02-16 Sist oppdatert: 2019-04-21bibliografisk kontrollert
    2. PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
    Åpne denne publikasjonen i ny fane eller vindu >>PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    PD-L1, immune check inhibitors, G3 GEP-NEN, immunohistochemistry
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-382058 (URN)
    Tilgjengelig fra: 2019-04-18 Laget: 2019-04-18 Sist oppdatert: 2019-04-21
    3. Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
    Åpne denne publikasjonen i ny fane eller vindu >>Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    PEA, FasL, CCL4, IL8, pancreatic neuroendocrine neoplasm, immunohistochemistry
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-382060 (URN)
    Tilgjengelig fra: 2019-04-18 Laget: 2019-04-18 Sist oppdatert: 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)
    Åpne denne publikasjonen i ny fane eller vindu >>Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)
    Vise andre…
    2018 (engelsk)Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, nr 4, artikkel-id 47Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Springer, 2018
    Emneord
    Chemotherapy, Intravenous, Oral, Etoposide, Neuroendocrine neoplasms, WHO G3
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-351690 (URN)10.1007/s12032-018-1103-x (DOI)000428784500004 ()29511910 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society, CAN558/2014
    Tilgjengelig fra: 2018-06-04 Laget: 2018-06-04 Sist oppdatert: 2019-04-21bibliografisk kontrollert
  • 3. Ali, Abir Salwa
    PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine NeoplasmsManuskript (preprint) (Annet vitenskapelig)
    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.

  • 4.
    Ali, Abir Salwa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Serum biomarkers in Pancreatic G3 Neuroendocrine NeoplasmsManuskript (preprint) (Annet vitenskapelig)
    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.

  • 5.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, Bergen, Norway.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikkel-id e0187667Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Langer, Seppo W.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Ladekarl, Morten
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Hjortland, Geir Olav
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Vestermark, Lene Weber
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Österlund, Pia
    Tampere Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Univ, Tampere, Finland.;Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Gronbaek, Henning
    Aarhus Univ Hosp, Dept Hepatol, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Gastroenterol, Aarhus, Denmark..
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Janson, Eva Tiensuu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)2018Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, nr 4, artikkel-id 47Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7.
    Alit, Abir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, s. 43-43Artikkel i tidsskrift (Fagfellevurdert)
  • 8.
    Dumanski, Jan P.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rasi, Chiara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Davies, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ali, Abir S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Sorbye, Halfdan
    Grønbæk, Henning
    Cunningham, Janet L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Forsberg, Lars A.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors2017Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, nr 8, s. 427-443Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    Söderquist, Fanny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Alit, Abir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Cunningham, Janet L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 10, artikkel-id e0164354Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/ Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.

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