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  • 51.
    Eriksson, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Selvaraju, Ram K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Kandeel, Fouad
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report2014Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, nr 5, s. 1519-1524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context:

    Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

    Objective:

    To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

    Design:

    Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

    Setting:

    Uppsala University Hospital, Uppsala, Sweden.

    Patients:

    A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

    Interventions:

    The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

    Main Outcome Measures:

    N/A

    Results:

    The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

    Conclusion:

    The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

  • 52.
    Falconi, M.
    et al.
    Univ Vita & Salute, Hosp San Raffaele, Dept Surg, Milan, Italy..
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kaltsas, G.
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol, Athens, Greece..
    Bartsch, D. K.
    Univ Marburg, Dept Surg, Marburg, Germany..
    Capdevila, J.
    Vall dHebron Univ Hosp, Inst Oncol VHIO, Barcelona, Spain..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, Pond St, London NW3 2QG, England..
    Kos-Kudla, B.
    Med Univ Silesia, Dept Endocrinol, Katowice, Poland..
    Kwekkeboom, D.
    Erasmus MC, Div Nucl Med, Dept Internal Med, Rotterdam, Netherlands..
    Rindi, G.
    Univ Cattolica Sacro Cuore, Policlin A Gemelli, Inst Pathol Anat, Rome, Italy..
    Kloeppel, G.
    Tech Univ Munich, Inst Pathol, D-80290 Munich, Germany..
    Reed, N.
    Gartnavel Royal Hosp, Beatson Oncol Ctr, Glasgow, Lanark, Scotland..
    Kianmanesh, R.
    CHU Robert Debre, Dept Surg, Reims, France..
    Jensen, R. T.
    NIH, Digest Dis Branch, Bldg 10, Bethesda, MD 20892 USA..
    ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors2016Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, nr 2, s. 153-171Artikkel i tidsskrift (Fagfellevurdert)
  • 53.
    Ferolla, P.
    et al.
    Umbria Reg Canc Network, Multidisciplinary NET Grp, Dept Med Oncol, Perugia, Italy.;Univ Perugia, Perugia, Italy..
    Brizzi, M. P.
    Univ Turin, Dept Oncol, Turin, Italy..
    Meyer, T.
    Royal Free Hosp, Oncol, London, England.;UCL, London, England..
    Mansoor, W.
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England..
    Mazieres, J.
    Hop Larrey, CHU Toulouse, Med Oncol, Toulouse, France..
    Cao, C. D.
    CHRU Lille, Med Oncol, Lille, France..
    Lena, H.
    Ctr Hosp Univ, Pneumol, Rennes, France..
    Berruti, A.
    Univ Brescia, Med Oncol, Brescia, Italy..
    Damiano, V.
    Azienda Osped Univ Policlin Federico II AOU Feder, Dept Dip Oncol, Endocr Mol Clin, Naples, Italy..
    Buikhuisen, W.
    Netherlands Canc Inst, Dept Thorac Oncol, Amsterdam, Netherlands..
    Stankovic, M.
    Novartis Pharma Serv Inc, Med Affairs, Novi Beograd, Serbia..
    Singh, N.
    Cognizant Technol Solut, PLS Clin Project Mgt, Bombay, Maharashtra, India..
    Chiodini, E.
    Parexel, Clin, Origgio, Italy..
    Gislimberti, G.
    OORE GMO, Gislimberti, Origgio, Italy..
    Öberg, Kjell E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Baudin, E.
    Inst Gustave Roussy, Endocrinol, Villejuif, France..
    Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: Results from the randomized, phase 2 LUNA study2016Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, nr 6, artikkel-id 4160Artikkel i tidsskrift (Fagfellevurdert)
  • 54.
    Ferolla, Piero
    et al.
    Umbria Reg Canc Network, Multidisciplinary NET Grp, Dept Med Oncol, I-06126 Perugia, Italy.;Univ Perugia, Perugia, Italy..
    Brizzi, Maria Pia
    San Luigi Hosp, Dept Oncol, Orbassano, Italy..
    Meyer, Tim
    Royal Free Hosp, Dept Med Oncol, London, England.;UCL, London, England..
    Mansoor, Wasat
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England..
    Mazieres, Julien
    Univ Paul Sabatier, CHU Toulouse, Pneumol, Toulouse, France..
    Do Cao, Christine
    CHRU Lille, Med Oncol, Lille, France..
    Lena, Herve
    Ctr Hosp Univ, Pneumol, Rennes, France..
    Berruti, Alfredo
    Univ Brescia, Med Oncol, Brescia, Italy..
    Damiano, Vincenzo
    Univ Naples Federico II, Mol Canc Therapy, Naples, Italy..
    Buikhuisen, Wieneke
    Netherlands Canc Inst, Dept Thorac Oncol, Amsterdam, Netherlands..
    Gronbaek, Henning
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark..
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Dept Med Oncol, Lyon, France..
    Grohe, Christian
    Evangel Lungenklin Berlin, Thorac Oncol, Berlin, Germany..
    Minotti, Vincenzo
    Osped S Maria Misericordia, Dept Med Oncol, Perugia, Italy..
    Tiseo, Marcello
    Univ Hosp Parma, Med Oncol, Parma, Italy..
    De Castro, Javier
    Hosp La Paz Madrid, Oncol, Madrid, Spain..
    Reed, Nicholas
    Gartnavel Royal Hosp, Clin Oncol, Glasgow, Lanark, Scotland..
    Gislimberti, Gabriella
    Novartis Farma SpA, Origgio, Italy..
    Singh, Neha
    Cognizant Technol Solut, Bombay, Maharashtra, India..
    Stankovic, Miona
    Novartis Pharma Serv Inc, Belgrade, Serbia..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Baudin, Eric
    Inst Gustave Roussy, Endocrine Oncol & Nucl Med, Villejuif, France..
    Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial2017Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, nr 12, s. 1652-1664Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.

    Methods

    LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0–2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.

    Findings

    Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2–55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6–49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1–73·7) in the combination group. The most common grade 1–2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3–4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.

    Interpretation

    The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.

  • 55.
    Fjällskog, Marie-Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Ludvigsen, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Janson, Eva T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors2003Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 20, nr 1, s. 59-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Somatostatin analogs are well established in the treatment of malignant endocrine pancreatic tumors (EPTs). Our goal is to individualize their treatment using receptor-subtype-specific analogs and, therefore, exploring the receptor expression is highly important. We have examined the expression of somatostatin receptor (sst) subtypes 1–5 on tumor cells and in intratumoral vessels in 28 tumor tissues from malignant EPTs with immunohistochemistry using sst-subtype-specific polyclonal antibodies. We found that sst2 and sst4 stained positive in 90% and sst1 in 70% of the tumor tissues, whereas sst3 and sst5 stained positive in only 50% of the tumor tissues. Sst expression in intratumoral vessels was high for sst2 and sst4 (80%), moderate for sst1 (40%), and low for sst3 and sst5 (10%). The ssts were evenly distributed among the different tumor subtypes. However, tumors belonging to the same subgroup of EPTs showed a variable expression of receptor subtypes. No differences in receptor-subtype expression could be seen between poorly and well-differentiated tumors, nor between primary tumors and metastases. Prior medical treatment did not influence sst expression pattern. In conclusion, sst2 and sst4 were expressed in most tumor tissues and intratumoral vessels from EPTs. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the intratumoral vessels. These differences indicate the importance of determining each tumor’s subset of receptors before treatment with receptor-subtype-specific analogs is initiated. The importance of sst expression in intratumoral vessels is not yet known.

  • 56.
    Garcia-Carbonero, Rocio
    et al.
    Univ Complutense, CNIO, Hosp Univ Doce Octubre, Med Oncol Dept.
    Rinke, Anja
    Univ Hosp Marburg UKGM, Div Gastroenterol & Endocrinol.
    Valle, Juan W.
    Univ Manchester, Inst Canc Sci, Christie NHS Fdn Trust, Dept Med Oncol, Manchester.
    Fazio, Nicola
    European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine.
    Caplin, Martyn
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Gorbounova, Vera
    Inst Russian Acad Med Sci, Dept Oncol.
    O'Connor, Juan
    Inst Alexander Fleming, Dept Clin Oncol, Buenos Aires.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol.
    Kulke, Matthew
    Harvard Med Sch, Dana Farber Canc Inst.
    Chen, Jie
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou.
    Falkerby, Jenny
    Uppsala Univ Hosp, Dept Endocrine Oncol.
    Costa, Frederico
    Hosp Sirio Libanes.
    de Herder, Wouter
    Erasmus MC, ENETS Ctr Excellence Rotterdam, Div Endocrinol, Dept Internal Med.
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Med Oncol Dept.
    Pavel, Marianne
    Charite Univ Med Berlin, Campus Virchow Klinikum, Dept Gastroenterol & Hepatol.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Chemotherapy2017Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, nr 3, s. 281-294Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Systemic chemotherapy is indicated in progressive or bulky advanced pancreatic neuroendocrine tumors (NETs) and in grade 3 (G3) neuroendocrine neoplasms (NENs) as per ENETS guidelines. Chemotherapy may be considered in NETs of other sites (lung, thymus, stomach, colon, and rectum) under certain conditions (e.g., when Ki-67 is at a high level [upper G2 range], in rapidly progressive disease and/or after failure of other therapies, or if somatostatin receptor imaging is negative). An ENETS Consensus Conference was held in Antibes (2015) to elaborate guidelines on the standards of care of different diagnostic procedures and therapeutic interventions in NENs. This article provides guidance on chemotherapy including therapeutic indications, dosing schedules, adverse events (including prevention and management), drug interactions, and evaluation of treatment effect for the chemotherapy agents most commonly used in NENs (streptozocin, dacarbazine, fluoropyrimidines, platinum compounds, etoposide, and irinotecan).

  • 57.
    Garske, Ulrike
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fröss-Baron, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Lundin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Khan, Tanweera Shaheena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    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 toxicity2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr 6, s. 970-988Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 58.
    Garske-Roman, Ulrike E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Fröss-Baron, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Favourable outcome after 177Lu-DOTA-octreotate therapy of patients with neuroendocrine of the rectum -an update2014Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, nr S2, s. S211-S211, artikkel-id OP235Artikkel i tidsskrift (Annet vitenskapelig)
  • 59.
    Georgantzi, Kleopatra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, Stockholm, Sweden.
    Jakobson, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Christofferson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma2019Inngår i: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 30, nr 3, s. 173-179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.

    Fulltekst (pdf)
    fulltext
  • 60.
    Ghosal, Suman
    et al.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA.
    Das, Shaoli
    NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA.
    Pang, Ying
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA.
    Gonzales, Melissa K.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA.
    Huynh, Thanh-Truc
    Yang, Yanqin
    NHLBI, DNA Sequencing & Genom Core, NIH, Bldg 10, Bethesda, MD 20892 USA.
    Taieb, David
    Aix Marseille Univ, La Timone Univ Hosp, Dept Nucl Med, Marseille, France;Aix Marseille Univ, European Ctr Res Med Imaging, Marseille, France.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA.
    Shankavaram, Uma T.
    NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA.
    Pacak, Karel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA.
    Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker2020Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, nr 8, s. 2326-2335Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in-depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA-Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine-learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis-free survival. The results were validated in independent samples using RT-PCR. From a pan-cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified five lincRNAs as prognostic markers for metastasis-free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.

  • 61.
    Giandomenico, V
    et al.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Boccherini, M.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala Univ Hosp, Uppsala, Sweden..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala Univ Hosp, Uppsala, Sweden..
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Paganelli, G.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    miR-196a Is Specifically Regulated in FDG-PET Positive and Negative Small Intestinal Neuroendocrine Tumor Patients at Late Stage of Disease2016Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, s. 115-115Artikkel i tidsskrift (Fagfellevurdert)
  • 62.
    Giandomenico, Valeria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Modlin, Irvin M.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Khan, Mohid S.
    Millar, Robert P.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Borlak, Jurgen
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Nielsen, Bengt
    Baltzer, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Waterton, John C.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Improving the Diagnosis and Management of Neuroendocrine Tumors: Utilizing New Advances in Biomarker and Molecular Imaging Science2013Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 98, nr 1, s. 16-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Oberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.

  • 63.
    Giandomenico, Valeria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Thirlwell, Chrissie
    UCL Canc Inst, Med Genom Lab, Canc Res UK, London, England..
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Other Novel Therapies: Biomarkers, microRNAs and microRNA Inhibitors, DNA Methylation, Epigenetics, Immunotherapy and Virotherapy2015Inngår i: Neuroendocrine Tumors: A Multidisciplinary Approach / [ed] Papotti, M; DeHerder, WW, S. Karger, 2015, s. 248-262Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Neuroendocrine tumors (NETs) consist of heterogeneous neoplasms. The neuroendocrine cells of the human body are confined to certain organs, such as the thyroid, pancreas and adrenals, or they are dispersed throughout the body in the respiratory tract and in the intestinal mucosa. The cells belong to the diffuse endocrine cell system, share a neuroendocrine phenotype, and accumulate precursor molecules which are then processed into hormones, peptides or amines. The tightly controlled release on stimulation is either to the blood stream or adjacent cells or neurons. Neuroendocrine cells regulate various processes in the human body, such as gastrointestinal secretion, blood pressure and response to stress. NETs present a wide spectrum of malignant diseases from rather benign to very malignant and lethal variants. NETs may occur in any organ, but are mainly detected in the gastroenteropancreatic system and in the lungs. The understanding of NET biology and treatments has changed dramatically during the last decade. Today, the main problems that clinicians and translational scientists face in overcoming these malignancies relate to various aspects within the molecular pathogenesis of NETs. This chapter focuses on the importance of novel biomarkers: microRNA and microRNA inhibitors; DNA methylation and epigenetics, and immunotherapy and virotherapy to develop novel treatments for NETs.

  • 64. Glasberg, S.
    et al.
    Thomas, D.
    Strosberg, J. R.
    Pape, U. F.
    Felder, S.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Alexandraki, K.
    Fraenkel, M.
    Saiegh, L.
    Reissman, P.
    Kaltsas, G.
    Gross, D. J.
    Metastatic Type 1 Gastric Carcinoid-A Real Threat or Just a Myth?2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 302-302Artikkel i tidsskrift (Annet vitenskapelig)
  • 65. Grimaldi, Franco
    et al.
    Fazio, Nicola
    Attanasio, Roberto
    Frasoldati, Andrea
    Papini, Enrico
    Cremonini, Nadia
    Davi, Mariavittoria
    Funicelli, Luigi
    Massironi, Sara
    Spada, Francesca
    Toscano, Vincenzo
    Versari, Annibale
    Zini, Michele
    Falconi, Massimo
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms2018Inngår i: Endocrine, Metabolic & Immune Disorders - Drug Targets, ISSN 1871-5303, E-ISSN 2212-3873, Vol. 18, nr 5, s. 419-449Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Well-established criteria for evaluating the response to treatment and the appropriate follow-up of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

  • 66.
    Halin Lejonklou, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    The MEN 1 Pancreas: Tumor Development and Haploinsufficiency2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization.

    We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas.

    Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets.

    Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals.

    It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.

    Delarbeid
    1. Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
    Åpne denne publikasjonen i ny fane eller vindu >>Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
    Vise andre…
    2009 (engelsk)Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 38, nr 3, s. 259-266Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES:

    To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.

    METHODS:

    The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.

    RESULTS:

    Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.

    CONCLUSIONS:

    Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.

    Emneord
    MEN1, pancreas, transcription factors, subcellular localization
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-110616 (URN)10.1097/MPA.0b013e3181930818 (DOI)000264763400004 ()19307926 (PubMedID)
    Tilgjengelig fra: 2009-11-18 Laget: 2009-11-18 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    2. Notch signaling factors in the transforming Men1 mouse pancreas
    Åpne denne publikasjonen i ny fane eller vindu >>Notch signaling factors in the transforming Men1 mouse pancreas
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-177595 (URN)
    Tilgjengelig fra: 2012-07-16 Laget: 2012-07-16 Sist oppdatert: 2018-06-04
    3. Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor
    Åpne denne publikasjonen i ny fane eller vindu >>Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor
    2012 (engelsk)Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, nr 6, s. 2588-2598Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-174062 (URN)10.1210/en.2011-1924 (DOI)000304370700011 ()22492302 (PubMedID)
    Tilgjengelig fra: 2012-05-10 Laget: 2012-05-10 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
    Åpne denne publikasjonen i ny fane eller vindu >>Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
    2012 (engelsk)Inngår i: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, nr 6, s. 1411-1418Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND:

    Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated.

    METHODS:

    A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.

    RESULTS:

    Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).

    CONCLUSIONS:

    High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-162584 (URN)10.1007/s00268-011-1345-7 (DOI)000304096800030 ()22089920 (PubMedID)
    Tilgjengelig fra: 2011-12-01 Laget: 2011-12-01 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    Fulltekst (pdf)
    fulltext
  • 67.
    Halin Lejonklou, Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Johansson, Térèse
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Ekeblad, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Notch signaling factors in the transforming Men1 mouse pancreasManuskript (preprint) (Annet vitenskapelig)
  • 68.
    Hoersch, D.
    et al.
    Zentralklin Bad Berka, Dept Internal Med, Bad Berka, Germany..
    Kulke, M. H.
    Dana Farber Canc Inst, Div Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England..
    Anthony, L.
    Univ Kentucky, Div Med Oncol, Chandler Med Ctr, Lexington, KY USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hereditary GI Canc Prevent Program, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Warner, R. R. P.
    Icahn Sch Med Mt Sinai, Div Gastroenterol, New York, NY 10029 USA..
    Kunz, P.
    Stanford Univ, Med Ctr, Div Oncol, Stanford, CA 94305 USA..
    Grande Pulido, E.
    Hosp Univ Ramon y Cajal, Dept Med Oncol, Madrid, Spain..
    Valle, J. W.
    Univ Manchester, Dept Med Oncol, Christie, Manchester, Lancs, England..
    Dillon, J. S.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Jackson, S.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Pavel, M.
    Charite, Dept Gastroenterol & Hepatol Endocrinol & Metab D, Berlin, Germany..
    Efficacy and safety of telotristat ethyl in patients with carcinoid syndrome inadequately controlled by somatostatin analogs: Analysis of the completed TELESTAR extension period2017Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, nr S5, artikkel-id 440PDArtikkel i tidsskrift (Annet vitenskapelig)
  • 69.
    Hrsch, D.
    et al.
    Zent Klin Bad Berka, Bad Berka, Germany..
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, London, England..
    Anthony, L.
    Univ Kentucky, Lexington, KY 40506 USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, C.
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, P.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Valle, J.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    Fleming, D.
    Ipsen BioSci, Cambridge, MA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Pavel, M.
    Charite, Berlin, Germany..
    Efficacy and Safety of Telotristat Etiprate in Patients with Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog Therapy: Analysis of the Ongoing TELESTAR Extension Period2016Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, s. 88-88Artikkel i tidsskrift (Fagfellevurdert)
  • 70.
    Hörsch, Dieter
    et al.
    Zent Klin Bad Berka, Bad Berka, Germany.
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA, USA.
    Caplin, Martyn E.
    Royal Free Hosp, ENETS Ctr Excellence, London, England.
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA.
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY, USA.
    Kunz, Pamela L.
    Stanford Univ, Stanford, CA, USA.
    Grande, Enrique
    Hosp Ramon & Cajal, Madrid, Spain.
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England.
    Dillon, Joseph S.
    Univ Iowa, Iowa City, IA USA.
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Banks, Phillip
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Jackson, Shanna
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Pavel, Marianne
    Charite, Berlin, Germany.;Friedrich Alexander Univ, Nurnberg, Germany..
    Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period2018Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, nr 3, s. 341-342Artikkel i tidsskrift (Annet vitenskapelig)
  • 71.
    Ilan, Ezgi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wassberg, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Garske-Román, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Dose Response of Pancreatic Neuroendocrine Tumors Treated with Peptide Receptor Radionuclide Therapy Using 177Lu-DOTATATE2015Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, nr 2, s. 177-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    UNLABELLED: Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE.

    METHODS: Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors.

    RESULTS: Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose of 170 Gy.

    CONCLUSION: The results imply a significant correlation between absorbed dose and tumor reduction. However, further studies are necessary to address the large variations in response for similar absorbed doses.

  • 72. Kaltsas, Gregory
    et al.
    Grozinsky-Glasberg, Simona
    Alexandraki, Krystallenia I.
    Thomas, Dimitrios
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Gross, David
    Grossman, Ashley B.
    Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms2014Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, nr 2, s. 157-168Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s.

  • 73. Kanakis, G. A.
    et al.
    Grimelius, L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kaltsas, G.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Immunohistochemical Expression of Connective Tissue Growth Factor and Insulin-like Growth Factor-1 in Lung Carcinoids2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 289-290Artikkel i tidsskrift (Annet vitenskapelig)
  • 74. Kanakis, George
    et al.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Spathis, Athanasios
    Tringidou, Rodoula
    Rassidakis, George Z.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Kaltsas, Gregory
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role2015Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, nr 3, s. 211-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

  • 75.
    Karlsson, Filip
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Antonodimitrakis, Pantelis Clewemar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Systematic screening of imaging biomarkers for the Islets of Langerhans, among clinically available positron emission tomography tracers2015Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, nr 10, s. 762-769Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Functional imaging could be utilized for visualizing pancreatic islets of Langerhans. Therefore, we present a stepwise algorithm for screening of clinically available positron emission tomography (PET) tracers for their use in imaging of the neuroendocrine pancreas in the context of diabetes. Methods: A stepwise procedure was developed for screening potential islet imaging agents. Suitable PET-tracer candidates were identified by their molecular mechanism of targeting. Clinical abdominal examinations were retrospectively analyzed for pancreatic uptake and retention. The target protein localization in the pancreas was assessed in silico by -omics approaches and the in vitro by binding assays to human pancreatic tissue. Results: Six putative candidates were identified and screened by using the stepwise procedure. Among the tested PET tracers, only [C-11]5-Hydroxy-tryptophan passed all steps. The remaining identified candidates were falsified as candidates and discarded following in silico and in vitro screening. Conclusions: Of the six clinically available PET tracers identified, [C-11]5-HTP was found to be a promising candidate for beta cell imaging, based on intensity of in vivo pancreatic uptake in humans, and islet specificity as assessed on human pancreatic cell preparations. The flow scheme described herein constitutes a methodology for evaluating putative islet imaging biomarkers among clinically available PET tracers.

  • 76. Kerkhofs, Tm
    et al.
    Baudin, E
    Terzolo, M
    Allolio, B
    Chadarevian, R
    Mueller, Hh
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Leboulleux, S
    Mantero, F
    Haak, Hr
    Fassnacht, M
    Comparison of Two Mitotane Starting dose Regimens in Patients with Advanced Adrenocortical Carcinoma2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 12, s. 2281-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context:

    Mitotane is the only approved drug for treatment of adrenocortical carcinoma(ACC). Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head-to-head.

    Objective:

    To investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens.

    Design/Setting:

    Prospective open-label multicenter trial of a predefined duration of twelve weeks.

    Patients/Interventions:

    Forty mitotane-naïve patients with metastatic ACC were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two could be evaluated in detail.

    Main Outcome Measure:

    Difference in median mitotane plasma levels between both treatment groups.

    Results:

    Despite a difference in mean cumulative dose (440±142g versus 272±121g), median maximum plasma levels were not significantly different between the two groups (high-dose 14.3mg/L (6.3-29.7,n=20) versus 11.3mg/L (5.5-20.0,n=12), p=0.235). Ten out of twenty patients on the high-dose regimen reached plasma concentrations ≥14mg/L after 46 days (18-81 days) compared to four of twelve patients on the low-dose regimen after 55 days (46-74 days,p=0.286). All patients who reached 14mg/L at 12 weeks displayed a level ≥4.1 mg/L on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013±494mg.d/L versus 555±168mg.d/L, p=0.080.

    Conclusions:

    The high-dose starting regimen did neither result in significantly different mitotane levels nor in a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

  • 77.
    Khan, Tanweera Shaheena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    New Diagnostic and Therapeutic Approaches in Adrenocortical Cancer2004Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Adrenocortical cancer (ACC) is a rare disease that is often difficult to diagnose, and therefore often presents at an advanced stage. Various cytotoxic treatments have been tried with little success. Evaluation of new diagnostic methods and improvement of medical therapies are therefore crucial.

    The diagnostic potential of 11C-metomidate positron emission tomography (PET) was evaluated in eleven ACC patients. PET visualized all viable tumors with high tracer uptake, including two lesions that CT failed to detect. Necrotic or fibrotic tumors were PET negative. Medication with adrenal steroid inhibitors and chemotherapy may decrease the tracer uptake.

    We performed a phase-II study with streptozocin and o,p’-DDD (SO) combination therapy in 40 ACC patients. The SO therapy was found to have impact on the disease-free interval (P = 0.02) as well as on survival (P = 0.01) in patients who received adjuvant therapy after curative resection. Complete or partial response was obtained in 36.4% of patients with measurable disease.

    The efficacy and tolerability of combination therapy with vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) were evaluated in eleven patients with advanced ACC after failure of SO therapy. The median survival was 21 months from the start of treatment. A partial response was achieved in two patients. Adverse events were mainly restricted to grade 1-2 toxicities, and grade 3 toxicities were observed in only two cycles.

    We tested 21 ACC tumors to analyze the expression of receptor tyrosine kinases and 15 ACC for mutation analysis of c-Kit exon 11, which can be targeted by antagonists such as imatinib. All ACCs expressed one or more kinases: c-Kit in 19 ACC and phospho-c-Kit in three while 14 ACCs expressed PDGFR-beta, suggesting the potential usefulness of tyrosine kinase inhibitors. No c-Kit mutations were detected in exon 11. Further evaluation of other mutations targeted by this drug may be needed.

    Delarbeid
    1. 11C-metomidate PET imaging of adrenocortical cancer
    Åpne denne publikasjonen i ny fane eller vindu >>11C-metomidate PET imaging of adrenocortical cancer
    Vise andre…
    2003 (engelsk)Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070 (Paper) 1619-7089 (Online), Vol. 30, nr 3, s. 403-410Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-91693 (URN)
    Tilgjengelig fra: 2004-05-03 Laget: 2004-05-03 Sist oppdatert: 2019-02-01
    2. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use
    Åpne denne publikasjonen i ny fane eller vindu >>Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use
    Vise andre…
    2000 (engelsk)Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, nr 10, s. 1281-1287Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND:

    To evaluate the efficacy of streptozocin and o.p'DDD (SO) in adrenocortical cancer (ACC) patients since other chemotherapeutic regimens have limited effects.

    PATIENTS AND METHODS:

    We performed a phase II study with SO therapy in 40 ACC patients (median age 44 years). Oral o,p'DDD administration (1-4 g/d, every day) was given together with intravenous streptozocin (1 g/d for five days, thereafter 2 g once every three weeks). 5HT3-receptor blocker was used as standard premedication for streptozocin.

    RESULTS:

    The SO therapy was found to have significant effects on disease-free interval (P = 0.02) as well as on survival (P = 0.01) in adjuvantly treated cases (n = 17) in comparison to the patients who did not get any therapy after complete resection (n = 11). Complete or partial response was obtained in 36.4% of patients with measurable disease (n = 22). The overall two-year and five-year survival rates were 70% and 32.5%, respectively. The presence of metastases at diagnosis was identified as a poor prognostic factor (P = 0.02).

    CONCLUSIONS:

    The present study necessitates further randomized clinical study of SO therapy in the treatment of ACC, mainly as adjuvant treatment immediately after curative intended surgery, and could be developed into a regular treatment regimen.

    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-91694 (URN)11106117 (PubMedID)
    Tilgjengelig fra: 2004-05-03 Laget: 2004-05-03 Sist oppdatert: 2019-02-01
    3. Vincristine, Cisplatin, Teniposide and Cyclophosphamide Combination in the Treatment of Recurrent or Metastatic Adrenocortical Cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Vincristine, Cisplatin, Teniposide and Cyclophosphamide Combination in the Treatment of Recurrent or Metastatic Adrenocortical Cancer
    Vise andre…
    2004 (engelsk)Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 21, nr 2, s. 167-177Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-91695 (URN)10.1385/MO:21:2:167 (DOI)15299189 (PubMedID)
    Tilgjengelig fra: 2004-05-03 Laget: 2004-05-03 Sist oppdatert: 2019-02-01
    4. Expression of c-Kit, phospho-c-kit, PDGFRβ and absence of c-Kit mutation in exon 11 in adrenocortical cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Expression of c-Kit, phospho-c-kit, PDGFRβ and absence of c-Kit mutation in exon 11 in adrenocortical cancer
    Vise andre…
    (engelsk)Manuskript (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-91696 (URN)
    Tilgjengelig fra: 2004-05-03 Laget: 2004-05-03 Sist oppdatert: 2019-02-01
    Fulltekst (pdf)
    FULLTEXT01
  • 78.
    Kidd, Mark
    et al.
    Yale Univ, Dept Surg, Sch Med, 333 Cedar St, New Haven, CT 06519 USA.
    Modlin, Irvin
    Yale Univ, Dept Surg, Sch Med, 333 Cedar St, New Haven, CT 06519 USA.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms.2016Inngår i: Nature Reviews Clinical Oncology, ISSN 1759-4774, E-ISSN 1759-4782, Vol. 13, nr 11, s. 691-705Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.

  • 79.
    Kulke, M.
    et al.
    Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA..
    Hoersch, D.
    Zent Klin Bad Berka GmbH, Ctr Neuroendocrine Tumors Bad Berka, Gastroenterol & Endocrinol, Bad Berka, Germany..
    Caplin, M.
    Royal Free Hosp, Sch Med, Gastroenterol & Neuroendocrine Tumours, London, England..
    Anthony, L.
    Univ Kentucky, Med Oncol, Lexington, KY USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hematol Oncol, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Warner, R.
    Mt SInai Med Coll, Gastroenterol, New York, NY USA..
    Bohas, C. Lombard
    Hop Edouard Herriot, Med Oncol, Pav E Bis, Lyon, France..
    Kunz, P. L.
    Stanford Univ, Sch Med, Med Oncol, Palo Alto, CA 94304 USA..
    Grande, E.
    Hosp Univ Ramon & Cajal, Med Oncol, Madrid, Spain..
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Med Oncol, Manchester, Lancs, England..
    Lapuerta, P.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Jackson, S.
    Lexicon Pharmaceut Inc, Clin Operat, The Woodlands, TX USA..
    Jiang, W.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Biran, T.
    Lexicon Pharmaceut Inc, Clin Operat, The Woodlands, TX USA..
    Pavel, M.
    Charite, Endocrinol, Berlin, Germany..
    Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome2016Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, nr suppl. 6, artikkel-id 422PDArtikkel i tidsskrift (Fagfellevurdert)
  • 80.
    Kulke, Matthew H.
    et al.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Hoersch, Dieter
    Zentralklin Bad Berka, Bad Berka, Germany..
    Caplin, Martyn
    Royal Free Hosp, Pond St, London NW3 2QG, England..
    Anthony, Lowell
    Univ Kentucky, Lexington, KY USA..
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala Univ, Uppsala, Sweden..
    Warner, Richard
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, Catherine
    Hos Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, Pamela
    Stanford Univ, Palo Alto, CA 94304 USA..
    Grande, Enrique
    Hosp Univ Ramon & Cajal, Madrid, Spain..
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdon Trust, Manchester, Lancs, England..
    Fleming, Douglas
    Ipsen BioSci, Cambridge, MA USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Banks, Phillip
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Jackson, Shanna
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Wheeler, Darren
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Zambrowicz, Brian
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Sands, Arthur
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Pavel, Marianne
    Charite, D-13353 Berlin, Germany..
    Telotristat Etiprate Shows Benefit in Treating Patients With Carcinoid Syndrome That is Inadequately Controlled by Somatostatin Analog Therapy in the Phase 3 TELESTAR Clinical Trial2016Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, nr 3, s. 478-478Artikkel i tidsskrift (Annet vitenskapelig)
  • 81.
    Kulke, Matthew H.
    et al.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Hoersch, Dieter
    Zentralklinik Bad Berka, Bad Berka, Germany..
    Caplin, Martyn E.
    Royal Free Hosp, London, England..
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA..
    Bergsland, Emily
    Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, Pamela L.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Grande, Enrique
    Hosp Univ Ramon y Cajal, Madrid, Spain..
    Valle, Juan W.
    Univ Manchester, Christie Natl Hlth Serv Fdn Trust, Manchester, Lancs, England..
    Fleming, Douglas
    Ipsen Biosci, Cambridge, MA USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Banks, Phillip
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Jackson, Shanna
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Zambrowicz, Brian
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Sands, Arthur T.
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Pavel, Marianne
    Charite, Berlin, Germany..
    Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome2017Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 35, nr 1, s. 14-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1: 1: 1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg (P < .001) and -0.69 for telotristat ethyl 500 mg (P,.001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction >= 30% from baseline for >= 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 (P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

  • 82.
    Lamarca, A.
    et al.
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Ronot, M.
    Beujon Univ Hosp, Dept Radiol, Clichy, France.
    Opalinska, M.
    Univ Hosp, Dept Endocrinol, Nucl Med Unit, Krakow, Poland.
    Lopez Lopez, C.
    Hosp Univ Marques de Valdecilla, Dept Med Oncol, Santander, Spain.
    Pezzutti, D.
    Israelita Albert Einstein Hosp, Dept Radiol, Sao Paulo, Brazil.
    Najran, P.
    Christie NHS Fdn Trust, Dept Radiol, Manchester, Lancs, England.
    Franca, R.
    Sirio Libanes Hosp, Dept Radiol, Sao Paulo, Brazil.
    Scaefer, N.
    CHUV Univ Hosp, Dept Med Oncol, Lausanne, Switzerland.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pavel, M.
    Univ Klinikum Erlangen, Dept Endocrinol, Erlangen, Germany.
    Dromain, C.
    CHUV Univ Hosp, Dept Radiol, Lausanne, Switzerland.
    Value of Tumor Growth Rate (TGR) as an Early Predictor of Patients' Outcome in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs): The Greponet Study2018Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, nr Supplement: 1, s. 178-178Artikkel i tidsskrift (Annet vitenskapelig)
  • 83.
    Lamarca, Angela
    et al.
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom .
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Ronot, Maxime
    Department of Radiology, Beaujon University Hospital, Clichy, France .
    Opalinska, Marta
    Nuclear Medicine Unit, Department of Endocrinology, University Hospital, Krakow, Poland .
    Lopez Lopez, Carlos
    Department of Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain .
    Pezzutti, Daniela
    Department of Radiology, Israelita Albert Einstein Hospital, Sao Paulo, Brazil .
    Najran, Pavan
    Department of Radiology, The Christie NHS Foundation Trust, Manchester, United Kingdom .
    Carvhalo, Luciana
    Department of Medical Oncology, Sirio‐Libanes Hospital, Sao Paulo, Brazil .
    Franca Bezerra, Regis Otaviano
    Department of Radiology, Sirio‐Libanes Hospital, Sao Paulo, Brazil ; São Paulo Cancer Institute Octavio Frias de Oliveira, Sao Paulo, Brazil .
    Borg, Philip
    Department of Radiology, The Christie NHS Foundation Trust, Manchester, United Kingdom .
    Vietti Violi, Naik
    Department of Radiology, CHUV University Hospital, Lausanne, Switzerland .
    Vidal Trueba, Hector
    Department of Radiology, Hospital Universitario Marques de Valdecilla, Santander, Spain .
    de Mestier, Louis
    Department of Gastroenterology, Beaujon University Hospital, Clichy, France.
    Schaefer, Niklaus
    Department of Medical Oncology, CHUV University Hospital, Lausanne, Switzerland .
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Costa, Frederico
    Department of Medical Oncology, Sirio‐Libanes Hospital, Sao Paulo, Brazil.
    Pavel, Marianne
    Department of Medicine 1, Division of Endocrinology, Friedrich‐Alexander University Erlangen‐Nürnberg, Erlangen, Germany.
    Dromain, Clarisse
    Department of Radiology, CHUV University Hospital, Lausanne, Switzerland .
    Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET): The GREPONET Study2019Inngår i: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 24, nr 11, s. E1082-E1090Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications.

    MATERIALS AND METHODS: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m).

    RESULTS: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS.

    CONCLUSION: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up.

    IMPLICATIONS FOR PRACTICE: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

  • 84. Lamarca, Angela
    et al.
    Ronot, Maxime
    Moalla, Salma
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Opalinska, Marta
    Lopez Lopez, Carlos
    Pezzutti, Daniela
    Najran, Pavan
    Carvalho, Luciana Franco do Prado de
    Bezerra, Regis Otaviano Franca
    Borg, Philip
    Vietti Violi, Naik
    Vidal Trueba, Hector
    de Mestier, Louis
    Schaefer, Niklaus
    Baudin, Eric
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Costa, Frederico P
    Pavel, Marianne
    Dromain, Clarisse
    Tumour Growth Rate as a validated early radiological biomarker able to reflect treatment-induced changes in Neuroendocrine Tumours: the GREPONET-2 study2019Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, nr 25, s. 6692-6699Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: TGR represents the percentage change in tumour volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in NETs.

    EXPERIMENTAL DESIGN: Pts from7 centres with advanced grade(G) 1/2 NETs from the pancreas(P)/small bowel(SB) initiating ST/WW were eligible. Computed tomography (CT) / magnetic resonance imaging (MRI) performed at pre-baseline, baseline and 3(+/-1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL) (paired T-test) and Aim-2: validate TGR3m (<0.8%/m vs ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox Regression).

    RESULTS: Out of 785 pts screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean(SD) ΔTGR3m-BL paired-difference was -6.8%/m(19.3) (p<0.001). Most marked ΔTGR3m-BL (mean (SD);p) were identified with targeted therapies (-11.3%/m(4.7);0.0237) and chemotherapy (-7.9%/m(3.4);0.0261). Multivariable analysis confirmed the absence of previous treatment (Odds Ratio (OR) 4.65 (95%CI 1.31-16.52); p-value0.018) and low TGR3m (continuous variable; OR 1.09 (95%CI 1.01-1.19); p-value0.042) to be independent predictors of radiological objective response. When the multivariable Cox Regression was adjusted to grade (p-value 0.004) and stage (p-value0.017), TGR3m≥0.8 (vs.<0.8) maintained its significance (p<0.001), while TGR0 and ΔTGR3m-BL did not. TGR3m was confirmed as an independent prognosis factor for PFS (external validation; Aim-2) (multivariable HR 2.21 (95%CI 1.21-3.70); p-value0.003).

    CONCLUSIONS: TGR has a role as biomarker for monitoring response to therapy for early prediction of PFS and radiological objective response.

  • 85.
    Lapuerta, P.
    et al.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Kulke, M. H.
    Dana Farber Canc Inst, Gastrointestinal Canc Treatment Ctr, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hereditary GI Canc Prevent Program, San Francisco, CA USA..
    Anthony, L.
    Univ Kentucky, Chandler Med Ctr, Div Med Oncol, Lexington, KY USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Pavel, M.
    Charite, Dept Gastroenterol & Hepatol Endocrinol & Metab D, Berlin, Germany..
    Hoersch, D.
    Zentralklin Bad Berka, Dept Internal Med, Bad Berka, Germany..
    O'Dorisio, T. M.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Dillon, J. S.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Kassler-Taub, K.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Jiang, W.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Long-term survival of patients with carcinoid syndrome in clinical trials of telotristat ethyl2017Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, nr S5, artikkel-id 442PArtikkel i tidsskrift (Annet vitenskapelig)
  • 86.
    Li, Su-Chen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Khan, Mohid
    Caplin, Martyn
    Meyer, Tim
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0125553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.

    Fulltekst (pdf)
    fulltext
  • 87.
    Malczewska, Anna
    et al.
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Katowice, Poland..
    Kidd, Mark
    Wren Labs, Branford, CT USA..
    Matar, Somer
    Wren Labs, Branford, CT USA..
    Kos-Kudla, Beata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Katowice, Poland..
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Modlin, Irvin M.
    Yale Univ, Sch Med, New Haven, CT USA..
    An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Systematic Review and Meta-Analysis2020Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 110, nr 3-4, s. 198-216Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background: Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors.

    Objectives: To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence.

    Methods: A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology.

    Results: Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1-200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 +/- 2.7% with a specificity of 93.8 +/- 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 x ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5-251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 +/- 6.8% and specificity 79.4 +/- 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 +/- 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified.

    Conclusion: The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.

  • 88.
    Malczewska, Anna
    et al.
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    Witkowska, Magdalena
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    Makulik, Karolina
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    Bocian, Agnes
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    Walter, Agata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    Pilch-Kowalczyk, Joanna
    Med Univ Silesia, Dept Radiol & Nucl Med, Katowice, Poland.
    Zajecki, Wojciech
    Med Univ Silesia, Dept Pathol Zabrze, Katowice, Poland.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, Mol Imaging & Therapy Serv, Dept Radiol, 1275 York Ave, New York, NY 10021 USA.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kos-Kudla, Beata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Dept Pathophysiol & Endocrinol, Katowice, Poland.
    NETest liquid biopsy is diagnostic of small intestine and pancreatic neuroendocrine tumors and correlates with imaging2019Inngår i: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 8, nr 4, s. 442-453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Current monoanalyte biomarkers are ineffective in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). NETest, a novel multianalyte signature, provides molecular information relevant to disease biology. Aim(s): Independently validate NETest to diagnose GEP-NETs and identify progression in a tertiary referral center. Materials and methods: Cohorts are 67 pancreatic NETs (PNETs), 44 small intestine NETs (SINETs) and 63 controls. Well-differentiated (WD) PNETs, n = 62, SINETs, all (n = 44). Disease extent assessment at blood draw: anatomical (n = 110) CT (n = 106), MRI (n = 7) and/or functional Ga-68-SSA-PET/CT (n = 69) or F-18-FDG-PET/CT (n = 8). Image-positive disease (IPD) was defined as either CT/MRI or Ga-68-SSA-PET/CT/F-18-FDG-PET/CT-positive. Both CT/MRI and Ga-68-SSA-PET/CT negative diagnosis in WD-NETs was considered image-negative disease (IND). NETest (normal: 20): PCR (spotted plate s). Data: mean +/- SD. Results: Diagnosis: NETest was significantly increased in NETs (n = 111; 26 +/- 21) vs controls (8 +/- 4, p < 0.0001). Seventy-five (42 PNET, 33 SINET) were image positive. Eleven (8 PNET, 3 SINET; all WD) were IND. In IPD, NETest was significantly high er (36 +/- 22) vs IND (8 +/- 7, P < 0.0001). NETest accuracy, sensitivity and specificity are 97, 99 and 95%, respectively. Concordance with imaging: NETest was 92% (101/110) concordant with anatomical imaging, 94% (65/69) with Ga-68-SSA-PET/CT and 96% (65/68) dual modality (CT/MRI and Ga-68-SSA-PET/CT). In 70 CT/MRI positive, NETest was elevated in all (37 +/- 22). In 40 CT/MRI negative, NETest was normal (11 +/- 10) in 31. In 56 Ga-68-SSA-PET/CT positive, NETest was elevated (36 +/- 22) in 55. In 13 Ga-68-SSA-PET/CT negative, NETest was normal (9 +/- 8) in ten. Disease status: NETest was significantly higher in progressive (61 +/- 26; n = 11) vs stable disease (29 +/- 14; n = 64; P < 0.0001) (RECIST 1.1). Conclusion: NETest is an effective diagnostic for PNETs and SINETs. Elevated NETest is as effective as imaging in diagnosis and accurately identifies progression.

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  • 89.
    Malczewska, Anna
    et al.
    Yale Univ, Sch Med, New Haven, CT USA;Med Univ Silesia, Katowice, Poland.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Univ Hosp, SE-75185 Uppsala, Sweden.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
    Aslanian, Harry
    Yale Univ, Sch Med, New Haven, CT USA.
    Lewczuk, Anna
    Med Univ Gdansk, Gdansk, Poland.
    Filosso, Pier Luigi
    Univ Turin, Turin, Italy.
    Wojcik-Giertuga, Monika
    Med Univ Silesia, Katowice, Poland.
    Rydel, Mateusz
    Med Univ Silesia, Katowice, Poland.
    Zielinska-Les, Izabela
    Med Univ Silesia, Katowice, Poland.
    Walter, Agata
    Med Univ Silesia, Katowice, Poland.
    Suarez, Alejandro L.
    Yale Univ, Sch Med, New Haven, CT USA.
    Kolasinska-Cwikla, Agnieszka
    Inst Oncol, Warsaw, Poland.
    Roffinella, Matteo
    Univ Turin, Turin, Italy.
    Jamidar, Priya
    Yale Univ, Sch Med, New Haven, CT USA.
    Ziora, Dariusz
    Med Univ Silesia, Katowice, Poland.
    Czyzewski, Damian
    Med Univ Silesia, Katowice, Poland.
    Kos-Kudla, Beata
    Med Univ Silesia, Katowice, Poland.
    Cwikla, Jaroslaw
    Univ Warmia & Mazury, Olsztyn, Poland.
    NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease2019Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, nr 3, s. 219-231Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status.

    Aim: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study.

    Material and Methods: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means +/- SD.

    Results: NETest levels were significantly increased in BPC (45 +/- 25) versus controls (9 +/- 8; p < 0.0001). The area under the ROC curve was 0.96 +/- 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 +/- 32) and LCNEC (28 +/- 7). NETest accurately distinguished progressive (61 +/- 26) from stable disease (35.5 +/- 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 +/- 21) and SCC (12 +/- 11) and benign disease (IPF) (18 +/- 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31).

    Conclusions: Elevated - NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.

  • 90.
    Matar, Somer
    et al.
    Wren Labs, Branford, CT USA..
    Malczewska, Anna
    Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT USA.;Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Katowice, Poland..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Aslanian, Harry
    Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT USA..
    Lewczuk-Myslicka, Anna
    Med Univ Gdansk, Dept Endocrinol & Internal Med, Gdansk, Poland..
    Filosso, Pier Luigi
    Univ Turin, Dept Thorac Surg, Turin, Italy..
    Suarez, Alejandro L.
    Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT USA..
    Kolasinska-Cwikla, Agnieszka
    Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland..
    Roffinella, Matteo
    Univ Turin, Dept Thorac Surg, Turin, Italy..
    Kos-Kudla, Beata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Tumors, Katowice, Poland..
    Cwikla, Jaroslaw B.
    Univ Warmia & Mazury, Dept Radiol, Olsztyn, Poland..
    Drozdov, Ignat A.
    Wren Labs, Branford, CT USA..
    Kidd, Mark
    Wren Labs, Branford, CT USA..
    Modlin, Irvin M.
    Yale Univ, Sch Med, Gastroenterol & Endoscop Surg, New Haven, CT USA..
    Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms2020Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 110, nr 3-4, s. 185-197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN.

    Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study.

    Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (+/- 25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISA(TM) kit (EuroDiagnostica).

    Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 +/- 0.05 p = 0.015. Test set the data were AUC 0.58 +/- 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 +/- 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 +/- 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression).

    Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

  • 91.
    Monazzam, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Razmara, Masoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

    Fulltekst (pdf)
    fulltext
  • 92.
    Monazzam, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Razifar, Pasha
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Centrum för bildanalys.
    Lindhe, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Josephsson, Raymond
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Långström, Bengt
    Bergström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A new, fast and semi-automated size determination method (SASDM) for studying multicellular tumor spheroids2005Inngår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, nr 5, s. 32-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation.

    RESULTS:

    SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining.

    CONCLUSION:

    The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments.

  • 93.
    Monazzan, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Chu, Xia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    MicroRNA Expression Profiling in adrenals of Multiple Endocrine Neoplasia type 1 MiceManuskript (preprint) (Annet vitenskapelig)
  • 94.
    Monazzma, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Razifar, Pasha
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Centrum för bildanalys.
    Simonsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Qvarnström, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Josephsson, Raymond
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Långström, Bengt
    Bergström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring2006Inngår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 6, s. 6-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    In order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.

    Methods

    The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.

    Results

    The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).

    Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.

    Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.

    No effect of Imatinib was observed.

    Conclusion

    MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.

    The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.

    In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.

  • 95.
    Muth, A.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, Gothenburg, Sweden.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Gimm, O.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Surg, Linkoping, Sweden.
    Elmgren, A.
    Sahlgrens Univ Hosp, Clin Chem, Gothenburg, Sweden.
    Filipsson, K.
    Skane Univ Hosp, Endocrinol, Lund, Sweden.
    Askmalm, M. Stenmark
    Off Med Serv, Div Lab Med, Dept Clin Genet, Lund, Sweden.
    Sandstedt, J.
    Sahlgrens Univ Hosp, Clin Chem, Gothenburg, Sweden.
    Tengvar, M.
    Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden.
    Tham, E.
    Karolinska Univ Hosp, Clin Genet, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma2019Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, nr 2, s. 187-204Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

  • 96. Nicolaou, Argyro
    et al.
    Thomas, Dimitrios
    Alexandraki, Krystallenia I.
    Sougioultzis, Stavros
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kaltsas, Gregory
    Predictive Value of Gastrin Levels for the Diagnosis of Gastric Enterochromaffin-Like Cell Hyperplasia in Patients with Hashimoto's Thyroiditis2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 2, s. 118-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT. Methods: A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B-12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophago-gastroduodenoscopy- obtained biopsies. Results: Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity x specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B-12 levels (96.1% specificity). Conclusion: Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B-12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up. 

  • 97. Nikolaou, A.
    et al.
    Thomas, D.
    Alexandraki, K.
    Sougioultzis, S.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kaltsas, G.
    The Predictive Value of Gastrin Levels for the Diagnosis of Gastric Enterochromaffin-like Cells Hyperplasia, in Patients with Hashimoto's Thyroiditis2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 256-256Artikkel i tidsskrift (Annet vitenskapelig)
  • 98. Paulsson, Johan O.
    et al.
    Backman, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Wang, Na
    Stenman, Adam
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Thutkawkorapin, Jessada
    Ghaderi, Mehran
    Tham, Emma
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Zedenius, Jan
    Juhlin, C. Christofer
    Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation2020Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 250, nr 2, s. 183-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole‐genome sequencing (WGS). The FTC displayed mutations in CALRRB1, and MSH2, and the PDTC exhibited mutations in TP53DROSHAAPCTERT, and additional DNA repair genes – associated with an immense increase in sub‐clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53‐associated regulation of DNA repair and identified important sub‐clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer.

  • 99.
    Pavel, M. E.
    et al.
    Charite, Dept Hepatol & Gastroenterol, Campus Virchow Klinikum, D-13353 Berlin, Germany..
    Baudin, E.
    Inst Gustave Roussy, Dept Nucl Med & Endocrine Oncol, Villejuif, France..
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Hainsworth, J. D.
    Sarah Cannon Res Inst, Nashville, TN USA..
    Voi, M.
    Novartis Pharmaceut, E Hanover, NJ USA..
    Rouyrre, N.
    Novartis Int AG, Basel, Switzerland..
    Peeters, M.
    Antwerp Univ Hosp, Dept Oncol, Edegem, Belgium..
    Gross, D. J.
    Hadassah Hebrew Univ, Med Ctr, Neuroendocrine Tumor Unit, Jerusalem, Israel..
    Yao, J. C.
    Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Div Canc Med, Houston, TX 77030 USA..
    Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study2017Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, nr 7, s. 1569-1575Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the pre-specified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2.

    Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated.

    Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm.

    Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov

  • 100.
    Pavel, M. E.
    et al.
    Univ Klinikum Erlangen, Erlangen, Germany..
    Gable, J.
    Clin Outcomes Solut, Tucson, AZ USA..
    Kulke, M. H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Anthony, L. B.
    Univ Kentucky, Lexington, KY 40506 USA..
    Caplin, M. E.
    Royal Free Hosp, London, England..
    Öberg, Kjell E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Banks, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Yang, Q. M.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Hudgens, S.
    Clin Outcomes Solut, Tucson, AZ USA..
    Evaluation of meaningful change in bowel move frequency for patients with carcinoid syndrome2017Inngår i: ONCOLOGY RESEARCH AND TREATMENT, ISSN 2296-5270, Vol. 40, s. 238-238Artikkel i tidsskrift (Annet vitenskapelig)
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