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Pancreatic Neoplasms: HELP
Articles by Dr. K Oberg
Based on 25 articles published since 2010
(Why 25 articles?)

Between 2010 and 2020, K. Oberg wrote the following 25 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Guideline None 2018

Grimaldi, Franco / Fazio, Nicola / Attanasio, Roberto / Frasoldati, Andrea / Papini, Enrico / Cremonini, Nadia / Davi, Maria V / Funicelli, Luigi / Massironi, Sara / Spada, Francesca / Toscano, Vincenzo / Versari, Annibale / Zini, Michele / Falconi, Massimo / Oberg, Kjell. ·Endocrinology and Metabolic Disease Unit, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumor, European Institute of Oncology, Milan, Italy. · Endocrinology Service, Galeazzi Institute IRCCS, Milan, Italy. · Endocrinology Unit, Azienda Ospedaliera S. Maria Nuova IRCCS, Reggio Emilia, Italy. · Department of Endocrinology and Metabolic Diseases, Regina Apostolorum Hospital, Albano Laziale (Rome), Italy. · Endocrinology Clinics, Clinica Villalba, Bologna, Italy. · Section of Endocrinology, Medicina Generale e Malattie Aterotrombotiche e Degenerative, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Division of Radiology, European Institute of Oncology, Milan, Italy. · Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. · Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. · Nuclear Medicine Unit, Azienda Ospedaliera S. Maria Nuova IRCCS, Reggio Emilia, Italy. · Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy. · Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. ·Endocr Metab Immune Disord Drug Targets · Pubmed #29237387.

ABSTRACT: Well-established criteria for evaluating the response to treatment and the appropriate followup 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.

2 Guideline ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. 2016

Pavel, M / O'Toole, D / Costa, F / Capdevila, J / Gross, D / Kianmanesh, R / Krenning, E / Knigge, U / Salazar, R / Pape, U-F / Öberg, K / Anonymous6200853. ·Charite Virchow Klinikum, Berlin, Germany. ·Neuroendocrinology · Pubmed #26731013.

ABSTRACT: -- No abstract --

3 Guideline Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2012

Öberg, K / Knigge, U / Kwekkeboom, D / Perren, A / Anonymous1821075. ·Department of Endocrine Oncology, University Hospital, Uppsala University, Uppsala, Sweden. ·Ann Oncol · Pubmed #22997445.

ABSTRACT: -- No abstract --

4 Guideline Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2010

Oberg, K / Akerström, G / Rindi, G / Jelic, S / Anonymous7691072. ·Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. ·Ann Oncol · Pubmed #20555086.

ABSTRACT: -- No abstract --

5 Guideline Nordic Guidelines 2010 for diagnosis and treatment of gastroenteropancreatic neuroendocrine tumours. 2010

Janson, Eva Tiensuu / Sørbye, Halfdan / Welin, Staffan / Federspiel, Birgitte / Grønbaek, Henning / Hellman, Per / Mathisen, Oystein / Mortensen, Jann / Sundin, Anders / Thiis-Evensen, Espen / Välimäki, Matti J / Oberg, Kjell / Knigge, Ulrich. ·Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Tiensuu_Janson@medsci.uu.se ·Acta Oncol · Pubmed #20553100.

ABSTRACT: The diagnostic work-up and treatment of patients with neuroendocrine tumours has undergone a major change during the last decade. New diagnostic possibilities and treatment options have been developed. These Nordic guidelines, written by a group with a major interest in the subject, summarises our current view on how to diagnose and treat these patients. The guidelines are meant to be useful in the daily practice for clinicians handling patients with neuroendocrine tumours.

6 Review Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future. 2016

Öberg, Kjell / Lamberts, Steven W J. ·University HospitalUppsala, Sweden kjell.oberg@medsci.uu.se. · Erasmus Medical CenterRotterdam, The Netherlands. ·Endocr Relat Cancer · Pubmed #27697899.

ABSTRACT: Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.

7 Review Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. 2016

Kidd, Mark / Modlin, Irvin / Öberg, Kjell. ·Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06519, USA. · Department of Endocrine Oncology, Uppsala University Hospital, Entrance 40, 5th floor, SE-751 85 Uppsala, Sweden. ·Nat Rev Clin Oncol · Pubmed #27273044.

ABSTRACT: 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.

8 Review Neuroendocrine gastro-enteropancreatic tumors - from eminence based to evidence-based medicine - A Scandinavian view. 2015

Öberg, Kjell. ·Department of Endocrine Oncology, Uppsala University Hospital , Entrance 40, 5th floor, SE-751 85 Uppsala , Sweden. ·Scand J Gastroenterol · Pubmed #25855088.

ABSTRACT: Neuroendocrine tumors (NETs) comprise a heterogenous group of neoplasms with variable clinical expression and progression. The primary tumors most frequently occur in the lungs, intestine and the pancreas. The NET incidence is approximately 6.1/100,000 per year with a prevalence higher than 35/100,000 per year. A NET may be functioning with symptoms related to hormone overproduction or non-functioning, not presenting any hormone-related symptoms. From the early 1980s and onwards, Uppsala University Hospital has contributed significantly to diagnosis, just to mention immunohistochemistry, radio-immunoassays for hormones and peptides and molecular imaging. On the therapeutic side, treatments with cytotoxics as well as biologicals such as, somatostatin analogs and interferons have been evaluated. We have furthermore been involved in important phase III trials for registration of so called, new targeted agents such as, RADIANT-3 and RADIANT-2. Our group were also the first to localize the gene for MEN I on chromosome 11 locus q13. Most recent developments have been the establishments of new biomarkers such as, olfactory receptor E51E1 as well as micro-RNAs in carcinoid tumors of the intestine and lung. A new oncolytic virus, Ad-Vince, for treatment of most NETs has been developed and is ready for the clinic. Furthermore, we have been involved in establishing Nordic and international collaborations. Today, NETs is an area with rapid development and recognized by international organizations at conferences, with large attendance. The Nordic countries continue to be significant contributors to the field.

9 Review Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors. 2014

Toumpanakis, Christos / Kim, Michelle K / Rinke, Anja / Bergestuen, Deidi S / Thirlwell, Christina / Khan, Mohid S / Salazar, Ramon / Oberg, Kjell. ·Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK. ·Neuroendocrinology · Pubmed #24458014.

ABSTRACT: Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 ((68)Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 ((11)C)-5-hydroxy-L-tryptophan (5-HTP) PET and (18)F-dihydroxyphenylalanine ((18)F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of (68)Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, (18)F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, (18)F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. (18)F-FDG PET and (68)Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.

10 Review Neuroendocrine tumours in 2012: Insights into signalling pathways could individualize therapy. 2013

Oberg, Kjell. ·Department of Endocrine Oncology, University Hospital of Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Nat Rev Endocrinol · Pubmed #23296177.

ABSTRACT: Neuroendocrine tumours are a heterogeneous group of neoplasms with various clinical presentations, growth rates and responses to available therapies. Studies published in 2012 have provided insights into tumour-cell signalling that will increase our knowledge of tumour biology and molecular genetics, making it possible to personalize patient care.

11 Review Biotherapies for GEP-NETs. 2012

Öberg, Kjell. ·Dept. of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Best Pract Res Clin Gastroenterol · Pubmed #23582922.

ABSTRACT: IN CONCLUSION: Somatostatin analogues and alpha interferons are still playing an important role and considered to be first-line treatment in functioning and in non-functioning well-differentiated NETs, (G1-tumours) and somatostatin analogues might also be applied to control clinical symptoms in G2-tumours with higher proliferation.

12 Review Neuroendocrine tumors of the digestive tract: impact of new classifications and new agents on therapeutic approaches. 2012

Oberg, Kjell. ·Department of Endocrine Oncology, Uppsala University, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Curr Opin Oncol · Pubmed #22510940.

ABSTRACT: PURPOSE OF REVIEW: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute a diverse group of neoplasms arising from the diffuse neuroendocrine cell system. During the last 2 years a new classification system, the WHO 2010, has come into clinical practice together with Tumor Nodes Metastases (TNM) staging and grading systems, developed by the European Neuroendocrine Tumor Society/American Joint Cancer Committee. At the same time new targeted agents have been developed for treatment of GEP-NETs and it is important discuss these new agents in relation to the classification and staging system. RECENT FINDINGS: The current article is reviewing the most important clinical trials of targeting agents within the field of neuroendocrine tumors. Tyrosine kinase inhibitors as well as PI3 kinase mTOR inhibitors have been applied in the treatment of neuroendocrine tumors. SUMMARY: Sunitinib and everolimus have recently been registered for treatment of pancreatic neuroendocrine tumors worldwide. The role of these new targeted agents in the treatment algorithm of neuroendocrine tumors will be discussed. A large number of phase I and phase II trials have been performed in GEP-NETs with rather limited results and no significant impact on the clinical management of patients with GEP-NETs. However, there are two phase III trials that have completely changed the treatment landscape for pancreatic neuroendocrine tumors, e.g., sunitinib and everolimus demonstrating an increased progression free survival of 11 vs. 5 months for the placebo group.

13 Review Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors. 2011

Lindholm, D P / Oberg, K. ·Department of Endocrine Oncology, Uppsala University Hospital, Sweden. daniel.lindholm@medsci.uu.se ·Horm Metab Res · Pubmed #22009449.

ABSTRACT: Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

14 Review Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. 2011

Oberg, Kjell. ·Department of Endocrine Oncology, University Hospital, Entrance 78, SE-751 85 Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Endocr Relat Cancer · Pubmed #22005113.

ABSTRACT: -- No abstract --

15 Review Pancreatic endocrine tumors. 2010

Oberg, Kjell. ·Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Semin Oncol · Pubmed #21167379.

ABSTRACT: Pancreatic endocrine tumors have been steadily growing in incidence and prevalence during the last two decades, showing an incidence of 4-5/1,000,000 population. They represent a heterogeneous group with very varying tumor biology and prognosis. About half of the patients present clinical symptoms and syndromes related to substances released from the tumors (Zollinger-Ellison syndrome, insulinoma, glucagonoma, etc) and the other half are so-called nonfunctioning tumors mainly presenting with symptoms such as obstruction, jaundice, bleeding, and abdominal mass. Ten percent to 15% of the pancreatic endocrine tumors are part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau (VHL), neurofibromatosis, or tuberousclerosis. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. Moreover, the biochemical diagnosis includes measurement of chromogranins A and B or specific hormones such as gastrin, insulin, glucagon, and vasoactive intestinal polypeptide (VIP) in the circulation. In addition to standard localization procedures, radiology (computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasound [US]), somatostatin receptor scintigraphy, and most recently positron emission tomography with specific isotopes such as (11)C-5 hydroxytryptamin ((11)C-5-HTP), fluorodopa and (68)Ga-1,4,7,10-tetra-azacyclododecane-N,N',N″,N‴-tetra-acetic acid (DOTA)-octreotate are performed. Surgery is still one of the cornerstones in the management of pancreatic endocrine tumors, but curative surgery is rarely obtained in most cases because of metastatic disease. Debulking and other cytoreductive procedures might facilitate systemic treatment. Cytotoxic drugs, biological agents, such as somatostatin analogs, alpha interferons, mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are routinely used. Tumor-targeted radioactive treatment is available in many centres in Europe and is effective in patients with tumors that express high content of somatostatin receptors type 2 and 5. In the future, treatment will be based on tumor biology and molecular genetics with the aim of so-called personalized medicine.

16 Review Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. 2010

Oberg, Kjell E / Reubi, Jean-Claude / Kwekkeboom, Dik J / Krenning, Eric P. ·Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Gastroenterology · Pubmed #20637207.

ABSTRACT: The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein-coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.

17 Clinical Trial Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. 2016

Yao, James C / Pavel, Marianne / Lombard-Bohas, Catherine / Van Cutsem, Eric / Voi, Maurizio / Brandt, Ulrike / He, Wei / Chen, David / Capdevila, Jaume / de Vries, Elisabeth G E / Tomassetti, Paola / Hobday, Timothy / Pommier, Rodney / Öberg, Kjell. ·James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX · Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ · Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN · Rodney Pommier, Oregon Health & Science University, Portland, OR · Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany · Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France · Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium · Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland · Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain · Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands · Paola Tomassetti, University of Bologna, Bologna, Italy · and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden. ·J Clin Oncol · Pubmed #27621394.

ABSTRACT: Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

18 Clinical Trial Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. 2011

Yao, James C / Pavel, Marianne / Phan, Alexandria T / Kulke, Matthew H / Hoosen, Sakina / St Peter, Jessica / Cherfi, Azzeddine / Öberg, Kjell E. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, Texas 77030, USA. jyao@mdanderson.org ·J Clin Endocrinol Metab · Pubmed #21994954.

ABSTRACT: CONTEXT: Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors. OBJECTIVE: The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus. PATIENTS AND METHODS: Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels. RESULTS: In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study. CONCLUSIONS: Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

19 Clinical Trial Everolimus for advanced pancreatic neuroendocrine tumors. 2011

Yao, James C / Shah, Manisha H / Ito, Tetsuhide / Bohas, Catherine Lombard / Wolin, Edward M / Van Cutsem, Eric / Hobday, Timothy J / Okusaka, Takuji / Capdevila, Jaume / de Vries, Elisabeth G E / Tomassetti, Paola / Pavel, Marianne E / Hoosen, Sakina / Haas, Tomas / Lincy, Jeremie / Lebwohl, David / Öberg, Kjell / Anonymous2070686. ·University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jyao@mdanderson.org ·N Engl J Med · Pubmed #21306238.

ABSTRACT: BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

20 Clinical Trial Five patients with malignant endocrine tumors treated with imatinib mesylate (Glivec). 2010

Kindmark, Henrik / Janson, Eva Tiensuu / Gustavsson, Bengt / Eriksson, Camilla / Larsson, Gunnel / Granberg, Dan / Kozlowacki, Gordana / Skogseid, Britt / Welin, Staffan / Oberg, Kjell / Eriksson, Barbro. ·Department of Medicine/Endocrine Oncology, University Hospital, Uppsala, Sweden. ·Acta Oncol · Pubmed #20100145.

ABSTRACT: -- No abstract --

21 Article Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. 2014

Grimaldi, Franco / Fazio, Nicola / Attanasio, Roberto / Frasoldati, Andrea / Papini, Enrico / Angelini, Francesco / Baldelli, Roberto / Berretti, Debora / Bianchetti, Sara / Bizzarri, Giancarlo / Caputo, Marco / Castello, Roberto / Cremonini, Nadia / Crescenzi, Anna / Davì, Maria Vittoria / D'Elia, Angela Valentina / Faggiano, Antongiulio / Pizzolitto, Stefano / Versari, Annibale / Zini, Michele / Rindi, Guido / Oberg, Kjell. ·Endocrinology and Metabolic Disease Unit, Azienda Ospedaliero-Universitaria "S. Maria della Misericordia", P.le S.M. della Misericordia, 15-33100, Udine, Italy, franco.grimaldi@aliceposta.it. ·J Endocrinol Invest · Pubmed #25038902.

ABSTRACT: -- No abstract --

22 Article The genetics of neuroendocrine tumors. 2013

Öberg, Kjell. ·Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Semin Oncol · Pubmed #23391111.

ABSTRACT: Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs.

23 Article Unusual complication of a pancreatic neuroendocrine tumor presenting with malignant hypercalcemia. 2012

Kanakis, G / Kaltsas, G / Granberg, D / Grimelius, L / Papaioannou, D / Tsolakis, A V / Öberg, K. ·Department of Pathophysiology (Endocrine Unit), University of Athens Medical School, Mikras Asias 75, 11527, Athens, Greece. geokan@endo.gr ·J Clin Endocrinol Metab · Pubmed #22319031.

ABSTRACT: CONTEXT: Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET). OBJECTIVE: The aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET. CASE ILLUSTRATION: A 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors. DISCUSSION: The manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.

24 Article Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management. 2010

Modlin, Irvin M / Moss, Steven F / Oberg, Kjell / Padbury, Robert / Hicks, Rodney J / Gustafsson, Bjorn I / Wright, Nicholas A / Kidd, Mark. ·School of Medicine, Yale University, New Haven, Conn, USA. irvin.modlin@yale.edu ·Med J Aust · Pubmed #20618115.

ABSTRACT: Neuroendocrine tumours (NETs) are increasing in both incidence and prevalence and, as a group, are more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any two of these cancers combined. Clinical awareness of the protean and intermittent symptoms of NETs (eg, sweating, flushing, diarrhoea, and bronchospasm) is critical for timely diagnosis; however, the classical carcinoid syndrome is relatively uncommon. The most useful diagnostic test for gastrointestinal NETs is measurement of plasma chromogranin A (CgA) levels. Disease extent is assessed by both anatomical imaging, and nuclear imaging with radiolabelled somatostatin analogues. Pathological evaluation comprises tumour-node-metastasis classification, a minimum pathological dataset, CgA and synaptophysin immunostaining, as well as mitotic count or Ki-67 index (a marker of cell proliferation) to define grading. Resection of the primary lesion and as much metastatic disease as possible increases the efficacy of medical therapy. Other management strategies include hepatic embolisation and peptide receptor radionuclide therapy. Patients with tumours expressing somatostatin receptors should be treated with somatostatin analogues. Depending on the tumour grade, other effective agents include cytotoxics, tyrosine kinase inhibitors, and antiangiogenics. The overarching requirement for best management of patients with NETs is to ensure that they have ready access to experienced multidisciplinary clinician groups located within centres of appropriate subspecialty expertise.

25 Article The cytotoxic agents NSC-95397, brefeldin A, bortezomib and sanguinarine induce apoptosis in neuroendocrine tumors in vitro. 2010

Larsson, Dhana E / Wickström, Malin / Hassan, Sadia / Oberg, Kjell / Granberg, Dan. ·Department of Endocrine Oncology, University Hospital, S-751 85 Uppsala, Sweden. dhana.larsson@medsci.uu.se ·Anticancer Res · Pubmed #20150630.

ABSTRACT: MATERIALS AND METHODS: A multiparametric high-content screening assay for measurement of apoptosis was used. The human pancreatic carcinoid cell line, BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were tested. After incubation with cytotoxic drugs, the DNA-binding dye Hoechst 33342, fluorescein-tagged probes that covalently bind active caspase-3 and chloromethyl-X-rosamine to detect mitochondrial membrane potential were added. Image acquisition and quantitative measurement of fluorescence was performed using automated image capture and analysis instrument ArrayScan. In addition, nuclear morphology was examined on microscopic slides stained with May-Grunewald-Giemsa. RESULTS: A time- and dose-dependent activation of caspase-3 and increase in nuclear fragmentation and condensation were observed for the drugs using a multiparametric apoptosis assay. These results were confirmed with nuclear morphological examination on microscopic slides. CONCLUSION: NSC 95397, brefeldin A, bortezomib and sanguinarine induced caspase-3 activation with modest changes in nuclear morphology.