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  • 401.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Polyzos, Nikolaos P.
    Role of Zoledronate in Aromatase Activity Should Be Considered in Future Studies In Reply2013In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 18, no 8, p. E26-E27Article in journal (Refereed)
  • 402.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Polyzos, Nikolaos P.
    Coleman, Robert E.
    Gnant, Michael
    Eidtmann, Holger
    Brufsky, Adam M.
    Aft, Rebecca
    Tevaarwerk, Amye J.
    Swenson, Karen
    Lind, Pehr
    Mauri, Davide
    Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis2013In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 18, no 4, p. 353-361Article, review/survey (Refereed)
    Abstract [en]

    Background. The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I-III) breast cancer. Materials and Methods. We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes. Results. Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70-1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio[OR], 0.94; 95% CI, 0.64-1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63-0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%. Conclusion. Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment. 

  • 403. Valentini, V.
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Frascino, V.
    Quality assurance and quality control for radiotherapy/medical oncology in Europe: Guideline development and implementation2013In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 39, no 9, p. 938-944Article, review/survey (Refereed)
    Abstract [en]

    The past two decades have brought tremendous changes to the practice of radiation oncology and medical oncology. To manage all the complexities related to the new technologies and the new drugs, the radiation and medical oncologists have to enhance their clinical action and professional skill profile. To accomplish this they have to find reliable tools in the quality of their medical practice and in future research activities. Quality assurance (QA) and quality control (QC) for radiation and medical oncologists mean to clarify the different components of the clinical decision, to supervise with proper methodology the required steps needed to accomplish the agreed outcomes and to control them. Quality for radiation and medical oncology means to supervise each clinical and technical component of the whole process to guarantee that all steps together will arrive at the final and best possible outcome. Key components are guidelines, specialization and a multidisciplinary approach. The research of global quality could represent a further complexity, but it is the best tool to give a perspective and a chance to further improvements of our disciplines and to promote better outcome in all cancer patients. 

  • 404. Van Cutsem, Eric
    et al.
    Tejpar, Sabine
    Vanbeckevoort, Dirk
    Peeters, Marc
    Humblet, Yves
    Gelderblom, Hans
    Vermorken, Jan B.
    Viret, Frederic
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gallerani, Elisa
    Hendlisz, Alain
    Cats, Annemieke
    Moehler, Markus
    Sagaert, Xavier
    Vlassak, Soetkin
    Schlichting, Michael
    Ciardiello, Fortunato
    Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 23, p. 2861-2868Article in journal (Refereed)
    Abstract [en]

    Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data.

    Patients and Methods After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with <= grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with >= grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C).

    Results The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions >= grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors.

    Conclusion Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

  • 405. van de Velde, Cornelis J. H.
    et al.
    Boelens, Petra G.
    Borras, Josep M.
    Coebergh, Jan-Willem
    Cervantes, Andres
    Blomqvist, Lennart
    Beets-Tan, Regina G. H.
    van den Broek, Colette B. M.
    Brown, Gina
    Van Cutsem, Eric
    Espin, Eloy
    Haustermans, Karin
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Iversen, Lene H.
    van Krieken, J. Han
    Marijnen, Corrie A. M.
    Henning, Geoffrey
    Gore-Booth, Jola
    Meldolesi, Elisa
    Mroczkowski, Pawel
    Nagtegaal, Iris
    Naredi, Peter
    Ortiz, Hector
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Quirke, Philip
    Roedel, Claus
    Roth, Arnaud
    Rutten, Harm
    Schmoll, Hans J.
    Smith, Jason J.
    Tanis, Pieter J.
    Taylor, Claire
    Wibe, Arne
    Wiggers, Theo
    Gambacorta, Maria A.
    Aristei, Cynthia
    Valentini, Vincenzo
    EURECCA colorectal: Multidisciplinary management: European consensus conference colon & rectum2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 1, p. UNSP 1.e1-Article in journal (Refereed)
    Abstract [en]

    Background

    Care for patients with colon and rectal cancer has improved in the last 20 years; however considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about cancer of the colon and rectum was held. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.

    Methods

    The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Consensus was achieved using the Delphi method. For the Delphi process, multidisciplinary experts were invited to comment and vote three web-based online voting rounds and to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. This manuscript covers all sentences of the consensus document with the result of the voting. The consensus document represents sections on diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and metastatic colorectal disease separately. Moreover, evidence based algorithms for diagnostics and treatment were composed which were also submitted to the Delphi process.

    Results

    The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members.

    Conclusions

    Multidisciplinary consensus on key diagnostic and treatment issues for colon and rectal cancer management using the Delphi method was successful. This consensus document embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

  • 406. van Gijn, Willem
    et al.
    Marijnen, Carrie A. M.
    Nagtegaal, Iris D.
    Kranenbarg, Elma Meershoek-Klein
    Putter, Hein
    Wiggers, Theo
    Rutten, Harm J. T.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    van de Velde, Cornelis J. H.
    Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial2011In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 12, no 6, p. 575-582Article in journal (Refereed)
    Abstract [en]
    Background The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. Methods Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 x 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. Findings 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0.0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0.032). Interpretation For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and Trim stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains.
  • 407.
    Varasteh, Zohreh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    In Vitro and In Vivo Evaluation of a F-18-Labeled High Affinity NOTA Conjugated Bombesin Antagonist as a PET Ligand for GRPR-Targeted Tumor Imaging2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81932-Article in journal (Refereed)
    Abstract [en]

    Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA) via a diethylene glycol (PEG(2)) spacer (NOTA-P2-RM26) labeled with Ga-68 and In-111. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a F-18-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with F-18 using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [F-nat]AlF-NOTA-P2-RM26 was compared to that of the Ga-nat-loaded peptide using I-125-Tyr(4)-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with F-18 within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/mu mol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [F-nat]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4 +/- 0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [F-18]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p. i. was 5.5 +/- 0.7 % ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87 +/- 42, 159 +/- 47, 38 +/- 16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p. i. The initial biological results suggest that [F-18]AlF-NOTA-P2-RM26 is a promising candidate for PET imaging of GRPR in vivo.

  • 408. Vijai, Joseph
    et al.
    Wang, Zhaoming
    Berndt, Sonja I.
    Skibola, Christine F.
    Slager, Susan L.
    de Sanjose, Silvia
    Melbye, Mads
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bracci, Paige M.
    Conde, Lucia
    Birmann, Brenda M.
    Wang, Sophia S.
    Brooks-Wilson, Angela R.
    Lan, Qing
    de Bakker, Paul I. W.
    Vermeulen, Roel C. H.
    Portlock, Carol
    Ansell, Stephen M.
    Link, Brian K.
    Riby, Jacques
    North, Kari E.
    Gu, Jian
    Hjalgrim, Henrik
    Cozen, Wendy
    Becker, Nikolaus
    Teras, Lauren R.
    Spinelli, John J.
    Turner, Jenny
    Zhang, Yawei
    Purdue, Mark P.
    Giles, Graham G.
    Kelly, Rachel S.
    Zeleniuch-Jacquotte, Anne
    Ennas, Maria Grazia
    Monnereau, Alain
    Bertrand, Kimberly A.
    Albanes, Demetrius
    Lightfoot, Tracy
    Yeager, Meredith
    Chung, Charles C.
    Burdett, Laurie
    Hutchinson, Amy
    Lawrence, Charles
    Montalvan, Rebecca
    Liang, Liming
    Huang, Jinyan
    Ma, Baoshan
    Villano, Danylo J.
    Maria, Ann
    Corines, Marina
    Thomas, Tinu
    Novak, Anne J.
    Dogan, Ahmet
    Liebow, Mark
    Thompson, Carrie A.
    Witzig, Thomas E.
    Habermann, Thomas M.
    Weiner, George J.
    Smith, Martyn T.
    Holly, Elizabeth A.
    Jackson, Rebecca D.
    Tinker, Lesley F.
    Ye, Yuanqing
    Adami, Hans-Olov
    Smedby, Karin E.
    De Roos, Anneclaire J.
    Hartge, Patricia
    Morton, Lindsay M.
    Severson, Richard K.
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Mckay, James
    Staines, Anthony
    Diver, W. Ryan
    Vajdic, Claire M.
    Armstrong, Bruce K.
    Kricker, Anne
    Zheng, Tongzhang
    Holford, Theodore R.
    Severi, Gianluca
    Vineis, Paolo
    Ferri, Giovanni M.
    Ricco, Rosalia
    Miligi, Lucia
    Clavel, Jacqueline
    Giovannucci, Edward
    Kraft, Peter
    Virtamo, Jarmo
    Smith, Alex
    Kane, Eleanor
    Roman, Eve
    Chiu, Brian C. H.
    Fraumeni, Joseph F.
    Wu, Xifeng
    Cerhan, James R.
    Offit, Kenneth
    Chanock, Stephen J.
    Rothman, Nathaniel
    Nieters, Alexandra
    A genome-wide association study of marginal zone lymphoma shows association to the HLA region2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id UNSP 5751Article in journal (Refereed)
    Abstract [en]

    Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P - 3.95 x 10(-15)) and HLA-B (rs2922994, P - 2.43 x 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

  • 409.
    von Heideman, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.

    List of papers
    1. Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients
    Open this publication in new window or tab >>Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients
    Show others...
    2000 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 10, p. 1301-1307Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Chemotherapy using multi-drug regimens is considered more active than single-agent therapy. This may be due to synergistic interactions or, simply, a higher probability of administering an active agent. We investigated in vitro the type of drug interactions in a recognized regimen in relationship to tumour type and drug sensitivity.

    PATIENTS AND METHODS:

    The possibility of synergistic and additive interactions between individual cytotoxic drugs was investigated for the component drugs of the established FEC regimen, i.e., 5-fluorouracil, epirubicin and cyclophosphamide, in 243 patient tumour samples representing various drug sensitivity using the non-clonogenic fluorometric microculture cytotoxicity assay.

    RESULTS:

    Using a cell survival of < or = 50% as a limit for drug activity and sample sensitivity, the overall response rates to the most active single drug (Dmax) and the combination were 56% and 64%, respectively, with a distribution among diagnoses similar to that in the clinic. For 86% of the samples there was concordance with respect to judgement of activity using either Dmax or the combination. For samples being sensitive to at least one single drug, 95% were also sensitive to the combination whereas for samples with insignificant Dmax effect, only 2% were sensitive to the combination. In samples with modest Dmax effects, i.e., cell survival in the range > 50%- < or = 80%, 45% responded to the combination. The effect of the combination was generally well predicted from the Dmax effect.

    CONCLUSIONS:

    The superior antitumour effect of drug combinations compared with single drugs may be due to the higher chance of selecting an active agent. However, for intermediately sensitive tumours, additional interaction effects of a combination may be of clinical significance.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-57287 (URN)11106120 (PubMedID)
    Available from: 2007-02-09 Created: 2007-02-09 Last updated: 2017-12-04Bibliographically approved
    2. Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
    Open this publication in new window or tab >>Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
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    2008 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 34, no 5, p. 547-552Article in journal (Refereed) Published
    Abstract [en]

    AIMS:

    To investigate if the pattern of cytotoxic drug sensitivity in vitro in patient samples of peritoneal carcinomatosis (PC) is supportive to the current standardized approach for drug selection for perioperative intraperitoneal chemotherapy (IPC).

    METHODS:

    The cytotoxic effect of cisplatin, oxaliplatin, irinotecan, 5-fluorouracil, mitomycin-C, doxorubicin and melphalan was investigated in vitro on tumour cells from 223 patient tumour samples of different PC origins.

    RESULTS:

    Considerable differences in cytotoxic drug sensitivity between tumour types of the PC entity and within each tumour type were observed. Cisplatin showed high cross-resistance with oxaliplatin but low cross-resistance with doxorubicin and irinotecan. No cross-resistance was found between irinotecan and doxorubicin. The dose-response relationships for melphalan and irinotecan in individual samples showed great variability.

    CONCLUSIONS:

    The activity in vitro of cytotoxic drugs commonly used in IPC for PC is very heterogeneous. Efforts for individualizing drug selection for PC patients undergoing IPC seem justified.

    Keywords
    Peritoneal carcinomatosis, Intraperitoneal chemotherapy, Cytotoxic drug, In vitro
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13245 (URN)10.1016/j.ejso.2007.05.002 (DOI)000256207400012 ()17574369 (PubMedID)
    Available from: 2008-06-24 Created: 2008-06-24 Last updated: 2017-12-11Bibliographically approved
    3. Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
    Open this publication in new window or tab >>Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Sensitivity of epithelial ovarian cancer to chemotherapeutic drugs relevant in treatment of this cancer type was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to histopathological subtypes, treatment status and clinical tumour response. For cisplatin, doxorubicin, 5-FU, cyclophosphamide and topotecan, seropapillary high grade and clear cell ovarian cancer were the most sensitive subtypes and the mucinous tumours the most resistant subtype, whereas endometrioid tumours and the seropapillary low grade/borderline tumours showed intermediate sensitivity. In contrast, docetaxel showed the opposite pattern of activity. Samples from patients previously treated with chemotherapy tended, for the majority of drugs, to be slightly more resistant than samples from treatment naïve patients. The activity of cisplatin correlated strongly with that of the other drugs with the exception of docetaxel, implicating non-cross resistance between these key drugs in ovarian cancer. Tumour samples from two sites in the same patient at the same occasion showed similar and samples taken at different occasions different cisplatin sensitivity, which may implicate tumour clonal selection over time. At group level, samples from patients clinically responding to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, optimized analyses of drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 90 – 100% and 54 – 83% ranges, respectively. In conclusion, ovarian cancer subtypes exhibit different chemotherapeutic drug sensitivity in vitro, which needs consideration in treatment decisions for this disease. Furthermore, in vitro assessment of ovarian cancer tumour cell chemotherapeutic drug sensitivity provides clinically relevant information that could be useful in efforts to optimize treatment in individual patients with this disease.

    Keywords
    ovarian cancer, chemotherapy, drug sensitivity testing, in vitro
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-151799 (URN)
    Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2013-08-15
    4. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data
    Open this publication in new window or tab >>Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data
    2010 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, no 6, p. 1165-1172Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE:

    Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.

    METHODS:

    A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.

    RESULTS:

    Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.

    CONCLUSIONS:

    Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

    Keywords
    Cancer, NAD depletion, Phase I clinical trial, CHS 828, FK866, GMX1777
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-130804 (URN)10.1007/s00280-009-1125-3 (DOI)000275632400019 ()19789873 (PubMedID)
    Available from: 2010-09-13 Created: 2010-09-13 Last updated: 2017-12-12Bibliographically approved
  • 410.
    von Heideman, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Cajander, Stefan
    Gerdin, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Holm, Leif
    Axelsson, Agneta
    Rosenberg, Per
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Daniel, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 2, p. 242-250Article in journal (Refereed)
    Abstract [en]

    Background

    A number of chemotherapeutic drugs are active in epithelial ovarian cancer (EOC) but so far choice of drugs for treatment is mostly empirically based. Testing of drug activity in tumour cells from patients might provide a rationale for a more individualised approach for drug selection.

    Material and methods

    Sensitivity of EOC to chemotherapeutic drugs was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to tumour histology, treatment status and clinical tumour response.

    Results

    For most EOC standard drugs serous high grade and clear cell EOC were the most sensitive subtypes and the mucinous tumours the most resistant subtype. Docetaxel, however, tended to show the opposite pattern. Samples from previously treated patients tended to be more resistant than those from treatment naive patients. The activity of cisplatin correlated with that of other drugs with the exception of docetaxel. Tumour samples from two sites in the same patient at the same occasion showed similar cisplatin sensitivity in contrast to samples taken at different occasions. Samples from patients responding in the clinic to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 83-100% and 55-83% ranges, respectively.

    Conclusions

    Assessment of EOC tumour cell drug sensitivity in vitro provides clinically relevant and potentially useful information for the optimisation of drug treatment.

  • 411.
    von Heideman, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Cajander, Stefan
    Gerdin, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Holm, Leif
    Axelsson, Agneta
    Rosenberg, Per
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from PatientsManuscript (preprint) (Other academic)
    Abstract [en]

    Sensitivity of epithelial ovarian cancer to chemotherapeutic drugs relevant in treatment of this cancer type was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to histopathological subtypes, treatment status and clinical tumour response. For cisplatin, doxorubicin, 5-FU, cyclophosphamide and topotecan, seropapillary high grade and clear cell ovarian cancer were the most sensitive subtypes and the mucinous tumours the most resistant subtype, whereas endometrioid tumours and the seropapillary low grade/borderline tumours showed intermediate sensitivity. In contrast, docetaxel showed the opposite pattern of activity. Samples from patients previously treated with chemotherapy tended, for the majority of drugs, to be slightly more resistant than samples from treatment naïve patients. The activity of cisplatin correlated strongly with that of the other drugs with the exception of docetaxel, implicating non-cross resistance between these key drugs in ovarian cancer. Tumour samples from two sites in the same patient at the same occasion showed similar and samples taken at different occasions different cisplatin sensitivity, which may implicate tumour clonal selection over time. At group level, samples from patients clinically responding to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, optimized analyses of drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 90 – 100% and 54 – 83% ranges, respectively. In conclusion, ovarian cancer subtypes exhibit different chemotherapeutic drug sensitivity in vitro, which needs consideration in treatment decisions for this disease. Furthermore, in vitro assessment of ovarian cancer tumour cell chemotherapeutic drug sensitivity provides clinically relevant information that could be useful in efforts to optimize treatment in individual patients with this disease.

  • 412. Wagenius, Gunnar
    et al.
    Ullenhag, Gustav J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Response to the letter to the editors from Inge Marie Svane on our manuscript "Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy"2012In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 61, no 5, p. 749-749Article in journal (Other academic)
  • 413. Wahlin, Björn Engelbrekt
    et al.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Holte, Harald
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Erlanson, Martin
    Nilsson-Ehle, Herman
    Lindén, Ola
    Nordström, Marie
    Ostenstad, Bjørn
    Geisler, Christian H
    Brown, Peter de Nully
    Lehtinen, Tuula
    Maisenhölder, Martin
    Tierens, Anne M
    Sander, Birgitta
    Christensson, Birger
    Kimby, Eva
    T cells in tumors and blood predict outcome in follicular lymphoma treated with rituximab2011In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, no 12, p. 4136-4144Article in journal (Refereed)
    Abstract [en]

    Purpose:

    T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown.

    Experimental Design:

    Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a–rituximab combinations.

    Results:

    In univariate analysis, higher levels of CD3+, CD4+, and CD8+ T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3+ (P = 0.011) and blood-CD4+ (P = 0.029) cells were independent. CD4+ cells were favorable regardless of treatment arm, but CD8+ cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8+ cell levels. Higher levels of blood-CD3+ (P = 0.003) and blood-CD4+ (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8+ cells longer times to next treatment (P = 0.046).

    Conclusions:

    We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4+ and CD8+ cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8+ cells.

  • 414.
    Wallin, Ulrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jirström, K.
    Darmanis, Spyros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nong, Rachel Yuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 10, p. 1619-1627Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta superfamily and has been associated with activation of the p53 pathway in human cancer. The aim of this study was to assess the prognostic value of GDF15 in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry and tissue microarrays were used to analyse GDF15 protein expression in 320 patients with CRC. In a subgroup of 60 patients, the level of GDF15 protein in plasma was also measured using a solid-phase proximity ligation assay. RESULTS: Patients with CRC with moderate to high intensity of GDF15 immunostaining had a higher recurrence rate compared with patients with no or low intensity in all stages (stages I-III) (HR, 3.9; 95% CI, 1.16-13.15) and in stage III (HR, 10.32; 95% CI, 1.15-92.51). Patients with high plasma levels of GDF15 had statistically shorter time to recurrence (P = 0.041) and reduced overall survival (P = 0.002). CONCLUSION: Growth differentiation factor 15 serves as a negative prognostic marker in CRC. High expression of GDF15 in tumour tissue and high plasma levels correlate with an increased risk of recurrence and reduced overall survival.

  • 415.
    Wassberg, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Reproducibility of quantitative parameters of F-18-Fluoride PET/CT in prostate bone metastases2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, p. S242-S242, article id OP367Article in journal (Other academic)
  • 416. Wasterlid, T.
    et al.
    Brown, P. N.
    Hagberg, O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hagberg, H.
    Pedersen, L. M.
    D'Amore, F.
    Jerkeman, M.
    Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 7, p. 1879-1886Article in journal (Refereed)
    Abstract [en]

    Background: Standard treatment of adult Burkitt lymphoma is not defined due to the lack of randomised trials. In this situation, population-based data may represent a useful contribution in order to identify an optimal treatment strategy. Patients and methods: The aims of this study were to investigate the outcome for adult HIV-negative BL with different chemotherapy regimens, and to assess possible improvement within the time frame of the study. The study population was identified through the Swedish and Danish lymphoma registries 2000-2009. Results: A total of 258 patients were identified. Since 2000, overall survival (OS) improved significantly only for younger patients (<65 years). Intensive regimens such as the Berlin-Frankfurt-Munster, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) were associated with a favourable 2-year OS of 82%, 83%, and 69%, respectively. The low-intensive CHOP/CHOEP regimens achieved a 2-year OS of 38.8%, confirming their inadequacy for the treatment of BL. In a multivariate analysis, rituximab was not significantly associated with improved OS. Conclusions: In this population-based retrospective series of adult BL, intensive chemotherapy regimens were associated with favourable outcome. The impact of the addition of rituximab remains uncertain and warrants further investigation.

  • 417.
    Wei, Q.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Shui, Y.
    Zheng, S.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy2011In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 25, no 1, p. 3-11Article in journal (Refereed)
    Abstract [en]

    Members of the epidermal growth factor receptor, EGER, family are interesting as targets for radionuclide therapy using targeting agents labeled with alpha- or beta-emitting radionuclides, especially when EGFR-positive colorectal carcinomas, CRC, are resistant to EGFR inhibiting agents like cetuximab and various tyrosine kinase inhibitors. The expression of EGFR, HER2 and HER3 was therefore analyzed in CRC samples from primary tumors, corresponding lymph node metastases and, in a few cases, liver metastases. The expression of HER2 and EGFR was scored from immunohistochemical preparations using the HercepTest criteria 0, 1+, 2+ or 3+ for cellular membrane staining while HER3 expression was scored as no, weak or strong cytoplasm staining. Material from 60 patients was analyzed. The number of EGFR 2+ or 3+ positive primary tumors was 16 out of 56 (29%) and for lymph node metastases 8 out of 56 (14%) whereas only one out of nine (11%) liver metastases were positive. Thus, there was lower EGFR positivity in the metastases. Only one among 53 patients was strongly HER2 positive and this in both the primary tumor and the metastasis. Eight out of 49 primary tumors (16%) were strongly HER3 positive and the corresponding numbers for lymph node metastases were 9 out of 49 (18%) and for liver metastases 2 out of 9 (22%). The observed number of strongly EGFR positive cases was somewhat low but EGFR might be, for the cases with high EGFR expression in metastases, a target for radionuclide therapy. HER2 seems not to be of such interest due to rare expression, neither HER3 due to mainly expression in the cytoplasm. The requirements for successful EGFR targeted radionuclide therapy are discussed, as well as patient inclusion criteria related to radionuclide therapy.

  • 418. Wennberg, Berit M.
    et al.
    Baumann, Pia
    Gagliardi, Giovanna
    Nyman, Jan
    Drugge, Ninni
    Hoyer, Morten
    Traberg, Anders
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Morhed, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Ekberg, Lars
    Wittgren, Lena
    Lund, Jo-Åsmund
    Levin, Nina
    Sederholm, Christer
    Lewensohn, Rolf
    Lax, Ingmar
    NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 4, p. 518-527Article in journal (Refereed)
    Abstract [en]

    Background. In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Material and methods. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman-Kutcher-Burman (LKB) model. In the LQ-correction alpha/beta = 3 Gy was used and the USC parameters used were: alpha/beta = 3 Gy, D-0 = 1.0 Gy, (n) over bar = 10, alpha = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. Results and Discussion. NTCP analysis with the LKB-model using parameters m = 0.4, D-50 = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D-50 = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ, USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

  • 419. Wettergren, Lena
    et al.
    Kettis, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ring, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Comparing two versions of the Schedule for Evaluation of Individual Quality of Life in patients with advanced cancer2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 5, p. 648-652Article in journal (Refereed)
    Abstract [en]

    Background. The aim was to compare two individualized patient reported outcomes or the Schedule for the Evaluation of Individual Quality of Life - Direct Weighting (SEIQoL-DW) measuring quality of life in general, and the disease-related version (SEIQoL-DR) measuring quality of life related to disease. Both instruments have been used in clinical practice settings within oncology. The instruments were compared with regard to feasibility, the areas nominated by patients as important and patients' ratings of how they were doing in these areas (Index scores). Material and methods. The study included 40 patients with gastrointestinal cancer. All patients completed both versions of the instrument on a touch screen computer in relation to a medical consultation. Firstly, the participants were invited to nominate the five domains she/he currently considered to be most important in life. Secondly, they were asked to rate how they were doing in each of these domains. Finally, they were asked to quantify the relative importance of each area. Cohen's effect sizes were calculated to illuminate the clinical importance of mean value differences. Results. Both instruments took less than ten minutes to complete and the procedure was considered feasible by both patients and interviewers. The proportion of patients nominating the same areas in the two versions did not differ, however, the SEIQoL-DW Index score was significantly higher than the corresponding score for the SEIQoL-DR. The detected difference in the mean score measured by effect size was medium. Conclusion. The magnitude of the effect size of the difference in Index score imply that the two versions tap into different constructs, i.e. quality of life (QoL) versus health-related QoL (HRQL), supporting the construct validity of the two versions of the instrument. The SEIQoL-DW and the SEIQoL-DR should be considered as complementary rather than interchangeable when used in patients with cancer.

  • 420. Wettergren, Lena
    et al.
    Lindberg, Mathilde Hedlund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Kettis, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ring, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Comparison of two instruments for measurement of quality of life in clinical practice - a qualitative study2014In: BMC Medical Research Methodology, ISSN 1471-2288, E-ISSN 1471-2288, Vol. 14, p. 115-Article in journal (Refereed)
    Abstract [en]

    Background: The study aimed to investigate the meaning patients assign to two measures of quality of life: the Schedule for Evaluation of Individual Quality of Life Direct Weighting (SEIQoL-DW) and the SEIQoL-DW Disease Related (DR) version, in a clinical oncology setting. Even though the use of quality of life assessments has increased during the past decades, uncertainty regarding how to choose the most suitable measure remains. SEIQoL-DW versions assesses the individual's perception of his or her present quality of life by allowing the individual to nominate the domains to be evaluated followed by a weighting procedure resulting in qualitative (domains) as well as quantitative outcomes (index score). Methods: The study applied a cross-sectional design with a qualitative approach and collected data from a purposeful sample of 40 patients with gastrointestinal cancer. Patients were asked to complete two measures, SEIQoL-DW and the SEIQoL-DR, to assess quality of life. This included nomination of the areas in life considered most important and rating of these areas; after completion patients participated in cognitive interviews around their selections of areas. Interviews were audiotaped and transcribed verbatim which was followed by analysis using a phenomenographic approach. Results: The analyses of nominated areas of the two measures resulted in 11 domains reflecting what patients perceived had greatest impact on their quality of life. Analysis of the cognitive interviews resulted in 16 thematic categories explaining the nominated domains. How patients reflected around their quality of life appeared to differ by version (DW vs. DR). The DW version more often related to positive aspects in life while the DR version more often related to negative changes in life due to having cancer. Conclusions: The two SEIQoL versions tap into different concepts; health-related quality of life, addressing losses and problems related to having cancer and, quality of life, more associated with aspects perceived as positive in life. The SEIQoL-DR and the SEIQoL-DW are recommended in clinical practice to take both negative and positive aspects into account and acting on the problems of greatest importance to the patient.

  • 421.
    Wickström, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Aminopeptidase N (CD13) as a target for cancer chemotherapy2011In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, no 3, p. 501-508Article, review/survey (Refereed)
    Abstract [en]

    The enzyme aminopeptidase N (APN, also known as CD13) is a Zn2+ dependent membrane-bound ectopeptidase that degrades preferentially proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N has been associated with the growth of different human cancers and suggested as a suitable target for anti-cancerous therapy. Different approaches have been used to develop new drugs directed to this target, including enzyme inhibitors as well as APN-targeted carrier constructs. This review discusses the prevalence and possible function of APN in malignant diseases, mainly solid tumors, as well as its “drugability” evaluated in preclinical in vivo models, and also provides a brief overview of current clinical trials focused on APN.

  • 422. Wigertz, Annette
    et al.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Holmqvist, Marit
    Fornander, Tommy
    Adolfsson, Jan
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Lambe, Mats
    Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 133, no 1, p. 367-373Article in journal (Refereed)
    Abstract [en]

    Adherence to long-term pharmacological treatment for chronic conditions is often less than optimal. Till date, a limited number of population-based studies have assessed adherence to adjuvant hormonal therapy in breast cancer, a therapy with proven benefits in terms of reductions of recurrence and mortality. We aimed to examine rates of adherence and early discontinuation in Sweden where prescribed medications are subsidized for all residents and made available at reduced out-of-pocket costs. Individual-level data were obtained from Regional Clinical Quality Breast Cancer Registers, the Swedish Prescribed Drug Register, and several other population-based registers. Multivariate logistic regression was used to analyze factors associated with adherence to prescribed medication for a period of 3 years. Between January 1 and December 31, 2005, 1,741 patients in central Sweden were identified with estrogen receptor positive breast cancer, and at least one prescription dispensation of either tamoxifen or an aromatase inhibitor. Of these women, 1,193 (69%) were fully adherent to therapy for 3 years (medication possession ratio of 80% or higher and a maximum of 180 days between refills). During the 3-year follow-up, 215 women (12%) had prematurely discontinued therapy. Adherence was positively associated with younger age, large tumor size, being married, and being born in the Nordic countries, while no clear association was observed with education or income. During the 3 years of follow-up, 31% of women were non-adherent to therapy. Further efforts must be undertaken to promote adherence over the entire recommended treatment period.

  • 423.
    Wu, Xuping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oesophageal cancer is a malignant and aggressive disease with very poor survival. The aim of this thesis was to evaluate novel therapeutic targets in oesophageal cancer.

    In paper I, Hsp90 was expressed in all 81 oesophageal cancer tissues and also in nine oesophageal cancer cell lines. A specific Hsp90 inhibitor, 17-AAG, could efficiently inhibit cell proliferation, cell survival and sensitise oesophageal cancer cells to gamma photon irradiation. By inhibition of Hsp90 using 17-AAG, EGFR- and IGF-1R-mediated signalling was downregulated.

    In paper II, tumour samples from 80 oesophageal cancer patients were investigated for the expression of EGFR and LRIG1-3. Based on a total score of intensity and expression fraction a trend towards survival differences was found for LRIG2 (p=0.18) and EGFR (p=0.09). Correlation analysis revealed a correlation between expression of EGFR and LRIG3 (p=0.0007). Significant correlations were found between LRIG1 mRNA expression levels and sensitivity to cisplatin (r = –0.74), docetaxel (r = –0.69), and vinorelbine (r = –0.82).

    In paper III, microtubule targeting drugs podophyllotoxin (PPT), vincristine and docetaxel inhibited survival and proliferation of oesophageal cancer cells. Unexpectedly, experiments showed that microtubule destabilising agents inhibited EGFR phosphorylation and signalling. A tyrosine phosphatase inhibitor, sodium orthovanadate, was able to reverse the EGFR dephosphorylation.

    In paper IV, imetelstat, a telomerase antagonist, inhibited telomerase activity, colony formation ability and decreased proliferation of oesophageal cancer cells. Inhibition of telomerase activity by imetelstat led to an increase of 53BP1 foci indicating induction of DSBs. Furthermore, the fraction and size of radiation-induced 53BP1 foci were increased by imetelstat pre-treatment.

    In conclusion, Hsp90 and telomerase represent potential therapeutic targets in oesophageal cancer. And, the implication of EGFR and LRIG as prognostic factors is limited. Furthermore, disruption of the microtubule network may activate a protein tyrosine phosphatase that can regulate EGFR phosphorylation.

    List of papers
    1. Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
    Open this publication in new window or tab >>Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
    Show others...
    2009 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 2, p. 334-343Article in journal (Refereed) Published
    Abstract [en]

    Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for gamma-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growthfactor -1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

    Keywords
    oesophageal cancer, Hsp90, 17-AAG, EGF, IGF-1, radiation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102928 (URN)10.1038/sj.bjc.6604855 (DOI)000262637800017 ()19142186 (PubMedID)
    Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2018-12-04
    2. Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
    Open this publication in new window or tab >>Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
    Show others...
    2012 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 69-76Article in journal (Refereed) Published
    Abstract [en]

    Background. Leucine-rich and immunoglobulin-like domains 1-3 (LRIG1-3) proteins have been implicated in the regulation of EGFR signalling. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1-3 in oesophageal carcinoma, as well as the correlation between their expression levels and the chemosensitivity of oesophageal carcinoma cell lines.

    Patients and methods. Tumours from 80 patients with oesophageal carcinoma were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Oesophageal carcinoma cell lines were investigated for their expression of EGFR and LRIG1, 2, and 3 by quantitative real time RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay.

    Results and discussion: Based on a total score of intensity and expression rates, a trend towards survival difference was found for EGFR (p = 0.09) and LRIG2 (p = 0.18) whereas for LRIG1 and -3 there was no trend towards any association with survival. Correlation analysis revealed a correlation with the clinical expression of EGFR and LRIG3 (p = 0.0007). Significant correlations were found between LRIG1 expression levels and sensitivity to cisplatin (r = -0.74), docetaxel (r = -0.69), and vinorelbine (r = -0.82) in oesophageal carcinoma cell lines. EGFR and the LRIG proteins may be functionally involved in oesophageal carcinoma, but larger materials are needed to fully elucidate the clinical implication.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-152606 (URN)10.3109/0284186X.2011.562239 (DOI)000298002000010 ()21417672 (PubMedID)
    Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2017-12-11Bibliographically approved
    3. Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
    Open this publication in new window or tab >>Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
    Show others...
    (English)Article in journal (Other academic) Submitted
    Abstract [en]

    Microtubules are important structures for a range of cellular functions including cell division. Drugs that interfere with microtubule function can prevent cells from mitosis and various microtubule targeting drugs are used in a clinical setting. In the current study we investigated the sensitivity of oesophageal cancer cells to different microtubule targeting agents. As expected, experiments demonstrated that these agents in a dose-dependent manner inhibited survival and proliferation of oesophageal cancer cells and disrupted the microtubule network. Unexpectedly, experiments showed that microtubule destabilising agents inhibited phosphorylation and activation of the EGF-receptor, and that a tyrosine phosphatase inhibitor, sodium orthovanadate, could reverse the EGFR dephosphorylation. We propose a model in which disruption of the microtubule network leads to activation of a protein tyrosine phosphatase that can regulate EGFR phosphorylation and activation, indicating an additional mechanism of action of microtubule targeting agents.

    Identifiers
    urn:nbn:se:uu:diva-152763 (URN)
    Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-22Bibliographically approved
    4. The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
    Open this publication in new window or tab >>The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, Imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that Imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only one week of Imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with Imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Cell cycle analysis demonstrated that short-term treatment with Imetelstat resulted in increased percentage of cells in G1 phase. Short-term Imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with Imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1 h of repair whereas the increase of foci size was prominent later on. This study supports the potential of Imetelstat as a therapeutic agent for the treatment of esophageal cancer.

    Identifiers
    urn:nbn:se:uu:diva-152761 (URN)
    Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-01
  • 424.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedman, Håkan
    Department of Radiation Sciences and Oncology, Umeå University.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, Umeå University.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hesselius, Patrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 69-76Article in journal (Refereed)
    Abstract [en]

    Background. Leucine-rich and immunoglobulin-like domains 1-3 (LRIG1-3) proteins have been implicated in the regulation of EGFR signalling. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1-3 in oesophageal carcinoma, as well as the correlation between their expression levels and the chemosensitivity of oesophageal carcinoma cell lines.

    Patients and methods. Tumours from 80 patients with oesophageal carcinoma were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Oesophageal carcinoma cell lines were investigated for their expression of EGFR and LRIG1, 2, and 3 by quantitative real time RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay.

    Results and discussion: Based on a total score of intensity and expression rates, a trend towards survival difference was found for EGFR (p = 0.09) and LRIG2 (p = 0.18) whereas for LRIG1 and -3 there was no trend towards any association with survival. Correlation analysis revealed a correlation with the clinical expression of EGFR and LRIG3 (p = 0.0007). Significant correlations were found between LRIG1 expression levels and sensitivity to cisplatin (r = -0.74), docetaxel (r = -0.69), and vinorelbine (r = -0.82) in oesophageal carcinoma cell lines. EGFR and the LRIG proteins may be functionally involved in oesophageal carcinoma, but larger materials are needed to fully elucidate the clinical implication.

  • 425.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylationArticle in journal (Other academic)
    Abstract [en]

    Microtubules are important structures for a range of cellular functions including cell division. Drugs that interfere with microtubule function can prevent cells from mitosis and various microtubule targeting drugs are used in a clinical setting. In the current study we investigated the sensitivity of oesophageal cancer cells to different microtubule targeting agents. As expected, experiments demonstrated that these agents in a dose-dependent manner inhibited survival and proliferation of oesophageal cancer cells and disrupted the microtubule network. Unexpectedly, experiments showed that microtubule destabilising agents inhibited phosphorylation and activation of the EGF-receptor, and that a tyrosine phosphatase inhibitor, sodium orthovanadate, could reverse the EGFR dephosphorylation. We propose a model in which disruption of the microtubule network leads to activation of a protein tyrosine phosphatase that can regulate EGFR phosphorylation and activation, indicating an additional mechanism of action of microtubule targeting agents.

  • 426.
    wu, xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Smavadati, Shirin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nordfjäll, Katarina
    Department of Medical Biosciences, pathology, Umeå University.
    Karlsson, Krister
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergquist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gryaznov, Sergei
    Geron Corporation, Menlo Park, CA, USA.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Paulsson-Karlsson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The effect of the telomerase antagonist Imetelstat in esophageal carcinomaManuscript (preprint) (Other academic)
    Abstract [en]

    Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, Imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that Imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only one week of Imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with Imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Cell cycle analysis demonstrated that short-term treatment with Imetelstat resulted in increased percentage of cells in G1 phase. Short-term Imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with Imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1 h of repair whereas the increase of foci size was prominent later on. This study supports the potential of Imetelstat as a therapeutic agent for the treatment of esophageal cancer.

  • 427.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sm