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  • 401.
    Valachis, Antonis
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Polyzos, Nikolaos P.
    Role of Zoledronate in Aromatase Activity Should Be Considered in Future Studies In Reply2013Inngår i: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 18, nr 8, s. E26-E27Artikkel i tidsskrift (Fagfellevurdert)
  • 402.
    Valachis, Antonis
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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-Analysis2013Inngår i: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 18, nr 4, s. 353-361Artikkel, forskningsoversikt (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Frascino, V.
    Quality assurance and quality control for radiotherapy/medical oncology in Europe: Guideline development and implementation2013Inngår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 39, nr 9, s. 938-944Artikkel, forskningsoversikt (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 Study2012Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, nr 23, s. 2861-2868Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    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 & rectum2014Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, nr 1, s. UNSP 1.e1-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 trial2011Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 12, nr 6, s. 575-582Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Åberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    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 Imaging2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e81932-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 region2015Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikkel-id UNSP 5751Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development2011Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients
    Åpne denne publikasjonen i ny fane eller vindu >>Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients
    Vise andre…
    2000 (engelsk)Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, nr 10, s. 1301-1307Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-57287 (URN)11106120 (PubMedID)
    Tilgjengelig fra: 2007-02-09 Laget: 2007-02-09 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    2. Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
    Åpne denne publikasjonen i ny fane eller vindu >>Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
    Vise andre…
    2008 (engelsk)Inngår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 34, nr 5, s. 547-552Artikkel i tidsskrift (Fagfellevurdert) 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.

    Emneord
    Peritoneal carcinomatosis, Intraperitoneal chemotherapy, Cytotoxic drug, In vitro
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-13245 (URN)10.1016/j.ejso.2007.05.002 (DOI)000256207400012 ()17574369 (PubMedID)
    Tilgjengelig fra: 2008-06-24 Laget: 2008-06-24 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
    Åpne denne publikasjonen i ny fane eller vindu >>Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    ovarian cancer, chemotherapy, drug sensitivity testing, in vitro
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-151799 (URN)
    Tilgjengelig fra: 2011-04-18 Laget: 2011-04-18 Sist oppdatert: 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
    Åpne denne publikasjonen i ny fane eller vindu >>Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data
    2010 (engelsk)Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, nr 6, s. 1165-1172Artikkel i tidsskrift (Fagfellevurdert) 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.

    Emneord
    Cancer, NAD depletion, Phase I clinical trial, CHS 828, FK866, GMX1777
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-130804 (URN)10.1007/s00280-009-1125-3 (DOI)000275632400019 ()19789873 (PubMedID)
    Tilgjengelig fra: 2010-09-13 Laget: 2010-09-13 Sist oppdatert: 2017-12-12bibliografisk kontrollert
  • 410.
    von Heideman, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Tholander, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Grundmark, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Cajander, Stefan
    Gerdin, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Holm, Leif
    Axelsson, Agneta
    Rosenberg, Per
    Mahteme, Haile
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Daniel, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome2014Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 2, s. 242-250Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Tholander, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Grundmark, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Cajander, Stefan
    Gerdin, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Holm, Leif
    Axelsson, Agneta
    Rosenberg, Per
    Mahteme, Haile
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from PatientsManuskript (preprint) (Annet vitenskapelig)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Tötterman, Thomas H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    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"2012Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 61, nr 5, s. 749-749Artikkel i tidsskrift (Annet vitenskapelig)
  • 413. Wahlin, Björn Engelbrekt
    et al.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Holte, Harald
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 rituximab2011Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, nr 12, s. 4136-4144Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Jirström, K.
    Darmanis, Spyros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nong, Rachel Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Johansson, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Påhlman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer2011Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, nr 10, s. 1619-1627Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Reproducibility of quantitative parameters of F-18-Fluoride PET/CT in prostate bone metastases2014Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, s. S242-S242, artikkel-id OP367Artikkel i tidsskrift (Annet vitenskapelig)
  • 416. Wasterlid, T.
    et al.
    Brown, P. N.
    Hagberg, O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    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 Group2013Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, nr 7, s. 1879-1886Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Shui, Y.
    Zheng, S.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Nordgren, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy2011Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 25, nr 1, s. 3-11Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Morhed, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    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 correction2011Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, nr 4, s. 518-527Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ring, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Comparing two versions of the Schedule for Evaluation of Individual Quality of Life in patients with advanced cancer2011Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, nr 5, s. 648-652Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Kettis, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ring, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Comparison of two instruments for measurement of quality of life in clinical practice - a qualitative study2014Inngår i: BMC Medical Research Methodology, ISSN 1471-2288, E-ISSN 1471-2288, Vol. 14, s. 115-Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Aminopeptidase N (CD13) as a target for cancer chemotherapy2011Inngår i: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, nr 3, s. 501-508Artikkel, forskningsoversikt (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Holmqvist, Marit
    Fornander, Tommy
    Adolfsson, Jan
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergkvist, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Lambe, Mats
    Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study2012Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 133, nr 1, s. 367-373Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase2011Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
    Åpne denne publikasjonen i ny fane eller vindu >>Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin
    Vise andre…
    2009 (engelsk)Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, nr 2, s. 334-343Artikkel i tidsskrift (Fagfellevurdert) 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.

    Emneord
    oesophageal cancer, Hsp90, 17-AAG, EGF, IGF-1, radiation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-102928 (URN)10.1038/sj.bjc.6604855 (DOI)000262637800017 ()19142186 (PubMedID)
    Tilgjengelig fra: 2009-05-12 Laget: 2009-05-12 Sist oppdatert: 2018-12-04
    2. Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
    Åpne denne publikasjonen i ny fane eller vindu >>Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity
    Vise andre…
    2012 (engelsk)Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, nr 1, s. 69-76Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-152606 (URN)10.3109/0284186X.2011.562239 (DOI)000298002000010 ()21417672 (PubMedID)
    Tilgjengelig fra: 2011-04-28 Laget: 2011-04-28 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
    Åpne denne publikasjonen i ny fane eller vindu >>Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) 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.

    Identifikatorer
    urn:nbn:se:uu:diva-152763 (URN)
    Tilgjengelig fra: 2011-05-02 Laget: 2011-05-02 Sist oppdatert: 2011-07-22bibliografisk kontrollert
    4. The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
    Åpne denne publikasjonen i ny fane eller vindu >>The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Identifikatorer
    urn:nbn:se:uu:diva-152761 (URN)
    Tilgjengelig fra: 2011-05-02 Laget: 2011-05-02 Sist oppdatert: 2011-07-01
  • 424.
    Wu, Xuping
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Hedman, Håkan
    Department of Radiation Sciences and Oncology, Umeå University.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergström, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, Umeå University.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Hesselius, Patrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Nationalekonomiska institutionen.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity2012Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, nr 1, s. 69-76Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Bergström, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylationArtikkel i tidsskrift (Annet vitenskapelig)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Smavadati, Shirin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Nordfjäll, Katarina
    Department of Medical Biosciences, pathology, Umeå University.
    Karlsson, Krister
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Qvarnström, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Simonsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergquist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gryaznov, Sergei
    Geron Corporation, Menlo Park, CA, USA.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Paulsson-Karlsson, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The effect of the telomerase antagonist Imetelstat in esophageal carcinomaManuskript (preprint) (Annet vitenskapelig)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Smavadati, Shirin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Nordfjäll, Katarina
    Karlsson, Krister
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Qvarnström, Fredrik
    Simonsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gryaznov, Sergei
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Paulsson-Karlsson, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks2012Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1823, nr 12, s. 2130-2135Artikkel i tidsskrift (Fagfellevurdert)
    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 1. 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. 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.

  • 428.
    Wu, Xuping
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sooman, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Bergström, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Microtubule inhibition causes epidermal growth factor receptor inactivation in oesophageal cancer cells2013Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 42, nr 1, s. 297-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drugs that interfere with microtubule function can prevent cells from mitosis and may cause cell cycle arrest or apoptosis. Various microtubule targeting agents, both stabilizers and inhibitors, are used in a clinical setting to treat cancer. In the current study, we investigated the sensitivity of oesophageal cancer cells to different microtubule targeting agents. The current study demonstrated that different microtubule targeting agents disrupted the microtubule network and inhibited survival of oesophageal cancer cells in a dose-dependent manner. Interestingly, an additional cellular effect with inhibition of tyrosine phosphorylation of the EGFR and subsequent downregulation of EGFR-induced signalling was also observed, suggesting an additional mechanism of action for microtubule destabilising agents. A tyrosine phosphatase inhibitor, sodium orthovanadate, could reverse the EGFR dephosphorylation effects induced by microtubule targeting agents. The EGFR dephosphorylation could be reversed by a tyrosine phosphatase inhibitor, indicating that disruption of the microtubule network may lead to activation of a protein tyrosine phosphatasc (PTP) that can regulate EGFR phosphorylation and activation, an effect of potential clinical relevance for combination therapies in patients.

  • 429. Wästerlid, Tove
    et al.
    Jonsson, Björn
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Jerkeman, Mats
    Population based study of prognostic factors and treatment in adult Burkitt lymphoma: a Swedish Lymphoma Registry study2011Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, nr 11, s. 2090-2096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Burkitt lymphoma (BL) is a rare neoplasm constituting 1-2% of adult lymphomas. Our aims in this study were to establish prognostic factors for overall survival in adult BL and evaluate the efficacy of different chemotherapy regimens in a population based setting. The study population was collected from the Swedish Lymphoma Registry 2000-2010. During this period, 156 adult patients with BL were identified. In multivariate analysis, age and performance status (PS) were significant adverse prognostic factors for overall survival. A modified prognostic index, based on: age >40 years, PS >1, and lactate dehydrogenase > upper limit of normal (ULN) was proposed. Patients with a score of 0-1, 2, and 3 were found to have a 2-year survival of 91.2%, 58.4%, and 27.5%, respectively. High-intensity regimens were associated with more favorable overall survival. Rituximab addition was not significantly associated with improvement in survival. A modified prognostic index may be valuable for adult BL, as proposed.

  • 430. Zduniak, K.
    et al.
    Ziolkowski, P.
    Ahlin, C.
    Agrawal, A.
    Agrawal, S.
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Weber, G. F.
    Nuclear osteopontin-c is a prognostic breast cancer marker2015Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, nr 4, s. 729-738Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available. Methods: Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues. Results: We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2. Conclusions: The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.

  • 431. Zhang, Xiaonan
    et al.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Hernlund, Emma
    Fayad, Walid
    De Milito, Angelo
    Olofsson, Maria Hagg
    Gogvadze, Vladimir
    Dang, Long
    Pahlman, Sven
    Schughart, Leoni A. Kunz
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Darcy, Padraig
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Linder, Stig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments2014Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, s. 3295-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

  • 432.
    Zhou, Wenjing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Jirström, Karin
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sollie, Thomas
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sørlie, Therese
    Blomqvist, Carl
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study2013Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, s. 512-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Different molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS.

    METHODS: TMA including 458 women from a population-based cohort with DCIS diagnosed 1986-2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models.

    RESULTS: Surrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty-two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).

    CONCLUSIONS: The results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence.

  • 433.
    Zhou, Wenjing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Johansson, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Jirström, Karin
    Department of Clinical Sciences, Pathology, Lund University.
    Ringberg, Anita
    Department of Plastic and Reconstructive Surgery, Malmö Hospital.
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital.
    Amini, Rose Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ2012Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArtikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Introduction:

    About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

    Methods:

    Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

    Results:

    One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

    Conclusions:

    Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

  • 434.
    Zhou, Wenjing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Johansson, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Jirström, Karin
    Ringberg, Anita
    Blomqvist, Carl
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ2013Inngår i: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, Vol. 2013, s. 582134-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction

    About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ).

    Methods

    Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses.

    Results

    One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2-5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3-0.9), EGFR+ (OR 0.4, 95% CI 0.2-0.9), and ER95-/HER2+ (OR 0.2, 95% CI 0.1-0.6) had a lower risk of a recurrence being invasive.

    Conclusions

    In this study, comparing type of recurrence after a DCIS showed that the ER-/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer.

  • 435.
    Zhou, Wenjing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Sollie, Thomas
    Tot, Tibor
    Pinder, Sarah E
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Blomqvist, Carl
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Christensson, Gunilla
    Abdsaleh, Shahin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Breast cancer with neoductgenesis: histopathological criteria and its correlation with mammographic and tumour features2014Inngår i: International Journal of Breast Cancer, ISSN 2090-3170, E-ISSN 2090-3189, Vol. 2014, artikkel-id 581706Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers.

    Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied.

    Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers).

    Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.

6789 401 - 435 of 435
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