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Lindman, Henrik
Publications (10 of 41) Show all publications
Matikas, A., Margolin, S., Hellström, M., Johansson, H., Bengtsson, N.-O., Karlsson, L., . . . Bergh, J. (2018). Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer. Breast Cancer Research and Treatment, 168(2), 349-355
Open this publication in new window or tab >>Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer
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2018 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 2, p. 349-355Article in journal (Refereed) Published
Abstract [en]

Although adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs. The SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18-65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up. A total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up. In this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keyword
Adjuvant chemotherapy, Breast cancer, Dose-dense, Randomized, Tailored dose
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-350272 (URN)10.1007/s10549-017-4599-4 (DOI)000426778200006 ()29190004 (PubMedID)
Funder
Swedish Cancer SocietyKing Gustaf V Jubilee FundThe Karolinska Institutet's Research FoundationSwedish Research CouncilStockholm County Council
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-05-14Bibliographically approved
Netterberg, I., Karlsson, M. O., Nielsen, E. I., Quartino, A. L., Lindman, H. & Friberg, L. E. (2018). The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.. British Journal of Clinical Pharmacology, 84(3), 490-500
Open this publication in new window or tab >>The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.
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2018 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 84, no 3, p. 490-500Article in journal (Refereed) Published
Abstract [en]

AIMS: Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)-6 and C-reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL-6 and CRP, and other model-derived and clinical variables, was explored.

METHODS: The IL-6 and CRP time courses in cycles 1 and 4 of breast cancer treatment were described by turnover models where the probability for an elevated production following initiation of chemotherapy was estimated. Parametric time-to-event models were developed to describe FN occurrence to assess: (i) predictors available before chemotherapy is initiated; (ii) predictors available before FN occurs; and (iii) predictors available when FN occurs.

RESULTS: The IL-6 and CRP time courses were successfully characterized with peak IL-6 typically occurring 2 days prior to CRP peak. Of all evaluated variables the CRP time course was most closely associated with the occurrence of FN. Since the CRP peak typically occurred at the time of FN diagnosis it will, however, have limited value for identifying the need for preventive treatment. The time course of IL-6 was the predictor that could best forecast FN events. Of the variables available at baseline, age was the best, although in comparison a relatively weak, predictor.

CONCLUSIONS: The developed models add quantitative knowledge about IL-6 and CRP and their relationship to the development of FN. The study suggests that IL-6 may have potential as a clinical predictor of FN if monitored during myelosuppressive chemotherapy.

Keyword
C-reactive protein, NONMEM, adjuvant chemotherapy, febrile neutropenia, interleukin-6
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-343812 (URN)10.1111/bcp.13477 (DOI)000424877400009 ()29178353 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-03-01 Created: 2018-03-01 Last updated: 2018-04-09Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2018-03-09Bibliographically approved
Joensuu, H., Kellokumpu-Lehtinen, P.-L., Huovinen, R., Jukkola-Vuorinen, A., Tanner, M., Kokko, R., . . . Lindman, H. (2017). Adjuvant Capecitabine in Combination With Docetaxel, Epirubicin, and Cyclophosphamide for Early Breast Cancer: The Randomized Clinical FinXX Trial. JAMA Oncology, 3(6), 793-800
Open this publication in new window or tab >>Adjuvant Capecitabine in Combination With Docetaxel, Epirubicin, and Cyclophosphamide for Early Breast Cancer: The Randomized Clinical FinXX Trial
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2017 (English)In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 6, p. 793-800Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE Capecitabine is not considered a standard agent in the adjuvant treatment of early breast cancer. The results of this study suggest that addition of adjuvant capecitabine to a regimen that contains docetaxel, epirubicin, and cyclophosphamide improves survival outcomes of patients with triple-negative breast cancer (TNBC).

OBJECTIVE To investigate the effect of capecitabine on long-term survival outcomes of patients with early breast cancer, particularly in subgroups defined by cancer estrogen receptor (ER) and progesterone receptor (PR) content, and HER2 content (human epidermal growth factor receptor 2).

DESIGN, SETTING, AND PARTICIPANTS This is an exploratory analysis of the multicenter FinXX randomized clinical trial that accrued 1500 women in Finland and Sweden between January 27, 2004, and May 29, 2007. About half received 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF), while the other half received 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Data analysis took place between January 27, 2004, and December 31, 2015.

MAIN OUTCOMES AND MEASURES Recurrence-free survival (RFS).

RESULTS Following random allocation, 747 women received T+CEF, and 753 women received TX+CEX. Five patients were excluded from the intention-to-treat population (3 had overt distant metastases at the time of randomization; 2 withdrew consent). The median age of the remaining 1495 patients was 53 years at the time of study entry; 157 (11%) had axillary node-negative disease; 1142 (76%) had ER-positive cancer; and 282 (19%) had HER2-positive cancer. The median follow-up time after random allocation was 10.3 years. There was no significant difference in RFS or overall survival between the groups (hazard ratio [HR], 0.88; 95% CI, 0.71-1.08; P = .23; and HR, 0.84, 95% CI, 0.66-1.07; P = .15; respectively). Breast cancer-specific survival tended to favor the capecitabine group (HR, 0.79; 95% CI, 0.60-1.04; P = .10). When RFS and survival of the patients were compared within the subgroups defined by cancer steroid hormone receptor status (ER and/or PR positive vs ER and PR negative) and HER2 status (positive vs negative), TX+CEX was more effective than T+CEF in the subset of patients with TNBC (HR, 0.53; 95% CI, 0.31-0.92; P = .02; and HR, 0.55, 95% CI, 0.31-0.96; P = .03; respectively).

CONCLUSIONS AND RELEVANCE Capecitabine administration with docetaxel, epirubicin, and cyclophosphamide did not prolong RFS or survival compared with a regimen that contained only standard agents. Patients with TNBC had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-329723 (URN)10.1001/jamaoncol.2016.6120 (DOI)000403478200011 ()28253390 (PubMedID)
Funder
AstraZeneca
Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2017-09-21Bibliographically approved
Fredholm, H., Magnusson, K., Lindstrom, L. S., Tobin, N. P., Lindman, H., Bergh, J., . . . Fredriksson, I. (2017). Breast cancer in young women and prognosis: How important are proliferation markers?. European Journal of Cancer, 84, 278-289
Open this publication in new window or tab >>Breast cancer in young women and prognosis: How important are proliferation markers?
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2017 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 84, p. 278-289Article in journal (Refereed) Published
Abstract [en]

Aim:

Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.

Methods:

Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged >= 40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins.

Results:

Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age < 40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A ( HR 6.21 [2.17-17.6]).

Conclusions:

The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.

Keyword
Breast cancer, Young, Age, Subtype, Luminal, Progesterone receptor, Ki-67, Cyclin, Prognosis, Population-based
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-336293 (URN)10.1016/j.ejca.2017.07.044 (DOI)000411333300032 ()28844016 (PubMedID)
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-01-23Bibliographically approved
Lindman, H., Nilsson, A. & Gullbo, J. (2017). Clinical characteristics of CNS metastases of different breast cancer subtypes - Results from a cohort study. Paper presented at San Antonio Breast Cancer Symposium, DEC 06-10, 2016, San Antonio, TX. Cancer Research, 77
Open this publication in new window or tab >>Clinical characteristics of CNS metastases of different breast cancer subtypes - Results from a cohort study
2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77Article in journal (Refereed) Published
Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-320980 (URN)10.1158/1538-7445.SABCS16-P1-12-09 (DOI)000397999000290 ()
Conference
San Antonio Breast Cancer Symposium, DEC 06-10, 2016, San Antonio, TX
Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2017-04-27Bibliographically approved
Sandberg, D. T., Tolmachev, V., Velikyan, I., Olofsson, H., Wennborg, A., Feldwisch, J., . . . Sörensen, J. (2017). Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.. European Journal of Nuclear Medicine and Molecular Imaging, 44(8), 1337-1346
Open this publication in new window or tab >>Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.
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2017 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, no 8, p. 1337-1346Article in journal (Refereed) Published
Abstract [en]

PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.

METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.

RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.

CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.

Keyword
Affibody, HER2-receptor, PET, SPECT, Shedding, T/R
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317746 (URN)10.1007/s00259-017-3650-3 (DOI)000403468900012 ()28261749 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-02-28Bibliographically approved
Rosell, J., Nordenskjöld, B., Bengtsson, N.-O., Fornander, T., Hatschek, T., Lindman, H., . . . Carstensen, J. (2017). Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen. Acta Oncologica, 56(4), 614-617
Open this publication in new window or tab >>Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen
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2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 4, p. 614-617Article in journal (Refereed) Published
Abstract [en]

Background: Tamoxifen is a well established treatment for breast cancer, but its long-term effects on the incidence of secondary cancers are not fully evaluated.Material and methods: We have studied 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after two years of tamoxifen, and who were randomized to receive totally two or five years of therapy.Results: Compared to patients randomized to two years of tamoxifen the incidence of contralateral breast cancer [hazard ratio (HR) 0.73; 95% CI 0.56-0.96] and of lung cancer (HR 0.45; 95% CI 0.27-0.77), especially squamous cell and small cell lung cancer, were reduced in the five-year group, and similar results were seen when restricting the analysis to the 10-year period after treatment stopped. An increased incidence of endometrial cancer was observed in the five-year group, but the excess risk decreased over time.Conclusion: Further studies of the effects of tamoxifen on the risk of different histological types of lung cancer are needed.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-322232 (URN)10.1080/0284186X.2016.1273547 (DOI)000399499600016 ()28080180 (PubMedID)
Available from: 2017-05-17 Created: 2017-05-17 Last updated: 2017-05-23Bibliographically approved
Frenzel, K., Heesen, L., Bolte, S., Bukur, V., Diken, M., Derhovanessian, E., . . . Sahin, U. (2017). Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer. Paper presented at ESMO Immuno Oncology Congress, DEC 07-10, 2017, Geneva, SWITZERLAND. Annals of Oncology, 28(suppl 11)
Open this publication in new window or tab >>Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer
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2017 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no suppl 11Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-348322 (URN)10.1093/annonc/mdx711.080 (DOI)000424778900089 ()
Conference
ESMO Immuno Oncology Congress, DEC 07-10, 2017, Geneva, SWITZERLAND
Funder
EU, FP7, Seventh Framework Programme
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-04-24Bibliographically approved
Sandström, M., Lindskog, K., Velikyan, I., Wennborg, A., Feldwisch, J., Sandberg, D., . . . Lubberink, M. (2016). Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients. Journal of Nuclear Medicine, 57(6), 867-871
Open this publication in new window or tab >>Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients
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2016 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 6, p. 867-871Article in journal (Refereed) Published
Abstract [en]

Ga-68-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of Ga-68-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD Ga-68-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 +/- 0.003 mSv/MBq for LD and 0.028 +/- 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of Ga-68-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other Ga-68-labeled tracers, such as 0.021 +/- 0.003 mSv/MBq for Ga-68-DOTATATE and Ga-68-DOTATOC, mainly because of higher uptake in liver and kidney.

Keyword
Affibody, breast cancer metastases, dosimetry, HER2-receptor, Ga-68-gallium
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-298861 (URN)10.2967/jnumed.115.169342 (DOI)000377052400035 ()26912439 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-11-28Bibliographically approved
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