| 1. |
- Einarsdottir, Berglind Osk, 1979, et al.
(author)
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A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
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In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
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Journal article (peer-reviewed)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
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| 2. |
- Johansson, Junko, 1989, et al.
(author)
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Isolated Limb Perfusion With Melphalan Triggers Immune Activation in Melanoma Patients
- 2018
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In: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 8
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Journal article (peer-reviewed)abstract
- Hyperthermic isolated limb perfusion with melphalan (M-ILP) is a treatment option for melanoma patients with metastases confined to the limbs. This study aimed at defining the role of cellular immunity for the clinical response to M-ILP in melanoma patients. It was observed that patients with enhanced cytotoxic CD8(+) T cell reactivity to common antigens (HCMV/EBV/influenza virus) prior to M-ILP were more likely to achieve a complete disappearance of macroscopic tumors (complete response). Following M-ILP treatment, the proportions of CD16(+) intermediate and non-classical monocytes in peripheral blood were significantly enhanced along with induction of HLA-DR on CD4(+) and CD8(+) T cells. For further studies of the mechanism behind melphalan-induced immune activation an in vitro model, aiming at mimicking the clinical M-ILP protocol, was established, where PBMCs were co-cultured with melanoma cells, which had been pre-exposed to melphalan under mild hyperthermia. Upon exposure to melphalan, melanoma cells showed increased expression of immune-related markers including MHC class I and Hsp70. Moreover, when the melphalan-treated melanoma cells were co-cultured with PBMCs, this triggered an increased proportion of CD33(+)CD14(+)CD16(++) non-classical monocytes among the PBMCs. Furthermore, the melphalan-treated melanoma cells stimulated the expansion of CD8(+) T cells in the co-cultured PBMCs. These cells produced enhanced levels of IFN-gamma and granzyme B and were capable of killing melanoma cells. To further verify an immunogenic role of melphalan, mice were vaccinated with melphalan-exposed murine melanoma cells. When challenged with live melanoma cells, vaccinated mice showed reduced tumor growth and enhanced infiltration of tumor-specific T cells into tumors. We conclude that melphalan-exposed melanoma cells trigger expansion of CD16(+) monocytes and activate cytotoxic T cells and that these events may contribute to the antitumoral efficacy of M-ILP.
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| 3. |
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| 4. |
- Katsarelias, Dimitrios, et al.
(author)
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The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion
- 2018
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In: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 25:7, s. 1836-1842
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Journal article (peer-reviewed)abstract
- Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival. A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986-May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database. Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39-40 A degrees C. Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined.
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| 5. |
- Nilsson, Jonas A, 1971, et al.
(author)
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Mouse avatars take off as cancer models.
- 2018
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 562:7726
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Journal article (other academic/artistic)
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| 6. |
- Pétursson, Hafsteinn Ingi, 1977, et al.
(author)
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Evaluation of intraoperative touch imprint cytology on axillary sentinel lymph nodes in invasive breast carcinomas, a retrospective study of 1227 patients comparing sensitivity in the different tumor subtypes
- 2018
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Journal article (peer-reviewed)abstract
- Background Intraoperative evaluation of the axillary sentinel lymph node (SLN) in patients with breast carcinoma reduces the need of re-operations in cases where an axillary completion lymph node dissection (CLND) is indicated. Different methods have been used to determine the SLN status intraoperatively, e.g. frozen section histology (FS) and touch imprint cytology (TIC). The sensitivity of intraoperative TIC examination on SLN is not consistent between different studies and varies according to different tumor histologic subtypes, tumor size and the age of the patient. The aim of this study was to describe the specificity and sensitivity of TIC and to compare TIC sensitivity in the different histological subtypes of breast carcinoma. A retrospective review was performed of 1227 consecutive clinically node negative breast cancer patients treated with sentinel lymph node biopsy (SLNB) with intraoperative TIC between the years 2003 and 2008. The SLN was bisected and stained using the May-Grun-wald-Giemsa method and immunocytochemically with the antibody MNF-116. The overall sensitivity of the TIC test was 68.6% and the specificity was 99.8%. There was no statistically significant difference between the detection of SLN metastases from ductal carcinoma versus lobular carcinoma. The sensitivity improved over the period of the study. TIC is highly specific with an acceptable overall sensitivity. The sensitivity increased under the period of the study and it was higher in cases with larger size of the primary tumor. There was no difference in TIC sensitivity between the different histological subtypes.
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| 7. |
- Wickberg, Åsa, 1972-
(author)
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Adjuvant treatments to prevent local reurrence after breast-conserving surgery for early breast cancer : radiation, endocrine- or brachytherapy
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Radiotherapy after breast-conserving surgery due to breast cancer is an established treatment, known to reduce the incidence of recurrence and even death from the disease. However some women are over-treated with sometimes serious adverse effects. De-escalating the treatment and find alternative adjuvant methods are becoming an important issue. In study I, we present the outcomes from a long-term follow-up trial randomising 381 women with breast cancer to surgery alone or to surgery with the addition of radiotherapy. The incidence of any first breast cancer event was significantly higher without radiotherapy but the protecting effect lasted for only the first five years. In study II, we collected the tissue samples from the tumours in study I to construct tissue micro-arrays. Immuno-histochemical analyses were performed and the tumours were classified into the intrinsic subtypes. The luminal B/HER2 negative subtype was found to be prognostic for ipsilateral breast cancer recurrence (IBTR). The intrinsic subtypes did not interact with radiotherapy. Study III was a multicentre prospective cohort study where the 601 study participants with early breast cancer were treated with surgery and endocrine therapy alone without postoperative radiotherapy. The cumulative incidence of IBTR after five years was low -1.2% and only one woman died of breast cancer. In study IV we evaluated the feasibility and treatment complications when introducing a new method for intraoperative brachytherapy (IOBT) using HDR equipment. We designed a pilot study including fifty women where half of them were treated during primary surgery and the others during a second procedure. The treatment was well tolerated and no logistic problems were reported. No acute adverse effects from IOBT were seen.
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