Institute of Fundamental Technological Research
Polish Academy of Sciences

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Dag Hoem

Haukeland University Hospital (NO)

Recent publications
1.  Dimcevski G., Kotopoulis S., Bjånes T., Hoem D., Schjøt J., Gjertsen B.T., Biermann M., Molven A., Sorbye H., McCormack E., Postema M., Gilja O.H., A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer, Journal of Controlled Release, ISSN: 0168-3659, DOI: 10.1016/j.jconrel.2016.10.007, Vol.243, pp.172-181, 2016

Abstract:
Background:
The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival.

Methods:
Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue® was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy.

Results:
The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls (n = 63 patients; average of 8.3 ± 6.0 cycles, versus 13.8 ± 5.6 cycles, p = 0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n = 10) was also increased from 8.9 months to 17.6 months (p = 0.011).

Conclusions:
It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.

Keywords:
Ultrasound, Microbubbles, Sonoporation, Pancreatic cancer, Image-guided therapy, Clinical trial

Affiliations:
Dimcevski G. - Haukeland University Hospital (NO)
Kotopoulis S. - Haukeland University Hospital (NO)
Bjånes T. - Haukeland University Hospital (NO)
Hoem D. - Haukeland University Hospital (NO)
Schjøt J. - Haukeland University Hospital (NO)
Gjertsen B.T. - University of Bergen (NO)
Biermann M. - Haukeland University Hospital (NO)
Molven A. - Haukeland University Hospital (NO)
Sorbye H. - Haukeland University Hospital (NO)
McCormack E. - Haukeland University Hospital (NO)
Postema M. - IPPT PAN
Gilja O.H. - Haukeland University Hospital (NO)
2.  Kotopoulis S., Dimcevski G., Gilja O.H., Hoem D., Postema M., Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: A clinical case study, Medical Physics, ISSN: 0094-2405, DOI: 10.1118/1.4808149, Vol.40, No.7, pp.072902-1-9, 2013

Abstract:
Purpose:
The purpose of this study was to investigate the ability and efficacy of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and extend the low Eastern Cooperative Oncology Group performance grade; as a result increasing the overall survival in patients with pancreatic adenocarcinoma.

Methods:
Patients were treated using a customized configuration of a commercial clinical ultrasound scanner over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue® ultrasound contrast agent was injected intravascularly during the treatment with the aim to induce sonoporation.

Results:
Using the authors’ custom acoustic settings, the authors’ patients were able to undergo an increased number of treatment cycles; from an average of 9 cycles, to an average of 16 cycles when comparing to a historical control group of 80 patients. In two out of five patients treated, the maximum tumor diameter was temporally decreased to 80 ± 5% and permanently to 70 ± 5% of their original size, while the other patients showed reduced growth. The authors also explain and characterize the settings and acoustic output obtained from a commercial clinical scanner used for combined ultrasound microbubble and chemotherapy treatment.

Conclusions:
It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles, prolonging the quality of life in patients with pancreatic adenocarcinoma compared to chemotherapy alone.

Keywords:
Ultrasound, Microbubbles, Sonoporation, Chemotherapy

Affiliations:
Kotopoulis S. - Haukeland University Hospital (NO)
Dimcevski G. - Haukeland University Hospital (NO)
Gilja O.H. - Haukeland University Hospital (NO)
Hoem D. - Haukeland University Hospital (NO)
Postema M. - other affiliation

Conference abstracts
1.  Dimcevski G.G., Kotopoulis S., Bjåne T., Hoem D., Schjött J., Gjertsen B.T., Biermann M., Molven A., Sorbye H., McCormack E., Postema M., Gilja O.H., Ultrasound and microbubble enhanced treatment of inoperable pancreatic adeonocarcinoma, ASCO Annual Meeting, 2016-06-03/06-07, Chicago (US), Vol.34, No.suppl; abstr e15703, pp.1, 2016

Abstract:
Background: Pancreatic Adenocarcinoma (PDAC) represents one of the most lethal human cancers. Surgery is often unfeasible, and the tumors respond poorly to radiation or chemotherapeutic drugs. Consequently, pancreatic cancer represents a huge burden to society and the need for new therapeutic options is evident. Experimental research using ultrasound to improve therapeutic delivery has soared in the past decade. We aimed toevaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary goal was to develop a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance grade, and prolongation of survival. Methods: Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of enhancing therapeutic efficacy. Results: The combined therapeutic regimen did not induce any additional toxicity or increase side effect frequency when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls (n = 63 patients; average of 8.3±6.0 cycles, versus 13.8±5.6 cycles). In five patients, the maximum tumor diameter was decreased during treatment. The median survival in our patients was also increased from 7.0 months to 17.6 months (p = 0.0044). Conclusions: We perform the first-in-human study evaluating the toxicity and efficacy of ultrasound and microbubble enhanced chemotherapy. It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting with no additional toxicity. This combined treatment may improve the clinical efficacy of chemotherapeutic agents, prolong the quality of life, and extend survival in patients with PDAC. Clinical trial information: NCT01674556.

Affiliations:
Dimcevski G.G. - Haukeland University Hospital (NO)
Kotopoulis S. - Haukeland University Hospital (NO)
Bjåne T. - Haukeland University Hospital (NO)
Hoem D. - Haukeland University Hospital (NO)
Schjött J. - other affiliation
Gjertsen B.T. - University of Bergen (NO)
Biermann M. - Haukeland University Hospital (NO)
Molven A. - Haukeland University Hospital (NO)
Sorbye H. - Haukeland University Hospital (NO)
McCormack E. - Haukeland University Hospital (NO)
Postema M. - other affiliation
Gilja O.H. - Haukeland University Hospital (NO)
2.  Kotopoulis S., Dimcevski G., Hoem D., Postema M., Gilja O.H., Ultrasound sonoporation in pancreatic adenocarcinoma, AIUM 2015, Ultrasound in Medicine and Biology Annual Convention, 2015-03-21/03-25, Lake Buena Vista (US), Vol.41, No.4, Supplement, pp.S94, 2015
3.  Dimcevski G., Kotopoulis S., Hoem D., Postema M., Gjertsen B.T., Bjåne T.K., Biermann M., McCormack E., Sorbye H., Molven A., Gilja O.H., Ultrasound-assisted treatment of an inoperable pancreatic cancer, MedViz Conference 2013, 2013/, Bergen (NO), pp.49-52, 2013

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