Arkiv for Forskning kategorien

Ophold i England med international forskning?

Ten Clinical Research International Fellowships in the Departments of Medical Oncology & Haematology

  • Breast cancer
  • Colorectal cancer
  • Experimental Cancer Medicine Team (phase I)
  • Gynaecological cancers
  • Haematology
  • Hepatopancreaticobiliary and Neuroendocrine tumours
  • Lung cancer
  • Lymphoma
  • Renal cancer
  • Upper-gastrointestinal cancer

Se mere her

Europæisk oversigt over behandlingen af hjernemetastaser fra lungecancer

EORTC Lung Cancer Group Young Investigators har lavet en europæisk opgørelse over screening og behandling af hjernemetastaser fra NSCLC. Her vises nogle tankevækkende forskelle.

Yngre onkologer (<40 år) med interesse for lungecancer kan kontakte Levy Antonin: Antonin.LEVY@gustaveroussy.fr, hvis man gerne vil vide mere om gruppen og engagere sig i et europæiske samarbejde.

European Journal of Cancer 93 (2018) 37-46

https://www.sciencedirect.com/science/article/pii/S0959804918300819

Nyt: Legatbogen

Legatbogen er et register over alle fonde og legater i Danmark. Drømmen er at gøre legatsøgning nemt og effektivt, og gøre legatbogen til det digitale mødested, hvor de bedste ansøgere møder de rigtige fonde. Søgemaskinen er gratis. Her er linket til hjemmesiden: https://www.legatbogen.dk

Calcium electroporation for treatment of cutaneous metastases;

a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.

Hanne Falk (1), Louise Wichmann Matthiessen (1), Gitte Wooler (2), Julie Gehl (1)

1) Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen. 2) Department of Pathology, Herlev and Gentofte Hospital, University of Copenhagen.

Background
Calcium electroporation is a novel anticancer treatment, which utilizes high voltage pulses to permeabilize cell membranes and expose the cell to supraphysiological doses of calcium. Preclinical studies on calcium electroporation have shown strikingly high tumor response with cell necrosis, associated with severe ATP depletion. Calcium electroporation builds on the treatment electrochemotherapy, where chemotherapeutic drugs, mostly bleomycin, are internalized by electroporation. This double blinded randomized study compared calcium electroporation to electrochemotherapy in terms of objective response measured six months after treatment.

Materials and methods
A total of 47 metastases were included in the protocol, six patients had breast cancer and one patient had malignant melanoma. A total of 37 cutaneous metastases were randomized and evaluated for response with six months follow up. Another 10 metastases were biopsied before or one week after treatment. This was a non-inferiority trial and metastases were randomized individually in each patient to either intratumoral calcium or intratumoral bleomycin followed by application of electric pulses to tumor site. All metastases were treated once, and after 6 months follow up, the randomization code was revealed. 

Results
Objective response of calcium electroporation was 72.2% (13/18) with complete response in 66.7% (12/18). For electrochemotherapy objective response was 84.2% (16/19) with complete response in 68.4% (13/19). There was no statistically significant difference between the two treatments (p=0.5). At one year follow up of 25 metastases, only three metastases had relapsed. Ulceration, itching and exudating were reported slightly more frequently in metastases treated with bleomycin compared to metastases treated with calcium. Hyperpigmentation was only seen in metastases treated with bleomycin.

Conclusion
This study shows that calcium electroporation is feasible and effective in patients with cutaneous metastases.

 

Multigene expression profile for predicting efficacy of cisplatin and vinorelbine in non-small cell lung cancer

Ida Kappel Buhl (1)(2), Ib Jarle Christensen (3), Eric Santoni-Rugiu (4), Jesper Ravn (5), Anker Hansen (2), Thomas Jensen (2), Jon Askaa (2), Peter Buhl Jensen (2), Steen Knudsen (6), Jens Benn Sørensen (7)

1) Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, 2) Medical Prognosis Institute, Hørsholm, Denmark, 3) Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark,

4) Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 5) Department of Thoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 6) Medical Prognosis Institute Inc, Scottsdale, Arizona 85258, USA, 7) Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background
There is a need for biomarkers to predict efficacy of adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a combined cisplatin and vinorelbine marker from a previously validated model system [1] tested in two cohorts.

Materials and methods
The profiles consist of correlated in vitro cytotoxicity of cisplatin and vinorelbine and mRNA expressions. Then each profile is correlated to mRNA expression of 3500 tumors.

The cohorts are 1) a publically available dataset with 133 completely resected stage Ib-II NSCLC patients, 71 of whom received adjuvant cisplatin and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS) [2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival.

Results
The combined cisplatin and vinorelbine profiles scored as a continuous covariate showed 1) a Hazard Ratio (HR) of 0.265 ((95% CI:0.079-0.889), p=0.032) in the ACT cohort (sensitive versus resistant), and no significant discrimination in the OBS cohort (HR=1.328 (95% CI:0.46-3.835), p=0.60). A multivariate model adjusted for stage demonstrated significance for ACT (HR=0.284 (95% CI:0.086-0.944), p=0.040) but not for OBS (HR=1.702 (95% CI: 0.575-5.036), p=0.34). The combined profiles resulted in 2) a significant prediction for up to 3 years from surgery (HR=0.143 (95% CI:0.038-0.542), p=0.004, scored as a continuous covariate). A multivariate model adjusting for stage showed that the predictor remained significant (HR=0.123 (95% CI:0.030-0.512), p=0.004).A pooled analysis of the two treated cohorts resulted in a significant prediction (HR=0.187, (95% CI:0.069-0.508), p=0.001) up to 3 years from surgery using a random effects model.

Conclusion
The combined profiles demonstrate that NSCLC patients who benefit from cisplatin and vinorelbine can be identified. The profiles did not discriminate patients in the untreated arm. This holds promise for a predictive effect of the profiles and it is currently being validated in a prospective study [4].

[1] PLoS ONE 2016, 11(2): e0148070. [2] Zhu et al JCO 2010;28:4417-4424. [3] ASCO 2016 abstract e20007.

[4] AACR 2016 Abstract CT154.

Copenhagen prospective personalized oncology (CoPPO): Genomic profiling to select patients for phase 1 trials

Ida Viller Tuxen (1), Christina Westmose Yde (2), Olga Østrup (2), Morten Mau-Sørensen (1), Eric Santoni-Rugiu (3), Ulrik Lassen (1), Finn Cilius Nielsen (2)

1) Department of Oncology, Rigshospitalet,Copenhagen.  2) Center of Genomic Medicine, Rigshospitalet, Copenhagen.

3) Department of Pathology, Rigshospitalet,Copenhagen.

Background
Advanced technologies can be used to portray genomic alterations (GA) that potentially drive tumor growth. We have established a sequencing and array based pipeline to identify GA to select patients (pts) who might benefit from novel targeted treatments and to enrich the population in phase 1 trials with pts that harbor specific targets.

Materials and methods
Adults with advanced solid tumors referred to a dedicated Phase 1 Unit were offered biopsy for mapping of GA. Three fresh tumors 18 G needle biopsies were taken, two were stored in RNAlater® (Life Technologies) for RNA expression analyses and DNA gene mutation analyses, while one biopsy was formalin-fixed and paraffin-embedded for histopathological analyses to confirm suitability of the material, including the presence of min. 100 tumor cells. SNP-array from tumor and whole exome sequencing (WES) from DNA (tumor and blood) were performed using sequence capture and Illumina sequencing to call tumor specific mutations. WES from blood was used to subtract germline polymorphisms. Expression levels of therapeutic targets were revealed by expression Array and RNA-seq from tumor RNA. A tumor board reviewed results. Pts with specific GA that could be targeted with drugs in development were enrolled in phase 1 trials. Individualized treatment with marketed drugs (Off-label) or non-approved drugs (Named patient program) were offered according to level of existing evidence. 

Results
Between May, 2013 and April, 2016, we screened 366 heavily pretreated pts with solid tumors. In 297 pts (81%) a biopsy was taken. In 283 (77%) we achieved sufficient tumor tissue to perform a full genomic profile. An actionable target was identified in 215 pts (75%) out of 283 pts. Mean time from biopsy to reporting of results was 36 days. 153 pts with an actionable target were eligible for treatment. 57 pts (20%) were treated according to the findings of either mutations or RNA expression levels of treatment targets in phase 1 trials (N=39) or Off-label treatment/Named patient program (N=18) 

Conclusion
Establishing sequencing and array-based pipeline for enrichment of patients to phase 1 trials is feasible in a Phase 1 Unit

Feasibility of preference-driven dose plan optimization to support shared decision making in anal cancer radiotherapy

Heidi S Rønde M.Sc. (1) ,Leonard Wee Ph.D. (2,3), John Pløen M.D. (3,4), Ane L Appelt Ph.D. (3,5).

1) Department of Medical Physics, Vejle Hospital, Denmark. 2) MAASTRO Clinic, School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands. 3) Danish Colorectal Cancer Centre South, Vejle Hospital, and Institute of Regional Health Research, University of Southern Denmark, Denmark. 4) Department of Oncology, Vejle Hospital, Denmark. 5) Leeds Institute of Cancer and Pathology, University of Leeds, and Leeds Cancer Centre, St. James’ University Hospital, Leeds, United Kingdom 

Background
Chemo-radiotherapy is an established primary curative treatment for anal cancer, but clinically equal rationale for different target doses exists. Joint preferences (physician and patient) can be used to determine acceptable trade-offs inherent during radiotherapy treatment planning. If so, it is essential to compare multiple simultaneously optimal plans. We have quantified the degree to which different toxicity priorities might be incorporated into treatment plan selection, to elucidate the feasible decision space for shared decision making in anal cancer radiotherapy.

Materials and methods
Retrospective IMRT plans were generated for 22 representative anal cancer patients. Multi-criteria optimisation handles dynamically changing priorities between clinical objectives while meeting fixed clinical constraints. Four unique dose distributions were designed to represent a wide span of clinically relevant objectives: high dose preference (60.2Gy tumour boost and 50.4Gy to elective nodes with physician-defined order of priorities), low dose preference (53.75Gy tumour boost, 45Gy to elective nodes, physician-defined priorities), bowel sparing preference (lower dose levels and priority for bowel avoidance) and bladder sparing preference (lower dose levels and priority for bladder avoidance). Dose metrics for bowel and bladder were compared for the different planning regimens using descriptive statistics and paired Wilcoxon signed rank tests. 

Results
All plans satisfied constraints for target coverage. A senior radiation oncologist approved a random subset of plans for quality assurance. Compared to a high dose preference, bowel sparing was clinically meaningful at the lower prescribed dose (median change in V45Gy : 234 cm3; inter-quartile range [66;247]; p<0.01) and for a bowel sparing preference (median change in V45Gy : 281 cm3; [73;488]; p<0.01). Compared to a high dose preference, bladder sparing was clinically meaningful at the lower prescribed dose (median change in V35Gy : 13.7%-points; [0.3;30.6]; p<0.01) and for a bladder sparing preference (median change in V35Gy : 30.3%-points; [12.4;43.1]; p<0.01).

Conclusion
There is space available in anal cancer radiotherapy planning to incorporate preferences, though trade-offs are highly patient-dependent. The dominant trade-off in these plans involved the bowel and the bladder, where significant dose-redistribution was possible. Preference-informed dose planning is feasible for clinical studies utilising shared decision making. Further work on tumour control and toxicity modelling is required.

Heterogeneity of miRNA expression in localized prostate cancer with clinico-pathological correlations

Ahmed Hussein Zedan (1,2), Søren Garm Blavnsfeldt (1), Torben Frøstrup Hansen (2), Boye Schnack Nielsen (3), Niels Marcussen (4), Mindaugas Pleckaitis (5), Palle Jörn Sloth Osther (1,6), Flemming Brandt Sørensen (5,6)

1) Urological Research Center, Department of Urology, Vejle Hospital, part of Lillebaelt Hospital,  Vejle, Denmark. 2) Department of Oncology, Vejle Hospital, part of Lillebaelt Hospital, Vejle, Denmark. 3) Bioneer A/S, Hørsholm, Denmark. 4) Department of Pathology, Odense University Hospital, Odense, Denmark. 5) Department of Clinical Pathology, Vejle Hospital, part of Lillebaelt Hospital, Vejle, Denmark. 6) Institute of Regional Health Research, University of Southern Denmark, Denmark.

Background
In the last decade microRNAs (miRNAs) have been widely investigated in prostate cancer (PCa) and have shown to be promising biomarkers in diagnostic, prognostic and predictive settings. However, tumor heterogeneity may influence miRNA expression. The aims of this study were to assess the impact of tumor heterogeneity, as demonstrated by a panel of selected miRNAs in PCa, and to correlate miRNA expression with risk profile and patient outcome.

Materials and methods
Prostatectomy specimens and matched, pre-operative needle biopsies from a retrospective series of 49 patients, who underwent curatively intended surgery for localized PCa, were investigated with a panel of 6 miRNAs (miRNA-21, miRNA-34a, miRNA-125b, miRNA-126, miRNA-143 and miRNA-145), using tissue micro-array (TMA) and in situ hybridization (ISH). Inter-and intra-patient variation was assessed using intra-class correlation (ICC). 

Results
Four miRNAs (miRNA-21, miRNA-34a, miRNA-125 and miRNA-126) were significantly upregulated in PCa compared to benign prostatic hyperplasia (BPH), and except for miRNA-21 these miRNAs documented a positive correlation between the expression level in PCa cores compared to their matched BPH cores, (r > 0.72). The ICC varied from 0.451 to 0.764, with miRNA-34a showing an intra-tumoral heterogeneity accounting for less than 50% of the total variation. Regarding clinico-pathological outcomes, only miRNA-143 showed potential as a prognostic marker, with a higher expression correlating with longer relapse-free survival (p = 0.016). 

Conclusion
The present study documents significant upregulation of the expression of miRNA-21, miRNA-34a, miRNA-125 and miRNA-126 in PCa compared to BPH, and suggests a possible prognostic value associated with the expression of miRNA-143. The results document, however, intra-tumoral heterogeneity in the expression of various miRNAs, calling for caution in using these tumor-tissue biomarkers in prognostic and predictive settings.

Stereotactic radiation therapy of cerebral metastases in patients with breast cancer. Clinical spectrum and prognosis

Mette Møller (1), Yasmin Alexandra Lassen (1), Anders Bonde Jensen (1)

1) Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

Background
Stereotactic radiation therapy (SRT) can be used for treatment of cerebral metastases, yet data describing the use of SRT in patients with breast cancer remain sparse. Therefore, we investigated patients with breast cancer and cerebral metastases treated with SRT in order to elucidate the clinical characteristics and outcome of the treatment.

Materials and methods
We conducted a retrospective study of all patients with breast cancer and cerebral metastases treated with first-time SRT at the Department of Oncology, Aarhus University Hospital, 2001 through 2015. Patients were identified by searching patient files and local hospital databases and all data were abstracted from the patient records. We characterized the study population using descriptive statistics and assessed the 3-year survival by the Kaplan-Meier method. Finally, we ascertained the occurrence of new cerebral metastases after SRT.

Results
Forty-five female patients with breast cancer and SRT-treated cerebral metastases were identified. Median age at the time of breast cancer diagnosis was 58 years (interquartile range (IQR), 46-61). Median time from breast cancer diagnosis to diagnosis of cerebral metastases was 3.4 years (IQR, 1.1-5.9). Size of the metastases was in the majority of the cases <20mm (n=25, 56%), and most patients had solitary cerebral metastasis (n=31, 69%). Survival after SRT was at one year 59.3% (95 CI, 43.4-72.2), after two years 19.9% (95% CI, 9.0-33.8), and 11.4% (95% CI, 3.7-23.9) after three years. A total of 23 patients (51%) were diagnosed with new cerebral metastases after first-time SRT during two years of follow-up (median time from first-time SRT to diagnosis of new cerebral metastases was 149 days (IQR, 111-273)). The majority of patients with new metastases were treated with whole brain radiation (n=14, 61%), 7 patients (30%) had surgery, 5 patients (22%) received additional SRT, and only 2 patients (9%) were not offered further treatment for their cerebral metastases.

Conclusion
Patients with breast cancer and cerebral metastases treated with first-time SRT had a high one-year survival at 59% and only half of the patients developed further brain metastases within two years of follow-up.