Publications by authors named "Marianne Nordsmark"

43 Publications

Oncological results and morbidity following intended curative resection and free jejunal graft reconstruction of cervical esophageal cancer: a retrospective Danish consecutive cohort study.

Dis Esophagus 2021 Jul 21. Epub 2021 Jul 21.

Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.

Background: The role of surgery in treatment of locally advanced cervical esophageal cancer (CEC) remains debated. In the European and American treatment guidelines, definitive chemoradiotherapy (dCRT) is preferred over surgery, while in the Danish guidelines, the two treatment modalities are equally recommended. Surgical treatment of CEC is centralized at our center in Denmark. We present our outcomes following neoadjuvant chemoradiotherapy (nCRT) when possible and resection as first-line therapy for CEC and compare with recent published dCRT results.

Method: We retrospectively reviewed the medical charts of patients treated for cervical esophageal cancer at Aarhus University Hospital from 2001-2018 with nCRT when possible and pharyngolaryngectomy followed by reconstruction with a free jejunal graft.

Results: Forty consecutive patients were included. About, 45% received nCRT. The median survival was 21 months. The overall, disease-specific and disease-free 5-year survival was 43.6%, 53.2%, and 47.4%, respectively. The rate of microscopically radical resection was 85%. The recurrence rate was 47% and 81% of recurrences were locoregional. The in-hospital and 30-day mortality rate was 0%. Major complications occurred in 27.9%. Anastomotic leakage, graft failure, fistulas and strictures occurred in 10%, 7.5%, 30%, and 30%, respectively.

Conclusion: Our treatment offers equal oncological results compared to the best internationally published results for dCRT for CEC. Results vary considerably between dCRT studies. Morbidity appears more pronounced following surgery. Future studies are warranted to investigate the Danish national outcomes following dCRT as first-line treatment for curable locally advanced CEC.
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http://dx.doi.org/10.1093/dote/doab048DOI Listing
July 2021

Strategies for Motion Robust Proton Therapy With Pencil Beam Scanning for Esophageal Cancer.

Int J Radiat Oncol Biol Phys 2021 10 8;111(2):539-548. Epub 2021 May 8.

Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Proton therapy of esophageal cancer is superior to photon radiation therapy in terms of normal tissue sparing. However, respiratory motion and anatomical changes may compromise target dose coverage owing to density changes, geometric misses, and interplay effects. Here we investigate the combined effect on clinical target volume (CTV) coverage and compare proton therapy with intensity modulated radiation therapy (IMRT).

Methods And Materials: This study includes 26 patients with esophageal cancer previously treated with IMRT planned on 4-dimensional computed tomography (4D-CT). For each patient, 7 proton pencil beam scanning (PBS) plans were created with different field configurations and optimization strategies. The effect of respiration was investigated by calculating the phase doses, 4D dose, and 4D dynamic dose (including interplay effects). The effect of anatomical changes was investigated by recalculating all plans on all phases of a 4D-CT surveillance scan.

Results: The most robust PBS plans were achieved using 2 posterior beams requiring coverage of planning target volume (PTV) and simultaneously using robust optimization (RO) of CTV (2PA), resulting in only 1 patient showing V95% <97% in 1 or more phases of the planning CT. For the least robust PBS plans obtained using lateral + posterior beams and CTV-RO, but not requiring PTV coverage (2LP), 10 patients showed underdosage. For IMRT, 2 patients showed underdosage. Interplay effects reduced V95% significantly when delivering only 1 fraction, but the effects generally averaged out after 10 fractions. The effect of interplay was significantly larger for RO-only plans compared with plans optimized with RO combined with PTV coverage. Combining the effect of anatomical changes and respiration on the 4D-CT surveillance scan resulted in V95% <97% for 3 2PA, 16 2LP, and 8 IMRT patients.

Conclusions: PBS using posterior beam angles was more robust to anatomical changes and respiration than IMRT. The effect of respiration was enhanced when anatomical changes were present. Single fraction interplay effects deteriorated the dose distribution but were averaged out after 10 fractions.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.040DOI Listing
October 2021

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

Radiother Oncol 2021 03 5;156:102-112. Epub 2020 Dec 5.

KU Leuven - University of Leuven, Department of Oncology - Laboratory of Experimental Radiotherapy, Belgium; University Hospitals Leuven, Department of Radiation Oncology, Belgium.

Purpose: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer.

Materials And Methods: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (H/H).

Results: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; H = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; H: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; H: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated.

Conclusion: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.
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http://dx.doi.org/10.1016/j.radonc.2020.11.032DOI Listing
March 2021

The impact of a tailored follow-up intervention on comprehensive geriatric assessment in older patients with cancer - a randomised controlled trial.

J Geriatr Oncol 2021 01 1;12(1):41-48. Epub 2020 Aug 1.

Department of Geriatric Medicine, Aarhus University, Denmark; Aarhus University, Denmark. Electronic address:

Purpose: Comprehensive Geriatric Assessment (CGA) can identify health problems in older persons. In addition, CGA includes intervention towards the identified problems. With follow up, more problems may be identified and the interventions can be adjusted. We wanted to compare CGA with or without tailored follow-up in a randomised design.

Patients And Methods: Patients 70+ years referred for oncology treatment with four primary tumour sites. Participants were randomised 1:1 to either control group with no follow-up or intervention group with a tailored follow-up by a multidisciplinary team. Primary outcome was adherence to cancer treatment. Secondary outcomes were daily life activities, physical performance and hospitalisation.

Results: In total, 363 participants were randomised. After randomisation only 301 were planned to receive specific cancer treatment. Median age was 75 years. Among the 301 participants, 52% of control group vs. 61% of intervention group completed treatment. Risk Rate (RR): 1.16 (95% Confidence Interval (CI): 0.95-1.42), p = .14. The impact varied between the included tumour-sites, p < .01. We found no difference in 90 days physical performance or daily life activities between groups. During the study period, 55% of controls vs. 47% in the intervention group were admitted to hospital, RR: 0.86 (95%CI: 0.69-1.07), p = .19.

Conclusion: In frail and vulnerable patients with cancer, a tailored follow-up on CGA showed no differences in ability to complete initially planned cancer treatment. The impact varied between the included tumour sites. We did not find any impact of tailored follow-up on daily life activities, physical performance or hospitalisation.
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http://dx.doi.org/10.1016/j.jgo.2020.07.011DOI Listing
January 2021

Venous thromboembolism during preoperative chemotherapy in the CRITICS gastric cancer trial.

Cancer Med 2020 09 31;9(18):6609-6616. Epub 2020 Jul 31.

Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: The occurrence of a venous thromboembolism (VTE) is common in patients with cancer. Gastric cancer has been associated with one of the highest risks for VTE. Chemotherapy, especially cisplatin has been associated with a high VTE risk. In this study, risk factors for VTE occurrence and their potential impact on subsequent therapeutic interventions were investigated in patients who underwent preoperative chemotherapy, in the CRITICS gastric cancer trial.

Patients And Methods: Patients with resectable gastric cancer were preoperatively treated with three cycles of 3-weekly epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC). VTE was defined as any thrombus in the venous system, excluding superficial and/or device related VTEs. Potential risk factors were analyzed in a multivariable regression model with age, gender, Body Mass Index (BMI), tumor localization, Lauren classification, type of chemotherapy (ECC/EOC), (cardiovascular) comorbidity, and previous VTE as independent risk factors. The impact of VTE on completion rate of preoperative chemotherapy, surgical resection rate, postoperative complications, and start of postoperative therapy were investigated.

Results: Of 781 patients, 78 (10%) of 781 patients developed a VTE during preoperative chemotherapy. On multivariable analysis, BMI ≥ 30 kg/m and previous VTE were associated with VTE occurrence (reference BMI < 25 kg/m ; OR 2.190; 95% CI 1.152-4.164; P = .017/previous VTE; OR 3.617; 95% CI 1.201-10.890; P = .022). Treatment with cisplatin was, compared to oxaliplatin, not significantly associated with VTE occurrence (OR 1.535; 95% CI 0.761-3.094; P = .231). VTE occurrence did not affect completion of preoperative chemotherapy, surgical resection rate, postoperative complications, or start of postoperative therapy.

Conclusion: High BMI and previous VTE were independent risk factors for VTE occurrence during preoperative chemotherapy in patients with resectable gastric cancer. VTE occurrence in the preoperative setting did not affect receipt of further treatment.
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http://dx.doi.org/10.1002/cam4.3118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520268PMC
September 2020

Delineation of whole heart and substructures in thoracic radiation therapy: National guidelines and contouring atlas by the Danish Multidisciplinary Cancer Groups.

Radiother Oncol 2020 09 13;150:121-127. Epub 2020 Jun 13.

Danish Centre for Particle Therapy, Aarhus, Denmark; Odense University Hospital, Laboratory of Radiation Physics, Odense, Denmark.

Background And Purpose: This study presents Danish consensus guidelines for delineation of the heart and cardiac substructures across relevant Danish Multidisciplinary Cancer Groups.

Material And Methods: Consensus guidelines for the heart and cardiac substructures were reached among 15 observers representing the radiotherapy (RT) committees of four Danish Multidisciplinary Cancer Groups. The guidelines were validated on CT scans of 12 patients, each with five independent contour sets. The Sørensen-Dice similarity coefficient (DSC), the distance between the centers of the arteries and the mean surface distance were used to evaluate the inter-observer variation.

Results: National guidelines for contouring the heart and cardiac substructures were achieved. The median DSC was 0.78-0.96 for the heart and the four cardiac chambers. For the four substructures of the left ventricle, the median DSC was 0.35-0.57. The coronary arteries were contoured in ten segments, with the best agreement for the left anterior descending coronary artery segments, with a median distance between the arteries ranging from 2.4-4.4 mm. The median variation was 3.7-12.8 mm for the right coronary artery segments and 3.7-6.2 mm for the left circumflex coronary artery segments, with the most pronounced inter-observer variation in the distal segment for all three coronary arteries.

Conclusion: National guidelines for contouring the heart and cardiac substructures were developed across relevant Danish Multidisciplinary Cancer Groups, where RT dose to the heart is of concern. The inter-observer contour overlap was best for the heart and chambers and decreased for smaller structures.
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http://dx.doi.org/10.1016/j.radonc.2020.06.015DOI Listing
September 2020

The risk of radiation-associated heart disease comes from many factors; the chain is as strong as the weakest link.

Radiother Oncol 2020 11 9;152:101-102. Epub 2020 Jun 9.

Department of Experimental Clinical Oncology and Department of Oncology, Aarhus University Hospital, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.radonc.2020.05.052DOI Listing
November 2020

Older versus younger adults with gastric cancer receiving perioperative treatment: Results from the CRITICS trial.

Eur J Cancer 2020 05 21;130:146-154. Epub 2020 Mar 21.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Aim: To evaluate treatment-related toxicity, treatment compliance, surgical complications and event-free survival (EFS) in older (≥70 years) versus younger (<70 years) adults who underwent perioperative treatment for gastric cancer.

Methods: In the CRITICS trial, 788 patients with resectable gastric cancer were randomised before start of any treatment and received preoperative chemotherapy (3 cycles of epirubicin, cisplatin or oxaliplatin and capecitabine), followed by surgery, followed by either postoperative chemotherapy or chemoradiotherapy (45Gy + cisplatin + capecitabine).

Results: 172 (22%) patients were older adults. During preoperative chemotherapy, 131 (77%) older adults versus 380 (62%) younger adults experienced severe toxicity (p < 0.001); older adults received significantly lower relative dose intensities (RDIs) for all chemotherapeutic drugs. Equal proportions of older versus younger adults underwent curative surgery: 137 (80%) versus 499 (81%), with comparable postoperative complications and postoperative mortality. Postoperative therapy after curative surgery started in 87 (64%) older adults versus 391 (78%) younger adults (p < 0.001). Incidence of severe toxicity during postoperative chemotherapy was 22 (54%) in older adults versus 113 (59%) in younger adults (p = 0.541); older adults received significantly lower RDIs for all chemotherapeutic drugs. Severe toxicity rates for postoperative chemoradiotherapy were 22 (48%) older adults versus 89 (45%) for younger adults (p = 0.703), with comparable chemotherapy RDIs and radiotherapy dose. Two-year EFS was 53% for older adults versus 51% for younger adults.

Conclusion: Perioperative treatment compliance, especially in the postoperative phase, was poorer in older adults compared with younger adults. As comparable proportions of patients underwent curative surgery, future studies should focus on neo-adjuvant treatment.

Trial Registration: ClinicalTrials.gov identifier: NCT00407186. EudraCT number: 2006-00413032.
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http://dx.doi.org/10.1016/j.ejca.2020.02.008DOI Listing
May 2020

White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer.

Nat Commun 2020 Jan 27;11(1):525. Epub 2020 Jan 27.

Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.
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http://dx.doi.org/10.1038/s41467-020-14310-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985115PMC
January 2020

Setup strategies and uncertainties in esophageal radiotherapy based on detailed intra- and interfractional tumor motion mapping.

Radiother Oncol 2019 07 20;136:161-168. Epub 2019 Apr 20.

Aarhus University Hospital, Department of Oncology, Denmark.

Background And Purpose: Detailed knowledge of target motion is important for improved accuracy and decreased toxicity of esophageal cancer radiotherapy. This study uses the 3D trajectories of implanted markers during setup CBCT scans to investigate the intra- and interfractional tumor motion in esophageal cancer radiotherapy.

Material And Methods: For 21 esophageal cancer patients with implanted fiducial markers, 60-s 3D marker trajectories were estimated from the 2D marker positions in the projections of daily setup CBCT scans by a probability-based method. The motion was separated into respiratory and cardiac components by frequency analysis and motion magnitude (2nd-98th percentile) was extracted for each marker. The mean motion was calculated over all markers. The daily mean setup interfraction error for bony-anatomy and soft-tissue setup was used to estimate the margin accounting for interfractional motion.

Results: A total of 1036 marker trajectories were extracted using 427 CBCT scans and 63 markers. The mean motion magnitude over all markers was 2.9 mm (left-right (LR)), 8.8 mm (cranio-caudal (CC)) and 4.1 mm (anterior-posterior (AP)) for the full motion during CBCT acquisition with mean magnitudes of 2.7 mm (LR), 8.4 mm (CC) and 3.5 mm (AP) for respiratory motion and 1.0 mm (LR), 1.5 mm (CC) and 1.4 mm (AP) for cardiac motion. Substantial daily marker shifts relative to bones resulted in margins of 8.9 mm (LR), 9.5 mm (CC), and 7.3 mm (AP). Soft-tissue based setup in and near the CTV combined with rescanning of patients with anatomical changes reduced the margins to 6.9 mm (LR), 6.8 mm (CC), and 5.6 mm (AP).

Conclusions: Esophageal tumor motion was mapped with unprecedented detail throughout the radiotherapy course. Respiratory motion dominated and was largest in the CC direction. Soft-tissue matching and an adaptive strategy reduced interfractional margins by 2-3 mm compared to bony-anatomy matching.
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http://dx.doi.org/10.1016/j.radonc.2019.04.014DOI Listing
July 2019

Validation of a robust strategy for proton spot scanning for oesophageal cancer in the presence of anatomical changes.

Radiother Oncol 2019 02 16;131:174-178. Epub 2018 Oct 16.

Department of Medical Physics, Aarhus University Hospital, Denmark.

SFUD strategies with one or two posterior proton beams and three target coverage strategies are compared with IMRT and tested for robustness towards anatomical changes by recalculation on surveillance CTs during treatment. We find posterior beam SFUD combining PTV coverage with robust optimization increases robustness towards anatomical changes compared to IMRT.
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http://dx.doi.org/10.1016/j.radonc.2018.09.018DOI Listing
February 2019

Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial.

Lancet Oncol 2018 05 9;19(5):616-628. Epub 2018 Apr 9.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Background: Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma.

Methods: In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m on day 1), cisplatin (60 mg/m on day 1) or oxaliplatin (130 mg/m on day 1), and capecitabine (1000 mg/m orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1·8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m orally twice daily on radiotherapy days) and cisplatin (20 mg/m intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.

Findings: Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61·4 months (IQR 43·3-82·8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1·01 (95% CI 0·84-1·22; p=0·90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment.

Interpretation: Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies.

Funding: Dutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(18)30132-3DOI Listing
May 2018

A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

Br J Cancer 2016 Oct 4;115(9):1096-1104. Epub 2016 Oct 4.

Department of Oncology, Aarhus University Hospital, Norrebrogade 44, Aarhus C 8000, Denmark.

Background: For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic and predictive biomarkers are essential for the use of this target in the clinic. This study investigates the prognostic value of a hypoxia-induced gene profile in localised soft tissue sarcoma (STS).

Methods: The hypoxia-induced gene quantification was performed by real-time quantitative PCR (RT-qPCR) of formalin-fixed, paraffin-embedded tissue samples. The gene expression cut-points were determined in a test cohort of 55 STS patients and used to allocate each patient into a more or a less hypoxic group. The cut-points found in the test cohort were applied to a cohort of 77 STS patients for validation.

Results: For patients with localised high-grade STS treated with surgery with or without postoperative radiation therapy, the prognostic value of the hypoxia-induced gene profile was proved in the test cohort and confirmed in the validation cohort. After adjustment for confounders, the hazard ratio (HR) was 3.2 (95% CI: 1.5; 7.0) for patients with more hypoxic tumours compared with patients with less hypoxic tumours regarding disease-specific survival. Moreover, for the development of metastatic disease, the HR was 2.61 (95% CI: 1.27; 5.33).

Conclusions: The hypoxia-induced gene profile is a validated independent prognostic marker that may help identify STS patients needing more aggressive or different adjuvant treatment.
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http://dx.doi.org/10.1038/bjc.2016.310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117798PMC
October 2016

Esophageal stenting for benign and malignant disease: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline.

Endoscopy 2016 Oct 14;48(10):939-48. Epub 2016 Sep 14.

Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE), endorsed by the European Society for Radiotherapy and Oncology (ESTRO), the European Society of Digestive Endoscopy (ESDO), and the European Society for Clinical Nutrition and Metabolism (ESPEN). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations for malignant disease 1 ESGE recommends placement of partially or fully covered self-expandable metal stents (SEMSs) for palliative treatment of malignant dysphagia over laser therapy, photodynamic therapy, and esophageal bypass (strong recommendation, high quality evidence). 2 For patients with longer life expectancy, ESGE recommends brachytherapy as a valid alternative or in addition to stenting in esophageal cancer patients with malignant dysphagia. Brachytherapy may provide a survival advantage and possibly a better quality of life compared to SEMS placement alone. (Strong recommendation, high quality evidence.) 3 ESGE recommends esophageal SEMS placement as the preferred treatment for sealing malignant tracheoesophageal or bronchoesophageal fistula (strong recommendation, low quality evidence). 4 ESGE does not recommend the use of concurrent external radiotherapy and esophageal stent treatment. SEMS placement is also not recommended as a bridge to surgery or prior to preoperative chemoradiotherapy. It is associated with a high incidence of adverse events and alternative satisfactory options such as placement of a feeding tube are available. (Strong recommendation, low quality evidence.) Main recommendations for benign disease 1 ESGE recommends against the use of self-expandable stents (SEMSs) as first-line therapy for the management of benign esophageal strictures because of the potential for adverse events, the availability of alternative therapies, and costs (strong recommendation, low quality evidence). 2 ESGE suggests consideration of temporary placement of SEMSs as therapy for refractory benign esophageal strictures (weak recommendation, moderate evidence). Stents should usually be removed at a maximum of 3 months (strong recommendation, weak quality evidence). 3 ESGE suggests that fully covered SEMSs be preferred over partially covered SEMSs for the treatment of refractory benign esophageal strictures, because of their lack of embedment and ease of removability (weak recommendation, low quality evidence). 4 For the removal of partially covered esophageal SEMSs that are embedded, ESGE recommends the stent-in-stent technique (strong recommendation, low quality evidence). 5 ESGE recommends that temporary stent placement can be considered for treating esophageal leaks, fistulas, and perforations. The optimal stenting duration remains unclear and should be individualized. (Strong recommendation, low quality evidence.) 6 ESGE recommends placement of a SEMS for the treatment of esophageal variceal bleeding refractory to medical, endoscopic, and/or radiological therapy, or as initial therapy for patients with massive esophageal variceal bleeding (strong recommendation, moderate quality evidence).
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http://dx.doi.org/10.1055/s-0042-114210DOI Listing
October 2016

Mixed Adenoneuroendocrine Carcinoma Is a Rare but Important Tumour Found in the Oesophagus.

Case Rep Gastrointest Med 2016 3;2016:9542687. Epub 2016 Feb 3.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8000 Aarhus C, Denmark.

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumour of the gastrointestinal tract that consists of a dual adenocarcinomatous and neuroendocrine differentiation, each component representing at least 30% of the tumour. We report a case of a 68-year-old man who presented with two-month history of postprandial pain and vomiting. Gastric endoscopy revealed a polypoid mass in the lower part of the oesophagus. In contrast to the majority of these tumours, this biopsy was immunohistochemically positive for chromogranin A, and synaptophysin and Ki-67 index was 50% and the tumour was diagnosed as poorly differentiated neuroendocrine carcinoma of the oesophagus. The patient underwent surgery and lower oesophagus resection was performed. Based on the histopathology and immunohistochemistry of the tumour in the oesophagogastrectomy specimen, a mixed adenoneuroendocrine carcinoma (MANEC) was diagnosed. The objective of this case report is to advocate for the focus on the MANEC diagnosis as such patients need to be referred to a centre of excellence with expertise in NET tumours, to have the correct diagnostic work-up, treatment, and secondary diagnostic procedures performed at progression, as this will have paramount influence of the choice of treatment.
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http://dx.doi.org/10.1155/2016/9542687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756141PMC
March 2016

Clinical Impact of a Novel MicroRNA Chemo-Sensitivity Predictor in Gastrooesophageal Cancer.

PLoS One 2016 17;11(2):e0148070. Epub 2016 Feb 17.

Dept. of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: miRNAs might be potentially useful biomarkers for prediction of response to chemotherapeutic agents, radiotherapy and survival. The aim of this retrospective study was to validate miRNA response predictors in a cohort of patients with gastrooesophageal cancer in order to predict overall survival (OS) and disease-specific survival (DSS).

Material And Methods: The study population encompassed 53 patients treated with curative intend for loco-regional gastrooesophageal cancer. miRNA expression was quantified from pre-therapeutic and diagnostic, formalin-fixed, paraffin embedded tumour specimens using Affymetrix GeneChip miRNA 1.0 Array. Based on growth inhibition of the NCI60 panel in the presence of cisplatin, epirubicine and capecitabine, a miRNA based response predictor was developed. The Cox proportional hazards model was applied to assess the correlations of the response predictor with OS and DSS.

Results: A univariate analysis demonstrated a statistical significant improvement of OS for patients who had undergone surgical resection with prediction scores above the median prediction score (HR: 0.41 (95% CI: 0.17-0.96). Adjusting for surgery and stage, this predictor was identified to be independently associated with both OS (HR: 0.37 (95% CI: 0.16-0.87)) and DSS (HR: 0.32 (0.12-0.87)).

Conclusion: The miRNA profile predictive for sensitivity to cisplatin, epirubicine and capecitabine was shown to be independently associated with OS and DSS in patients with gastrooesophageal cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757421PMC
July 2016

Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer.

Anticancer Res 2016 Feb;36(2):721-30

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background/aim: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC).

Materials And Methods: microRNA expression changes induced by hypoxia in human GEC cell lines were measured with microarrays and validated by quantitative real-time polymerase chain reaction. Candidate HRMs were measured in pre-therapeutic tumor samples from 195 patients with GEC.

Results: Expression of miR-210 was shown to be significantly induced in esophageal squamous cell carcinoma (9.26-fold, p<0.001) and adenocarcinoma cell lines (4.95-fold, p<0.001) and miR-27a-star was significantly up-regulated in adenocarcinoma cell lines (4.79-fold, p=0.04). A weak but significant correlation between miR-210 expression and a 15-gene hypoxia signature was observed (Pearson r correlation: r=0.38, p<0.001). No significant associations of HRMs and clinical outcome in patients with GEC were identified.

Conclusion: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM.
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February 2016

Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer.

Acta Oncol 2015 ;54(9):1582-91

e Department of Oncology , Aarhus University Hospital , Aarhus , Denmark.

Background: MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR-375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC).

Material And Methods: Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports.

Results: In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41-8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC.

Conclusion: In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology.
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http://dx.doi.org/10.3109/0284186X.2015.1064161DOI Listing
July 2016

Dosimetric evaluation of anatomical changes during treatment to identify criteria for adaptive radiotherapy in oesophageal cancer patients.

Acta Oncol 2015 29;54(9):1467-73. Epub 2015 Jul 29.

a Department of Medical Physics , Aarhus University Hospital , Denmark.

Background: Some oesophageal cancer patients undergoing chemotherapy and concomitant radiotherapy (chemoRT) show large interfractional anatomical changes during treatment. These changes may modify the dose delivered to the target and organs at risk (OARs). The aim of the presenwt study was to investigate the dosimetric consequences of anatomical changes during treatment to obtain criteria for an adaptive RT decision support system.

Material And Methods: Twenty-nine patients were treated with chemoRT for oesophageal and gastro-oesophageal junction cancer and set up according to daily cone beam computed tomography (CBCTs) scans. All patients had an additional replanning CT scan at median fraction number 10 (9-14), which was deformably registered to the original planning CT. Gross tumour volumes (GTVs), clinical target volumes (CTVs) and OARs were transferred to the additional CT and corrected by an exwperienced physician. Treatment plans were recalculated and dose to targets and OARs was evaluated. Treatment was adapted if the volume receiving 95% of the prescribed dose (V95%) coverage of CTV decreased > 1% or planning target volume (PTV) decreased by > 3%.

Results: In total, nine adaptive events were observed: All nine were triggered by PTV V95% decrease > 3% [median 11% (5-41%)] and six of these were additionally triggered by CTV V95% decrease > 1% [median 5% (2-35%)]. The largest discrepancies were caused by interfractional baseline or amplitude shifts in diaphragm position (n = 5). Mediastinal (n = 6), oesophageal (n = 6) and bowel filling changes (n = 2) caused the remainder of the changes. For patients with dosimetric changes exceeding the adaptation limits, the discrepancies were confirmed by inspecting the daily CBCTs. In 31% of all patients, heart V30Gy increased more than 2% (maximum 5%). Only minor changes in lung dose or liver dose were seen.

Conclusion: Target coverage throughout the course of chemoRT treatment is compromised in some patients due to interfractional anatomical changes. Dose to the heart may increase as well.
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http://dx.doi.org/10.3109/0284186X.2015.1068449DOI Listing
January 2016

The importance of reference gene analysis of formalin-fixed, paraffin-embedded samples from sarcoma patients - an often underestimated problem.

Transl Oncol 2014 Dec;7(6):687-93

Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.

Objective: Reverse transcription quantitative real-time polymerase chain reaction is efficient for quantification of gene expression, but the choice of reference genes is of paramount importance as it is essential for correct interpretation of data. This is complicated by the fact that the materials often available are routinely collected formalin-fixed, paraffin-embedded (FFPE) samples in which the mRNA is known to be highly degraded. The purpose of this study was to investigate 22 potential reference genes in sarcoma FFPE samples and to study the variation in expression level within different samples taken from the same tumor and between different histologic types.

Methods: Twenty-nine patients treated for sarcoma were enrolled. The samples encompassed 82 (FFPE) specimens. Extraction of total RNA from 7-μm FFPE sections was performed using a fully automated, bead-base RNA isolation procedure, and 22 potential reference genes were analyzed by reverse transcription quantitative real-time polymerase chain reaction. The stability of the genes was analyzed by RealTime Statminer. The intrasamples variation and the interclass correlation coefficients were calculated. The linear regression model was used to calculate the degradation of the mRNA over time.

Results: The quality of RNA was sufficient for analysis in 84% of the samples. Recommended reference genes differed with histologic types. However, PPIA, SF3A1, and MRPL19 were stably expressed regardless of the histologic type included. The variation in ∆Cq value for samples from the same patients was similar to the variation between patients. It was possible to compensate for the time-dependent degradation of the mRNA when normalization was made using the selected reference genes.

Conclusion: PPIA, SF3A1, and MRPL19 are suitable reference genes for normalization in gene expression studies of FFPE samples from sarcoma regardless of the histology.
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http://dx.doi.org/10.1016/j.tranon.2014.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311021PMC
December 2014

PET imaging of tumor hypoxia using 18F-labeled pimonidazole.

Acta Oncol 2013 Oct 21;52(7):1300-7. Epub 2013 Aug 21.

Department of Experimental Clinical Oncology, Aarhus University Hospital (AUH) , Aarhus , Denmark.

Background: Tumor hypoxia contributes to loco-regional failure, and for optimal treatment planning, knowledge about tumor hypoxia in individual patients is required. Nitroimidazole-based tracers, which are retained in hypoxic cells, allow PET-based assessment of tumor hypoxia, but current tracers are characterized by slow tracer retention and clearance, resulting in low inter-tissue contrast. Pimonidazole is an immune detectable hypoxia marker widely used for detection of hypoxia in tumor samples. Pimonidazole has excellent chemical properties for hypoxia imaging, but labeling for non- invasive assay has not been attempted. Here we labeled pimonidazole with (18)F ([(18)F]FPIMO).

Material And Methods: [(18)F]FPIMO was produced by fluorination of 1-[2-O-tosyl-3-(2-nitroimidazole-1-yl)-propyl]-piperidine, which resulted in two isomeric interchangeable forms (named "5" and "6") with a radiochemical purity of 91-100%. [(18)F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [(18)F]FPIMO was also administered to tumor-bearing mice and tracer retention in tumors, non-hypoxic reference tissues and tissues involved in drug metabolism/clearance was evaluated by various techniques.

Results And Conclusions: Retention of [(18)F]FPIMO was strongly hypoxia-driven in vitro, but isomeric form "5" was particularly promising and reached impressive anoxic-to-oxic retention ratios of 36 and 102, in FaDuDD and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [(18)F]FAZA. [(18)F]FPIMO also accumulated in tumors grown in mice, and reached tumor levels that were two to six-fold higher than in muscle three hours post-administration. Furthermore, the intra-tumoral distribution of [(18)F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [(18)F]FPIMO proved inferior to [(18)F]FAZA, since absolute tumor signal and intra-tumoral contrast was low, thus compromising PET imaging. Low tumor signal was coupled to extensive tracer accumulation in liver and kidneys, and analysis of blood metabolites revealed that [(18)F]FPIMO was metabolized rapidly, with little parent compound remaining 15 minutes post-administration. Ongoing work focuses on the possibility of labeling pimonidazole in different positions with (18)F to improve tracer stability in vivo.
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http://dx.doi.org/10.3109/0284186X.2013.815797DOI Listing
October 2013

Hypoxia-regulated gene expression and prognosis in loco-regional gastroesophageal cancer.

Acta Oncol 2013 Oct 19;52(7):1327-35. Epub 2013 Aug 19.

Department of Experimental Clinical Oncology, Aarhus University Hospital , Aarhus , Denmark.

Unlabelled: Gastroesophageal cancers are heterogeneous diseases with a poor outcome. Prognostic and predictive factors are needed to improve patient survival. Hypoxia is an adverse prognostic factor and is associated with resistance to chemo- and radiotherapy in various cancers. However, knowledge on the impact of hypoxia in gastroesophageal cancer is limited. The aim of this study was to evaluate potential prognostic factors in terms of a subset of hypoxia-responsive genes and clinicopathological parameters in patients with gastroesophageal cancer.

Material And Methods: Ninety-five patients with loco-regional gastroesophageal cancer treated with curative intent were retrospectively analyzed. Based on formalin-fixed paraffin-embedded diagnostic biopsies gene expressions of 15 hypoxia-induced and pH-independent genes from a previously described hypoxia gene expression classifier was quantified. The prognostic impact was evaluated for overall survival (OS) and disease-specific survival (DSS). Uni- and multivariate Cox proportional hazards model was used to identify hypoxia-responsive gene expression and clinicopathological parameters as prognostic markers.

Results: An unsupervised hierarchical clustering of hypoxia regulated genes showed two well-differentiated patient clusters: One cluster of tumors with high gene expression and another with low gene expression, indicating a more hypoxic genotype versus a less hypoxic genotype respectively. As the group of esophageal squamous cell carcinomas (ESCC) alone showed intra-group heterogeneity this group was ranked according to the gene expression of the 15 genes. The most hypoxic third showed a trend towards a poorer outcome in terms of OS [HR = 0.48 (CI 0.21-1.07), p = 0.07] and DSS [HR = 0.48 (CI 0.18-1.24), p = 0.13]. Treatment response was identified as an independent prognostic factor for DSS in the group of ESCC [HR = 0.21 (CI 0.05-0.95), p = 0.04].

Conclusion: Gene expression analysis of 15 hypoxia-responsive genes was identified as a promising prognostic marker in patients with ESCC. Further studies confirming these results in larger patient cohorts are needed.
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http://dx.doi.org/10.3109/0284186X.2013.818247DOI Listing
October 2013

Advanced hepatocellular carcinoma in adolescence associated with congenital cholestasis: a case description.

Case Rep Oncol 2013 Jan 19;6(1):98-103. Epub 2013 Feb 19.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark, Norway.

This case describes the clinical course and treatment of a 17-year-old male patient with advanced hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. The disease was thought to be caused by a congenital cholestatic syndrome associated with intermittent oedema in childhood, resembling the rare Aagenaes syndrome. Treatment choices in advanced HCC arising in adolescence are discussed.
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http://dx.doi.org/10.1159/000348715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617980PMC
January 2013

FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial.

Radiother Oncol 2012 Oct 16;105(1):14-20. Epub 2012 Oct 16.

Aarhus University Hospital, Denmark.

Purpose: Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate (18)F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy.

Material And Methods: Forty patients with HNSCC treated with radiotherapy (66-76 Gy) were included. Static FAZA PET/CT imaging 2h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value ≥ 1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment.

Results: A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm(3). The T(max)/M(med) ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19 months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected.

Conclusion: This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.
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http://dx.doi.org/10.1016/j.radonc.2012.09.015DOI Listing
October 2012

[Danish Esophagus, Cardia and Stomach Neoplasm Database].

Ugeskr Laeger 2012 Oct;174(42):2536

Afdeling C, Rigshospitalet, Blegdamsvej 9, Copenhagen.

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October 2012

Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer.

Cancer Res 2011 Sep 16;71(17):5923-31. Epub 2011 Aug 16.

Department of Experimental Clinical Oncology, Aarhus University Hospital and Bioinformatics Research Centre, Aarhus University, Aarhus C, Denmark.

Hypoxia, a common feature of the microenvironment in solid tumors, is associated with resistance to radiotherapy, reduced therapeutic response, and a poorer clinical outcome. In head and neck squamous cell carcinomas (HNSCC), the negative effect of hypoxia on radiotherapy can be counteracted via addition of hypoxic modification to the radiotherapy. To predict which patients harbor hypoxic tumors and would therefore benefit from hypoxic modification, clinically applicable methods for pretherapeutic hypoxic evaluation and categorization are needed. In this study, we developed a hypoxia classifier based on gene expression. Through study of xenograft tumors from human squamous cell carcinoma cell lines, we verified the in vivo relevance of previously identified in vitro derived hypoxia-induced genes. We then evaluated a training set of 58 hypoxia-evaluated HNSCCs to generate a gene expression classifier containing 15 genes. This 15-gene hypoxia classifier was validated in 323 patients with HNSCC randomized for hypoxic modification or placebo in combination with radiotherapy. Tumors categorized as hypoxic on the basis of the classifier were associated with a significantly poorer clinical outcome than nonhypoxic tumors. This outcome was improved and equalized to the nonhypoxic tumors by addition of hypoxic modification. Thus, findings show that the classifier attained both prognostic and predictive impact, and its pretherapeutic use may provide a method to identify those patients who will benefit from hypoxic modification of radiotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-1182DOI Listing
September 2011

Characterization of positron emission tomography hypoxia tracer uptake and tissue oxygenation via electrochemical modeling.

Nucl Med Biol 2011 Aug 5;38(6):771-80. Epub 2011 May 5.

University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI 53706, USA.

Purpose: Unique uptake and retention mechanisms of positron emission tomography (PET) hypoxia tracers make in vivo comparison between them challenging. Differences in imaged uptake of two common hypoxia radiotracers, [(61)Cu]Cu-ATSM and [(18)F]FMISO, were characterized via computational modeling to address these challenges.

Materials And Methods: An electrochemical formalism describing bioreductive retention mechanisms of these tracers under steady-state conditions was adopted to relate time-averaged activity concentration to tissue partial oxygen tension (PO(2)), a common metric of hypoxia. Chemical equilibrium constants of product concentration to reactant concentration ratios were determined from free energy changes and reduction potentials of pertinent reactions reported in the literature. Resulting transformation functions between tracer uptake and PO(2) were compared against measured values in preclinical models. Additionally, calculated PO(2) distributions from imaged Cu-ATSM tracer activity concentrations of 12 head and neck squamous cell carcinoma (HNSCC) patients were validated against microelectrode PO(2) measurements in 69 HNSCC patients.

Results: Both Cu-ASTM- and FMISO-modeled PO(2) transformation functions were in agreement with preclinical measured values within single-deviation confidence intervals. High correlation (r(2)=0.94, P<.05) was achieved between modeled PO(2) distributions and measured distributions in the patient populations. On average, microelectrode hypoxia thresholds (2.5 and 5.0 mmHg) corresponded to higher Cu-ATSM uptake [2.5 and 2.0 standardized uptake value (SUV)] and lower FMISO uptake (2.0 and 1.4 SUV). Uncertainties in the models were dominated by variations in the estimated specific activity and intracellular acidity.

Conclusions: Results indicated that the high dynamic range of Cu-ATSM uptake was representative of a narrow range of low oxygen tension whose values were dependent on microenvironment acidity, while FMISO uptake was representative of a wide range of PO(2) values that were independent of acidity. The models shed light on possible causes of these discrepancies, particularly as it pertains to image contrast, and may prove to be a useful methodology in quantifying relationships between other hypoxia tracers. Comprehensive and robust assessment of tumor hypoxia prior to as well as in response to therapy may be best provided by imaging of multiple hypoxia markers that provide complementary rather than interchangeable information.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157049PMC
August 2011

Accessing radiation response using hypoxia PET imaging and oxygen sensitive electrodes: a preclinical study.

Radiother Oncol 2011 Jun 1;99(3):418-23. Epub 2011 Jul 1.

Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.

Purpose: Tumor hypoxia is a known cause of resistance to radiotherapy. The aim of this study was to investigate the prognostic value of hypoxia measured by (18)F-fluoroazomycin arabinoside ((18)F-FAZA) PET or the Eppendorf oxygen electrode in a pre-clinical tumor model.

Material/methods: Pretreatment (18)F-FAZA PET scans and blood sampling was conducted in 92 Female CDF1 mice with subcutaneous C3H mammary carcinomas grown in the right foot. Similarly, oxygenation status of 80 equivalent tumors was assessed using an invasive oxygen sensitive electrode. Tumors were then irradiated with a single dose of 55 Gy and local tumor control up to 90 days after the treatment was determined.

Results: A significant difference in local tumor control between "more hypoxic" or "less hypoxic" groups separated either by a median (18)F-FAZA PET determined tumor-to-blood ratio (P=0.007; hazard ratio, HR=0.21 [95% CI: 0.06-0.74]), or the fraction of oxygen partial pressure (pO(2)) values ≤2.5 mmHg (P=0.018; HR=0.31 [95% CI: 0.11-0.87]), was found. Both assays showed that the more hypoxic tumors had significantly lower tumor control.

Conclusion: (18)F-FAZA PET analysis showed that pre treatment tumor hypoxia was prognostic of radiation response. Similar results were obtained when oxygenation status was assessed by the Eppendorf pO(2) Histograph. The results of this study support the role of (18)F-FAZA as a non-invasive prognostic marker for tumor hypoxia.
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http://dx.doi.org/10.1016/j.radonc.2011.06.034DOI Listing
June 2011

Daily cone-beam computed tomography used to determine tumour shrinkage and localisation in lung cancer patients.

Acta Oncol 2010 Oct;49(7):1077-84

Aarhus University Hospital, Department of Oncology, Aarhus, Denmark.

Purpose/objective: Daily Cone-beam computed tomography (CBCT) in room imaging is used to determine tumour shrinkage during a full radiotherapy (RT) course. In addition, relative interfractional tumour and lymph node motion is determined for each RT fraction.

Material And Methods: From November 2009 to March 2010, 20 consecutive lung cancer patients (14 NSCLC, 6 SCLC) were followed with daily CBCT during RT. The gross tumour volume for lung tumour (GTV-t) was visible in all daily CBCT scans and was delineated at the beginning, at the tenth and the 20th fraction, and at the end of treatment. Whenever visible, the gross tumour volume for lymph nodes (GTV-n) was also delineated. The GTV-t and GTV-n volumes were determined. All patients were setup according to an online bony anatomy match. Retrospectively, matching based on the internal target volume (ITV), the GTV-t or the GTV-n was performed.

Results: In eight patients, we observed a significant GTV-t shrinkage (15-40%) from the planning CT until the last CBCT. Only five patients presented a significant shrinkage (21-37%) in the GTV-n. Using the daily CBCT imaging, it was found that the mean value of the difference between a setup using the skin tattoo and an online matching using the ITV was 7.3±2.9 mm (3D vector in the direction of ITV). The mean difference between the ITV and bony anatomy matching was 3.0±1.3 mm. Finally, the mean distance between the GTV-t and the GTV-N was 2.9±1.6 mm.

Conclusion: One third of all patients with lung cancer undergoing chemo-RT achieved significant tumour shrinkage from planning CT until the end of the radiotherapy. Differences in GTV-t and GTV-n motion was observed and matching using the ITV including both GTV-t and GTV-n is therefore preferable.
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http://dx.doi.org/10.3109/0284186X.2010.498434DOI Listing
October 2010

Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode.

Acta Oncol 2010 Oct;49(7):934-40

Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.

Introduction: Polarographic oxygen-sensitive electrodes have demonstrated prognostic significance of hypoxia. However, its routine application is limited. (18)F-FMISO PET scans are a noninvasive approach, able to measure spatial and temporal changes in hypoxia. The aim of this study was to examine the association between measures of hypoxia defined by functional imaging and Eppendorf pO(2) electrodes.

Materials And Methods: A total of 18 patients were included, nine squamous cell carcinoma of the head and neck and nine soft tissue tumors. The tumor volume was defined by CT, MRI, (18)FDG-PET or by clinical examination. The oxygenation status of the tumors was assessed using (18)F-FMISO PET imaging followed by Eppendorf pO(2) electrode measurements. Data were compared in a 'virtual voxel', resulting in individual histograms from each tumor.

Results: The percentages of pO(2) ≤ 5 mmHg ranged from 9 to 94% (median 43%) for all 18 tumors. For (18)F-FMISO PET the T/M ratio ranged from 0.70 to 2.38 (median 1.13). Analyzing the virtual voxel histograms tumors could be categorized in three groups: Well oxygenated tumors with no hypoxia and concordance between the (18)F-FMISO data and the Eppendorf measurements, hypoxic tumors likewise with concordance between the two assays and inconclusive tumors with no concordance between the assays.

Conclusion: This study analyzed the relationship between (18)F-FMISO PET and Eppendorf pO(2) electrode measurements by use of a virtual voxel model. There was a spectrum of hypoxia among tumors that can be detected by both assays. However no correlation was observed, and in general tumors were more hypoxic based on Eppendorf pO(2) measurements as compared to (18)F-FMISO PET.
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http://dx.doi.org/10.3109/0284186X.2010.516274DOI Listing
October 2010
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