Kasper Toustrup - Academia.edu (original) (raw)
Papers by Kasper Toustrup
Acta Oncologica, May 10, 2016
Background: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be redu... more Background: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. Material and methods: Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n ¼ 96), 24 (n ¼ 40), and IAEA Hypo (n ¼ 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDu DD , UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible. Results: Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions. Conclusion: Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.
European Journal of Cancer, 2013
Acta Oncologica, 2011
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organization and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient fl ow. Material and methods. Initiatives were implemented throughout the year 2007. Focus was on optimizing logistics for all patients referred to the center with suspected head and neck cancer. Initiatives included a fulltime case manager, pre-booked slots for clinical work-up and weekly tumor-boards. Key-dates were registered and relevant intervals were quantitatively evaluated and compared to a reference-group from 2006. Results. We registered 446 patients. Waiting times for fi rst clinical examination on ENT department were reduced from median eight to median two days through 2007 (p Ͻ 0.0001). Time from fi rst clinical examination and until referral for treatment was reduced from median 21 to median nine days (p Ͻ 0.0001). Time from referral to treatment and until initiation of treatment was reduced from median 26 to median 15 days (p Ͻ 0.001). The net result of these reductions was a reduced overall time from median 57 days ultimo 2006 to median 29 days ultimo 2007 (p Ͻ 0.0001). Conclusion. The current project has shown that it is possible to reduce waiting times in head and neck cancer. Through logistic changes, employment of a full-time case manager, strengthening the multidisciplinary tumor board and giving higher priority for head and neck cancer patients, the overall time from fi rst suspicion of cancer until treatment start was reduced from 57 calendar days to 29 calendar days.
Acta oncologica (Stockholm, Sweden), Jan 10, 2016
In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use o... more In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenog...
Clinical and Translational Radiation Oncology, 2017
British journal of cancer, Jan 4, 2016
For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic an... more 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). 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. 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 ...
Ugeskrift For Laeger, Jan 25, 2010
In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs fo... more In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs for head and neck cancer patients. The median period from referral to initiation of treatment was reduced from 57 to 29 calendar days. This article reports the results of a qualitative study, which examined whether it was possible for patients to keep up with the program mentally as well as emotionally. The study is based on semi-structured interviews with 20 head and neck cancer patients. The patients expressed great satisfaction with the accelerated programmes. Even though patients experienced the accelerated programs as very overwhelming, the vast majority did not at any time wish to postpone continuation of the programme. The study, however, shows that what is most important for the patient is fast treatment, good information and communication and good personal contact with the staff during the programme. Repetition of information and programme continuity is important as these factors allow patients to "keep up" with the programme. Personal contact and communication between patient and staff is essential for a successful accelerated programme. Time of diagnosis, scheduling of a date for the initial treatment or the start-up of the initial treatment are crucial turning points during the programme - points at which patients started feeling more calm.
Ugeskrift for laeger
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organisation and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. The initiatives were implemented throughout 2007. Focus was on optimizing logistics for all patients referred to the centre with suspected head and neck cancer. Initiatives included a full-time coordinator, pre-booked slots for clinical work-up and weekly tumour boards. Key dates were registered and relevant intervals were quantitatively evaluated and compared to a reference group from 2006. We registered 446 patients. Waiting times for first clinical examination at the ENT department were reduced from medially eight to two days through 2007 (p < 0.0001). Time from first clinical examination to referral for treatment was reduced from medially 21 to nine days (p < 0.0001). Time from referral to treatment to initiation of treatment was reduced from medially 26 to 15 days (p < 0,001). The net result of these reductions was a reduced overall median time (from primary referral to initiation of treatment) from medially 57 days by end of 2006 to medially 29 days by end of 2007 (p < 0,0001). Logistic changes and especially introduction of a full-time coordinator, a multidisciplinary tumour board and a generally higher priority for head and neck cancer patients resulted in a significant acceleration regarding diagnosis and start of treatment from 2006 to 2007.
Radiotherapy and Oncology, 2014
Ugeskrift for laeger, Jan 25, 2010
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organisation and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. The initiatives were implemented throughout 2007. Focus was on optimizing logistics for all patients referred to the centre with suspected head and neck cancer. Initiatives included a full-time coordinator, pre-booked slots for clinical work-up and weekly tumour boards. Key dates were registered and relevant intervals were quantitatively evaluated and compared to a reference group from 2006. We registered 446 patients. Waiting times for first clinical examination at the ENT department were reduced from medially eight to two days through 2007 (p < 0.0001). Time from first clinical examination to referral for treatment was reduced from medially 21 to nine days (p < 0.0001). Time from referral to treatment to initiation of trea...
Ugeskrift for laeger, Jan 25, 2010
In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs fo... more In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs for head and neck cancer patients. The median period from referral to initiation of treatment was reduced from 57 to 29 calendar days. This article reports the results of a qualitative study, which examined whether it was possible for patients to keep up with the program mentally as well as emotionally. The study is based on semi-structured interviews with 20 head and neck cancer patients. The patients expressed great satisfaction with the accelerated programmes. Even though patients experienced the accelerated programs as very overwhelming, the vast majority did not at any time wish to postpone continuation of the programme. The study, however, shows that what is most important for the patient is fast treatment, good information and communication and good personal contact with the staff during the programme. Repetition of information and programme continuity is important as these factors ...
Acta Oncologica, 2015
Purpose/Objective. A phase II clinical trial evaluating the feasibility and outcome of treating l... more Purpose/Objective. A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma (HNSCC) with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Material and methods. A total of 227 patients with stage III or IV HNSCC of the larynx, oropharynx, hypopharynx, or oral cavity where included between January 2007 and December 2010. The prescribed radiotherapy (RT) dose was 66-68 Gy in 2 Gy fractions, 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m(2) before each fraction. Concomitant cisplatin (40 mg/m(2)) i.v. was given once a week for a maximum of six cycles. Outcome data were evaluated in terms of loco-regional tumour control (LRC), event-free survival (EFS) and overall survival (OS). Morbidity data were evaluated based on the DAHANCA routine registration. Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16. Results. Included were 178 (78%) men and 49 (22%) women with a median age of 57 years. All except five patients received RT as prescribed. At least five series of cisplatin was given to 164 (72%) of the patients, and 149 patients (66%) received the full dose of nimorazole. The five-year actuarial LRC, EFS and OS rates were 80%, 67% and 72%, respectively. The LRC rates according to site were: oropharynx: 88%, larynx: 77%, hypopharynx 72% and oral cavity 49%, respectively. HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers. Of these, 112 (79%) were p16 pos and 29 (21%) were p16 neg. LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos (74% vs. 91%; p = 0.02). Tube feeding during treatment was necessary for 146 (64%) patients. At 12 months this number was reduced to 6%. Conclusion. The treatment was tolerable in this cohort of locally advanced HNSCC patients. Acute and late toxicity was comparable to similar studies of chemoradiotherapy, and the outcome superior to the data reported in the literature. This strongly indicates that RT of advanced head and neck cancer must include as well hypoxic modification, accelerated fractionation as chemoradiotherapy to yield optimal outcome.
Journal of enzyme inhibition and medicinal chemistry, Jan 27, 2014
The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which t... more The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as po...
Radiotherapy and Oncology, 2012
Radiotherapy and Oncology, 2011
Purpose: Morbimortalty review is now recommended by the French Health Authority (Haute Autorit Sa... more Purpose: Morbimortalty review is now recommended by the French Health Authority (Haute Autorit SantAS]) in all hospital settings. As regularly done in radiotherapy centres, this a posteriori analysis may be completed by a systemic analysis of precursors which may potentially result in medical damage, even thought no damage has yet occurred.Frequently overloaded, medical teams do not favour analysis of precursors as a current practice as far as it requires a method difficult to learn and difficult to use. It is the reason why ORION ® has been set up. Materials: ORION ® is based on experience acquired in aeronautics which is the main precursor in risk management since aircraft crashes are considered as unacceptable even though the mortality from aircraft crashes is extremely low compared to the mortality from medical errors in hospital settings. ORION ® is an easy-to-learn but nevertheless rigorous analytic method. It permits to build the chronology of facts resulting in the considered event, to identify the causes of the event and to propose corrective actions aiming at improving the overall system of working. The systemic analysis is divided in 6 steps: Step I: Collecting data Step II: Rebuilding the chronology of facts Step III: Identifying the deltas Step IV: Identifying contributing and influential factors Step V: Proposing actions to put in place Step VI: Writing the analysis report. When identifying contributing and influential factors, four kinds of factors favouring the event are considered: technical domain, working environment, organisation and procedures, human factors. Although they are essentials, human factors are not always correctly considered. The systemic analysis is done by a special committee, set up in each service of the hospital and including all categories of people acting in the setting: assistants, nurses, health managers, quality managers, pharmacists, physicians & Results: ORION®is now used in more than 400 French hospital settings for systemic analysis of either event precursors or morbimortality cases. Generally, and particularly in 145 radiotherapy centres, systemic analysis of event precursors is carried out through CREX (Comite Retour d'Expence), monthly committees analysing experience feedback. Conclusions: As shown by the number of hospital settings currently the method, ORION ® , the easy-to-use analytic method is successful. It permits medical teams to make systemic analysis of both event precursors and medical events leading to effective corrective actions favouring right hospital working and improving patients' care.
BMC Cancer, 2011
Background: Tumor hypoxia is linked to poor prognosis, but identification and quantification of t... more Background: Tumor hypoxia is linked to poor prognosis, but identification and quantification of tissue hypoxia remains a challenge. The hypoxia-specificity of HIF-1α target genes in vivo has been questioned due to the confounding influence of other microenvironmental abnormalities known to affect gene expression (e.g., low pH). Here we describe a new technique that by exploiting intratumoral oxygenation heterogeneity allows us to identify and objectively rank the most robust mRNA hypoxia biomarkers. Methods: Mice carrying human (FaDu dd) or murine (SCCVII) tumors were injected with the PET hypoxia tracer FAZA. Four hours post-injection tumors were removed, frozen, and crushed into milligram-sized fragments, which were transferred individually to pre-weighed tubes containing RNAlater and then weighed. For each fragment radioactivity per tissue mass and expression patterns of selected mRNA biomarkers were analyzed and compared. Results: In both tumour models, fragmentation into pieces weighing 10 to 60 mg resulted in tissue fragments with highly variable relative content of hypoxic cells as evidenced by an up to 13-fold variation in FAZA radioactivity per mass of tissue. Linear regression analysis comparing FAZA retention with patterns of gene expression in individual tissue fragments revealed that CA9, GLUT1 and LOX mRNA levels were equally and strongly correlated to hypoxic extent in FaDu dd. The same link between hypoxia and gene expression profile was observed for CA9 and GLUT1, but not LOX, in SCCVII tumors. Apparent in vivo hypoxia-specificity for other putative molecular markers of tissue hypoxia was considerably weaker. Conclusions: The portrayed technique allows multiple pairwise measurements of mRNA transcript levels and extent of hypoxia in individual tumors at a smallest possible volumetric scale which (by limiting averaging effects inherent to whole-tumor analysis) strengthen the conclusiveness on true hypoxia-specificity of candidate genes while limiting the required number of tumors. Among tested genes, our study identified CA9, GLUT1 and possibly LOX as highly specific biomarkers of tumor hypoxia in vivo.
Reliable methods for identification of hypoxia in radiotherapy-treated tumors have been a desirab... more Reliable methods for identification of hypoxia in radiotherapy-treated tumors have been a desirable aim in radiation oncology for decades. Hypoxia is a common feature of the microenvironment in solid tumors, and it is associated with increased aggressiveness, reduced therapeutic response, and a poorer clinical outcome. In head and neck squamous cell carcinomas, the negative effect of hypoxia on radiotherapeutic response can be counteracted and minimized by applying hypoxic modification to radiotherapy, which favors the clinical outcome after treatment. However, not all tumors are hypoxic, hence not all patients benefit from the addition of hypoxic modification. Therefore, predictive and clinically applicable methods for pretherapeutic hypoxic evaluation and categorization are needed. Hypoxia gene expression signatures are a developing strategy to approach this obstacle. This method has evolved along with the development of complementary DNA microarray analysis and classifies tumors in accordance to the expression of specific hypoxia-responsive genes in the tumor biopsy. Thus, tumors are classified and categorized in terms of the biological behavior to hypoxic conditions in the microenvironment. Until now, most of the developed hypoxia signatures have only been evaluated in terms of their prognostic impact; however, recently, a predictive impact for hypoxic modification of radiotherapy was verified. Here, we provide an overview of the hypoxic issue in radiotherapy and present the most promising hypoxia gene expression signatures developed to date.
Radiotherapy and Oncology, 2012
Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squam... more 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. 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. 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. This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.
Acta Oncologica, May 10, 2016
Background: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be redu... more Background: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. Material and methods: Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n ¼ 96), 24 (n ¼ 40), and IAEA Hypo (n ¼ 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDu DD , UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible. Results: Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions. Conclusion: Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.
European Journal of Cancer, 2013
Acta Oncologica, 2011
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organization and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient fl ow. Material and methods. Initiatives were implemented throughout the year 2007. Focus was on optimizing logistics for all patients referred to the center with suspected head and neck cancer. Initiatives included a fulltime case manager, pre-booked slots for clinical work-up and weekly tumor-boards. Key-dates were registered and relevant intervals were quantitatively evaluated and compared to a reference-group from 2006. Results. We registered 446 patients. Waiting times for fi rst clinical examination on ENT department were reduced from median eight to median two days through 2007 (p Ͻ 0.0001). Time from fi rst clinical examination and until referral for treatment was reduced from median 21 to median nine days (p Ͻ 0.0001). Time from referral to treatment and until initiation of treatment was reduced from median 26 to median 15 days (p Ͻ 0.001). The net result of these reductions was a reduced overall time from median 57 days ultimo 2006 to median 29 days ultimo 2007 (p Ͻ 0.0001). Conclusion. The current project has shown that it is possible to reduce waiting times in head and neck cancer. Through logistic changes, employment of a full-time case manager, strengthening the multidisciplinary tumor board and giving higher priority for head and neck cancer patients, the overall time from fi rst suspicion of cancer until treatment start was reduced from 57 calendar days to 29 calendar days.
Acta oncologica (Stockholm, Sweden), Jan 10, 2016
In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use o... more In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenog...
Clinical and Translational Radiation Oncology, 2017
British journal of cancer, Jan 4, 2016
For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic an... more 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). 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. 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 ...
Ugeskrift For Laeger, Jan 25, 2010
In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs fo... more In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs for head and neck cancer patients. The median period from referral to initiation of treatment was reduced from 57 to 29 calendar days. This article reports the results of a qualitative study, which examined whether it was possible for patients to keep up with the program mentally as well as emotionally. The study is based on semi-structured interviews with 20 head and neck cancer patients. The patients expressed great satisfaction with the accelerated programmes. Even though patients experienced the accelerated programs as very overwhelming, the vast majority did not at any time wish to postpone continuation of the programme. The study, however, shows that what is most important for the patient is fast treatment, good information and communication and good personal contact with the staff during the programme. Repetition of information and programme continuity is important as these factors allow patients to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;keep up&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; with the programme. Personal contact and communication between patient and staff is essential for a successful accelerated programme. Time of diagnosis, scheduling of a date for the initial treatment or the start-up of the initial treatment are crucial turning points during the programme - points at which patients started feeling more calm.
Ugeskrift for laeger
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organisation and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. The initiatives were implemented throughout 2007. Focus was on optimizing logistics for all patients referred to the centre with suspected head and neck cancer. Initiatives included a full-time coordinator, pre-booked slots for clinical work-up and weekly tumour boards. Key dates were registered and relevant intervals were quantitatively evaluated and compared to a reference group from 2006. We registered 446 patients. Waiting times for first clinical examination at the ENT department were reduced from medially eight to two days through 2007 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Time from first clinical examination to referral for treatment was reduced from medially 21 to nine days (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Time from referral to treatment to initiation of treatment was reduced from medially 26 to 15 days (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0,001). The net result of these reductions was a reduced overall median time (from primary referral to initiation of treatment) from medially 57 days by end of 2006 to medially 29 days by end of 2007 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0,0001). Logistic changes and especially introduction of a full-time coordinator, a multidisciplinary tumour board and a generally higher priority for head and neck cancer patients resulted in a significant acceleration regarding diagnosis and start of treatment from 2006 to 2007.
Radiotherapy and Oncology, 2014
Ugeskrift for laeger, Jan 25, 2010
Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal o... more Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organisation and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. The initiatives were implemented throughout 2007. Focus was on optimizing logistics for all patients referred to the centre with suspected head and neck cancer. Initiatives included a full-time coordinator, pre-booked slots for clinical work-up and weekly tumour boards. Key dates were registered and relevant intervals were quantitatively evaluated and compared to a reference group from 2006. We registered 446 patients. Waiting times for first clinical examination at the ENT department were reduced from medially eight to two days through 2007 (p < 0.0001). Time from first clinical examination to referral for treatment was reduced from medially 21 to nine days (p < 0.0001). Time from referral to treatment to initiation of trea...
Ugeskrift for laeger, Jan 25, 2010
In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs fo... more In 2007 Aarhus University Hospital succeeded in accelerating diagnostic and treatment programs for head and neck cancer patients. The median period from referral to initiation of treatment was reduced from 57 to 29 calendar days. This article reports the results of a qualitative study, which examined whether it was possible for patients to keep up with the program mentally as well as emotionally. The study is based on semi-structured interviews with 20 head and neck cancer patients. The patients expressed great satisfaction with the accelerated programmes. Even though patients experienced the accelerated programs as very overwhelming, the vast majority did not at any time wish to postpone continuation of the programme. The study, however, shows that what is most important for the patient is fast treatment, good information and communication and good personal contact with the staff during the programme. Repetition of information and programme continuity is important as these factors ...
Acta Oncologica, 2015
Purpose/Objective. A phase II clinical trial evaluating the feasibility and outcome of treating l... more Purpose/Objective. A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma (HNSCC) with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Material and methods. A total of 227 patients with stage III or IV HNSCC of the larynx, oropharynx, hypopharynx, or oral cavity where included between January 2007 and December 2010. The prescribed radiotherapy (RT) dose was 66-68 Gy in 2 Gy fractions, 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m(2) before each fraction. Concomitant cisplatin (40 mg/m(2)) i.v. was given once a week for a maximum of six cycles. Outcome data were evaluated in terms of loco-regional tumour control (LRC), event-free survival (EFS) and overall survival (OS). Morbidity data were evaluated based on the DAHANCA routine registration. Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16. Results. Included were 178 (78%) men and 49 (22%) women with a median age of 57 years. All except five patients received RT as prescribed. At least five series of cisplatin was given to 164 (72%) of the patients, and 149 patients (66%) received the full dose of nimorazole. The five-year actuarial LRC, EFS and OS rates were 80%, 67% and 72%, respectively. The LRC rates according to site were: oropharynx: 88%, larynx: 77%, hypopharynx 72% and oral cavity 49%, respectively. HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers. Of these, 112 (79%) were p16 pos and 29 (21%) were p16 neg. LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos (74% vs. 91%; p = 0.02). Tube feeding during treatment was necessary for 146 (64%) patients. At 12 months this number was reduced to 6%. Conclusion. The treatment was tolerable in this cohort of locally advanced HNSCC patients. Acute and late toxicity was comparable to similar studies of chemoradiotherapy, and the outcome superior to the data reported in the literature. This strongly indicates that RT of advanced head and neck cancer must include as well hypoxic modification, accelerated fractionation as chemoradiotherapy to yield optimal outcome.
Journal of enzyme inhibition and medicinal chemistry, Jan 27, 2014
The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which t... more The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as po...
Radiotherapy and Oncology, 2012
Radiotherapy and Oncology, 2011
Purpose: Morbimortalty review is now recommended by the French Health Authority (Haute Autorit Sa... more Purpose: Morbimortalty review is now recommended by the French Health Authority (Haute Autorit SantAS]) in all hospital settings. As regularly done in radiotherapy centres, this a posteriori analysis may be completed by a systemic analysis of precursors which may potentially result in medical damage, even thought no damage has yet occurred.Frequently overloaded, medical teams do not favour analysis of precursors as a current practice as far as it requires a method difficult to learn and difficult to use. It is the reason why ORION ® has been set up. Materials: ORION ® is based on experience acquired in aeronautics which is the main precursor in risk management since aircraft crashes are considered as unacceptable even though the mortality from aircraft crashes is extremely low compared to the mortality from medical errors in hospital settings. ORION ® is an easy-to-learn but nevertheless rigorous analytic method. It permits to build the chronology of facts resulting in the considered event, to identify the causes of the event and to propose corrective actions aiming at improving the overall system of working. The systemic analysis is divided in 6 steps: Step I: Collecting data Step II: Rebuilding the chronology of facts Step III: Identifying the deltas Step IV: Identifying contributing and influential factors Step V: Proposing actions to put in place Step VI: Writing the analysis report. When identifying contributing and influential factors, four kinds of factors favouring the event are considered: technical domain, working environment, organisation and procedures, human factors. Although they are essentials, human factors are not always correctly considered. The systemic analysis is done by a special committee, set up in each service of the hospital and including all categories of people acting in the setting: assistants, nurses, health managers, quality managers, pharmacists, physicians & Results: ORION®is now used in more than 400 French hospital settings for systemic analysis of either event precursors or morbimortality cases. Generally, and particularly in 145 radiotherapy centres, systemic analysis of event precursors is carried out through CREX (Comite Retour d'Expence), monthly committees analysing experience feedback. Conclusions: As shown by the number of hospital settings currently the method, ORION ® , the easy-to-use analytic method is successful. It permits medical teams to make systemic analysis of both event precursors and medical events leading to effective corrective actions favouring right hospital working and improving patients' care.
BMC Cancer, 2011
Background: Tumor hypoxia is linked to poor prognosis, but identification and quantification of t... more Background: Tumor hypoxia is linked to poor prognosis, but identification and quantification of tissue hypoxia remains a challenge. The hypoxia-specificity of HIF-1α target genes in vivo has been questioned due to the confounding influence of other microenvironmental abnormalities known to affect gene expression (e.g., low pH). Here we describe a new technique that by exploiting intratumoral oxygenation heterogeneity allows us to identify and objectively rank the most robust mRNA hypoxia biomarkers. Methods: Mice carrying human (FaDu dd) or murine (SCCVII) tumors were injected with the PET hypoxia tracer FAZA. Four hours post-injection tumors were removed, frozen, and crushed into milligram-sized fragments, which were transferred individually to pre-weighed tubes containing RNAlater and then weighed. For each fragment radioactivity per tissue mass and expression patterns of selected mRNA biomarkers were analyzed and compared. Results: In both tumour models, fragmentation into pieces weighing 10 to 60 mg resulted in tissue fragments with highly variable relative content of hypoxic cells as evidenced by an up to 13-fold variation in FAZA radioactivity per mass of tissue. Linear regression analysis comparing FAZA retention with patterns of gene expression in individual tissue fragments revealed that CA9, GLUT1 and LOX mRNA levels were equally and strongly correlated to hypoxic extent in FaDu dd. The same link between hypoxia and gene expression profile was observed for CA9 and GLUT1, but not LOX, in SCCVII tumors. Apparent in vivo hypoxia-specificity for other putative molecular markers of tissue hypoxia was considerably weaker. Conclusions: The portrayed technique allows multiple pairwise measurements of mRNA transcript levels and extent of hypoxia in individual tumors at a smallest possible volumetric scale which (by limiting averaging effects inherent to whole-tumor analysis) strengthen the conclusiveness on true hypoxia-specificity of candidate genes while limiting the required number of tumors. Among tested genes, our study identified CA9, GLUT1 and possibly LOX as highly specific biomarkers of tumor hypoxia in vivo.
Reliable methods for identification of hypoxia in radiotherapy-treated tumors have been a desirab... more Reliable methods for identification of hypoxia in radiotherapy-treated tumors have been a desirable aim in radiation oncology for decades. Hypoxia is a common feature of the microenvironment in solid tumors, and it is associated with increased aggressiveness, reduced therapeutic response, and a poorer clinical outcome. In head and neck squamous cell carcinomas, the negative effect of hypoxia on radiotherapeutic response can be counteracted and minimized by applying hypoxic modification to radiotherapy, which favors the clinical outcome after treatment. However, not all tumors are hypoxic, hence not all patients benefit from the addition of hypoxic modification. Therefore, predictive and clinically applicable methods for pretherapeutic hypoxic evaluation and categorization are needed. Hypoxia gene expression signatures are a developing strategy to approach this obstacle. This method has evolved along with the development of complementary DNA microarray analysis and classifies tumors in accordance to the expression of specific hypoxia-responsive genes in the tumor biopsy. Thus, tumors are classified and categorized in terms of the biological behavior to hypoxic conditions in the microenvironment. Until now, most of the developed hypoxia signatures have only been evaluated in terms of their prognostic impact; however, recently, a predictive impact for hypoxic modification of radiotherapy was verified. Here, we provide an overview of the hypoxic issue in radiotherapy and present the most promising hypoxia gene expression signatures developed to date.
Radiotherapy and Oncology, 2012
Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squam... more 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. 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. 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. This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.