Martin-Immanuel Bittner

Exploratory geographical analysis of hypoxic subvolumes using 18F-MISO-PET imaging in patients with head and neck cancer in the course of primary chemoradiotherapy

BACKGROUND AND PURPOSE Hypoxia in head and neck tumours is associated with poor prognosis and outcome, and can be visualized using (18)F-MISO-PET imaging; however, it is not clear whether the size and location of hypoxic subvolumes remain stable during therapy. In a pilot project, we conducted an exploratory analysis of persistent tumour hypoxia during treatment. MATERIALS AND METHODS Sixteen patients with locally advanced head and neck tumours underwent consecutive (18)F-MISO-PET scans before and during primary chemoradiotherapy. The size, location and overlap of the hypoxic subvolumes were analysed using a semi-automatic algorithm based on a tumour to normal tissue ratio of 1.5. RESULTS Quantitative evaluation showed tumour hypoxia in week 0 in 16 out of 16 and in week 2 in 5 out of 14 patients. For the five patients with persistent hypoxia, both increased and decreased hypoxic subvolumes could be observed. Mean hypoxic subvolume overlap was 55% of the hypoxic volume of the first scan and 72% of the hypoxic volume of the second scan. A stationary (in four out of five patients) and dynamic component (in three out of five patients) could be differentiated. CONCLUSION In patients with persistent hypoxia after 2 weeks of treatment, the hypoxic subvolumes showed mostly a geographically relatively stable conformation.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Hypoxia in Head and Neck Tumors: Characteristics and Development during Therapy

Cancers of the head and neck are a malignancy causing a considerable health burden. In head and neck cancer patients, tumor hypoxia has been shown to be an important predictor of response to therapy and outcome. Several imaging modalities can be used to determine the amount and localization of tumor hypoxia. Especially PET has been used in a number of studies analyzing this phenomenon. However, only few studies have reported the characteristics and development during (chemoradio-) therapy. Yet, the characterization of tumor hypoxia in the course of treatment is of great clinical importance. Successful delineation of hypoxic subvolumes could make an inclusion into radiation treatment planning feasible, where dose painting is hypothesized to improve the tumor control probability. So far, hypoxic subvolumes have been shown to undergo changes during therapy; in most cases, a reduction in tumor hypoxia can be seen, but there are also differing observations. In addition, the hypoxic subvolumes have mostly been described as geographically rather stable. However, studies specifically addressing these issues are needed to provide more data regarding these initial findings and the hypotheses connected with them.

How is intensive care reimbursed? A review of eight European countries

Reimbursement schemes in intensive care are more complex than in other areas of healthcare, due to special procedures and high care needs. Knowledge regarding the principles of functioning in other countries can lead to increased understanding and awareness of potential for improvement. This can be achieved through mutual exchange of solutions found in other countries. In this review, experts from eight European countries explain their respective intensive care unit reimbursement schemes. Important conclusions include the apparent differences in the countries’ reimbursement schemes-despite all of them originating from a DRG system-, the high degree of complexity found, and the difficulties faced in several countries when collecting the data for this collaborative work. This review has been designed to assist the intensivist clinician and researcher in understanding neighbouring countries’ approaches and in putting research into the context of a European perspective. In addition, steering committees and decision makers might find this a valuable source to compare different reimbursement schemes.

The radiosensitizing effects of Nelfinavir on pancreatic cancer with and without pancreatic stellate cells

AIMS We have previously shown in a phase I trial that nelfinavir (NFV) is safe with chemoradiation in PDAC with good signs for efficacy. Reverse translationally, we aimed to test the influence of PSCs on nelfinavir mediated radiosensitization to PDAC preclinically, because PDAC is very rich in desmoplasia and PSCs are known to mediate radioresistance. METHODS In a direct co-culture model of several PDAC cell lines with PSC we performed clonogenic assays +/- nelfinavir. This was repeated exposing cells to hypoxic conditions. In xenograft PDAC tumors we tested radiation +/- nelfinavir +/- PSC. RESULTS NFV sensitized both, PDAC only and PDAC cocultured with PSC (PDAC: Panc-1, MiaPaCa-2, PSN-1). In Panc-1 and PSN-1 this effect was larger +PSC compared to -PSC. Human pancreatic stellate cells (hPSC) were also sensitized by NFV which reduced p-FAK levels in hPSC, an effect that we previously found to sensitize specifically PDAC/PSC coculture. Contrarily, LY294002 reduced p-Akt in PSC (hPSC and LTC-14) but had no impact on PSC radiation survival. In vitro, nelfinavir sensitized Panc-1 and PSN-1 under normoxic and hypoxic conditions. In PSN-1 xenografts, +PSC led to faster tumor regrowth after radiation vs -PSC. The regrowth delay effect of nelfinavir after radiation was dramatically larger +PSC vs -PSC (time to reach 250mm(3) 183% vs 22%). CONCLUSION NFV mediated radiosensitization in PDAC with stroma is partly mediated by p-FAK inhibition (Chen et al., 2013). In vitro, NFV sensitizes both normoxic and hypoxic PDAC +/- PSC to a roughly similar extent. The dramatic increased effect of xenograft regrowth inhibition by nelfinavir in tumors with PSC is attributed to vascular normalization (Brunner et al., 2014) rather than direct modification of hypoxia as shown by the tumor regrowth after gemcitabine with NFV.

A systematic review of antiproton radiotherapy

Antiprotons have been proposed as possible particles for radiotherapy; over the past years, the renewed interest in the potential biomedical relevance led to an increased research activity. It is the aim of this review to deliver a comprehensive overview regarding the evidence accumulated so far, analysing the background and depicting the current status of antiprotons in radiotherapy. A literature search has been conducted, including major scientific and commercial databases. All articles and a number of relevant conference abstracts published in the respective field have been included in this systematic review. The physical basis of antiproton radiotherapy is complex; however, the characterisation of the energy deposition profile supports its potential use in radiotherapy. Also the dosimetry improved considerably over the past few years. Regarding the biological properties, data on the effects on cells are presented; however, definite conclusions regarding the relative biological effectiveness cannot be made at the moment and radiobiological evidence of enhanced effectiveness remains scarce. In addition, there is new evidence supporting the potential imaging properties, for example for online dose verification. Clinical settings which might profit from the use of antiprotons have been further tracked. Judging from the evidence available so far, clinical constellations requiring optimal sparing in the entrance region of the beam and re-irradiations might profit most from antiproton radiotherapy. While several open questions remain to be answered, first steps towards a thorough characterisation of this interesting modality have been made.

Information Technology in Radiation Oncology – A Brave New World?

The introduction of information technology (IT) into clinical practice has changed the way healthcare is being delivered. Electronic medical records (EMRs) replace paper records. In disciplines with high volumes of information to be processed, archived, and retrieved, the modern work scope would be difficult to navigate without the support of high capacity and secure servers, computers, and specialized robust software platforms. Radiation oncology is an informatics based discipline that requires implementation of modern IT solutions. The use of modern informatics platforms has made possible vast progresses in radiation treatment planning over the last decade. In addition, radiation oncology is strongly dedicated to quality assurance issues. This is also an area where IT can help collect, audit, and archive the necessary data. Kirkpatrick et al. (2013) describe the implementation of an EMR for a radiation oncology department as part of a large health enterprise. Their report outlines the process leading to the successful project completion, articulating reasons for the change as well as difficulties encountered of both technical and human nature. The new system improved secure access to the department data both from intramural and extramural sources. This is one important advantage of IT solutions. Provided the hardware and software is available, data can easily be accessed and used simultaneously by several users at different places. In this case, clinical patient data from the Department of Radiation Oncology are also available to Emergency Department officers. In addition, there is a notable decrease in paper and stationary consumption, as well as needed archive space. However, the system still includes paper-based components. Patient questionnaires and consent forms still have to be completed in a written form and scanned afterwards. The same is true for external documents which are to be available in the EMR. This may lead to error or limited efficiency. Therefore, what are the next steps? Where will the future development migrate? The hybrid use of electronic and paper-based records is an initial strategy. The capabilities of modern mobile electronic devices and the variety of software solutions often freely available on the internet may alter healthcare delivery in the next decade. Will the ward-round be completed using a hand-held device with access to the patient’s data, being updated in real-time, and allowing for ordering of tests from the bedside? Is the radiation treatment planning going to be fully integrated in the digital workflow? Are quality assurance protocols part of an encompassing IT solution? Will data from EMRs directly be transferrable into clinical trials data capture systems, thereby dispensing of the need of redundant data entries? All of these examples are currently in use in multiple institutions (Siochi et al., 2009; Patel et al., 2012; Yamamoto et al., 2012; Rohner et al., 2013). The integration of these informatics tools into one department will develop a new paradigm. A paperless, digital workflow, readily accessible to multiple clinicians and investigators, including interfaces to other departments’ and external healthcare providers’ data is at our horizon. However, there are also considerations clouding this vision. How are sensible personal data secured? Who can view or alter them? Legal restrictions play an increasing role in working with personal data, as it is recognized that data protection will be a challenge moving forward. With more systems interconnected, a complete caption of patient characteristics and history are rendered possible. It has to be doubted whether our old concepts of data and data protection will remain valid given the potential of a fully digital environment. Concepts like the use of signatures for the verification of documents have to be reconsidered in a rapidly changing IT-driven world, where login details and user histories theoretically provide much more detailed information (Victoroff, 2012). Other hindrances include rivaling industrial standards which will have to be overcome to be able to exploit the full potential of integrated IT solutions within larger health networks (Takabayashi et al., 2011). Kirkpatrick et al. (2013) report an important step on the way to an easier, safer, and more effective way to administer radiation oncology department data. However, the future of IT and electronic devices in healthcare has only just begun. It remains to be seen where it is heading.