Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Technical note: MR-compatible pedal ergometer with electromechanical pedal resistance and exercise triggering enhanced by visual feedback via video display.

BACKGROUND: During and after exercise, dynamic 31 P MR parameters are typically measured using an MR-compatible ergometer. Self-built equipment for local condition can be constructed where possible. PURPOSE: To develop a pedal resistance ergometer with rocker arm based on a system that combines electric weight displacement, visual self-monitoring, and exercise triggering. The repeatability and reproducibility were tested. METHODS: The hardware and software for the ergometer were constructed from commercial components in a home laboratory. Twelve volunteers participated in the testing of the ergometer. RESULTS: A fully automated ergometer system was developed, allowing the pedal resistance to be adjusted during the examination. The system includes a self-monitoring and triggering mechanism that enables both the operator and subject to monitor pedal frequency and force. The operator can modify the pedal resistance as desired during the exercise. This self-monitoring solution is simple and cost-effective, requiring only a commercial potentiometer, an Arduino converter, and a conventional video projector with a personal computer (PC). Additionally, all system components are located outside the magnetic resonance (MR) room, avoiding interference with the MR system. Results of several test of the reproducibility/repeatability of power at three pedal resistance values (15%, 24%, 25% maximal voluntary force) were expressed both as a coefficient of variation ranging from 6% to 3.1% and as an intraclass correlation of coefficient ranging from 0.96 to 0.99. Similar values were also found for other dynamic parameters of 31 P MR spectroscopy. These findings are similar to published data obtained on different types of ergometers. CONCLUSIONS: Based on more than 1 year of usage, the ergometer proved successful in handling stationary and variable loads, and can be easily operated by a single user.

[Role of Robotic Surgery in ENT]. / Bedeutung der transoralen robotischen Chirurgie in der HNO.

Since the beginning of the 21st century, surgical robots have been used in the ENT-environment. They primarily support surgeons in minimal invasive transoral operations, especially in multidisciplinary treatment concepts of head and neck tumors, but also in snoring surgery the robot provides a complement to the established transoral laser surgery. In the meantime there is a large number of data that deals with the importance of oncological results, function maintenance, economics and future perspectives.Operation areas of the current robot devices are still limited in the ENT-environment. As the number of cases are small, efforts are being made to connect centres on a national and international level. Thus, uniform training standards, targeted knowledge and data exchange as well as further development of systems would be managed better. The creation of small and agile ENT-specific equipment could expand the possibilities as a next step for the future and finally lead to a wide scale of ENT-surgical applications.

[Current immuno-oncology in head and neck cancer]. / Status quo der Immunonkologie bei Plattenepithelkarzinomen des Kopf-Halsbereichs.

For many years surgery, radiotherapy and chemotherapy dominated the treatment in head and neck malignancies. Refinements of the particular techniques, either in surgery or in radiooncology, brought some progress. However, clinical outcome data are still not satisfying and side effects and long term toxicities are significant. Apart of the improvement of overall results, the reduction of side effects stays a main goal in this field. Targeted therapies as well as immune modulating therapies represent a new generation in the treatment of cancer. The development of new and highly effective substances makes rapid progress and immunotherapy has become a standard in the treatment of recurrent head and neck cancer. The following chapter will give you an actual review about the status quo of immunotherapy in head neck malignancies.

In Vitro 31P MR Chemical Shifts of In Vivo-Detectable Metabolites at 3T as a Basis Set for a Pilot Evaluation of Skeletal Muscle and Liver 31P Spectra with LCModel Software.

Most in vivo 31P MR studies are realized on 3T MR systems that provide sufficient signal intensity for prominent phosphorus metabolites. The identification of these metabolites in the in vivo spectra is performed by comparing their chemical shifts with the chemical shifts measured in vitro on high-field NMR spectrometers. To approach in vivo conditions at 3T, a set of phantoms with defined metabolite solutions were measured in a 3T whole-body MR system at 7.0 and 7.5 pH, at 37 °C. A free induction decay (FID) sequence with and without 1H decoupling was used. Chemical shifts were obtained of phosphoenolpyruvate (PEP), phosphatidylcholine (PtdC), phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC), glycerophosphoetanolamine (GPE), uridine diphosphoglucose (UDPG), glucose-6-phosphate (G6P), glucose-1-phosphate (G1P), 2,3-diphosphoglycerate (2,3-DPG), nicotinamide adenine dinucleotide (NADH and NAD+), phosphocreatine (PCr), adenosine triphosphate (ATP), adenosine diphosphate (ADP), and inorganic phosphate (Pi). The measured chemical shifts were used to construct a basis set of 31P MR spectra for the evaluation of 31P in vivo spectra of muscle and the liver using LCModel software (linear combination model). Prior knowledge was successfully employed in the analysis of previously acquired in vivo data.

Lipid Profile and Hepatic Fat Content Measured by 1H MR Spectroscopy in Patients before and after Liver Transplantation.

Increased hepatic fat content (HFC) is a hallmark of non-alcoholic fatty liver (NAFL) disease, a common condition in liver transplant recipients. Proton MR spectroscopy (1H MRS) and MR imaging-based proton density fat fraction as the only diagnosis modality enable precise non-invasive measurement of HFC and, also, fatty acid profiles in vivo. Using 1H MRS at 3T, we examined 47 liver transplantation candidates and 101 liver graft recipients. A point-resolved spectroscopy sequence was used to calculate the steatosis grade along with the saturated, unsaturated and polyunsaturated fractions of fatty acids in the liver. The steatosis grade measured by MRS was compared with the histological steatosis grade. HFC, represented by fat fraction values, is adept at distinguishing non-alcoholic steatohepatitis (NASH), NAFL and non-steatotic liver transplant patients. Relative hepatic lipid saturation increases while unsaturation decreases in response to increased HFC. Additionally, relative hepatic lipid saturation increases while unsaturation and polyunsaturation both decrease in liver recipients with histologically proven post-transplant NASH or NAFL compared to non-steatotic patients. HFC, measured by in vivo 1H MRS, correlated well with histological results. 1H MRS is a simple and fast method for in vivo analysis of HFC and its composition. It provides non-invasive support for NAFL and NASH diagnoses.

Docetaxel, cisplatin and 5-FU compared with docetaxel, cisplatin and cetuximab as induction chemotherapy in advanced squamous cell carcinoma of the head and neck: Results of a randomised phase II AGMT trial.

PURPOSE: Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C). PATIENTS AND METHODS: In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. RESULTS: On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0-93.1%] in the TPC arm and 78.5% [95% CI, 63.7-87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification. CONCLUSION: TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted.

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation.

Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt(-1)·day(-1)). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH- and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-α, TLR4, IL-1ß, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation.

Positive effects of voluntary running on metabolic syndrome-related disorders in non-obese hereditary hypertriacylglycerolemic rats.

While metabolic syndrome is often associated with obesity, 25% of humans suffering from it are not obese and the effect of physical activity remains unclear in such cases. Therefore, we used hereditary hypertriaclyglycerolemic (HHTg) rats as a unique model for studying the effect of spontaneous physical activity [voluntary running (VR)] on metabolic syndrome-related disorders, such as dyslipidemia, in non-obese subjects. Adult HHTg males were fed standard (CD) or high-sucrose (HSD) diets ad libitum for four weeks. Within both dietary groups, some of the rats had free access to a running wheel (CD+VR, HSD+VR), whereas the controls (CD, HSD) had no possibility of extra physical activity. At the end of the four weeks, we measured the effects of VR on various metabolic syndrome-associated parameters: (i) biochemical parameters, (ii) the content and composition of triacylglycerols (TAG), diacylglycerols (DAG), ceramides and membrane phospholipids, and (iii) substrate utilization in brown adipose tissue. In both dietary groups, VR led to various positive effects: reduced epididymal and perirenal fat depots; increased epididymal adipose tissue lipolysis; decreased amounts of serum TAG, non-esterified fatty acids and insulin; a higher insulin sensitivity index. While tissue ceramide content was not affected, decreased TAG accumulation resulted in reduced and modified liver, heart and skeletal muscle DAG. VR also had a beneficial effect on muscle membrane phospholipid composition. In addition, compared with the CD group, the CD+VR rats exhibited increased fatty acid oxidation and protein content in brown adipose tissue. Our results confirm that physical activity in a non-obese model of severe dyslipidemia has many beneficial effects and can even counteract the negative effects of sucrose consumption. Furthermore, they suggest that the mechanism by which these effects are modulated involves a combination of several positive changes in lipid metabolism.

Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: The purpose of this study was to investigate the efficacy of bevacizumab ("Avastin") for the treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT). METHODS: In this double blind, placebo controlled trial, 15 adult patients with HHT with a minimum of 2 epistaxis episodes per week were randomized. A history of thromboembolic events or recent or planned surgery led to exclusion. Patients received a single intranasal submucosal injection (10 mL) of 100 mg bevacizumab or placebo. The primary outcome was the relative reduction of average daily epistaxis visual analog score (VAS). RESULTS: Average daily posttreatment VAS scores decreased by 27% in the bevacizumab group and by 3% in the placebo group (p = .57). The reduction in HHT epistaxis severity scores was -0.61 greater in the bevacizumab group compared to the placebo group (p = .34). CONCLUSION: Results show a trend toward reduced epistaxis with bevacizumab. This further supports the use of bevacizumab in HHT. Clincial Trials. gov number: NCT01314274

Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: To determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer. PATIENTS AND METHODS: Forty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75mg/m(2) day 1, cisplatin 75mg/m(2) day 1 and infusional 5-fluorouracil 750mg/m(2)/day on days 1-5 followed by radiotherapy plus C at 250mg/m(2)/week (after an initial loading dose of 400mg/m(2)). RESULTS: After completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively. CONCLUSION: Concurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted.

Influence of resection extent on morbidity in surgery for squamous cell cancer at the pharyngoesophageal junction.

PURPOSE: Squamous cell cancer (SCC) of the pharyngoesophageal junction area has a poor prognosis mainly due to late symptom manifestation and diagnosis. Treatment of choice is still pharyngolaryngoesophagectomy, substantially affecting quality of life. Limited surgical procedures have been adopted as well. The aim of this retrospective study was to evaluate whether the extent of resection influences postoperative safety and mortality. METHODS: From 1984 to 2006, 66 patients were operated at a single tertiary referral center. Nineteen patients (28.8 %) had SCC of the hypopharynx and 47 patients (71.2 %) had SCC of the cervical and cervicothoracic esophagus. Thirty-five patients (53.0 %) underwent cervical esophageal resection (CE) and 31 underwent total esophagectomy (TE). In 39 patients (59.1 %), the larynx was preserved. Thirteen patients (19.7 %) underwent multimodal treatment. RESULTS: Overall postoperative morbidity was 69.7 % and reoperation rate reached 28.8 %. TE (P = 0.03) and larynx preservation (P = 0.02) were followed by a higher rate of non-lung infections compared with CE and pharyngolaryngectomy, respectively. Pulmonary complications have been observed more frequently after larynx preservation (P = 0.02). Hospital mortality was 9.1 %. Four patients died after TE (12.9 %) and two patients died after CE (5.7 %). In all of them, the larynx had been preserved (15.4 %). Overall, 53 patients (80.3 %) died until follow-up. One-year and 5-year survival in patients with the major tumor burden at the cervicothoracic site was 35.7 and 0 %. CONCLUSIONS: CE can be recommended as long as R0 resection is warranted. The advantage of larynx preservation is gained by higher morbidity and mortality rates and may not be recommended as standard procedure. Surgery may not be appropriate for advanced SCC in the cervicothoracic region.

The effect of a gadolinium-based contrast agent on diffusion tensor imaging.

OBJECTIVE: The aim of this study was to investigate in detail the effect of gadolinium contrast on diffusion tensor imaging scans. As the present literature offers conflicting results, we have included a large selection of indices in the analysis. MATERIALS AND METHODS: Sixteen patients harboring an intra-axial contrast enhancing brain tumor were included in this study. Two diffusion tensor imaging scans were performed-one natively, and the second following a gadolinium contrast agent application. Maps of the invariant indices fractional anisotropy (FA), linear, planar, and spherical indices, trace, eigenvalues λ(1), λ(2), λ(3) as well as of the components of the diffusion tensor matrix Dxx, Dyy, Dzz, Dxy, Dxz and Dyz were co-registered and compared statistically with matching ROI pairs in the contrast enhancing areas, peritumoral edema and the normal appearing white matter. RESULTS: We have observed a significant increase in the FA and disproportional decrease of the eigenvalues in the post-contrast scans. In accordance with these findings, the spherical index was decreased and the linear and planar indices were increased. There was a significant decrease of all diagonal components of the diffusion tensor matrix. These changes have been strongest in the contrast enhancing areas, but there were also significant changes in the peritumoral edema and the normal appearing white matter. CONCLUSION: Diffusion tensor imaging scans performed after gadolinium contrast agent administration may display artificially increased FA values due to disproportional changes of the measured eigenvalues. The distortion of the diffusion measurement is strongest in, but not limited to the contrasting areas.

Survival of patients with HPV-positive oropharyngeal cancer after radiochemotherapy is significantly enhanced.

BACKGROUND: The purpose of this study was to evaluate the incidence and clinical significance of HPV (Human papilloma virus) infection in patients with head and neck cancer who had received radiotherapy in Eastern Austria. PATIENTS AND METHODS: 88 patients with head and neck cancer including 26 patients with oral cavity cancer, 45 patients with oropharyngeal cancer, seven patients with laryngeal carcinoma and ten patients with carcinoma of the hypopharynx were screened for high risk HPV by immunohistochemistry, PCR (Polymerase Chain Reaction) and in-situ hybridization. 29 out of 45 patients with a squamous cell carcinoma of the oropharynx received radiotherapy alone, radiotherapy in combination with cisplatin or cetuximab. RESULTS: Of the investigated 29 patients with oropharyngeal cancer receiving conservative treatment, 11 had a HPV-positive and 18 a HPV-negative tumor. Patients received radiation ± cisplatin or cetuximab, where the HPV-positive patients had a significant better response to treatment and overall survival (p = 0.015) as well as disease-free survival (p = 0.001) after therapy. CONCLUSION: Patients with oropharyngeal carcinoma and a positive HPV status respond considerably better to radiochemotherapy than patients with HPV-negative tumors. HPV screening is a simple procedure and can easily be implemented in routine pathology investigations and should be included in standard operational procedures for the diagnosis and therapy of head and neck cancer patients.

HPMA-RGD hydrogels seeded with mesenchymal stem cells improve functional outcome in chronic spinal cord injury.

Chronic spinal cord injury (SCI) is characterized by tissue loss and a stable functional deficit. While several experimental therapies have proven to be partly successful for the treatment of acute SCI, treatment of chronic SCI is still challenging. We studied whether we can bridge a chronic spinal cord lesion by implantation of our newly developed hydrogel based on 2-hydroxypropyl methacrylamide, either alone or seeded with mesenchymal stem cells (MSCs), and whether this treatment leads to functional improvement. A balloon-induced compression lesion was performed in adult 2-month-old male Wistar rats. Five weeks after injury, HPMA-RGD hydrogels [N-(2-hydroxypropyl)-methacrylamide with attached amino acid sequences--Arg-Gly-Asp] were implanted into the lesion, either with or without seeded MSCs. Animals with chronic SCI served as controls. The animals were behaviorally tested using the Basso­Beattie-Breshnahan (BBB) (motor) and plantar (sensory) tests once a week for 6 months. Behavioral analysis showed a statistically significant improvement in rats with combined treatment, hydrogel and MSCs, compared with the control group (P < 0.05). Although a tendency toward improvement was found in rats treated with hydrogel only, this was not significant. Subsequently, the animals were sacrificed 6 months after SCI, and the spinal cord lesions evaluated histologically. The combined therapy (hydrogel with MSCs) prevented tissue atrophy (P < 0.05), and the hydrogels were infiltrated with axons myelinated with Schwann cells. Blood vessels and astrocytes also grew inside the implant. MSCs were present in the hydrogels even 5 months after implantation. We conclude that 5 weeks after injury, HPMA-RGD hydrogels seeded with MSCs can successfully bridge a spinal cord cavity and provide a scaffold for tissue regeneration. This treatment leads to functional improvement even in chronic SCI.

[Recommendation for guidelines in the treatment of squamous cell cancer of the upper aerodigestive tract]. / Ein Vorschlag für Leitlinien der Behandlung von Plattenepithelkarzinomen des oberen Aerodigestivtraktes.

If we look at the historical development of the treatment of head and neck cancer, we can see that initially, decisions about therapy lay solely in the hands of the surgeons (Otorhinolaryngologists, oral and maxilla-facial surgeons) This was also true of the decision as to whether an operation was feasible or whether primary radio therapy was to be carried out. At the end of the last century, after chemotherapy had become an integral part of curative therapy, inter-disciplinary conferences (tumour boards) were set up so that the surgeons could make joint decisions about therapy together with radio oncologists and medical oncologists. In addition, the increasingly important role of chemotherapy in curative therapy in the last fifteen years has led to a marked increase in the number of clinical studies in head and neck cancer. Inter-disciplinary treatment decisions can be based only on current scientific knowledge and are geared towards a standard treatment as recommended for an individual tumour stage. It is precisely in the upper aerodigestive tract that there are various therapeutical procedures, due to the different site of primaries (oral cavity, oro-, hypoparynx and larynx) and the different grade of locoregional metastasis. One possible way to assure a high degree of transparency of these various therapies and making them available to a high number of colleagues is the development guidelines [1]. Many medical associations and organisations in Austria are currently engaged in the formulation and definition of guidelines, in order to provide the highest possible quality of medical treatment and care for each individual patient. By guidelines are meant recommendations for treatments which allow a certain amount of flexibility in the treatment and provide a medical consensus in line with current scientific knowledge. In principle, they are binding, but in exceptional but reasonable cases, they may (and even must) be departed from. The following proposal is designed to provide a basis for the formulation of guidelines for the treatment of head and neck cancer in Austria. It was put together with help from ENT specialists, medical oncologists and radio oncologists from across Austria. One advantage was certainly the fact that several foreign associations had already drawn up guidelines which could be referred to [2, 3]. Since guidelines are dynamic in nature and must be constantly adapted to correspond to current medical knowledge and research, they are often only available today on websites. For this reason, links to relevant sites are given at the end of this article.

Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat.

OBJECT: Hydrogels are nontoxic, chemically inert synthetic polymers with a high water content and large surface area that provide mechanical support for cells and axons when implanted into spinal cord tissue. METHODS: Macroporous hydrogels based on 2-hydroxyethyl methacrylate (HEMA) were prepared by radical copolymerization of monomers in the presence of fractionated NaCl particles. Male Wistar rats underwent complete spinal cord transection at the T-9 level. To bridge the lesion, positively charged HEMA hydrogels were implanted either immediately or 1 week after spinal cord transection; control animals were left untreated. Histological evaluation was performed 3 months after spinal cord transection to measure the volume of the pseudocyst cavities and the ingrowth of tissue elements into the hydrogels. RESULTS: The hydrogel implants adhered well to the spinal cord tissue. Histological evaluation showed ingrowth of connective tissue elements, blood vessels, neurofilaments, and Schwann cells into the hydrogels. Morphometric analysis of lesions showed a statistically significant reduction in pseudocyst volume in the treated animals compared with controls and in the delayed treatment group compared with the immediate treatment group (p < 0.001 and p < 0.05, respectively). CONCLUSIONS: Positively charged HEMA hydrogels can bridge a posttraumatic spinal cord cavity and provide a scaffold for the ingrowth of regenerating axons. The results indicate that delayed implantation can be more effective than immediate reconstructive surgery.

Low concentration of isoflurane promotes the development of neurogenic pulmonary edema in spinal cord injured rats.

Anesthetics can either promote or inhibit the development of neurogenic pulmonary edema (NPE) after central nervous system (CNS) injury. The influence of isoflurane was examined in male Wistar rats using 1.5%, 2%, 2.5%, 3%, 4%, or 5% isoflurane in air. Epidural balloon compression of the thoracic spinal cord was performed. The development of NPE was examined in vivo and on histologic sections of lung tissue. Animals anesthetized with 1.5% or 3% isoflurane were behaviorally monitored using the BBB and plantar tests for 7 weeks post-injury. The spinal cord was examined using MRI and morphometry of the spared white and gray matter. All animals from the 1.5% and 2% groups developed NPE. Almost 42% of the animals in the 1.5% group died of severe pulmonary hemorrhage and suffocation; x-rays, the pulmonary index, and the histological picture revealed a massive NPE. More than 71% of the animals from the 2.5% and 3% groups did not develop any signs of NPE. Blood pressure after spinal cord compression rose more in the 1.5% group than in the 3% one. In the 1.5% group, the sympathetic ganglionic blockade prevented the neurogenic pulmonary edema development. Animals from the 3% group recovered behaviorally more rapidly than did the animals from the 1.5% group; morphometry and MRI of the lesions showed no differences. Thus, low levels of isoflurane anesthesia promote NPE in rats with a compressed spinal cord and significantly complicates their recovery. The optimal concentration of anesthesia for performing a spinal cord compression lesion is 2.5-3% isoflurane in air.

Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats.

Emerging clinical studies of treating brain and spinal cord injury (SCI) with autologous adult stem cells led us to compare the effect of an intravenous injection of mesenchymal stem cells (MSCs), an injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) or bone marrow cell mobilization induced by granulocyte colony stimulating factor (G-CSF) in rats with a balloon- induced spinal cord compression lesion. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Seven days after injury, rats received an intravenous injection of MSCs or BMCs or a subcutaneous injection of GCSF (from day 7 to 11 post-injury). Functional status was assessed weekly for 5 weeks after SCI, using the Basso-Beattie-Bresnehan (BBB) locomotor rating score and the plantar test. Animals with SCI treated with MSCs, BMCs, or G-CSF had higher BBB scores and better recovery of hind limb sensitivity than controls injected with saline. Morphometric measurements showed an increase in the spared white matter. MR images of the spinal cords were taken ex vivo 5 weeks after SCI using a Bruker 4.7-T spectrometer. The lesions populated by grafted MSCs appeared as dark hypointense areas. Histology confirmed a large number of iron-containing and PKH 26-positive cells in the lesion site. We conclude that treatment with three different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI, which was most pronounced after MSC injection.