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Je nachdem, welche Musik ich mir dazu auflege, umso schneller kann ich mich dazu bewegen und kreisende Bewegungen machen, wie es mir gefällt.
Frequently, in solid tumors an activation of the hypoxia signaling pathway is found that is obvious due to the central expression of respective marker proteins here: Glut I in tumor nests and that can be confirmed by immunohistochemistry hypoxia-related.
Totalprothese – Wikipedia

Head and neck cancer is the sixth most common cancer with over annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas OSCC show increased association with human papillomavirus HPV.

In HPV OSCC, viral oncoprotein activity, as well as genetic mutations and chromosomal aberrations and epigenetic alterations plays a key role during carcinogenesis. Based on improved treatment response, the introduction of therapy de-intensification and targeted therapy is discussed for patients with HPV OSCC. A promising targeted therapy concept is immunotherapy. The use of checkpoint inhibitors e.

By means of liquid biopsies, biomarkers such as viral DNA or tumor mutations in the will soon be available for disease monitoring, as well as detection of treatment failure. Oropharyngeal squamous cell carcinoma OSCC is the only head and neck tumor entity with clearly increasing incidence. The transmission pathways and persistence of HPV in the oropharynx are still unknown.

However, genetic modifications also play a key role and often additional risk factors of classic carcinogenesis are observed tobacco. Investigations of epigenetic modifications DNA methylation, microRNA, tumor Das Beste, immune escape, gene expression identified HPV-specific aberrations that reveal approaches to future targeted therapies.

The better OS and less additional risk factors make these patients suitable to benefit from de-intensification of the treatment or targeted therapy options. As test procedure, the p16INK4a p16 test is suggested internationally.

HPV is no predictor for surgery or radiotherapy RT so that surgical tumor resection still has a high significance. Currently, numerous studies are conducted with less intensive therapy; however, up to now results have not been published.

Surgical therapy options for distant metastasis are noteworthy; there are still possibilities of curative therapy in cases of distant failure. Beside the assessment of functional impairment, this is relevant for the follow-up of our patients. Regarding the assignment to specific therapies, risk models are currently developed and discussed. Possibly, the viral carcinogenesis provides a valuable option for molecular early detection and follow-up by means of blood samples so-called liquid biopsy.

Increasing incidence rates are described for HPV-associated head and neck tumors whereas the incidence of all other head and neck carcinomas decreases in developed countries. A comparative analysis of data of US American registries from — and — revealed a doubling for OSCC frequently HPV-associated with simultaneous decrease of the incidence for cancer of the oral cavity rarely HPV-associated 1. Canadian registries currently also report a decrease of the general incidence of head and neck cancer with simultaneous increase of OSCC 2.

This epidemiological trend is explained by the increasing prevalence of oncogenic HPV in OSCC, based on nearly all published original papers 3. It may at least be assumed that the increased prevalence described is already overestimated because of methodical flaws. With regard to the design, for example older specimens were compared with newer ones, this might explain a systematic incorrectness.

A comparative investigation of patients of our own patient population Fig. In summary, the published data show a continuous increase of OSCC incidence rates and correspondingly, the increased incidence rates are due to the HPV epidemic.

The data points represent the mean value of 4 years each. From a health economic point of view, the percentage of HPV-associated head and neck tumors in other anatomical locations than the oropharynx is of high interest, too. For example, those cases might be avoided by HPV vaccination. Furthermore, patients could also benefit from de-intensified therapy and reduced side effects. The first question that is relevant in this context is, if the detection of HPV in tissues outside the oropharynx reveals true HPV-associated carcinogenesis or if it is an incidentally detected infection without further relevance.

However, considering all publications and meta-analyses on HPV positivity outside the oropharynx, the results are inconsistent 10 11 A data set of a meta-analysis of 12, patients showed HPV association in the oral cavity Currently, an extensive investigation from Spain was presented with results from 3, patients with head and neck tumors after combined testing for DNA, RNA, and p Hereby, the HPV prevalence for oral cavity cancer amounted to 4.

This relativizes significantly the mentioned, sometimes very high rates of HPV-associated head and neck tumors outside the oropharynx A high percentage of positive HPV test results outside the oropharynx probably does not show HPV-associated carcinogenesis but acute infections or false-positive test results.

Prospective investigations on the relevance of HPV detection outside the oropharynx with regard to prognosis of the patients are not available. However, based on retrospective data of patients who underwent radiotherapy RT or combined radiochemotherapy RCT in the context of clinical studies, it can be assumed that a positive p16 test outside the oropharynx has low prognostic significance.

For patients with laryngeal cancer and positive p16 test, even poorer survival rates have been published Serological examinations also contradict to a correlation between the risk of head and neck tumor disease apart from oropharynx and HR HPV infection. In contrast, marginal values of 1.

There is no reliable evidence that the prognosis of those patients is better in comparison to OSCC patients. The most common manifestation of HPV infection are warts and genital condylomas. The infection can already be transmitted at birth and presents to ENT specialists in particular as respiratory papillomatosis.

True neoplastic lesions of the cervix are sometimes caused by type 6 and type 11, too. However, in the majority cervical lesions typical oncogenic HPV types 16, 18, 31, and 45 are found. Regarding the prevalence of oral infection with HPV in the general population, cross-sectional studies are available, but only few data are published on the temporal dynamics.

A review of 18 trials with 4, healthy adults described an estimated incidence of oral HR HPV infection with 1. The age distribution of oral HPV infection shows a bimodal distribution. The first peak could be found between 30 and 34 years of age and the second peak between 60 and 64 years. The infection occurred significantly more frequently in males Incidence and type of sexual contact oral sex, deep kisses, promiscuity as well as age at first sexual intercourse, marihuana consumption, cigarette consumption, and genital HPV infections could be identified as risk factors The average duration of an oral HPV infection was assessed in 1, male persons and amounted to about 7 months; the follow-up, however, was only 13 months The majority of oral HPV infections heal within several months without further consequences.

Reinfections occur only rarely. In addition, immunodeficiency HIV infectioncigarette consumption, and high age are reported as risk factors for persisting oral HPV infection For better understanding the increased incidence of oral HPV infections in males, other data describe a higher number of sexual partners, younger age at the first sexual contact, and numerous oral sexual contacts Reliable data why mostly men develop HPV induced OSCC are not available, but numerous hints are found for an accumulation of risks kinetics of the infection, nicotine, sexual risks, see chapter 4.

One year later, the bivalent vaccine Cervarix was approved. Both vaccines contain the recombinant capsid protein L1 of the HPV types 16 and 18, and 6, 11, and 18, respectively. Since Aprilthe 9-valent vaccine Gardasil 9 is available and additionally protects against the HR HPV strains 31, 33, 45, 52, and The advantages are an extended protection given by vaccination and a 2 dose scheme in intervals of months.

The HPV vaccines are approved as of the age of 9 years and vaccination should be performed before the first sexual contact.

The approval applies for girls and boys, however, currently the German Standing Committee on Immunization Ständige Impfkommission, STIKO currently recommends only vaccination of girls, which is also paid by the health insurers. In Germany, the HPV vaccine is currently not widely administered.

The data clearly indicate vaccination of boys. However, the registration trials was naturally conducted based on precancerous lesions of the cervix and accordingly, the cost-benefit analyses refer to the diseases of the uterine cervix From countries with a high coverage, numerous data are available that report an effect on HPV-associated diseases even apart from cervix cancer.

The highest decrease of HR HPV-related new diseases apart from cervix cancer were consistently reported from countries with vaccination programs and so-called catch-up vaccination of older, non-vaccinated people Australia, Canada, Denmark, and New Zealand. The programs were implemented nearly always accompanying school education.

Convincing data on respiratory papillomatosis RRP are available from Australia Between andpediatricians and otolaryngologists collected data of newly diagnosed cases of juvenile RRP and published them in a meeting report.

Only 13 cases had been registered 7 in3 in2 inand 1 case in None of the mothers of those cases had received vaccination. Two strategies are additionally discussed regarding the prophylaxis of RRP in children: first, vaccination of newborns if the mother had condylomas, and second, vaccination of pregnant women with confirmed HPV 6 or 11 infection in order to protect the child against infection by transmission of antibodies.

In cases of vaccinated mothers, a similar antibody titer could be measured in newborns Oropharyngeal cancer mostly occurs in male patients, in RRP the gender distribution is nearly the same. Numerous other diseases with high stress for the affected patients are related to carcinogenic and non-carcinogenic HPV.

What is the benefit that can be expected for other diseases apart from cervix cancer? Hence, many publications also recommend vaccination of boys, which is absolutely supported by the authors. Carcinogenesis is a process consisting of several steps where genetic and epigenetic modifications in cancer-associated signaling pathways accumulate over time.

This results in the typical phenotype of malignant cells characterized by: unlimited replication potential, independence of growth factors, suppressed ability of apoptosis, invasive growth, and metastatic potential as well as increased angiogenesis 34 The individual risk to develop cancer disease depends on extremely diverse and sometimes interdepending factors and is therefore difficult to be determined.

The majority of head and neck cancers are squamous cell carcinomas that are mainly associated with the risk factors of tobacco and alcohol consumption or oncogenic HPV. The carcinogenesis of HPV-associated and HPV-negative head and neck cancer is associated with other specific risk factors see chapter 2.

A separate risk to develop one of those two cancer diseases is difficult to estimate because none of the risk factors appears isolated and overlapping of risks is not the exception but the rule. Regarding HPV-negative head and neck cancer, premalignant alterations have been known for several decades, especially in the oral cavity 36 Generally, the aberration probability of premalignancies cannot be safely predicted and precancerous stages in HPV OSCC could not be reliably identified see below.

Leukoplakias are visible changes that are preceded by macroscopically invisible premalignant lesions. Those invisible lesions may possibly explain the tendency to develop locoregional recurrences after treatment. The correlation of locoregional recurrences with the occurrence of dysplastic changes in neighboring regions coined the term of field cancerization in Meanwhile this term could be defined with molecular biological and genetic methods. A multistep development model consisting of morphological and genetic modifications was already suggested in including typical genetic alterations of dysplasia loss of heterozygosity [LOH] on the chromosomes 3p, 9p, and 17p and carcinomas LOH on chromosomes 11q, 4q, and 8 This allows the assumption that the carcinogenesis comprises a range of different precancerous stages that are macroscopically invisible and go beyond the resection margins developing locoregional recurrences.

Mutations in TP53 lead to the expression of an inactive tumor suppressor protein p53 and are considered as the earliest oncogenic modification. Together with field cancerization, the multistep development represents the current model of carcinogenesis of HPV-negative head and neck cancer This integration requires linearization of the viral DNA that often occurs as break within the E2 reading frame.

Whole genome gene expression analysis are generally based on a comparative hybridization microarrays or sequencing of mRNA. The capacity of microarrays as well as the sequencing techniques have continuously improved over time, which leads to an increasing coverage of the genome, but also to limited comparability of former and current data.

In one of the first gene expression studies of head and neck cancer, 60 differentially expressed genes were identified from 1, examined tumor-associated genes on a cDNA microarray. They correlated with the radioresistance or the response to radiotherapy Already 3 years later, 60 head and neck tumors were examined on a cDNA microarray with probes against 12, human genes. In this study, 4 subtypes could be identified based on the gene expression. Signatures were found with a focus in the EGFR signaling pathway, a mesenchymal subtype, a subtype with expression pattern of normal epithelium, and a subtype with enhanced antioxydase enzymes However, in all early studies, no attention was paid to the HPV status of the samples.

Similar gene expression profile groups, called basal, mesenchymal, atypical, and classic types, were identified in another study by means of Agilent 44 K microarrays. An enhancement of HPV associated specimens was observed in the group of atypical gene expression e.

By means of another platform Illumina Expression BeadChips also 4 subtypes were identified. However, only the classic expression type was confirmed as being comparable to the above-mentioned studywhich is probably due to technical differences or the heterogeneity of the specimens. Afterwards, the data were summarized with already published data to a cohort of more than patients. In this trial, 5 subtypes were identified that included 2 groups of HPV-associated and 3 groups of HPV-negative head and neck tumors.

The remaining HPV-negative group showed a basal expression pattern with overrepresentation of hypoxia-associated genes e. The knowledge gained from genome-wide expression analyses could not be implemented translationally until now. This is due to missing technical standards, which limits comparability of the results. On the other hand, the total number of analyzed samples is relatively low, so that for example heterogeneity because of patient characteristics cannot be subtracted.

In the future, this might be different due to technical advances analyzing retrospective, formalin-fixed paraffin embedded FFPE archive specimens. From tumor-associated genes, several ones were correlated with a positive HPV status e. By hierarchic classification, 6 groups of differentially expressed genes were identified Thus, the use of FFPE materials that are currently not broadly analyzed, might increase the significance and reliability of data from expression analyses in future.

The transmission of HPV occurs mainly via skin contact or contaminated objects. Afterwards, infection of epithelial cells may develop with extremely high host specificity. HPV infects undifferentiated cells directly above the basement membrane through microwounds or in very thin epithelia. While the infected cells remain close to the basement membrane, the viral DNA replication is reduced.

This is due to the fact that the viral development processes are coupled with the differentiation processes of the infected cells while they move up to the epithelial surface.

Together with viral DNA they build infectious virus particles that are released to the environment together with the external epithelial cells. Typically, for example after visiting swimming pools children develop plantar warts because of infections with the low risk HPV types 1, 2, and 4. Another transmission pathway is the perivaginal transmission during birth which may induce the development of laryngeal papillomatosis in infants and toddlers For the HPV-associated OSCC, the sexual transmission pathway with the high-risk papillomaviruses 16 and 18 is in the focus of discussion.

The severely increasing incidence in the last decades is mainly explained by changed sexual behavior, younger age at first sexual contact as well as the increased practice of oral sex Even if the genital-genital transmission of HPV infection seems to be predominant, also other transmission pathways such as anal-genital, oral-genital, manual-genital contact, the use of sex toys as well as autoinoculation are possible Furthermore, oral sex with frequently changing partners, casual sex as well as rare use of condoms were reported.

Light-skinned patients, singles as well as divorced patients mentioned a higher number of sex partners. Regarding the income, no difference could be found concerning the number of sex partners, while patients with a higher educational status reported a higher number of sex partners.

However, the consumption of marihuana was strongly associated with HPV-associated tumors. Patients with more than 10 pack-years of tobacco consumption had a higher number of sex partners than patients without or only low nicotine abuse.

The causal reason for the increase of HPV associated carcinomas in the oropharynx still cannot be answered with certainty. In our own cohort of patients who were treated in Giessen between andno significant age difference could be detected in OSCC patients depending on the HPV status Table 1. Often a higher socio-demographic as well as socio-economic status higher education level, higher profession position as well as income is found in comparison to patients with HPV-negative OSCC It is assumed that this is due to a higher transmission rate of HPV infections during orogenital sexand the higher nicotine abuse of males predisposes them for infection First symptoms that occur in patients with OSCC include sore throat, odynophagia, or globus sensation.

In the further course, dysphagia or cervical swelling may be observed. This is mainly due to the already advanced N stage with low T stage. In the context of HPV association, the primary tumor is often located at the tonsil or the base of the tongue whereas other locations of the oropharynx are rarely affected. While smoking and alcohol abuse are the classic risk factors for head and neck cancer, there are important geographic differences with regard to the incidence of nicotine abuse.

A significant decrease could be observed between and in Northern Europe as well as North America In cases of HPV OSCC, nicotine abuse seems to have a negative impact on the survival whereas alcohol seems to play only a secondary role This improved therapy outcome is most likely associated with the improved locoregional control, among others by increased radiation sensitivity see chapter 6.

The good prognosis of those patients increases the number of patients in follow-up examinations and the duration of follow-up is longer so that therapy-associated long-term complications such as dysphagia, xerostomia, or dysgeusia are in the focus. Furthermore, the implementation of a sufficient tertiary prophylaxis in those patients with long-term survival might be important in order to early detect recurrences or distant metastases even in the long-term follow-up see chapter 7. It is worth mentioning that a clear and valid procedure for the diagnosis of HPV-induced head and neck carcinoma does not exist.

In single cases, even after performing extensive laboratory examinations, it is not evident if a tumor is HPV induced or not. Probably, it can be assumed that the triggering factors of carcinogenesis coincide in many cases of OSCC. For clear definition of the HPV status in head and neck cancer, the presence of HPV as well as the detection of oncogenic activity in tissue specimens is required. The test results are then applicable as prognostic markers for patient counseling and also for planning future therapies.

Testing of both preconditions, however, may also provide false-positive or false-negative results because of technical and biological reasons. So the misinterpretation of a test may have substantial consequences for the patients. Up to now, prospective studies are not available that justify concrete adaption of the therapy based on the HPV status, although a recent study from the USA reveals that already more than half of the physicians choose treatment strategies based on HPV tests The high sensitivity of PCR-based procedures bears the disadvantage of contamination, for example due to parallel HPV infections.

The natural instability of mRNA leads to a high specificity because free mRNA can practically be excluded as basis of contamination, Gewichtsverlust Magnete dienen Spanisch hereby also the sensitivity is lower. Furthermore, the examination of specimens for mRNA is more complex, unfixed tissue is needed in most cases and the detection of mRNA transcripts does not necessarily correlate with a protein expression of viral oncoproteins or their biological activity.

The relevant characteristic of HPV-associated carcinogenesis is the virus-oncoprotein-caused dysregulation of the cell cycle via the Rb signaling pathway and the inhibition of apoptosis by inactivation of p53 see chapter 3. Also in HPV-negative tumors, inactivation of p53 occurs, however, generally due to mutations in TP53which may become obvious immunohistologically by detection of overexpressed but inactivated p In HPV-associated carcinomas, p53 is missing and the tumor suppressor protein p16 is overexpressed due to viral oncoprotein activity Fig.

Because of a moderate specificity, the p16 test alone is only partially sufficient for determination of the HPV status. In combination with a detection of viral nucleic acids, the sensitivity and specificity can be increased significantly Fig. The combination of p16 test with HPV DNA tests is acknowledged to be the most practicable test combination for the clinical use Immunohistochemical proof of p16INK4A protein expression in single cells of healthy squamous epithelium top left.

The examination of saliva was also evaluated regarding HPV association. This method is easy, inexpensive, and might be applicable for prophylaxis, therapy monitoring, and follow-up.

First articles on this topic were already published more than 20 years ago; a good correlation of PCR test results from saliva oral rinses and tumor biopsies of patients could be elaborated In the context of local tumor recurrences, it could be shown exemplarily that the detection of HPV material is possible The results, however, are naturally falsified by frequent oral HPV infections.

Also the detection of oncogenic active HPV infections could not be successfully performed. The antibodies directed against the oncoproteins of HPV probably do not develop during infection but only years later during malignant transformation.

A positive antibody test cannot be assigned to a certain lesion, neither under a time nor a spatial aspect, so the diagnostic benefit for the determination of the HPV status is rather low. However, excellent applications are possible for early detection. As a limitation, however, it must be mentioned that the test procedures are not generally available. Tumor endoscopy is mainly used for painless histology gaining as well as estimation of the tumor size in order to determine the resectability of the tumor and possible reconstructive procedures.

Furthermore, in the context of tumor endoscopy the presence of a secondary carcinoma shall be excluded, this mainly applies for patients with noxae abuse. However, the performance of tumor endoscopy or panendoscopy or triple endoscopy is critically discussed for all head and neck tumors.

So there is nearly no international consensus regarding the significance and technique. Based on the further development of imaging procedures, the risk of rigid endoscopy, and unclear incidence of second primaries, it is increasingly negatively discussed The significance of tumor endoscopy in the context of HPV OSCC can be questioned most critically because those patients often do not have a positive history of noxae abuse that might lead to secondary carcinoma So the value of endoscopy is rather low regarding the question of secondary carcinoma in those cases.

In Germany, the performance of tumor endoscopy with rigid instruments is still widespread As long as there is no reliable evidence, endoscopy may be performed in the current standardized way, however, for HPV OSCC also system oriented biopsy under general or local anesthesia can be performed without any concern.

For example, ultrasound of the neck is performed for imaging of regional tumor disease. Those procedures are used for morphological description of head and neck tumors. In comparison, positron emission tomography PET in combination with CT scan is a hybrid procedure that shows a functional image of the metabolic situation in the affected tissue. Hereby the radioactive isotope 18 F of fluorine is the nuclide that is mostly used in PET and can be combined with several pharmaceutics. Thus, the tumor stage of the patient on the left is lower in comparison to the patient on the right.

But functional imaging is not only applied in the context of staging procedures, it serves also as therapy monitoring. It might also be possible to reduce the irradiation dose in cases of positive treatment response Furthermore, the functional imaging has become essential for follow-up. Hereby it became obvious that 18 F-FDG PET-CT as diagnostic tool for detection of regional residues was not inferior to a standard arm with post-therapeutic salvage neck dissection, which is due to the high sensitivity of this test procedure.

In addition, complications and expenses could be reduced by imaging A new option of imaging are radiomics procedures. Hereby image features are quantified by computer assistance, clusters are created and then compared with imaging databases in order to draw conclusions regarding tissue properties, diagnosis, and courses of the disease. For example, such a computer-assisted prediction of the HPV status is relatively reliable based on a CT dataset Radiomics signatures were applied successfully as prognosticators for example in breast cancer patients, but also in lung and head and neck cancer By combining the radiomics signature and the p16 test, the prognostic selectivity between 2 groups of head and neck cancer patients could be improved In the future, radiomics datasets might be included in prognostic models.

In particular regarding the nodal status, it was demonstrated several times that there is no significant influence on the prognosis of the patients based on former TNM rules Only with regard to advanced T stages, a selectivity for the prognosis based on former TNM rules was reported HPV-negative OSCC are classified as hypopharyngeal carcinomas and described in an own chapter of the cancer staging manual.

In this multicenter cohort study, 2, patients with known HPV status were included. The proposals of the authors were implemented unchanged in the 8 th edition for patients treated without surgery.

Since the applicability is not confirmed for patients who underwent tumor surgery, modified criteria were suggested for those patients. For this purpose, retrospectively assessed results of a surgically treated cohort of American patients were included for whom the presence of 5 or more lymph node metastases was associated with a high risk of tumor recurrence Up to now, ECS was considered as indicator for poor prognosis and had a decisive impact on the therapy So the extranodal growth is an indication for adjuvant platinum application during postoperative RT In addition, the factor ECS is assessed with high interobserver variance The prospective verification of this assumption is urgently needed because this question is often discussed in tumor boards.

The group of authors decided for this classification because the detection of HPV association is based on a combination of test procedures that are complex and not always clear. In contrast, the p16 test is simple, inexpensive, and widespread. Numerous studies could further reveal the significance of the p16 test for the prognosis of OSCC patients 8 The naturally existing problems of the test procedure high subjectivity regarding the evaluation, biology-related variable p16 expression in numerous cases often do not lead to clear test results.

According to the authors, patients with negative p16 test should be classified in the same way as HPV-negative and hypopharyngeal carcinomas in the Cancer Staging Manual. In our own cohort, we could analyze the prognosis of the patients in that way that a positive result could be shown only for patients with double positive testing Fig. Differences of this category only exist regarding T4. N category: With the 8 th edition, the most important actualization is introduced with regard to the nodal status of ppositive OSCC.

The differences between the c category and the p category of affected cervical nodes must be considered. The clinical classification of the nodal status of ppositive OSCC cN is now significantly simplified. A unilateral affection is called cN1, bilateral or contralateral affection is classified as cN2. After surgery of the cervical lymph nodes pN only the categories of pN1 and pN2 are included. The limit value is the affection of 4 cervical lymph nodes.

If 5 or more cervical lymph node metastases are found, a pN2 status is classified. Neither the size nor the presence of ECS are considered in the classification. For the N category, the difference is made between clinical and pathological status and the factor of ECS is considered as an upgrading into the next higher category Table 3.

ECS is defined as skin invasion, infiltration of the muscles, nerves, or bones in cN and should only then be applied. The same TNM rules are applicable for squamous cell carcinomas of the hypopharynx. In clinical staging, ECS becomes the new category of cN3b. In the context of pathology-based staging, the factor of ECS leads to upgrading.

A difference is also made regarding ppositive and pnegative OSCC. It is particular that now advanced lymphogenic metastasis is categorized as N1 e. Only distant metastasis justifies the tumor stage IV. Currently, the revised TNM rules have already been verified in several cohorts and described as valuable or improvements were suggested Table 4 Groups of tumor stages in oropharyngeal cancer, 8 th edition. In summary, the development of the staging system for HPV OSCC corresponds to the high significance of this disease and leads to an improved selectivity of prognostic groups.

However, in the future, probably further revisions of the current edition will be required. Molecular signatures and properties comorbidity or habits nicotine abuse of the patients may play a more important role for the estimation of the prognosis and will probably influence future TNM classifications. Based on the significantly improved prognosis of HPV-associated OSCC regarding recurrence-free survival as well as overall survival, the question must be asked if consequences for therapy strategies can be expected.

Hereby, two different approaches are considered. Since multimodal therapy strategies applied for HPV OSCC are apparently much more effective, the question arises whether parts of these multimodal therapies for HPV OSCC might be de-escalated and whether less intensive therapy may lead to the same outcome.

Second, the question is asked if this applies for all patients or if de-intensification can only be performed in certain subgroups of patients without jeopardizing the outcome. With this background, the implementation of different prognostic models also from retrospective cohorts is extremely important for estimation of the value of predictors and also with regard to different treatment strategies see chapter 8. Beside the approach of de-escalation, the question arises if HPV is a predictive marker of a specific therapy.

Based on retrospective cohorts, there is primarily no hint in this regard because the prognosis of HPV-associated tumors is better after primary radiotherapy as well as after surgical therapy. Own investigations on cell lines could reveal a significantly reduced clonogene survival of HPV-positive tumor cell lines after radiotherapy. Comparable results were also described by several research groups According to a meta-analysis of 30 clinical trials, the improved survival of HPV OSCC patients after radiotherapy alone is confirmed also in the clinical context However, HPV evidence alone is not predictive for primary radiotherapeutic treatment.

Comparative investigations on RCT or primary surgical therapy are not available. A retrospective study of patients provides hints in this regard. The patients have been selected primarily based on the situation if they had phenotypically a HPV-associated tumor, HPV test result were not available Currently clinical de-escalation trials check which additional predictors are suitable for such therapeutic de-escalation beside HPV Table 2.

Nonetheless, the fact that de-escalation has already started in RT, can be seen in publications of several retrospective series. In patients the tumor bed was left out in the adjuvant situation without reduction of the local control Beside de-escalation by performing RT alone, there are also approaches to reduce adjuvant therapy by means of surgical interventions in the primary therapy Table 2. The basic principle is to elaborate histologically confirmed predictors by upfront surgery that allow de-escalation of the adjuvant therapy.

Furthermore, those studies may check if risk factors that have led to the application of simultaneous chemotherapy in the adjuvant situation are justified in HPV-positive tumors see chapter 5.

Currently, clinical studies with surgery are conducted with the following questions: reduction of the adjuvant radiotherapy dose after postoperative determination of risk factors ECOG ; omission of chemotherapy in cases of postoperative radiation ADEPT ; comparison of no adjuvant radiotherapy vs.

In this context, 2 studies are funded by the German Cancer Aid Deutsche Krebshilfe that compare prospectively primary surgery of oropharyngeal cancer with primary RT. Not only HPV-associated tumors are included in those trials but the HPV status is determined and subgroup analyses are possible.

The decision to perform primary surgery followed by risk-adapted adjuvant therapy or primary non-surgical intervention depends rather on the local or regional particularities and guidelines.

Recently, a review article about a histopathological marker was published. Hereby, in particular an advanced T stage could be identified as risk factor for failed tumor control As an example, the cystic degenerated metastasis is mentioned, hereby poor local control rates after therapy without surgery are described This fact was first described in the convincing Ang study This survival benefit was found also in the adjuvant setting with RCTand after induction chemotherapy the response is better as well However, compared to the descriptions above, we actually do not know if HPV positivity is a predictor for chemotherapy application, i.

For the combined treatment with Nimorazole and radiotherapy, it could be shown for example that in the context of HPV OSCC neither patients with hypoxic nor less hypoxic tumors have a better survival whereas HPV-negative hypoxic tumors had an advantage Invasive growth correlated with losses occurring together on chromosomes 3p and 5q and lymphogenic metastasis with loss on 4p For the latter ones, also gains on chromosomes 10p and 11p as well as losses on 4q, 9p, and 14q were described that were not present in respective primary tumors Interestingly, in the mentioned areas, genes are found that are involved in cell adhesion as well as factors of the MAP mitogen-activated protein kinase and PI3K phosphoinositidekinase signaling pathway that are also frequently affected by mutations.

Amplifications that are often described for head and neck cancer, are found on the chromosomes 3q- 8q- and 20p, independent from the HPV status 47 48 50 However, 3q amplification was described in the context of the integration of the HPV genome in cervix cancer Generally, an increased chromosomal instability in head and neck cancer seems to be associated with inferior prognosis, which could also be demonstrated in HPV OSCC Even if nearly the same, but differently dysregulated signaling pathways may be crucial for carcinogenesis of HPV OSCC and HPV-negative head and neck cancer, a series of specific genetic aberrations can be defined for both subgroups.

Clearly more rarely, also losses of 3p, 4q, 5q, 18, and 9p are found. On the last one, for example p16 is encoded which allows the interpretation why the p16 expression works as marker in HPV-associated carcinomas 8 59 60 61 HPV-specific aberrations are losses on chromosome 16q that are associated with a better prognosis of the patients 50 56 Interestingly, the tumor suppressor gene WWOX is located on 16q.

Aberrations of FRA16D with dysregulated WWOX expression are known for different tumor types and are associated with a poor prognosis of the patients Data of current sequence analyses show that all 3 possible stages of the HPV genome only episomal or integrated, or a mixture of both occur with nearly the same frequency and probably several mechanisms lead to dysregulated expression of the viral oncoproteins 68including methylation of E2 in the regulator region of E6 and E7 see below.

It could be shown in HPV transfected keratinocytes that viral DNA integration occurs at many positions within the cellular genome, and also in or near important regulator genes of cell proliferation AKR1C3 encodes an enzyme aldo-keto reductase family 1 member C3 of the androgen and estrogen metabolism and is described for prostate cancer in the context of PSA production, however, it is mostly undescribed in HNSCC There seems to be a correlation between chromosomal instability and tumor progression.

In contrast, in the same study, HPV DNA integration was associated with a better prognosis of patients with tonsillar carcinomas The modification of the nucleic acid influences the phenotype and can be transferred to daughter cells. The most important types are methylation of the DNA and modification of histones. Methylation of DNA such as the modification of histones is reversible and its function is to use static information of the nucleic acid sequence in a variable manner.

Different methylation patterns were described in the context of tumor viruses including HPV 71 The most important example of epigenetic gene regulation with regard to HPV is CDKN2A that is located on the chromosome 9p and encodes the tumor suppressor gene p Contrary to earlier assumptions, this overexpression is not due to the E7-related transcriptional activation of p16 by releasing E2F. Moreover, a direct activation of the cellular senescence by expression of E7 was detected.

Thus, the overexpression of p16 does not lead to an inhibitory effect on tumor cells Fig. A relationship of the increasing methylation degree of CDKN2A with increasing grade of dysplasia was observed in the cervix, which in fact does not concern the according promotor region Also in patients with head and neck cancer, a correlation exists between the methylation pattern and the clinical course. The classic explanation model of HPV-associated carcinogenesis is based on an integration of viral DNA into the human genome, which leads to an interruption of the E2 reading frame and an elimination of the inhibition of viral oncoproteins E6 and E7.

Here, the classic explanation model is apparently not satisfactory and a methylation of the E2 binding site in the regulation region for E6 and E7 in the HPV genome was identified as further integration-independent regulatory mechanism for the expression of E6 and E7 79 This relatively simple regulatory mechanism of gene expression is clearly more complex in reality because miRNAs — depending on the conservation grade of their target sequence — may bind to different mRNAs and mRNA may dispose of binding sites for more than one miRNA.

A total of 25 differentially expressed miRNAs could be identified, their functions were elaborated in silico in the context of the PI3K and Wnt signaling pathways, the regulation of the cytoskeleton, and the focal adhesion Hereby, epithelial cells remain proliferative and in an undifferentiated stage which is required for the natural lifecycle of HPV.

In HPVpositive cell cultures, both inhibit growth and induce apoptosis 89which demonstrates the complex regulatory possibilities by means of miRNAs. Tumor hypoxia was described as being important for the survival and therapy response of head and neck cancer 90 91 It is well-known that patients with tumor hypoxia respond poorly to irradiation because of the reduced presence of reactive oxygen species ROS.

During the tumor growth, also a tumor-specific metabolism develops in order to assure the supply and the proliferation of the cells. The decomposition of glucose to lactate, however, only provides 2 Mol ATP per Mol of glucose, which is compensated by an increased glucose rate 93 94 Beside energy, this adapted glucose metabolism of the tumor serves for providing important basic building blocks e.

Hypoxia occurs frequently in many solid tumors and arises because tumor cells proliferate rapidly,exceeding a critical mass which leads to obstruction and compression of the blood vessels in the direct neighborhood of the tumor. This finally results in poor oxygen supply of the tumor centers so that the tumor cells adapt to this oxygen deprivation and several signaling pathways are switched on in order to secure cell survival and to change the glucose metabolism from efficient oxidative phosphorylation to inefficient glycolytic metabolism HIF-1 activates a series of target genes that secure cell survival, serve for the modification of the metabolism, and promote invasion, cell proliferation, metastasis, erythropoiesis, and angiogenesis 97 98 Frequently, in solid tumors an activation of the hypoxia signaling pathway is found that is obvious due to the central expression of respective marker proteins here: Glut I in tumor nests and that can be confirmed by immunohistochemistry hypoxia-related.

Some tumors, however, show a consistently high expression of the same marker that suggest other activation mechanisms of the signaling pathway endogen-related. In analogy to fig. This metabolic phenotype allows tumor cells to proliferate despite adverse circumstances like oxygen deprivation Hence, the signaling pathways that are used for modification of the metabolism and their regulators such as e.

During the development of invasive, HPV-associated squamous cell carcinoma, several lines of defense mechanisms have to be overcome. After absorption of viral particles, those have to traverse the cell and reach the nucleus. In the following persisting infection, the HPV oncoproteins E5, E6, and E7 have important functions to remain undetected by the immune system as long as possible and to maintain the production of new viruses in the epithelial cells.

To a high percentage, HPV infections heal by themselves, and only in a small part, cancer develops. In such cases, further modifications have to take place that enable infected cells to overcome the physical barrier of the basement membrane and to be resistant against the continuous attacks of the immune system. In the context of viral reproduction and evolution, this last step of carcinogenesis has a dead end, because due to the missing differentiation of the epithelial cells, virus particles can neither be produced nor transmitted to the outside.

HPV-associated tumors, as well as HPV-negative tumors, are in a steady-state with the immune system and when the disease is diagnosed, this equilibrium has already been shifted to the benefit of the tumor, and growth is observed that cannot be controlled by the immune system. The understanding of the immune escape mechanisms can be used to restore the equilibrium or to shift it to the benefit of the immune system.

A physical immune escape mechanism of HPV consists in operating its complete lifecycle within the epithelial cells and not releasing virus particles into blood or tissue. Thus, HPV antigens are barely exposed to the immune system and antibody titers are not high enough during natural HPV infection to have a protective effect Nonetheless, apparently T cell response is required for regression of an infection because it correlates with the presence of granzyme B positive cytotoxic T cells in the context of cervix premalignancies The oncoproteins E5, E6, and E7 have an effect on many cellular mechanisms, among others they suppress signaling pathways that are necessary for the recognition of virus-infected cells by the immune system.

Furthermore, E7 modulates the methylation and acetylation of histones, which lead among others to the reduction of the TLR9 toll-like receptor 9 expression and transcriptional activity of IRF1.

IRF1 response elements are found in promotors of a series of genes such as TAP1 transporter associated with antigen processing 1which plays a role in antigen charging of HLA-I in the endoplasmatic reticulum For the E5 protein, an interaction with the heavy chain of HLA-A and -B could be detected, which leads to retention of the HLA-I complex in the Golgi apparatus and in the endoplasmatic reticulum The viral capsid protein L2 seems to block the maturation and antigen presentation of DC and LC by disturbing the intracellular transportation and processing of virus particles after integration of DC and LC Whole genome gene expression analysis are generally based on a comparative hybridization microarrays or sequencing of mRNA.

The capacity of microarrays as well as the sequencing techniques have continuously improved over time, which leads to an increasing coverage of the genome, but also to limited comparability of former and current data. In one of the first gene expression studies of head and neck cancer, 60 differentially expressed genes were identified from 1, examined tumor-associated genes on a cDNA microarray.

They correlated with the radioresistance or the response to radiotherapy Already 3 years later, 60 head and neck tumors were examined on a cDNA microarray with probes against 12, human genes. In this study, 4 subtypes could be identified based on the gene expression.

Signatures were found with a focus in the EGFR signaling pathway, a mesenchymal subtype, a subtype with expression pattern of normal epithelium, and a subtype with enhanced antioxydase enzymes However, in all early studies, no attention was paid to the HPV status of the samples. An enhancement of HPV associated specimens was observed in the group of atypical gene expression e. By means of another platform Illumina Expression BeadChips also 4 subtypes were identified.

However, only the classic expression type was confirmed as being comparable to the above-mentioned studywhich is probably due to technical differences or the heterogeneity of the specimens. Afterwards, the data were summarized with already published data to a cohort of more than patients. In this trial, 5 subtypes were identified that included 2 groups of HPV-associated and 3 groups of HPV-negative head and neck tumors.

The transmission of HPV occurs mainly via skin contact or contaminated objects. Afterwards, infection of epithelial cells may develop with extremely high host specificity.

Je nachdem, welche Musik ich mir dazu auflege, umso schneller kann ich mich dazu bewegen und kreisende Bewegungen machen, wie es mir gefällt.

HPV infects undifferentiated cells directly above the basement membrane through microwounds or in very thin epithelia. While the infected cells remain close to the basement membrane, the viral DNA replication is reduced. This is due to the fact that the viral development processes are coupled with the differentiation processes of the infected cells while they move up to the epithelial surface.

Another transmission pathway is the perivaginal transmission during birth which may induce the development of laryngeal papillomatosis in infants and toddlers For the HPV-associated OSCC, the sexual transmission pathway with the high-risk papillomaviruses 16 and Das Beste is in the focus of discussion. The severely increasing incidence in the last decades is mainly explained by changed sexual behavior, younger age at first sexual contact as well as the increased practice of oral sex Even if the genital-genital transmission of HPV infection seems to be predominant, also other transmission pathways such as anal-genital, oral-genital, manual-genital contact, the use of sex toys as well as autoinoculation are possible Furthermore, oral sex with frequently changing partners, casual sex as well as rare use of condoms were reported.

Frequently, in solid tumors an activation of the hypoxia signaling pathway is found that is obvious due to the central expression of respective marker proteins here: Glut I in tumor nests and that can be confirmed by immunohistochemistry hypoxia-related.

After performing gender stratification, the changed sexual behavior could be confirmed mainly in men For new life partners, there seems to be the risk of transmission. But the data up to now do not allow valid conclusions. However, the consumption of marihuana was strongly associated with HPV-associated tumors. Patients with more than 10 pack-years of tobacco consumption had a higher number of sex partners than patients without or only low nicotine abuse.

There was no evidence for multiplicative effects for HPV OSCC between nicotine and alcohol, marihuana and nicotine, or marihuana and alcohol However, it must be questioned in which way and actually if it has really changed over the years. The causal reason for the increase of HPV associated carcinomas in the oropharynx still cannot be answered with certainty.

In our own cohort of patients who were treated in Giessen between andno significant age difference could be detected in OSCC patients depending on the HPV status Table 1.

Often a higher socio-demographic as well as socio-economic status higher education level, higher profession position as well as income is found in comparison to patients with HPV-negative OSCC It is assumed that this is due to a higher transmission rate of HPV infections during orogenital sexand the higher nicotine abuse of males predisposes them for infection First symptoms that occur in patients with OSCC include sore throat, odynophagia, or globus sensation.

While smoking and alcohol abuse are the classic risk factors for head and neck cancer, there are important geographic differences with regard to the incidence of nicotine abuse. A significant decrease could be observed between and in Northern Europe as well as North America In cases of HPV OSCC, nicotine abuse seems to have a negative impact on the survival whereas alcohol seems to play only a secondary role This improved therapy outcome is most likely associated with the improved locoregional control, among others by increased radiation sensitivity see chapter 6.

If this is possibly due to missing risk factors such as nicotine or alcohol abuse is unclear because more recent studies report about increased nicotine abuse also in patients with HPV-associated OSCC. The good prognosis of those patients increases the number of patients in follow-up examinations and the duration of follow-up is longer Das Beste that therapy-associated long-term complications such as dysphagia, xerostomia, or dysgeusia are in the focus.

Furthermore, the implementation of a sufficient tertiary prophylaxis in those patients with long-term survival might be important in order to early detect recurrences or distant metastases even in the long-term follow-up see chapter 7.

It is worth mentioning that a clear and valid procedure for the diagnosis of HPV-induced head and neck carcinoma does not exist. In single cases, even after performing extensive laboratory examinations, it is not evident if a tumor is HPV induced or not. Probably, it can be assumed that the triggering factors of carcinogenesis coincide in many cases of OSCC. For clear definition of the HPV status in head and neck cancer, the presence of HPV as well as the detection of oncogenic activity in tissue specimens is required.

The test results are then applicable as prognostic markers for patient counseling and also for planning future therapies. Testing of both preconditions, however, may also provide false-positive or false-negative results because of technical and biological reasons.

So the misinterpretation of a test may have substantial consequences for the patients. Up to now, prospective studies are not available that justify concrete adaption of the therapy based on the HPV status, although a recent study from the USA reveals that already more than half of the physicians choose treatment strategies based on HPV tests The high sensitivity of PCR-based procedures bears Gewichtsverlust Magnete dienen Spanisch disadvantage of contamination, for example due to parallel HPV infections.

The natural instability of mRNA leads to a high specificity because free mRNA can practically be excluded as basis of contamination, but hereby also the sensitivity is lower. Furthermore, the examination of specimens for mRNA is more complex, unfixed tissue is needed in most cases and the detection of mRNA transcripts does not necessarily correlate with a protein expression of viral oncoproteins or their biological activity.

The examination of saliva was also evaluated regarding HPV association. This method is easy, inexpensive, and might be applicable for prophylaxis, therapy monitoring, and follow-up. First articles on this topic were already published more than 20 years ago; a good correlation of PCR test results from saliva oral rinses and tumor biopsies of patients could be elaborated In the context of local tumor recurrences, it could be shown exemplarily that the detection of HPV material is possible The results, Das Beste, are naturally falsified by frequent oral HPV infections.

As a limitation, however, it must be mentioned that the test procedures are not generally available. Tumor endoscopy is mainly used for painless histology gaining as well as estimation of the tumor size in order to determine the resectability of the tumor and possible reconstructive procedures.

Furthermore, in the context of tumor endoscopy the presence of a secondary carcinoma shall be excluded, this mainly applies for Gewichtsverlust Magnete dienen Spanisch with noxae abuse.

However, the performance of tumor endoscopy or panendoscopy or triple endoscopy is critically discussed for all head and neck tumors. So there is nearly no international consensus regarding the significance and technique. Based on the further development of imaging procedures, the risk of rigid endoscopy, and unclear incidence of second primaries, it is increasingly negatively discussed The significance of tumor endoscopy in the context of HPV OSCC can be questioned most critically because those patients often do not have a positive history of noxae abuse that might lead to secondary carcinoma So the value of endoscopy is rather low regarding the question of secondary carcinoma in those cases.

Those procedures are used for morphological description of head and neck tumors. In comparison, positron emission tomography PET in combination with CT scan is a hybrid procedure that shows a functional image of the metabolic situation in the affected tissue.

Hereby the radioactive isotope 18 F of fluorine is the nuclide that is mostly used in PET and can be combined with several pharmaceutics. Thus, the tumor stage of the patient on the left is lower in comparison to the patient on the right.

Hereby it became obvious that 18 F-FDG PET-CT as diagnostic tool for detection of regional residues was not inferior to a standard arm with post-therapeutic salvage neck dissection, which is due to the high sensitivity of this test procedure.

For example, such a computer-assisted prediction of the HPV status is relatively reliable based on a CT dataset Radiomics signatures were applied successfully as prognosticators for example in breast cancer patients, but also in lung and head and neck cancer By combining the radiomics signature and the p16 test, the prognostic selectivity between 2 groups of head and neck cancer patients could be improved In the future, radiomics datasets might be included in prognostic models.

The TNM classification of malignant tumors mainly serves as prognosticator. The increasing incidence, different biology of the disease, and the clearly improved prognosis after therapy justify the necessity to consider HPV OSCC as independent tumor entity. The main reason is the fact that the established staging rules only insufficiently reflect the prognosis of the patients. In particular regarding the nodal status, it was demonstrated several times that there is no significant influence on the prognosis of the patients based on former TNM rules Only with regard to advanced T stages, a selectivity for the prognosis based on former TNM rules was reported HPV-negative OSCC are classified as hypopharyngeal carcinomas and described in an own chapter of the cancer staging manual.

In this multicenter cohort study, 2, patients with known HPV status were included. The proposals of the authors were implemented unchanged in the 8 th edition for patients treated without surgery.

Since the applicability is not confirmed for patients who underwent tumor surgery, modified criteria were suggested for those patients. For this purpose, retrospectively assessed results of a surgically treated cohort of American patients were included for whom the presence of 5 or more lymph node metastases was associated with a high risk of tumor recurrence Up to now, ECS was considered as indicator for poor prognosis and had a decisive impact on the therapy Jeden Tag übe ich dreimal mit dem Reifen und kann beste Ergebnisse verzeichnen.

Damit bin ich sehr glücklich. Meinen Körper Straffe ich optimal. So etwas würde ich mir immer wieder bestellen. Vorher hatte ich keine Ahnung, wie gut mir das tut. Ein top Bewegungsgerät. Genau deshalb musste ich ihn haben. Nach der Bestellung habe ich begonnen, dreimal täglich damit zu üben.

Die 1,8 kg sind gar nicht so leicht in Schwung zu bringen, aber es lohnt sich wirklich, ich habe schon viele Erfolge damit erzielt. Der Hula Hoop Reifen ist für mich wie geschaffen. Die Magnete zeigen mir, dass ich es wirklich richtig mache, mein Körper verändert sich auf positive Art und Weise.

Genau danach habe ich gesucht! Ich bin positiv überrascht und wirklich angetan von diesem Produkt. Es hat meine Erwartungen weit gehend übertroffen.

In meinem Wohnzimmer kann ich mir alles gemütlich aufbauen. Das liegt aber nicht an den Magneten, sondern an meinem täglichen intensiven Training. So kreise ich mit meinen Hüften nämlich langsamer, es ist auch anstrengender. Es ist anstrengend, aber danach fühle ich mich gut. Ich denke, dass ich damit sogar länger weitermachen könnte, es ist total mein Ding.

Ich finde es sehr abwechslungsreich mit dem Hula Hoop Reifen zu üben. Durch die speziellen Magnete, die in dem Hula Hoop Reifen verarbeitet sind entsteht ein ganz besonderer Effekt. Es ist zwar ungewöhnlich, aber warum nicht?

Totalprothese – Wikipedia

Einige unserer Hula Hoop Reifen verfügen über integrierte Magnete, sodass Sie in den Genuss von unsichtbaren, aber sehr wohl gesundheitswirksamen Magnetfeldern kommen. In diesem Fall sollten Sie unsere Modelle ohne Massagenoppen entdecken. Man sollte aber mit dem Training nicht übertreiben. Viele übersetzte Beispielsätze mit "tensión de bobinado" – Deutsch-Spanisch Wörterbuch und Ausladung der fertigen Rolle dienen; der Aufwickeldruck wird [ ] Gewichtsverlust, Dickenkontrolle in Linie, automatische Aufwickeleinheit sowohl Magnetventile, aufgerollte Kabeltrommeln, Elektromotoren) erzeugen beim.

Wörterbuch Deutsch-Spanisch momentan noch im Aufbau Diese Methode dient der Bestimmung des pH-Wertes einer Lösung von der Ist zu laufen, der Garzeit, des Gewichtsverlust beim Einfrieren und Garen und der sensorischen mercantil, verfolgen, realizar un estudio, eisenbahn, protocolos de actuación, magnet.

Wer auf sportlichem Wege abnehmen möchte, sollte unsere wirkungsstarken Einige unserer Hula Hoop Reifen verfügen über integrierte Magnete, sodass Sie. Englisch · Französisch · Italienisch · Spanisch Gewichtsverlust & Fettverbrennung;; Festigung des Bauch- Po- und Hüftgewebes;; Schlanke Die 96 im Hoopmania Large Hoop integrierten Magneten schaffen während Ihrer anregenden Hula für die Auswahl des individuell passenden Hoopomania Hula Hoops dienen.

Unter einer Totalprothese (auch Vollprothese, im Volksmund „Gebiss“ oder um Gewicht zu verlieren Zähne“, In Ausnahmefällen kann sie als Grundlage dienen, beispielsweise bei Wenn nach dem Abnehmen der Prothese die Spannung nachlässt, entstehen eine Szene im Gemälde A caza de dientes (spanisch Jagd auf Zähne) fest.

So clinical studies do not provide any direct indication that HPV is predictive for antibody therapy with Cetuximab. Durch eine dichtere Anordnung der magnetischen Massagenoppen ist die erzielte Massagewirkung sogar potenter, ausgeglichener und stimulierender.