[Diagnosis and Treatment in frontobasal fractures]. / Vorgehen bei frontobasalen Frakturen.

Traumatic brain injury can result in frontobasal fractures (FBF). The goals of treatment for FBF are to eliminate primary morbidity and/or prevent secondary morbidity. Of particular importance in this regard is the proximity of important sensory organs for hearing, vision, smell, and taste, as well as their supplying nervous structures. Medical history, clinical findings, or CT scan are necessary and should lead to an individual evaluation. Depending on the severity of the fractures, the following disciplines may be involved in the treatment of FBF: neurosurgery, plastic surgery, oral and maxillofacial surgery, and/or otorhinolaryngology. Particularly less invasive endoscopic endonasal therapy is a specialty of otorhinolaryngologic surgeons and has not been widely established in other disciplines. The present work provides an overview of the current state of the art in terms of the following aspects, taking into account the current literature: anatomic principles, classification of fractures, diagnostics (in particular clinical examination, imaging, and laboratory chemistry tests), clinical symptoms, and treatment.

[Traumatology of the nose]. / Traumatologie der Nase.

Isolated nasal bone fractures are the most common injuries of the central midface. They can be divided into different fracture types, depending on the exposure and orientation of violence. It is essential to ensure that there is no septal hematoma or abscess, which would require an emergency surgical intervention. A closed reposition can be offered if misalignment of the nose can still be observed after the edema swelling has gone down. In case of insufficient aesthetic and functional results, rhinoplasty/septal reconstruction can be performed 6 to 12 months after the trauma at the earliest. In children the, the decision for repositioning should be taken carefully in order to protect the nasal growing zone.

Infrasound a new weapon in cancer therapy?

BACKGROUND: Researchers take different positions when describing the effects of infrasound on the human body. Although several studies investigated the likely harmful effects of infrasound exposure from wind turbines a significant connection has not been found yet. There is evidence that infrasound interacts with cell metabolism and may disrupt cell membrane integrity. OBJECTIVES: The suggested impairment of the cells' ultrastructure by infrasound leads to the question of whether infrasound can be therapeutically used, for instance in cancer therapy. This review provides the current state of the literature. METHOD: Current literature on infrasound in cancer therapy including all studies with the search terms 'cancer' and 'infrasound' were identified and reviewed until the year 2020. RESULTS: The present state of research reveals promising effects of targeted infrasound in cancer therapy. Infrasound directly affects the tumor cells' ultrastructure and seems to sensitize several types of cancer to chemotherapy, presumably due to membrane permeabilization. The application of infrasound on tumor cells without other therapeutic agents demonstrates different effects that probably depend on the type of cells, the applied frequency and sound pressure level as well as the time of exposure. CONCLUSIONS: The mechanism of infrasound on cancer cells is not completely understood yet, hence, further studies have to be conducted to clarify the ultrastructural and metabolic changes inside the tumor cells. The development of suitable infrasound generators for the application in a clinical setting would be an important course of action.

Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.

BACKGROUND: Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. METHODS: Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. RESULTS: TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. CONCLUSIONS: Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

Influence of travel burden on tumor classification and survival of head and neck cancer patients.

PURPOSE: Cancer patients have to overcome various barriers to obtain diagnostics and treatment at head and neck cancer centers. Travel distance to a specialized hospital may result in psychosocial and financial distress, thus interfering with diagnostics, treatment, and follow-up care. In this study, we have aimed to analyze the association of travel distance with cTNM status, UICC stage at primary diagnosis, and survival outcomes of head and neck cancer (HNC) patients. METHODS: We have analyzed data of 1921 consecutive HNC patients diagnosed between 2014 and 2019 at the head and neck cancer center of the Comprehensive Cancer Center Ulm (CCCU), Germany. Postal code-based travel distance calculation in kilometers, TNM status, and UICC stage were recorded at initial diagnosis. The assembly of travel distance-related groups (short, intermediate, long-distance) has been investigated. Moreover, group-related survival and recurrence analysis have been performed. RESULTS: In contrast to observations from overseas, no association of travel distance and higher cTNM status or UICC stage at primary diagnosis has been observed. Furthermore, no significant differences for recurrence-free survival and overall survival by travel distance were detected. CONCLUSION: In southern Germany, travel distance to head and neck cancer centers seems to be tolerable. Travel burden is not synonymous with travel distance alone but also involves sociodemographic, monetary, and disease-specific aspects as well as accessibility to proper infrastructure of transport and health care system.

[Radicality of maxillary sinus surgery and size of the maxillary sinus ostium]. / Radikalität der Kieferhöhlenoperation und Größe des Kieferhöhlenfensters.

Until the 1990s, radical sinus surgery was considered a standard procedure for maxillary sinus diseases, but it is no longer favored due to the high morbidity. Today, functional endoscopic sinus surgery (FESS) is considered the gold standard in sinus surgery. Modifications of surgical approaches also allow access to regions of the maxillary sinus that were previously difficult to reach. Depending on anatomy and pathology, different methods for widening the maxillary ostium can be selected. In type I sinusotomy, the natural ostium is widened dorsally by a maximum of 1 cm. Sinusotomy type II involves widening the natural ostium up to a maximum diameter of 2 cm. In sinusotomy type III, the natural ostium is widened dorsally to the posterior wall of the maxillary sinus and caudally to the base of the inferior turbinate. Beside the prelacrimal approach, more invasive approaches are the medial maxillectomy, in which the dorsal part of the inferior turbinate and the adjacent medial wall of the maxillary sinus is resected, as well as its modifications "mega antrostomy" and "extended maxillary antrostomy." Correct selection of the size of the maxillary sinus window is prerequisite for successful treatment and long-term postoperative success. Isolated purulent maxillary sinusitis can usually be treated by a type I sinusotomy. Sinusotomy type II addresses nasal polyps with involvement of the mucosa of the ostium, recurrent stenosis after previous surgery, chronic maxillary sinusitis due to cystic fibrosis, and purulent maxillary sinusitis with involvement of other adjacent sinuses. Sinusotomy type III is required for choanal polyps with attachment to the floor of the maxillary sinus, for extensive polyposis and fungal sinusitis, and for inverted papilloma. Particularly for (recurrent) disease and extensive interventions in the maxillary sinus, medial maxillectomy or a modification thereof may be required.

[Exosomes as immune regulators in head and neck cancer]. / Exosomen als Immunregulatoren in Kopf-Hals-Karzinomen.

Exosomes, virus-sized nanovesicles, are utilized as messenger systems of our body to communicate with other body cells and regulate immune functions. Almost all cells produce exosomes and are able to interact with immune cells in the blood stream and peripheral body areas. Different markers on the surface of exosomes are necessary for immune cell adhesion and interaction. Furthermore, many types of exosome-immune cell interaction, such as surface receptor contact and phagocytosis, are known. As carriers of different cargos, exosomes affect different immune cell types in head and neck cancers: So far, T cells, natural killer cells, macrophages, and dendritic cells have been described in this context. For diagnostic purposes, a combined analysis of different parameters including protein amount, nucleic acid/protein expression, and the immunosuppressive impact of exosomes could empower exosomes as useful tools for evaluation of tumor promotion and progression in the future.

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.

INTRODUCTION: The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. METHODS: The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (n = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: n = 13; TIL: n = 17) and elderly cancer patients (70-90 yrs.; blood: n = 20; TIL: n = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4+ and CD8+ T cells as well as regulatory T cells (Treg) were assessed by flow cytometry. RESULTS: We observed lower frequencies of CD8+ cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. CONCLUSION: Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.

Adenosine production in mesenchymal stromal cells in relation to their developmental status.

BACKGROUND: Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status. METHODS: We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry. RESULTS: Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC. CONCLUSION: Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.

Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck.

PURPOSE: Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. METHODS: In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. RESULTS: CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. CONCLUSION: Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs.

Exosomes in HNSCC plasma as surrogate markers of tumour progression and immune competence.

Exosomes in plasma of head and neck squamous cell carcinoma (HNSCC) patients comprise subsets of vesicles derived from various cells. Recently, we separated CD3(+) from CD3(-) exosomes by immune capture. CD3(-) exosomes were largely tumour-derived (CD44v3+ ). Both subsets carried immunosuppressive proteins and inhibited functions of human immune cells. The role of these subsets in immune cell reprogramming by the tumour was investigated by focusing on the adenosine pathway components. Spontaneous adenosine production by CD3(+) or CD3(-) exosomes was measured by mass spectrometry, as was the production of adenosine by CD4+ CD39+ regulatory T cells (Treg ) co-incubated with these exosomes. The highest level of CD39/CD73 ectoenzymes and of adenosine production was found in CD3(-) exosomes in patients with the stages III/IV HNSCCs). Also, the production of 5'-AMP and purines was significantly higher in Treg co-incubated with CD3(-) than CD3(+) exosomes. Consistently, CD26 and adenosine deaminase (ADA) levels were higher in CD3(+) than CD3(-) exosomes. ADA and CD26 levels in CD3(+) exosomes were significantly higher in patients with early (stages I/II) than advanced (stages III/IV) disease. HNSCC patients receiving and responding to photodynamic therapy had increased ADA levels in CD3(+) exosomes with no increase in CD3(-) exosomes. The opposite roles of CD3(+) ADA+ CD26+ and CD3(-) CD44v3+ adenosine-producing exosomes in early versus advanced HNSCC suggest that, like their parent cells, these exosomes serve as surrogates of immune suppression in cancer.

Separation of plasma-derived exosomes into CD3(+) and CD3(-) fractions allows for association of immune cell and tumour cell markers with disease activity in HNSCC patients.

Head and neck squamous cell carcinoma (HNSCC) is a highly immunosuppressive malignancy. Exosomes in HNSCC patients' plasma are enriched in inhibitory cargo and mediate immunosuppression. As these exosomes are products of various cells, the cellular origin of immunoregulatory proteins they carry is unknown. To test whether tumour- or T cell-derived exosomes in patients' plasma are immunosuppressive and impact upon disease activity, we separated CD3(-) from CD3(+) exosomes by immunocapture using anti-CD3 antibodies. The exosome protein cargo was evaluated for immunoregulatory proteins using on-bead flow cytometry. Tumour protein-enriched CD3(-) exosomes were CD44v3(+) . Surprisingly, mean levels of programmed death ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4) and cyclooxygenase-2 (COX-2) were similar in CD3(+) and CD3(-) exosomes, although the latter induced higher (P < 0·0025) ex-vivo apoptosis of CD8(+) T cells and greater (P < 0·005) conversion of CD4+ T cells to CD4(+) CD39(+) regulatory T cells (Treg ). CD3(+) and CD3(-) exosomes carrying high levels of immunosuppressive proteins were highly effective in mediating these functions. Exosomes of patients with Union for International Cancer Control (UICC) stages III/IV disease had higher levels of PD-L1 and COX-2 than stages I/II patients (P < 0·005). Patients with nodal involvement had exosomes with the higher inhibitory protein content than N0 patients (P < 0·03). CD3(+) and CD3(-) exosomes of HNSCC patients had higher PD-L1, COX-2 and CD15s levels than healthy donors' exosomes (P < 0·009), although levels of immunostimulatory OX40 or OX40L were not different. By isolating CD3(-) /CD44v3-enriched and CD3(+) exosomes from plasma, the cellular origins of immunoregulatory proteins they carry were identified. Association of exosome molecular profiles with disease progression supports the exosome potential as future cancer biomarkers.

Synchronous bilateral tonsil carcinoma: case presentation and review of the literature.

BACKGROUND: The incidence of synchronous bilateral tonsil carcinoma seems to be underreported. For adequate oncologic treatment, it is mandatory to remove all primaries to prevent recurrence or metachronic disease. The purpose of this manuscript is to provide a comprehensive review on this topic and to emphasize the need of bilateral tonsillectomy in cases of cancer of unknown primary (CUP) as well as in the case of a unilateral tonsillar carcinoma. MATERIAL AND METHODS: A systematic review of the literature was performed for "bilateral tonsillar neoplasm", "synchronous cancer of the oropharynx" and "cancer of unknown primary in head and neck". RESULTS: We present a clinical case with bilateral tonsillar carcinoma in initially suggested cancer of unknown primary. Clinically, both tonsillar sites were unsuspicious, but in PET/CT an ipsilateral enhancement of the tonsil area was detected. The pathological work up of bilateral tonsillectomy specimens revealed bilateral squamous cell carcinoma with HPV-type 16 positivity. The review of the literature revealed 29 cases of bilateral tonsil cancer. CONCLUSION: The handling of tonsillar tissue in the frame of panendoscopy in the case of CUP is still controversial. We recommend a bilateral tonsillectomy as a routine procedure for cancer of unknown primary as well as unilateral tonsillar carcinoma. Herewith the detrimental consequences of occult metachronous contralateral tonsillar carcinoma can be prevented.

Influence of photodynamic therapy on peripheral immune cell populations and cytokine concentrations in head and neck cancer.

BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment option for a selected group of patients with head and neck squamous cell carcinoma (HNSCC). PDT induces a local inflammatory reaction with the potential to initiate antitumor immune responses. However, the systemic impact on peripheral immune cells has not been described so far. METHODS: HNSCC patients (n=9) were treated with PDT in a palliative setting. All patients had previously undergone several oncologic treatment regimens. Blood samples were taken before, during and after PDT. Age-matched healthy donors served as control group (NC, n=15). The frequency and absolute number of T- and B-lymphocytes, CD4+CD39+ regulatory T-cells (Treg) and NK-cells were measured by 10-color flow cytometry. Serum concentrations of T cell related cytokine panel, including HMGB1, IL-6, IL-10 and perforin were measured by bead array and ELISA. RESULTS: In heavily pretreated HNSCC patients, the number and frequency of Treg and NK-cells were increased as compared to NC. PDT induced a further increase of the frequency of Treg and NK-cells in the peripheral blood. Additionally, the serum concentrations of HMGB1, IL-6 and IL-10 showed a significant elevation after treatment with simultaneously decreased perforin levels. CONCLUSION: Although PDT is a local treatment regimen, a systemic inflammatory response with altered peripheral immune cell populations and cytokine concentrations is visible. The increased Treg and NK cell numbers after PDT support the hypothesis that PDT may successfully be combined with NK cell or T cell activating immune checkpoint modulators in HNSCC patients to improve HNSCC specific immunity.

[Mucosal Melanoma of the Head and Neck]. / Schleimhautmelanome des Kopf-Hals-Bereichs.

Primary mucosal malignant melanoma of the head and neck is a rare tumor entity with poor clinical outcome. Its growth pattern is characterized by an infiltrative and local destructive behavior. So far no risk factors could be identified. There are practically no early symptoms of the disease, as intermitting nose bleeding or nasal obstruction typically occur in advanced stage. The standard of care remains radical tumor resection with adjuvant radiation in cases of close margin resection. Other therapeutic options like the use of interferon, antibodies or conventional chemotherapeutics have not demonstrated significant clinical benefit so far. Current efforts to investigate the biological and genomic characteristics of these tumors have been constrained by its low incidence. In order to better characterize this rare tumor entity and to establish effective novel targeted therapies it will be necessary to establish an interdisciplinary and multicentric task force.

Mental distress and effort to engage an image-guided navigation system in the surgical training of endoscopic sinus surgery: a prospective, randomised clinical trial.

The use of image-guided navigation systems in the training of FESS is discussed controversy. Many experienced sinus surgeons report a better spatial orientation and an improved situational awareness intraoperatively. But many fear that the navigation system could be a disadvantage in the surgical training because of a higher mental demand and a possible loss of surgical skills. This clinical field study investigates mental and physical demands during transnasal surgery with and without the aid of a navigation system at an early stage in FESS training. Thirty-two endonasal sinus surgeries done by eight different trainee surgeons were included. After randomization, one side of each patient was operated by use of a navigation system, the other side without. During the whole surgery, the surgeons were connected to a biofeedback device measuring the heart rate, the heart rate variability, the respiratory frequency and the masticator EMG. Stress situations could be identified by an increase of the heart rate frequency and a decrease of the heart rate variability. The mental workload during a FESS procedure is high compared to the baseline before and after surgery. The mental workload level when using the navigation did not significantly differ from the side without using the navigation. Residents with more than 30 FESS procedures already done, showed a slightly decreased mental workload when using the navigation. An additional workload shift toward the navigation system could not be observed in any surgeon. Remarkable other stressors could be identified during this study: the behavior of the supervisor or the use of the 45° endoscope, other colleagues or students entering the theatre, poor vision due to bleeding and the preoperative waiting when measuring the baseline. The mental load of young surgeons in FESS surgery is tremendous. The application of a navigation system did not cause a higher mental workload or distress. The device showed a positive effort to engage for the trainees with more than 30 FESS procedures done. In this subgroup it even leads to decreased mental workload.

Specific stressors in endonasal skull base surgery with and without navigation.

The goal of modern organizational psychology is to recognize, anticipate and finally avoid stress situations. The aim of this study was to measure objectively the mental and physical demands during transnasal surgery with and without the aid of a navigation system. Forty endonasal surgeries (20 with and 20 without navigation, not blinded and not randomized) done by four different experienced rhinosurgeons (>250 FESS procedures done) were included. The heart rate, the heart rate variability, the respiratory frequency and the masseter tone were monitored as biometrical parameters by the surgeons during the whole surgery for the quantification of mental demand. Stress situations could be identified during the procedures by an increase in the heart rate and a decrease in the heart rate variability. Stress level in procedures with navigation did not significantly differ from procedures without navigation. Interestingly, in 10 % of the cases a navigation system would have been helpful, although the surgeon stated before the procedure that such a system would not be necessary. Other stressors could be identified like time pressure, students or colleagues speaking with the surgeon or chatting in the OR and system failure of medical devices, i.e. navigation, sinus drill, electrocautery or shaver. Surgical stressors blurred vision due to diffuse bleeding and drill out procedures in the sphenoid sinus. Calming situations were a quiet atmosphere in the OR (i.e. closed doors) and the participation of another experienced colleague, especially a neurosurgeon. Stress situations occur when complex medical devices like the navigation do not work. For their proper function it is important that the whole OR-team is trained with it. Unqualified or unmotivated OR personnel create stress for the surgeon and disharmony in the team, which then ends in inadequate behaviour.