[The role of chemoradiotherapy in curative treatment of head and neck cancer]. / Kurative Radiochemotherapie von Kopf-Hals-Tumoren.

Radiotherapy and chemotherapy are integral parts of definitive and adjuvant therapy in the treatment of head and neck squamous cell carcinoma (HNSCC). The outcome of therapy is essentially dependent on selection and dosage of chemotherapeutical substances and on the other hand on the radiotherapeutical setting concerning fractionation, time of therapy and technical aspects. Immunotherapeutical substances have an increasing role in the therapy of HNSCC as well as particle therapy is investigated as part of radiotherapy in actual studies. Further challenges relate to treatment of HPV-induced tumors with regard to their differences in tumor biology and consecutively better prognosis.

Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease.

We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist therapy. These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms.

Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC. METHODS: Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases. RESULTS: ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients' survival as a prognostic signature. CONCLUSIONS: Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.

Social support, negative social exchange, and response to case formulation-based cognitive behavior therapy.

We investigated associations between pretreatment social support, negative social exchange, and slope of weekly symptom change for depression, anxiety, and stress over the course of ideographic, case formulation-based, cognitive behavior therapy. Participants were 74 adults treated in a private practice setting. We used self-report measures to assess social support and negative social exchange at intake and to assess symptoms on a weekly basis. At pretreatment, a higher level of social support was associated with lower levels of depression, and a higher level of negative social exchanges was associated with higher levels of depression and stress. Pretreatment social support was not significantly associated with slope of symptom change. However, a higher level of pretreatment negative social exchanges was associated with steeper slope of change in symptoms of depression and stress during treatment. These findings suggest that the association between pretreatment negative social exchanges and subsequent symptoms may be stronger than that of social support and subsequent symptoms. Additionally, we discuss the possibility that having data on negative social exchanges at the start of treatment may benefit the outcome of ideographic, case formulation-based, cognitive behavior therapy.

High control rates of proton- and carbon-ion-beam treatment with intensity-modulated active raster scanning in 101 patients with skull base chondrosarcoma at the Heidelberg Ion Beam Therapy Center.

BACKGROUND: The current study compares the results of irradiation with protons and irradiation with carbon ions via a raster scan technique in patients with G1 and G2 skull base chondrosarcomas. METHODS: Between 2009 and 2014, a total of 101 patients (40 men and 61 women) with a median age of 44 years (range, 19-77 years) were irradiated with carbon ions (79 patients) or protons (22 patients) via a raster scan technique at the Heidelberg Ion Beam Therapy Center. The median total dose was 60 Gy (relative biological effectiveness [RBE]) at 3 Gy per fraction for carbon ions and 70 Gy (RBE) at 2 Gy per fraction for protons. The median boost planning target volume was 38 cm3 (range, 8-133 cm3 ). Overall survival (OS) and local control (LC) were evaluated with the Kaplan-Meier method. RESULTS: The median follow-up period was 40 months (range, 0.8-78.1 months). At the start of the irradiation, all patients had residual macroscopic tumors. Five patients (5%) developed a local recurrence during the follow-up. The 1-, 2-, and 4-year LC rates were 100%, 100%, and 100%, respectively, for protons and 98.6%, 97.2%, and 90.5%, respectively, for carbon ions. The OS rates during the same periods of time were 100%, 100%, and 100%, respectively, for protons and 100%, 98.5%, and 92.9%, respectively, for carbon ions. An age ≤ 44 years was associated with a trend for a better outcome. No toxicity worse than Common Toxicity Criteria grade 3 was observed after treatment. CONCLUSIONS: No significant difference between carbon ions and protons in the therapy of skull base chondrosarcoma could be detected in these initial retrospective results. Cancer 2018;124:2036-44. © 2018 American Cancer Society.

Radiosensibilisierung durch BRAF Inhibitoren.

HINTERGRUND: In der letzten Zeit wurden in der Literatur vermehrt erhöhte Hauttoxizitäten während einer Kombinationstherapie mit BRAF Inhibitoren und Radiotherapie beschrieben. MATERIAL UND METHODIK: Wir berichten über sieben Melanompatienten in einem nicht resezierbaren Stadium III oder IV, die eine kombinierte Behandlung aus Bestrahlung und BRAF-Inhibitor erhielten. ERGEBNISSE: Bei allen Patienten konnte durch die Kombinationstherapie ein gutes lokales Ansprechen erreicht werden. Nur bei zwei Patienten wurde eine schwere Radiodermatitis (CTCAE Grad 3 bzw. 4) beobachtet. Bei diesen Patienten, die beide Vemurafenib erhielten, trat die Radiodermatitis nach ein bzw. zwei Wochen auf und resultierte in einer Unterbrechung der BRAF-Inhibitor Behandlung.. Die kumulative Dosis bis zum Zeitpunkt der Strahlendermatitis betrug 10 Gy bzw. 35 Gy. Bei allen anderen Vemurafenibpatienten konnten nur milde Reaktionen im Sinne einer Radiodermatitis CTCAE Grad 2, beim Dabrafenibpatienten CTCAE Grade 1 diagnostiziert werden. Bei einem Patienten wurde eine Recalldermatitis nach 14 Tagen einer beendeten Strahlentherapie mit einer kumulativen Dosis von 30 Gy diagnostiziert. SCHLUSSFOLGERUNGEN: Schwere Toxizitätsreaktionen der Haut unter einer BRAF-Inhibitionen treten nicht häufig auf und sind meistens gut therapierbar. Deshalb sollte die Kombinationstherapie bei aggressiv wachsenden Melanomen eine Therapieoption bleiben. Obwohl ein erhöhtes Risiko der Hauttoxizität unter einer Kombinationstherapie von Radiatio und BRAF-Inhibitoren besteht, wird diese von den meisten Patienten gut toleriert. Sequenzielle Therapie anstelle von gleichzeitiger Behandlung scheint die Toxizitätreaktionen nicht zu verhindern.

Radiosensitization by BRAF inhibitors.

BACKGROUND: Increased skin toxicity during combination therapy with a BRAF inhibitor and radiation therapy has recently been reported. MATERIAL AND METHODS: We present seven melanoma patients with non-resectable stage III or IV disease and concomitant treatment with a BRAF inhibitor and radiation therapy. RESULTS: In all patients, combination therapy yielded a good local response. Only two patients, both on vemurafenib, showed severe radiation dermatitis (CTCAE grade 3/4) after one and two weeks, respectively, resulting in interruption of BRAF inhibitor treatment. The respective cumulative radiation dose was 10 Gy and 35 Gy. The remaining vemurafenib patients displayed only mild radiation dermatitis CTCAE grade 2; the only dabrafenib patient CTCAE grade 1. In one patient, recall dermatitis was diagnosed 14 days after completion of radiation therapy with a cumulative dose of 30 Gy. CONCLUSIONS: Severe skin toxicity caused by BRAF inhibitor-induced radiosensitization is not common and usually amenable to treatment. Thus, combination treatment should remain a therapeutic option, especially in melanoma patients characterized by aggressive tumor growth. Although there is an increased risk of skin toxicity during combination therapy, it is usually well tolerated by most patients. Sequential - instead of simultaneous - treatment does not seem to prevent such toxicity reactions.

Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival.

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.

Carbon ion beam treatment in patients with primary and recurrent sacrococcygeal chordoma.

PURPOSE: The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity-modulated radiation treatment (IMRT), in patients with sacral chordoma. MATERIALS AND METHODS: Between 2009 and 2012, 56 patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33 patients and in S3 or below in 23 patients. In all, 41 patients received radiation therapy for the primary tumor, while 15 patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan-Meier method. RESULTS: A total of 23 patients were irradiated with carbon ions in combination with photon IMRT, while 33 received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244 ml (range 5-1188 ml). The median total dose was 66 Gy (range 60-74 Gy; RBE). After a median follow-up time of 25 months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time. CONCLUSION: High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy.

Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results.

BACKGROUND: The current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas. METHODS: Between 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires. RESULTS: The median follow-up was 72 months (range, 12 months-165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5-year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age <48 years and a boost volume >75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment. CONCLUSIONS: Carbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates.

High control rate in patients with chondrosarcoma of the skull base after carbon ion therapy: first report of long-term results.

BACKGROUND: The current study was performed to evaluate the safety and effectiveness of irradiation with carbon ions using raster scanning as well as prognostic factors in patients with skull base chondrosarcomas. METHODS: Between 1998 and 2008, 79 patients with chondrosarcoma of the skull base were treated using carbon ions in raster scanning. The applied median total dose was 60 gray equivalent (GyE) at 3 GyE per fraction. Local control and overall survival (OS) were evaluated using the Kaplan-Meier method. Long-term toxicity was quantitatively assessed using questionnaires. RESULTS: The median follow-up after irradiation was 91 months (range, 3 months-175 months). Within the follow-up, 10 patients developed local disease recurrence. The 3-year, 5-year, and 10-year local control rates were 95.9%, 88%, and 88%, respectively; the corresponding OS rates were 96.1%, 96.1%, and 78.9%, respectively. With a median follow-up of 110 months after first diagnosis, the corresponding 3-year, 5-year, and 10-year OS rates were 97.5%, 97.5%, and 91.5%, respectively. Age ≤ 45 years and boost volume ≤ 55 mL were associated with significantly better local control rates. We observed a clinically relevant improvement in cranial nerve deficits 7 to 10 years after treatment (range, 45.5%-53.3%) compared with the baseline (73.4%). During follow-up, none of the patients in the current study developed a secondary malignancy. CONCLUSIONS: Carbon ion therapy is a safe and effective treatment in patients with chondrosarcoma of the skull base. For further evaluation, a prospective randomized phase 3 trial comparing protons versus carbon ions has been recruiting patients with low-grade and intermediate-grade chondrosarcoma of the skull base since 2009.

Active raster scanning with carbon ions: reirradiation in patients with recurrent skull base chordomas and chondrosarcomas.

PURPOSE: To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma. PATIENTS AND METHODS: Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan-Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03). RESULTS: The treatment could be finished in all patients without interruption. In 80% of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3%. A PTV volume of < 100 ml or a total dose of > 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12% of patients had tympanic effusion with mild hypacusis (grade 2), while 20% developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis. CONCLUSION: Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base.

Long-Term Maintenance of Viable Human Endometrial Epithelial Cells to Analyze Estrogen and Progestin Effects.

There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell-cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies.

Functional improvements of patients admitted to an inpatient rehabilitation facility after bilateral lung transplant due to severe COVID-19 pulmonary disease.

BACKGROUND: Coronavirus disease (COVID-19) has introduced a new subset of patients with acute end-stage lung damage for which lung transplantation has been successfully performed. OBJECTIVE: To describe the inpatient rehabilitation course of patients who underwent bilateral lung transplant due to severe COVID-19 pulmonary disease. DESIGN: Retrospective chart review. SETTING: Free-standing, academic, urban inpatient rehabilitation hospital. PARTICIPANTS: Seventeen patients aged 28-67 years old (mean 53.9 ± 10.7) who developed COVID-19 respiratory failure and underwent bilateral lung transplant. INTERVENTIONS: Patients participated in a comprehensive inpatient rehabilitation program including physical, occupational, and speech therapy tailored to the unique functional needs of each individual. MAIN OUTCOME MEASURES: Primary outcome measures of functional improvements, include mobility and self-care scores on section GG of the Functional Abilities and Goals of the Improving Post-Acute Care Transformation Act, as defined as quality measures by the Centers for Medicare and Medicaid Services. Other functional measures included 6 minute walk test, Berg balance scale, Mann Assessment of Swallowing Ability (MASA), and Cognition and Memory Functional Independence Measure (FIM) scores. Wilcoxon signed rank sum test was used to evaluate statistical significance of change between admission and discharge scores. RESULTS: Fourteen patients completed inpatient rehabilitation. Self-care (GG0130) mean score improved from 20.9 to 36.1. Mobility (GG0170) mean score improved from 30.7 to 70.7. Mean 6-minute walk distance improved from 174.1 to 467.6 feet. Mean Berg balance scores improved from 18.6/56 to 36.3/56. MASA scores improved from 171.3 to 182.3. All functional measures demonstrated statistically significant improvements with p value ≤ .008, except for cognition and memory FIM scores, which did not show a statistically significant difference. A majority (76%) of patients discharged home. CONCLUSION: This new and unique patient population can successfully participate in a comprehensive inpatient rehabilitation program and achieve functional improvements despite medical complications.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT-SNT Prospective Phase 2 Trial.

PURPOSE: Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. METHODS AND MATERIALS: Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. RESULTS: Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. CONCLUSIONS: To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

Treatment of squamous cell carcinoma of the mobile tongue or tongue margins: an interdisciplinary challenge.

BACKGROUND: Standard treatment is surgery with stage dependent postoperative radio(chemo)therapy, however, for organ preservation preoperative radio(chemo)therapy is used as an individual approach. The present analysis was performed to access outcome and toxicity of radiotherapeutical treatment of squamous cell carcinoma of the tongue. PATIENTS AND METHODS: Sixty-six patients (median age 55 years) with cancer of the mobile tongue (n=30) or tongue margins (n=36) treated between 1982 and 2006 were retrospectively analyzed. Treatment consisted of definitive- (n=13, median dose 66 Gy), adjuvant- (n=31, median dose 60 Gy) or neoadjuvant radiotherapy (n=22, median dose 40 Gy) and chemotherapy (n=34) or immunotherapy (n=1). RESULTS: After a median follow-up of 29 months the three- and five-year overall survival (OS) rates were 59% and 46%, respectively. The median OS was 54 months. Forty-two patients achieved complete remission whereas 14 patients showed partial remission. The one- and two-year loco-regional progression-free survival (LRPFS) rates were 76% and 58%, respectively. The median LRPFS time was 36 months. In χ(2)-test, T-stage showed a trend towards impact on local recurrence (Pearson, p=0.082). In multivariate analysis, alcohol consumption (p=0.003) and gender (p=0.031) were prognostic. Grade III/IV acute toxicity was seen in 52% of patients. None of the locally controlled patients reported grade IV or higher late toxicity. CONCLUSION: No statistically significant differences between treatment modalities were found, but one should keep in mind that organ preservation plays a major role for quality of life. None of the locally controlled patients reported grade IV or higher late toxicity. However, tumor recurrence is common, especially in advanced tumor stage. Interdisciplinary concepts, further increasing the chance of tumor control are warranted.

Characterization and therapy monitoring of head and neck carcinomas using diffusion-imaging-based intravoxel incoherent motion parameters-preliminary results.

INTRODUCTION: Using the intravoxel incoherent motion (IVIM) model, diffusion-related coefficient (D) and perfusion-related parameter (f) can be measured. Here, we used IVIM imaging to characterize squamous cell carcinomas of head and neck (HNSCC) and evaluated its application in follow-up after nonsurgical organ preserving therapy. METHODS: Twenty-two patients with locally advanced HNSCC (clinical stage III to IVb) were examined before treatment using eight different b values (b = 0, 50, 100, 150, 200, 250, 700, 800 s/mm(2)). All patients were followed for at least 7.5 months after conclusion of therapy. In 16 of these patients, follow-up MRI was available. Using the IVIM approach, f and D were extracted using a bi-exponential fit. For comparison, ADC maps were calculated. RESULTS: The initial values of f before therapy were located between 5.9 % and 12.9 % (mean: 9.4 ± 2.4 %) except for two outliers (f = 17.9 % and 18.2 %). These two patients exclusively displayed poor initial treatment response. Overall, high initial f (13.1 ± 4.1 % vs. 9.1 ± 2.4 %) and ADC (1.17 ± 0.08 × 10(-3) mm(2)/s vs. 0.98 ± 0.19 × 10(-3) mm(2)/s) were associated with poor short term outcome (n = 6) after 7.5 months follow-up. D values before treatment were 0.98 × 10(-3) ± 0.18 mm(2)/s and ADC values were 1.03 × 10(-3) ± 0.18 mm(2)/s. At follow-up, in all primary responders, D (69 ± 52 %), f (65 ± 46 %), and ADC (68 ± 49%) increased. CONCLUSIONS: Our preliminary evaluation indicates that an initial high f may predict poor prognosis in HNSCC. In responders, a significant increase of all IVIM parameters after therapy was demonstrated.

Transmigration of macrophages through primary adult rat Sertoli cells.

The blood testis barrier (BTB) is often studied with isolated immature Sertoli cells (SCs), transepithelial resistance (TER) measurements and FITC dextran diffusion assays. Recently, it was found that even in the absence of SCs, only few immune cells enter the seminiferous tubules. Thus, in this study, we evaluated the testicular immunological barrier (TIB) in vitro by transmigration of macrophages through SCs with and without peritubular cells (PCs) and with or without matrigel (MG). Primary PCs were isolated from adult rat testis and kept in mono- or co-cultures with the conditionally reprogrammed primary adult Sertoli cell line (PASC1) from rat that has been recently generated by our group. Rat monocytes isolated from fresh blood were differentiated into M0 macrophages, and after polarization to M1 or M2 macrophages characterized by gene expression of CXCL11 and TNF-α for M1, or CCL17 and CCL22 for M2. Transmigration of LeukoTracker-labeled M0, M1, and M2 macrophages through mono- and co-cultures of PCs/SCs with and without MG demonstrated that SCs are the main constituent of the TIB in vitro with only a negligible contribution of PCs or MG. Moreover, M2 macrophages showed less migration activity compared to M0 or M1. Treatment of SCs with testosterone (T) showed positive effects on the barrier in contrast to negative effects by interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α). The new transmigration model is suitable to evaluate transmigration of macrophages through a barrier consisting of testicular cells and can be applied to study the integrity of testicular barriers with respect to immunological aspects.

Geriatric Radiation Oncology: What We Know and What Can We Do Better?

Elderly patients represent a growing subgroup of cancer patients for whom the role of radiation therapy is poorly defined. Older patients are still clearly underrepresented in clinical trials, resulting in very limited high-level evidence. Moreover, elderly patients are less likely to receive radiation therapy in similar clinical scenarios compared to younger patients. However, there is no clear evidence for a generally reduced radiation tolerance with increasing age. Modern radiation techniques have clearly reduced acute and late side effects, thus extending the boundaries of the possible regarding treatment intensity in elderly or frail patients. Hypofractionated regimens have further decreased the socioeconomic burden of radiation treatments by reducing the overall treatment time. The current review aims at summarizing the existing data for the use of radiation therapy or chemoradiation in elderly patients focusing on the main cancer types. It provides an overview of treatment tolerability and outcomes with current standard radiation therapy regimens, including possible predictive factors in the elderly population. Strategies for patient selection for standard or tailored radiation therapy approaches based on age, performance score or comorbidity, including the use of prediction tests or geriatric assessments, are discussed. Current and future possibilities for improvements of routine care and creation of high-level evidence in elderly patients receiving radiation therapy are highlighted.