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Purpose: Lymphatic fistulas are common complications after vascular surgery, especially in the groin, and can lead to a prolongation of the inpatient stay, wound infections, and follow-up operations. Radiation therapy is one of the nonsurgical treatment options; however, evidence and discussion about the ideal dosage and timing are limited.Methods and Materials: The analysis was performed on patients from a German university hospital and included 191 patients with 206 lymphatic fistulas from 2005 to 2016. Four different endpoints were analyzed. The patients were irradiated with a fraction dose of 3 Gy up to a cumulative dose of 9 Gy (94 cases) or 18 Gy (112 cases). The median age of the patients was 70.5 years; 74% were male and 26% were female. Vascular surgery included bypass grafts (52%), thromboendarterectomy/patch angioplasty (26%), and vascular access for aortic endografts (22%).Results: The response to radiation therapy for the 4 different endpoints was 88% (25% decrease in secretion volume), 80% (secretion <50 mL per 24 hours), 81% (removal of the drainage), and 75% (freedom from any intervention). The overall response for all 4 endpoints was 63% (129 of 206) after completion of radiation therapy and 34% (70 of 206) after 1 course with a total dose up to 9 Gy. The median lymphatic secretion was 150 mL per 24 hours before radiation therapy and 60 mL per 24 hours 1 day after the end of therapy. The drainage could be removed a median of 3 days after radiation therapy completion. There was no significant difference between patients starting the radiation within 5 to 9 days or ≥10 days postoperatively (P = .971; OR, 0.99; 95% confidence interval, 0.56-1.74). No relevant factors influencing the response rate could be identified. Reoperation was required in 50 of the 206 cases (25%): 24 (12%) owing to persistent lymphatic fistula and complications and 26 (13%) owing to wound and/or vascular complications.Conclusions: Radiation therapy seems to be an effective nonsurgical treatment option for reducing lymphatic secretion after vascular surgery in the groin. Starting radiation early (≤9 days) or late (≥10 days) postoperatively did not affect the success rate. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the influence of CD4+, CD8+ and Forkhead box protein 3 (FoxP3+) tumor-infiltrating lymphocytes, as well as CD1a+ tumor-infiltrating dendritic cells on the radiosensitivity and survival of primarily chemoirradiated advanced head and neck squamous cell carcinomas.Study Design: Immunohistochemical staining for CD4, CD8, FoxP3 and CD1a was performed in 82 primarily chemoirradiated head and neck squamous cell carcinomas. Associations with clinicopathologic data, programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), p16, radiation response, and survival were examined.Results: High CD4 expression was associated with complete response after radiation (P = .006) and high CD1a expression (P = .024). High CD8+ tumor-infiltrating lymphocyte counts were associated with absence of tumor relapse (P = .032) and better disease-free survival (P = .051). Strong overall T-cell infiltration was found more often in tumors with high-grade differentiation (P = .004), complete response after radiation (P = .022), and better overall survival and disease-specific survival (each P = .052). Tumors with high FoxP3+ T regulatory (Treg) infiltration more often showed high-grade tumor differentiation (P = .017), advanced patient age (P = .02), high PD-1 (P = .007), high CD4 (P = .002), and high CD8 expression (P = .002), as well as better disease-free survival (P = .019).Conclusions: T-cell activation (high CD4, CD8 and FoxP3 expression) is associated with radio response and favorable survival in advanced head and neck cancer treated with definitive chemoradiation. [ABSTRACT FROM AUTHOR]

Purpose To study implant-based prosthetic rehabilitation of head and neck cancer patients with focus on implant survival and quality of life. Materials and methods The prospective observational study presents preliminary results of 29 edentulous head neck cancer patients (20 patients after radiotherapy) with 165 OsseoSpeed implants. Implant success after 1-year follow-up was evaluated by means of the Albrektsson criteria. Quality of life was analysed with the EORTC QLQ-C30, QLQ-H&N35, and OHIP 14 questionnaires. Results The overall implant survival rate after 1 year was 95.2% (157/165). Implant success measured by the Albrektsson criteria showed a lower success rate of 86.7% (143/165), mainly because of peri-implant marginal bone loss with a mean of 0.8 mm after 1 year. Xerostomia (p = 0.008), implant insertion within the radiation target volume (p = 0.09), implantation in transplanted bone (p = 0.05), and smoking (p = 0.041) were the main reasons for implant failure, followed by D4 bone quality, maxillary implant site, and insufficient primary stability. Speaking, swallowing, eating, as well as social integration and individual self-confidence had considerably improved 1 year after denture placement compared to before treatment. Conclusion Implant-based prosthetic rehabilitation of head and neck cancer patients is possible at a calculable risk and significantly improves patients' quality of life. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to analyse the impact of surgical margins on tumour recurrence and survival of patients with carcinomas of the head and neck.Material and Methods: A cohort of 156 patients with primary squamous cell carcinoma of the head and neck treated by local resection with negative margins and neck dissection between 2004 and 2012 was investigated. Margin status in frozen sections and permanent paraffin tissues were analysed and compared to clinical and histopathological parameters as well as to tumour recurrence (local, regional and distant) and disease-specific survival (DSS).Results: Close margins (<5mm) on permanent sections were correlated to high-grade differentiation (p=0.070), lymphangiosis (p=0.009) and positive neck nodes (p=0.025) implicating regional and distant recurrence (p=0.001) as well as unfavorable DSS (p=0.002). Positive margins on initial frozen section analysis revised into negative margins during further surgery were the strongest predictor for local recurrence in uni- and multivariate analysis (p<0.001, hazard ratio 3.34). However, positive frozen section margins were not significantly predictive for DSS (p=0.150). Significant predictors for DSS in univariate analysis were local recurrence (p=0.026), T-stage (p=0.02), N-stage (p<0.001), grading (p=0.02) and lymphangiosis (p=0.001). Multivariate DSS analysis revealed lymph node metastasis (p=0.005) and local recurrence (p=0.017) as significant negative predictors.Conclusion: Close margins on permanent sections are associated with aggressive tumour characteristics, regional and distant metastasis implicating worse DSS. The accuracy of frozen section analysis seems limited as positive frozen section margins revised into negative margins bear a high risk of local recurrence. [ABSTRACT FROM AUTHOR]

Summary Objectives Induction of apoptosis is a major mechanism of radiosensitivity in different types of cancer. In contrast, EGFR/PI3K/AKT signalling and recently the presence of so-called cancer stem cells are discussed as reasons for radioresistance. Materials and methods The study investigates mechanisms of apoptosis, key oncogenes of the PI3K/AKT pathway and the presence of cancer cells with stem cell properties during irradiation in two cell lines (PCI-9A, and PCI-15) of head and neck squamous cell carcinoma. WST-1-tests, qRT-PCR, western blots and FACS analysis were performed for analysis. Results The two cell lines presented different degrees of cell death upon irradiation. The radiosensitive cell line PCI-9A showed increased apoptosis after irradiation measured by expressed cleaved caspases 3 and 7 while the radioresistant cell line PCI-15 upregulated antiapoptotic Survivin and BCL2A1 mRNA. Besides, increased PI3K/AKT- and ERK1/2-signalling was associated with radioresistance accompanied by loss of PTEN function through phosphorylation on S380. Blockade of pAKT increased radiation-induced cell death, and moreover, led to an upregulation of pMET in the radioresistant cell line. The percentage of ALDH-positive tumour cells was markedly decreased after irradiation in the radiosensitive cell line. Conclusions Functional apoptosis is mandatory for sensitivity to irradiation in head neck cancer cells. Upregulation of the AKT-pathway seems to be one reason for poor radioresponse. Activated MET may also predict radioresistance, possibly through ERK1/2 signalling. Moreover MET may indicate the presence of cancer stem cells facilitating radioresistance as shown by increased ALDH expression. [ABSTRACT FROM AUTHOR]

• Peripheral blood immune parameters predict efficacy of chemoimmunotherapy in HNSCC. • Various differences of immune parameters before and after treatment allowed the best prediction. • Cells of the innate immune system are prominent predictors. • Polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells serve as best predictors. Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC. [ABSTRACT FROM AUTHOR]

Purpose/objective(s) Intensification of radiotherapy and chemotherapy for head-and-neck cancer (HNC) may lead to increased rates of long term dysphagia as a severe side effect. Mucositis and consequent swallowing problems require artificial nutrition in many HNC patients undergoing radiotherapy or chemoradiation. It is unknown, which predict factors for prophylactic PEG tube insertion appear useful. Materials/methods From an institutional database, 101 patients (72 male, 29 female, mean age 59.5 years) were identified who underwent radiotherapy or chemoradiation for HNC. Primary end point of the investigation was the need for artificial nutrition for more than 4 days during radiotherapy. Dose volume parameters of defined normal tissue structures potentially of relevance for swallowing ability as well as clinical factors were used to develop a predictive model using a binary multiple logistic regression model. Results Whereas several dosimetric and clinical factors were significant predictors for the need of artificial nutrition on univariate analysis, on multivariate analysis only three factors remained independently significant: mean dose to the oropharynx + 1 cm circumferential margin, ECOG performance state (0–1 vs. 2–4), and the use of chemotherapy (yes vs. no). Conclusions Using a 3 parameter model we could distinguish HNC-patients with different risks for the need of artificial nutrition during radiotherapy. After independent validation, the model could be helpful to decision on prophylactic PEG tube insertion. [ABSTRACT FROM AUTHOR]

Objective: Are 6 weekly cycles of cis-Platinum (DDP) plus one cycle of 5-FU with concurrent hyperfractionated radiotherapy (HART) superior to 2 cycles of Mitomycin C (MMC) plus one cycle of 5-FU with HART in terms of overall survival (OS), progression-free (PFS) and metastases-free survival (MFS), local (LC), regional (RC) and loco-regional control (LRC)? Methods: Eligibility: Stage IV SCC of the oro- and hypopharynx (OP and HP), KFS of ⩾80% stratified for sites, N-status, grading, haemoglobin and centres. The HART schedule was reported elsewhere (V.Budach, JCO 23; 2005). HART was applied concurrently with DDP/5-FU at 30mg/m2 days 1, 8, 15, 22, 29 and 36 or MMC/5-FU at 10mg/m2 day 1+36 and for both arms with 600mg/m2 5-FU days 1-5 as 120 hrs. continuous infusion. TVD dose prescription was 72 Gy for macroscopic disease, 60 Gy for surrounding nodes of high-risk and 50 Gy of low-risk for microscopic involvement. 3D-conformal or IMRT-TP was used. 364 patients were analysed using the ITT principle. Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 54 mos. for both treatment arms. Mean age was 55.4 years, 83% were males and 17% females. All patients had stage IV at diagnosis (UICC 2002). 58.5% suffered from OP-cancer and 41.5% from HP-cancer. The OS, PFS and MFS at 5 years for the DDP-arm was 39.1%, 47.2% and 66.8% versus 32.8% (n.s.), 37.2% (n.s., HR: 0.74, 95%-CI: 0.55-1.00, p=.05) and 53.5% (p=.044, hazard ratio: 0.63, 95% CI: 0.43-0.94, p=0.023) for the MMC-arm, respectively. The corresponding LC, RC and LRC was 66.2%, 77.3% and 59,1% for the DDP-arm versus 65.9% (n.s), 73.3% (n.s.) and 56.1% (n.s.), for the Mitomycin C arm, respectively. Eight items recorded for acute toxicity (dysphagia, mucositis, dermatitis, xerostomia, pain, weight, leukopenia and creatinine showed no differences between the two treatment arms except for an elevated creatinine level for the DDP-arm (p<.001). Nine items for late morbidity (Dysphagia, Xerostomia, oedema, subcutaneous fibrosis, laryngeal oedema, osteoradionecrosis, plexopathia, L’hermittes syndrome, tracheostomia and PEG showed no significant differences between the treatment arms using nonparametric analyses of variances for repeated measurements. The overall compliance rate for the HART scheme was 96%, DDP: 72%, 5-FU: 97% and MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen against two cycles of Mitomycin C. In terms of MFS and DFS @5 yrs., DDP/5-FU HART is superior to MMC/5-FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, LC, RC or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation. [Copyright &y& Elsevier]