Long-term health-related quality of life in head and neck cancer survivors: A large multinational study.

Head and neck cancer (HNC) patients suffer from a range of health-related quality of life (HRQoL) issues, but little is known about their long-term HRQoL. This study explored associations between treatment group and HRQoL at least 5 years' post-diagnosis in HNC survivors. In an international cross-sectional study, HNC survivors completed the European Organization for Research and Treatment of Cancer (EORTC) quality of life core questionnaire (EORTC-QLQ-C30) and its HNC module (EORTC-QLQ-H&N35). Meaningful HRQoL differences were examined between five treatment groups: (a) surgery, (b) radiotherapy, (c) chemo-radiotherapy, (d) radiotherapy ± chemotherapy and neck dissection and (e) any other surgery (meaning any tumour surgery that is not a neck dissection) and radiotherapy ± chemotherapy. Twenty-six sites in 11 countries enrolled 1105 survivors. They had a median time since diagnosis of 8 years, a mean age of 66 years and 71% were male. After adjusting for age, sex, tumour site and UICC stage, there was evidence for meaningful differences (10 points or more) in HRQoL between treatment groups in seven domains (Fatigue, Mouth Pain, Swallowing, Senses, Opening Mouth, Dry Mouth and Sticky Saliva). Survivors who had single-modality treatment had better or equal HRQoL in every domain compared to survivors with multimodal treatment, with the largest differences for Dry Mouth and Sticky Saliva. For Global Quality of Life, Physical and Social Functioning, Constipation, Dyspnoea and Financial Difficulties, at least some treatment groups had better outcomes compared to a general population. Our data suggest that multimodal treatment is associated with worse HRQoL in the long-term compared to single modality.

Adjuvant chemoradiotherapy in elderly patients with head and neck cancer: a monoinstitutional, two-to-one pair-matching analysis.

PURPOSE: About one fifth of patients with head and neck cancer are aged 70 years and older at the time of diagnosis. In these patients, risk factors (R1 status or extracapsular extension of lymph node metastases, ECE) often lead to a need for combined chemoradiotherapy (CRT) in the postoperative setting. However, there is considerable concern about the toxicity of such therapy in this age group. METHODS: Retrospective evaluation of the data of 53 patients ≥ 70 years of age who underwent surgery in our hospital between 1999 and 2015 for tumors of the oral cavity, the oropharynx, the hypopharynx, or the larynx, who subsequently received adjuvant radiation therapy. Two younger patients (< 70 years) were assigned to each of the elderly patients in a matching procedure based on anatomic sublocalization and tumor stage. The total cohort was comprised of 154 patients. RESULTS: Univariate analyses revealed a statistically significant influence of many factors on overall survival (OS) and progression-free survival (PFS), including Karnofsky performance score (KPS), alcohol consumption, smoking, R status, ECE, chemotherapy, and discontinuation of RT. Younger patients had better OS and PFS compared to the elderly (p = 0.013 and 0.012, respectively). In a multivariate Cox regression, no independent influence of age on OS and PFS was found. Survival was primarily dependent on the addition of chemotherapy to radiotherapy (RT), application of the full course of RT, continued alcohol abuse, KPS, and the presence of ECE. Toxicity analysis showed a higher incidence of chronic renal failure but, generally, side effects for elderly patients were not substantially greater. CONCLUSION: Performance status and behavioral risk factors but not chronological age are crucial for the prognosis of patients who require adjuvant chemoradiation.

Effects of throat packs in upper airway surgery under intubation anesthesia: a randomized controlled trial.

INTRODUCTION: Throat packs (TP) are used in upper airway surgery to avoid accumulation and aspiration of blood, foreign bodies, and fluids. But side effects such as sore throat and TP retention have been reported and challenge the standardized use of TP. The aim of this study is to compare benefits and side effects of TP versus no TP for upper airway procedures in intubation anesthesia. MATERIAL AND METHODS: One hundred forty-eight patients with surgical interventions at the upper airway under intubation anesthesia were included. Of those, n = 74 each were treated without (A, control) and with (B) TP. Study group B was subdivided whether TP was placed by the surgeon (B1; n = 37) or by the anesthesiologist (B2; n = 37). TP-related side effects such as sore throat, foreign body sensation, hoarseness, dyspnea, difficulty of swallowing, nausea, retching, nausea, aspiration, and pneumonia as well as the influence of TP design and the applicant (surgeon or anesthetist) were analyzed. RESULTS: A significantly increased rate of difficulty of swallowing (p = 0.045), intensity of sore throat (p = 0.04), and foreign body sensation (p = 0.024) was found in group B when compared to group A. There was no correlation between hoarseness, dyspnea, nausea, retching, and TP. No case of aspiration or pneumonia was seen but one TP was accidentally forgotten in the patient. B2 showed an increased frequency of difficulty swallowing, followed by A and B1. B1 led to the highest incidence of nausea followed by the A and B2. CONCLUSION: The use of TP led to a high rate of side effects without showing the propagated advantages. CLINICAL RELEVANCE: The use of TP must be considered critically and cannot generally be recommended without specific reasons, such as high aspiration risk.

Clinical efficacy of an antibody-based detection system for human papilloma virus infection in oral squamous cell carcinoma.

OBJECTIVES: There is an increasing number of oral squamous cell carcinoma (OSCC) associated with HPV-16. However, p16 expression by immunohistochemistry as the current gold standard for a surrogate marker for virus infection reveals unsatisfying diagnostic accuracy. The aim of this study was to investigate a new rapid test for L1 antibody detection (Prevocheck®) and to validate its diagnostic performance. MATERIALS AND METHODS: In a prospective study, the HPV 16 association of all consecutive patients with an OSCC treated between 2015 and 2019 were analyzed by L1 seropositivity (via PrevoCheck®), p16 immunostaining, and partly multiplex PCR for subtype analysis. RESULTS: Overall (n = 107), p16 expression was positive in 17 cases (15.9%), and L1 antibody seropositivity in 7 cases (6.5%). In PCR analysis, two cases of HPV35 and 50 were found. Total HPV prevalence was 8.4% overall and 6.5% for HPV-16. An inferior diagnostic accuracy for HPV-16-associated OSCC in comparison to PrevoCheck® was revealed. CONCLUSION: The rapid test for L1 antibodies showed an optimal sensitivity and specificity, positive and negative predictive value, and an overall diagnostic accuracy of 100%. However, HPV prevalence seems low in OSCC. CLINICAL RELEVANCE: L1 rapid test may represent an additional diagnostic staging method to detect HPV-16 association rather than p16 immunohistochemistry.

Cigarette smoke modulates binding of the transcription factor MZF1 to the VEGF promoter and regulates VEGF expression in dependence of genetic variation SNP 405.

BACKGROUND: Vascular endothelial growth factor (VEGF) affects carcinogenesis of the upper aerodigestive tract. Cigarette smoke (CSE) influences VEGF-gene regulation. The single nucleotide polymorphism +405 G/C (SNP +405 G/C) and the transcriptional factor (TF) myeloid zinc finger 1 (MZF1) are endogenic regulators of the VEGFpromoter as the polymorphism 405 potentially affects binding of the transcription factor MZF1. Therefore, this in vitro study analysed cancer cells of the upper aerodigestive tract after CSE incubation concerning MZF1-binding specificity and VEGF expression in dependency of VEGF polymorphism +405 G/C compared to wild type (wt). METHODS: In human alveolar epithelial-like type-II cells (A549) and oral squamous cell cancer cells (HNSCCUM-02T) SNP +405 G/C- and MZF1-dependent VEGF promoter activity and VEGF expression were analysed by qRT-PCR and Western blot after incubation with 10% CSE. Temporary knock-down of MZF1 was performed using siRNA. MZF1 binding was analysed by Co-Chromatin-Immunoprecipitation (Co-ChiP) (each test n = 3). RESULTS: We found a stronger MZF1 binding to VEGF polymorphism 405 in A549 cells (P < .05) compared to HNSCCUM-02T cells (P = .02), where MZF1 binding was reduced. MZF1 knock out reduced VEGF promoter activity in HNSCCUM-02T cells, showing the relevance of the factor for transcriptional activation of the VEGF promoter. Finally, we found that CSE increases promoter activity in both cell lines and no significant differences between the two analysed polymorphisms concerning their activating capacity. CONCLUSION: In summary, both VEGF promoter polymorphisms are similar effective in terms of transcriptional activity, and MZF1 is a transcriptional activator of VEGF promoter. Moreover, cigarette smoke increases MZF1 binding of VEGF-promoter and directly affects VEGF-gene regulation.

The impact of cigarette smoke on activity of single nucleotide polymorphisms of the vascular endothelial growth factor-promoter gene in cells of the upper aerodigestive tract.

BACKGROUND: The vascular endothelial growth factor (VEGF) is involved in tumorigenesis of the upper aerodigestive tract. Different single nucleotide polymorphisms (SNPs) turn the regulation of the VEGF gene into a highly complex process, particularly influenced by exogenic factors like cigarette smoke (CSE). Analysis of the SNP- and CSE-dependent VEGF-gene regulation can help to improve antiangiogenic therapies and prognosis. Therefore, the aim of this study was to analyse the influence of CSE on the SNP-dependent regulation of the VEGF-gene in vitro. METHODS: Human alveolar epithelial-like type-II cells (A549) were transfected with different SNPs and incubated with CSE. SNP- and CSE-dependent VEGF-promoter activity and mRNA stability was measured using qRT-PCR and Western blot analysis. RESULTS: Transfection with SNP -460 (ATC) and incubation with 10% CSE resulted in +19% elevated VEGF-promoter activity (P < 0.05). Transfection with SNP -2578/-460 (CTC) and 10% CSE incubation resulted in a 14% reduction of VEGF-promoter activity (P < 0.05). Regarding mRNA stability, transfection with SNP +936 T allele led to half-life of 1.11 hours, which decreased to 0.2 hours after incubation with CSE. In contrast, on protein level SNP +936 T transfection showed a not significant increase up to 176% (P > 0.05), while incubation with CSE led to a significant decrease to 61% (P = 0.002). CONCLUSION: Transcriptional regulation of the VEGF gene by SNP -460 (ATC) in combination with CSE represents a mechanism for elevated VEGF expression and may be associated with a worse prognosis. The influence of +SNP 936 on mRNA stability may be responsible for regulation of VEGF plasma levels.

Vascular architecture in free flaps: Analysis of vessel morphology and morphometry in murine free flaps.

The aim of this study was to analyze the development of vascular architecture as well as vascular morphometry and morphology of anastomosed microvascular free flaps. Free pectoral skin flaps were raised in 25 rats and anastomosed to the femoral vessels in the groin region. CD31 immunohistology was performed after 3, 7 and 12 d (each 5 animals each) to analyze microvessel density (MVD), microvessel area (MVA) and microvessel size (MVS). Microvascular corrosion casting was performed after 7 and 12 d (5 animals each) to analyze vessel diameter (VD), intervascular distance (IVD), interbranching distance (IBD), and branching angle (BA). Further on, sprout and pillar density as hallmarks of sprouting and intussusceptive angiogenesis were analyzed. Pectoral skin isles from the contralateral side served as controls. A significantly increased MVD was found after 7 and 12 d (p each <0.001). MVA was significantly increased after 3, 7 and 12 d (p each <0.001) and a significantly increased MVS was analyzed after 3 and 7 d (p each <0.001). VD and IVD were significantly increased after 7 and 12 d (p each <0.001). For IBD, a significantly increase was measured after 7 d (p < 0.001). For IBA, sprout and pillar density, no significant differences were found (p each ≥0.05). Significant changes in the vascular architecture of free flaps after successful microvascular anastomosis were seen. Since there was no evidence for sprout and pillar formation within the free flaps, the increased MVD and flap revascularization might be induced by the receiving site.

[Oral health-related quality of life in cancer patients]. / Mundgesundheitsbezogene Lebensqualität bei Krebspatienten.

OBJECTIVE: To date, only a few studies have investigated oral health-related quality of life (OH-QoL) in cancer patients. The European Organisation for Research and Treatment of Cancer (EORTC) has therefore developed a questionnaire, the Quality of Life Questionnaire - Oral Health Module 15 (EORTC QLQ-OH15), to enable investigation of OH-QoL. The aim of this study was to examine OH-QoL in a real-world setting. PATIENTS AND METHODS: OH-QoL was measured using the EORTC QLQ-OH15 in cancer patients at a non-specified time during treatment (t1) as well as two weeks (t2) and three months (t3) after baseline. Potential predictors of OH-QoL such as age, sex, education, cancer entity and therapy were explored. RESULTS: At baseline 40 patients participated in the study. At t2, patients suffered more often from sticky saliva and experienced a higher sensitivity during eating or drinking compared to t1. Additionally, dentures were worn less often. At t3, patients were less often satisfied with information concerning oral side effects. Furthermore, patients older than 50 years, women, patients with poorer education, patients with head and neck cancer, and patients undergoing palliative therapy, surgery or targeted therapy indicated worse OH-QoL at t2 than other patients. CONCLUSIONS: OH-QoL is of clinical importance in cancer patients. It seems to be decreased after the end of treatment, and not only in patients with head and neck cancer. Despite its brevity, the EORTC QLQ-OH15 is able to capture these differences, and is well accepted by patients. It can be recommended for future studies in this area.

Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients.

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

Influence of porcine-derived collagen matrix on endothelial progenitor cells: an in vitro study.

Porcine-derived collagen matrix (PDCM) has been reported as a promising alternative to autogenous soft tissue grafts in periodontal plastic surgery. The aim of this study was to analyze the influence of a novel PDCM on endothelial progenitor cells (EPC) in vitro. EPC were isolated from human peripheral blood, cultured and transferred on the PDCM (mucoderm®). Tissue culture polystyrene surface (TCPS) served as control. Cell viability of EPC on PDCM was measured by a MTT and PrestoBlue® assay. Migration ability was tested using a Boyden migration assay. A ToxiLight® assay was performed to analyze the influence of PDCM on adenylate kinase (ADK) release and apoptosis rate of EPC. Using the MTT assay, EPC cultured on PDCM demonstrated a significantly increased cell viability compared to the control group at days 3, 6 and 12 (p each <0.001). According to the PrestoBlue® assay, EPC showed a significant increase of cell viability compared to the control group at 48, 72, and 96 h (p each <0.001). In the Boyden migration assay, a significantly increased EPC migration ability could be observed after 3-12 days (p each ≤0.001). No significantly increased apoptosis rate of EPC on PDCM could be observed with exception after 96 h (p each >0.05). Overall, our results suggest a good biocompatibility of PDCM without any cytotoxic effects on EPC, which might support a rapid revascularization and therefore a sufficient ingrowth of the PDCM.

The impact of GSTM1/GSTT1 polymorphism for the risk of oral cancer.

OBJECTIVES: Since development of oral squamous cell cancer (OSCC) is triggered by various noxa, different variants of the antioxidant glutathione S-transferases (GSTs) can counteract toxic compounds (e.g., tobacco smoke). Because different polymorphisms of GST are known to have an increased sensitivity to carcinogenic agents, the aim of this study was to analyze whether GSTM1 or GSTT1 polymorphisms increase the risk for the development of OSCC. MATERIALS AND METHODS: GSTM1 and GSTT1 polymorphism was examined in healthy volunteers (n = 93) and in patients with OSCC (n = 100) by PCR after brush biopsy of oral mucosa. Odds ratio (OR) was calculated to evaluate the risk of oral cancer development. RESULTS: GSTM1 and GSTT1 deletion was found in 57% (53/93) and 18% (17/93), respectively, in healthy patients, while the OSCC group showed 57% (57/100) for GSTM1 deletion and 22% (22/100) with a deletion of GSTT1. Odds ratio for GSTM1 polymorphism was 1.00 and for GSTT1 1.26. Comparing smokers and nonsmokers with GSTM1 deletion polymorphism, OR was 4.35, while smokers without GSTM1 deletion showed an OR of 1.45. Adapting these data to the smoking habits of the general population in Germany, the OR was 9.25 for smokers with a GSTM1 deletion and OR 6.68 for smokers without a GSTM1 deletion. In smokers with GSTT1 deletion polymorphism, OR was 1.6 (adapted to the smoking habits of the general population: OR 6.16) and 3.16 (OR 8.56) in smokers without deletion in GSTT1 gene. CONCLUSIONS: Analysis of GST-M1 polymorphism in smokers could help to identify patients with a higher risk for the development of oral cancer. CLINICAL RELEVANCE: Early detection of OSCC due to a close meshed monitoring program for patients with GST-M1 polymorphism could help to improve the patient outcome. For polymorphism investigations, the oral brush biopsy is a sufficient method to gain DNA material.

Is bilateral radiotherapy necessary for patients with unilateral squamous cell carcinoma of unknown primary of the head and neck region?

Background and Purpose: Squamous cell carcinoma of unknown primary (SCC-CUP) of the head and neck region remains a clinical challenge, with uncertainty surrounding the necessity of contralateral irradiation of cervical lymphatic drainage in cases of unilateral involvement. Materials and Methods: A retrospective study was conducted at the Department of Radiation Oncology, University Medical Center Mainz, on a cohort of 50 patients with unilateral SCC-CUP of the head and neck region treated between 2005 and 2019. 30 patients received bilateral and 20 received unilateral cervical radiotherapy. The majority (n = 38, 76 %) were treated with modern IMRT/ VMAT (Intensity-modulated Radiation Therapy/ Volumetric Modulated Arc Therapy) techniques. Results: After a median follow-up of 64.5 months, locoregional recurrences occurred in 26 % of cases (n = 13/50), all of which were ipsilateral and predominantly within the volume of the previous irradiated CTV (clinical target volume) (85 %, n = 11/13). No patient treated unilaterally developed a contralateral recurrence in the neck. After 3 years, we observed 7 locoregional recurrences in the bilateral irradiated group (n = 7/30, 23 %), and 5 locoregional recurrences in the unilateral irradiated group (n = 5/20, 25 %). After 3 years, 12 patients had died in the bilateral irradiated group (n = 12/30, 40 %), and 7 in the unilateral irradiated group (n = 7/20, 35 %). 7 Patients showed distant metastases after 3 years in the bilateral irradiated group (n = 7/30, 23 %), and 2 in the unilateral irradiated group (n = 2/20, 10 %). Locoregional control (LRC) at 5 years was 66.2 % in the bilaterally irradiated group, and 70.0 % in the unilaterally irradiated group. Overall survival (OS) was 52.6 % (bilateral) and 64.0 % (unilateral). Distant metastasis-free survival (DMFS) was 74.7 % (bilateral) and 84.4 % (unilateral). No significant differences were observed in OS (p = 0.37), LRC (p = 0.91), and DMFS (p = 0.91) between the groups.Acute toxicity ≥ °2 accordingly CTCAE (Common Terminology Criteria of Adverse Events) was high with 97% while late toxicity ≥ °2 was moderate with 31%. There was no statistically significant difference between the group of unilateral and bilateral irradiated patients. Conclusion: These data suggest that contralateral cervical irradiation may be of limited benefit in patients with SCC-CUP, as recurrences occured ipsilaterally, and predominantly within the area of prior irradiation. Unilateral irradiation seems to be adequate for carefully selected patients.

The Perfect Timing-Immediate versus Delayed Microvascular Reconstruction of the Mandible.

In this retrospective study, the clinical and economic implications of microvascular reconstruction of the mandible were assessed, comparing immediate versus delayed surgical approaches. Utilizing data from two German university departments for oral and maxillofacial surgery, the study included patients who underwent mandibular reconstruction following continuity resection. The data assessed included demographic information, reconstruction details, medical history, dental rehabilitation status, and flap survival rates. In total, 177 cases (131 male and 46 females; mean age: 59 years) of bony free flap reconstruction (72 immediate and 105 delayed) were included. Most patients received adjuvant treatment (81% with radiotherapy and 51% combined radiochemotherapy), primarily for tumor resection. Flap survival was not significantly influenced by the timing of reconstruction, radiotherapy status, or the mean interval (14.5 months) between resection and reconstruction. However, immediate reconstruction had consumed significantly fewer resources. The rate of implant-supported masticatory rehabilitation was only 18% overall. This study suggests that immediate jaw reconstruction is economically advantageous without impacting flap survival rates. It emphasizes patient welfare as paramount over financial aspects in clinical decisions. Furthermore, this study highlights the need for improved pathways for masticatory rehabilitation, as evidenced by only 18% of patients with implant-supported dentures, to enhance quality of life and social integration.

High-Multiplex Aptamer-Based Serum Proteomics to Identify Candidate Serum Biomarkers of Oral Squamous Cell Carcinoma.

Improved serological biomarkers are needed for the early detection, risk stratification and treatment surveillance of patients with oral squamous cell carcinoma (OSCC). We performed an exploratory study using advanced, highly specific, DNA-aptamer-based serum proteomics (SOMAscan, 1305-plex) to identify distinct proteomic changes in patients with OSCC pre- vs. post-resection and compared to healthy controls. A total of 63 significantly differentially expressed serum proteins (each p < 0.05) were found that could discriminate between OSCC and healthy controls with 100% accuracy. Furthermore, 121 proteins were detected that were significantly altered between pre- and post-resection sera, and 12 OSCC-associated proteins reversed to levels equivalent to healthy controls after resection. Of these, 6 were increased and 6 were decreased relative to healthy controls, highlighting the potential relevance of these proteins as OSCC tumor markers. Pathway analyses revealed potential pathophysiological mechanisms associated with OSCC. Hence, quantitative proteome analysis using SOMAscan technology is promising and may aid in the development of defined serum marker assays to predict tumor occurrence, progression and recurrence in OSCC, and to guide personalized therapies.

Serious Long-Term Effects of Head and Neck Cancer from the Survivors' Point of View.

The long-term problems of head and neck cancer survivors (HNCS) are not well known. In a cross-sectional international study aimed at exploring the long-term quality of life in this population, 1114 HNCS were asked to state their two most serious long-term effects. A clinician recorded the responses during face-to-face appointments. A list of 15 example problems was provided, but a free text field was also available. A total of 1033 survivors responded to the question. The most frequent problems were 'dry mouth' (DM) (n = 476; 46%), 'difficulty swallowing/eating' (DSE) (n = 408; 40%), 'hoarseness/difficulty speaking' (HDS) (n = 169; 16%), and 'pain in the head and neck' (PHN) (n = 142; 14%). A total of 5% reported no problems. Logistic regression adjusted for age, gender, treatment, and tumor stage and site showed increased odds of reporting DM and DSE for chemo-radiotherapy (CRT) alone compared to surgery alone (odds ratio (OR): 4.7, 95% confidence interval (CI): 2.5-9.0; OR: 2.1, CI: 1.1-3.9), but decreased odds for HDS and PHN (OR: 0.3, CI: 0.1-0.6; OR: 0.2, CI: 0.1-0.5). Survivors with UICC stage IV at diagnosis compared to stage I had increased odds of reporting HDS (OR: 1.9, CI: 1.2-3.0). Laryngeal cancer survivors had reduced odds compared to oropharynx cancer survivors of reporting DM (OR: 0.4, CI: 0.3-0.6) but increased odds of HDS (OR: 7.2, CI: 4.3-12.3). This study provides evidence of the serious long-term problems among HNCS.

Differences in PD-L1 Expression between oral and oropharyngeal squamous cell carcinoma.

Treatment of metastasized or recurrent oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinoma remains challenging. Targeted antibody-based therapy inter alia for PD-1 / PD-L1 axis shows promising results, but whether PD-L1 expression varies between the subentities remains unclear. The expression pattern of PD-L1 (EPR19759 antibody, Abcam, Berlin, Germany) and p16 (CINtech® Histology Kit, Ventana, Oro Valley, USA) was determined immunohistochemically and analyzed by HALO™ Image Analysis Software (Indica Lab, Albuquerque, USA). For PD-L1, combined positivity score (CPS), tumor proportion score (TPS) and histoscore, were assessed and results correlated with epidemiological data. In total, 161 patients (OSCC: n = 78, OPSCC: n = 83) were included. A mean of 43.6% (±34.0%) of the specimen showed increased PD-L1 expression that did not differ quantitatively between subentities (TPS: p = 0.159, CPS: p = 0.078), but qualitatively (histoscore: p = 0.003). In the mean follow-up period (45.6 months), contrary to age (p = 0.006) and advanced T-Status (p = 0.018), PD-L1 expression did not correlate with overall (OS, p = 0.191) and recurrence free survival (RFS: p = 0.193) in both subentities. No correlation of p16 and PD-L1 expression was found (p = 0.844). PD-L1 is differentially expressed between OSCC and OPSCC, however without influence on OS. Furthermore, p16 status was not related to PD-L1 expression. This may have implications for future (immune) therapeutical approaches for oral cancer.

Tumor Recurrence and Follow-Up Intervals in Oral Squamous Cell Carcinoma.

Tumor recurrence in oral squamous cell carcinoma (OSCC) is frequent. However, no consensus about follow-up interval is available. The aim of this study was to analyze the recurrence pattern, detection method and associated parameters for possible risk stratification. Histopathological and epidemiological features were obtained retrospectively and correlated with tumor recurrence and overall survival, distant and lymph node metastases. A total of 760 patients were included, of which 216 patients showed tumor recurrence (mean after 24 ± 26 months). Within the first 12 months, 24% of the recurrences were detected. The primary detection method was clinical examination (n = 123, 57%). Tumor recurrence significantly correlated with advanced histopathological grading (G2/3 vs. G1, p < 0.000) and lymph node metastasis (p = 0.004). Tumor recurrence was frequent. Clinical examination was the primary detection method and manifestation within the first 6−12 months was high. The degree of histopathological grading may be useful for risk stratification.

Non-Interventional Prospective Observational Study of Platelet Rich Fibrin as a Therapy Adjunctive in Patients with Medication-Related Osteonecrosis of the Jaw.

BACKGROUND: Medication-related osteonecrosis (MRONJ) of the jaw is a severe and feared side effect of antiresorptive therapy in the oncological setting. With growing evidence that impaired angiogenesis may represent a key factor in pathogenesis, the aim of this study was to evaluate an autologous platelet concentrate as a possible additive in surgical therapy to optimize vascularization and, subsequently, resolution rates. MATERIAL AND METHODS: A non-interventional, prospective, multicenter study was conducted, and all patients with stage I-III MRONJ, undergoing antiresorptive therapy for an oncological indication, were included. The necrosis was treated surgically without (study arm A) or with (arm B) the addition of an autologous platelet concentrate (platelet-rich fibrin, PRF). RESULTS: After 5, 14, and 42 days postoperative, wound healing (primary outcome: mucosal integrity) as well as downstaging, pain perception, and oral health-related quality of life (secondary outcome) were assessed via clinical evaluation. Among the 52 patients included, primarily with MRONJ stage I and II, the use of PRF as an additive in surgical therapy did not display a significant advantage for wound healing (p = 0.302), downstaging (p = 0.9), pain reduction (p = 0.169), or quality of life (p = 0.9). SUMMARY: In conclusion, PRF as an adjunct did not significantly optimize wound healing. Further, no significant changes in terms of downstaging, pain sensation, and oral health-related quality of life were found.

DRH1 - a novel blood-based HPV tumour marker.

BACKGROUND: To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for screening, monitoring therapy response or early detection of recurrence. This study aims to assess the clinical performance of a newly developed HPV16-L1 DRH1 epitope-specific serological assay. METHODS: In a multi-centre study sera of 1486 patients (301 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, 12 HIV+ anal cancer patients, 80 HIV-positive patients, 29 Gardasil-9-vaccinees, 1064 healthy controls) were tested for human HPV16-L1 DRH1 antibodies. Analytical specificity was determined using WHO reference-sera for HPV16/18 and 29 pre- and post-immune sera of Gardasil-9-vaccinees. Tumour-tissue was immunochemically stained for HPV-L1-capsidprotein-expression. FINDINGS: The DRH1-competitive-serological-assay showed a sensitivity of 95% (95% CI, 77.2-99.9%) for HPV16-driven HNSCC, and 90% (95% CI, 55.5-99.7%) for HPV16-induced anal cancer in HIV-positives. Overall diagnostic specificity was 99.46% for men and 99.29% for women ≥ 30 years. After vaccination, antibody level increased from average 364 ng/ml to 37,500 ng/ml. During post-therapy-monitoring, HNSCC patients showing an antibody decrease in the range of 30-100% lived disease free over a period of up to 26 months. The increase of antibodies from 2750 to 12,000 ng/ml mirrored recurrent disease. We can also show that the L1-capsidprotein is expressed in HPV16-DNA positive tumour-tissue. INTERPRETATION: HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced malignant disease. As post-treatment biomarker, the assay allows independent post-therapy monitoring as well as early diagnosis of tumour recurrence. An AUC of 0.96 indicates high sensitivity and specificity for early detection of HPV16-induced disease. FUNDING: The manufacturer provided assays free of charge.

Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis.

PON2 (paraoxonase-2) is a ubiquitously expressed antioxidative protein which is largely found in the ER (endoplasmic reticulum). Addressing the cytoprotective functions of PON2, we observed that PON2 overexpression provided significant resistance to ER-stress-induced caspase 3 activation when the ER stress was induced by interference with protein modification (by tunicamycin or dithiothreitol), but not when ER stress was induced by disturbance of Ca(2+) homoeostasis (by thapsigargin or A23187). When analysing the underlying molecular events, we found an activation of the PON2 promoter in response to all tested ER-stress-inducing stimuli. However, only tunicamycin and dithiothreitol resulted in increased PON2 mRNA and protein levels. In contrast, when ER stress was caused by thapsigargin or A23187, we observed a Ca(2+)-dependent active degradation of PON2 mRNA, elicited by its 5'-untranslated region. In addition, thapsigargin and A23187 also induced PON2 protein degradation by a Ca(2+)-dependent calpain-mediated mechanism. Thus we provide evidence that independent mechanisms mediate the degradation of PON2 mRNA and protein after disturbance of Ca(2+) homoeostasis. Furthermore, because Ca(2+)-disturbance induces ER stress, but abrogates the otherwise protective function of PON2 against ER-stress-induced apoptosis, we propose that the underlying cause of ER stress determines the efficacy of putative cellular defence mechanisms.