Medical practitioners' educational competence about oral and oropharyngeal carcinoma: a systematic review and meta-analysis.

Medical practitioners' (MP) role is pivotal in primary prevention, early diagnosis, prompt referral and effective management of oral and oropharyngeal carcinomas (OC/OPC), which raises the importance of their effective OC/OPC education at all levels of medical education. The purpose of this systematic review was to summarise the available scientific evidence about their educational competence in dealing with OC/OPC. We made a systematic search of papers in the English language in MEDLINE, Scopus, Cochrane Library CENTRAL and CINAHL databases from their inception until December 2018. Overall, 23 cross-sectional and three interventional studies have been selected for the systematic review and 18 of these were included in the meta-analyses. Excluding tobacco use (synthesised estimate of 95% of respondents identified tobacco as an OC/OPC risk factor, 95% CI of synthesised estimate 92% to 97%) and alcohol consumption (65%, 95%CI 52% to 77%), less than half of MP (approximately) were knowledgeable about important OC/OPC risk factors including human papilloma virus (42%, 95% CI 30% to 54%), poor diet (34%, 95% CI 17% to 54%), and advancing age (45%, 95% CI 21% to 70%). There was a low to moderate level of awareness among MP regarding common precancerous oral lesions involving leukoplakia (56%, 95% CI 32% to 79%), erythroplakia (30%, 95% CI 8% to 58%), and oral lichen planus (13%, 95% CI 0 to 41%). Moderate knowledge was also recorded about frequent sites of OC development involving the tongue (48%, 95% CI 33% to 64%) and floor of the mouth (37%, 95% CI 19% to 57%). Most MP enquired about tobacco use (86%, 95% CI 74% to 96%), and alcohol consumption (73%, 95% CI 47% to 94%) during history taking, and expressed willingness to be given supplementary OC/OPC education (78%, 95% CI 54% to 96%), as well. With regard to the incidence of intraoral screening, 27% of MP (95% CI 12% to 46%) make an intraoral examination as a routine. Interestingly, studies from each continent yielded significantly different outcomes to some research questions in the review. From the MP's perspective, clinical time restrictions and deficiencies in organised training were recognised as the main barriers towards their OC/OPC educational competence. The findings of this systematic review indicated the existence of deficiencies in knowledge and misconceptions, neglected preventive responsibilities, and associated barriers towards OC/OPC. A need for improved OC/OPC training at all levels of medical education is required to increase competence worldwide.

In vitro effects of particulate bone substitute materials on the resorption activity of human osteoclasts.

Much research has been done on bone cells, but only a few studies deal with biomaterial-induced effects on human osteoclasts, which may take on an important role in the successful regeneration of bone. In order to highlight such effects, human peripheral blood mononuclear cells (PBMCs) were extracted from venous blood, differentiated to osteoclasts and then cultured in, the presence of five particulate hydroxyapatite (HA)/ß-tricalcium phosphate (TCP) biomaterials, on bovine bone slices and glass cover slips. The biomaterials, AlgOSS 50/50 (50 % HA/50 % TCP), AlgOSS 20/80 (20 % HA/80 % TCP), Algipore (98 % HA), Cerasorb (100 % TCP) and Bio-Oss (100 % HA) were chosen to assess their influence on cell morphology and numbers. Light microscopic evaluation was performed during ongoing cell culture. After 21 d of cultivation, the biomaterial-induced effects on osteoclastic resorption of the bone slices were evaluated by scanning electron microscopy (SEM). Osteoclast-like cells were identified by TRAP staining. All five biomaterials showed larger area fractions of resorbed bone than the control (5.6 ± 6.8 %), as measured on SEM images. The purely hydroxyapatite-based Algipore (9.8 ± 9.7 %) and Bio-Oss (7.9 ± 8.8 %) showed significantly elevated area fraction rates (p ≤ 0.05) of bone resorption. Light microscope evaluation revealed a significant, but inhibiting effect of Cerasorb (p = 0.05). These data indicated that introducing of small biomaterial hydroxyapatite particles may have improved the performance of bone substitute materials.

Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma.

BACKGROUND: Successful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent. PATIENTS AND METHODS: We developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD-L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15). RESULTS: PD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76-92.72, P = 0.002). CONCLUSIONS: We demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment.

Importance of chewing, saliva, and swallowing function in patients with advanced oral cancer undergoing preoperative chemoradiotherapy: a prospective study of quality of life.

The primary objective of this study was to investigate the quality of life (QOL) of patients with oral squamous cell carcinoma (OSCC) undergoing curative neoadjuvant chemoradiotherapy followed by radical tumour resection and simultaneous oral cavity reconstruction, using two validated questionnaires. A secondary objective was to assess clinical variables predicting post-treatment dysfunction in chewing, saliva, and swallowing. Thirty-five patients with locally advanced OSCC who underwent preoperative chemoradiotherapy were recruited prospectively. All patients completed both the University of Washington Quality of Life version 4 questionnaire (UW-QOL) and the Functional Assessment of Cancer Therapy-Head & Neck version 4 questionnaire (FACT-H&N). UW-QOL and FACT-H&N items were associated with clinical variables. Nearly three-quarters of OSCC patients perceived good to excellent levels of overall QOL after preoperative chemoradiotherapy. Chewing difficulties, decreased salivary function, and swallowing dysfunction were the most frequent complaints of OSCC patients. Items related to food intake were significantly worse in OSCC patients older than 60 years and those with T4 tumours, as well as those without alcohol intake. Chewing, saliva, and swallowing are the most significant issues in patients with OSCC undergoing preoperative chemoradiotherapy. The results of this study may help guide treatment decisions for OSCC patients based on more accurate expectations of adverse effects of cancer treatment.

The promise of immunotherapy in head and neck squamous cell carcinoma.

Squamous cell cancers of the head and neck (HNSCC) comprise a diverse group of malignancies that includes tobacco-related tumors in addition to an increasing number of human papillomavirus-associated cancers. Independently of cause, there is a growing body of evidence supporting that the immune system plays a pivotal role in HNSCC development, as tumor cells evade immunosurveillance by exploiting inhibitory checkpoint pathways that suppress anti-tumor T-cell responses. HNSCC cells have the ability to manipulate the immune system through a variety of different mechanisms, forcing it to promote tumor growth and spread. Over the last decade, discoveries in immunologic research resulted in increased understanding of complex interactions between HNSCC and the host immune system as well as T-cell regulatory mechanisms, promoting the development of a variety of novel immunotherapies. Following the availability of novel immunotherapeutic strategies, the challenge for clinicians is to understand how and in which clinical setting to use these agents in order to provide greater clinical benefit for patients. Combination of immunotherapies with standard treatment approaches also represents an evolving field of research. Herein, we provide a comprehensive review of immune escape mechanisms in HNSCC, as well as current immunotherapy approaches under investigation.

Prognostic role of pretreatment plasma fibrinogen in patients with solid tumors: A systematic review and meta-analysis.

BACKGROUND: Plasma fibrinogen may be involved in several stages of cancer progression. Clinical studies have demonstrated that pretreatment plasma fibrinogen is associated with poor survival in various cancers. The aim of this meta-analysis was to examine the prognostic effect of circulating fibrinogen in solid tumors. MATERIALS AND METHODS: We searched Medline, EMBASE, Cochrane Database of Systematic Reviews, and meeting proceedings to identify studies assessing the effect of pretreatment plasma fibrinogen on survival of cancer patients. Pooled multivariable-adjusted hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were estimated using random-effects models. RESULTS: Data from 52 observational studies and 15,371 patients were summarized. An elevated baseline plasma fibrinogen was significantly associated with worse OS (pooled HR = 1.69; 95% CI = 1.48­1.92). The highest negative effect of elevated plasma fibrinogen on OS was demonstrated in renal cell carcinoma (pooled HR = 2.22), followed by head and neck cancer (pooled HR = 2.02), and colorectal cancer (pooled HR = 1.89). The adverse prognostic impact of high plasma fibrinogen remained in both non-metastatic and metastatic disease and patients of different ethnicity. Patients with high baseline fibrinogen had a significantly shorter DFS (pooled HR = 1.52) and CSS (pooled HR = 2.50). CONCLUSIONS: An elevated pretreatment plasma fibrinogen significantly correlates with decreased survival in patients with solid tumors. Future clinical trials are warranted to determine whether plasma fibrinogen could be incorporated in cancer staging systems and whether fibrinogen-lowering therapies have a favorable effect on disease recurrence and mortality.

Tricalcium phosphate-based biocomposites for mandibular bone regeneration--A histological study in sheep.

The present study investigated the suitability of three different absorbable biocomposites for the repair of critical sized bone defects created at the mandibular angle of adult sheep. Each biocomposite was composed of a three-dimensional individualized polylactide scaffold, containing a tricalcium phosphate biomaterial (chronOS). Either autologous bone marrow (chOS/BoneMarrow) or coagulation factor XIII (chOS/FactorXIII) was added to the biomaterial for osteopromotion. Venous whole blood (chOS/Blood) added to the biomaterial served as a control. A total of 18 adult sheep were used for implantation studies, subdivided into three groups of six animals each. After 12 weeks of observation, the animals were sacrificed and the mandibles were retrieved for qualitative and quantitative histologic assessment within three regions of interest (transitional zone, center, and periphery) throughout the biocomposites. Successful bone regeneration was defined by the absence of scaffold deformation and the presence of new bone formation within the biocomposites. In histomorphometry, only chOS/BoneMarrow showed elevated area fractions of newly formed bone in all regions of interest (transitional zone 50.7 ± 7.5, center 31.9 ± 9.3, periphery 23.1 ± 13.5). This led to preservation of the macroscopic scaffold structure in all specimens. Zero hurdle regression confirmed this by validating the factor biocomposite as significant (p < 0.001) for regeneration success. In our experiment, chOS/BoneMarrow was the only biocomposite passing the hurdle of regeneration in all three regions of interest. In contrast, bone formation was less pronounced and uniform in chOS/FactorXIII and chOS/blood-containing specimens. In these groups, scaffolds showed obvious to significant deformation. Overall, autologous bone marrow showed the most promising results in our experimental setting. As opposed to reports in the literature, we could not confirm the suitability of coagulation factor XIII to promote bone formation, since bone formation rates were comparable only to those of the control venous blood.

Upregulation of osteoprotegerin expression correlates with bone invasion and predicts poor clinical outcome in oral cancer.

OBJECTIVES: We aimed to determine the prognostic significance of receptor activator of nuclear factor kappa-B ligand (RANKL), RANK and osteoprotegerin (OPG) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The protein expression of RANKL, RANK and OPG was assessed by immunohistochemistry on pretreatment biopsies of 93 patients with locally advanced OSCC who received preoperative chemoradiotherapy (CRT). The primary endpoint was cancer-specific survival. Secondary endpoints were correlation of biomarkers with bone invasion and pathological tumor response. Kaplan-Meier curves and Cox regression models were used for survival analyses. RESULTS: A significantly higher OPG expression was demonstrated in patients with malignant bone invasion and non-responders to CRT as compared to patients without bone invasion and responders (p=0.032 and p=0.033, respectively). Multivariate analysis revealed that higher OPG expression was independently associated with shorter cancer-specific survival (p=0.04). The expression status of RANKL and RANK was not significantly related to clinicopathological characteristics and had no impact on survival of OSCC patients. CONCLUSION: Upregulation of OPG expression is associated with bone invasion, poor pathological tumor regression to neoadjuvant CRT, and worse long-term cancer-specific survival in patients with locally advanced OSCC. Our results indicate that OPG may be a novel prognostic biomarker in oral cancer.

Molecular profile of head and neck squamous cell carcinomas bearing p16 high phenotype.

BACKGROUND: We sought to determine biomarker expression differences in head and neck squamous cell cancers (HNSCCs) based on p16/human papillomavirus (HPV) classification. In addition, our aim was to explore how expression of biomarkers is modulated after E6/E7 repression in HPV16⁺ oropharyngeal cancer cells. METHODS: HPV16⁺ and HPV⁻ HNSCC cells were infected with retroviruses expressing short hairpin RNA targeting HPV16 E6/E7. Components of the epidermal growth factor receptor (EGFR) pathway before and after E6/E7 gene silencing were analyzed by immunoblotting and qRT-PCR. Protein expression of 13 biomarkers was analyzed using AQUA on a tissue microarray (TMA). The HPV16 status was determined using HPV16 in situ hybridization (ISH). RESULTS: In HPV16⁺ cells, E6/E7 silencing was associated with PTEN upregulation and reduction of phosphorylated EGFR. Tumors were classified into four categories based on the HPV and p16 status. HPV⁺/p16⁺ tumors expressed significantly higher levels of E-cadherin (P = 0.003), PTEN (P = 0.004), lower levels of PI3Kp110 and ß-catenin (P = 0.07). There was a significant difference in overall survival (OS, P = 0.016) among the four subsets. The median OS was 24.83 months for p16⁻/HPV⁻ patients, 11.63 for p16⁻/HPV⁺ patients and was not reached for p16⁺/HPV⁻ and p16⁺/HPV⁺ groups. CONCLUSIONS: Aberrant EGFR signaling contributes to malignant conversion of HPV16⁺ HNSCC cells. These results validate ß-catenin as a distinct biomarker in HPV⁺/p16⁺ HNSCC. Wnt signaling inhibitors merit exploration in HPV⁺/p16⁺ HNSCC.

Ultrasound-guided combined intermediate and deep cervical plexus nerve block for regional anaesthesia in oral and maxillofacial surgery.

OBJECTIVES: We examined the application of an ultrasound-guided combined intermediate and deep cervical plexus nerve block for regional anaesthesia in patients undergoing oral and maxillofacial surgery. METHODS: A total of 19 patients receiving ultrasound-guided combined intermediate and deep cervical plexus anaesthesia followed by neck surgery were examined prospectively. The sternocleidomastoid and the levator of the scapula muscles as well as the cervical transverse processes were used as easily depicted ultrasound landmarks for the injection of local anaesthetics. Under ultrasound guidance, a needle was advanced in the fascial band between the sternocleidomastoid and the levator of the scapula muscles and 15 ml of ropivacaine 0.75% was injected. Afterwards, the needle was advanced between the levator of the scapula and the hyperechoic contour of the cervical transverse processes and a further 15 ml of ropivacaine 0.75% was injected. The sensory block of the cervical nerve plexus, the analgesic efficacy of the block within 24 h after injection and potential block-related complications were assessed. RESULTS: All patients showed a complete cervical plexus nerve block. No patient required analgesics within the first 24 h after anaesthesia. Two cases of blood aspiration were recorded. No further cervical plexus block-related complications were observed. CONCLUSIONS: Ultrasound-guided combined intermediate and deep cervical plexus block is a feasible, effective and safe method for oral and maxillofacial surgical procedures.

HCRP1 expression status is a significant prognostic marker in oral and oropharyngeal cancer.

OBJECTIVE: The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS: HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses. RESULTS: Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02). CONCLUSION: Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy.

Is failure of condylar neck osteosynthesis predictable based on orthopantomography?

BACKGROUND: Osteosynthesis failure rates of 11.3% with 1 miniplate, 6.7% with 2 miniplates, and 4.4% with a single Medartis condyle plate were reported in previous studies of our clinic. Current science is still focused on the osteosynthesis material. Besides clinical parameters, conventional radiographs are still the first choice to detect osteosynthesis failures. This study scrutinized several factors assessable in postoperative orthopantomographs which might elevate the risk of osteosynthesis failure. STUDY DESIGN: A total of 136 patients (22 with osteosynthesis failure, 114 without) with 151 mandibular condyle fractures were included in this study. Eight parameters were assessed in postoperative orthopantomographs. RESULTS: The best predictor of osteosynthesis failure was a simplified concept of ramus height. In cases of reduced or normal ramus height, the odds of osteosynthesis failure was significantly (P = .000001) reduced to a 10th. Isolated fractures were significantly more error prone (P = .0009). CONCLUSIONS: Postoperative orthopantomographs depict factors which increase the risk of osteosynthesis failure.

Anticoagulant-induced changes on antibiotic concentrations in the serum and bones.

The aim of this study was to determine whether the co-administration of acenocoumarin as anticoagulant and certain quinolones, i.e., cefapirin, pefloxacin and ciprofloxacin increased the levels of the given antibiotics and whether this resulted in a prolongation of prothrombin time. Seventy male albino Wistar rats aged 8-10 weeks and weighed 170 +/- 14 g were used and divided into seven groups (I, II, III, IV, V, VI, VII: n=10). The rats in group I received cefapirin via 1 g/kg/8h im injection. Group II received cefapirin via of 1 g/kg/8h im injection and 0.1 mg/kg/24h p.o. acenocoumarin. Group III received ciprofloxacin 0.18 mg/kg/24h im. Group IV received ciprofloxacin 0.18 mg/kg/24h im and 0.1 mg/kg/24h p.o. acenocoumarin. Group V received 10 mg/kg/24h pefloxacin im. Group VI received 10 mg/kg/24h pefloxacin im and 0.1 mg/kg/24h p.o. acenocoumarin while Group VII received only acenocoumarin 0.1 mg/kg/24h p.o. Drug administration was performed over a total of 5 doses in order to obtain steady state concentrations in the plasma and tissues. The animals were sacrificed by decapitation 2 h after the last antibiotic administration. Prothrombin time and antibiotic concentrations in the serum, femur and mandible were assessed. In the study, all the antibiotics were found to prolong prothrombine time following acenocoumarin administration. In addition, perfloxacin and ciproflaxin concentrations were increased in the serum and mandible after acenocoumarin treatment. Cepafirin levels remained unaffected after the administration of this anticoagulant. In conclusion, anticoagulant and quinolone co-administration led to significant pharmacokinetic interactions. Thus particular attention should be paid in the case of these drugs being used in combination in clinical practice.

In vitro binding of lidocaine to liver tissue under the influence of propranolol: another mechanism of interaction?

The co-administration of lidocaine and propranolol leads to significant drug-drug interactions. Beta-blockers decrease liver perfusion and inhibit the activity of hepatic microsomal lidocaine metabolizing enzymes of the P450_2D subfamily. Hence, there is a resulting reduction in the hepatic breakdown of lidocaine and an increase in its serum concentrations. In this study the ability of propranolol to displace lidocaine from its binding sites in liver tissue has been examined through an in vitro model. Rat liver slices were incubated together with propranolol and/or lidocaine in human serum and the percentage of the bound fraction of lidocaine in the experimental mixture was assessed. The present results indicate that propranolol significantly decreases the binding process of lidocaine in liver tissue. This effect develops only when blood is used as incubation medium and the incubation period lasts 60 min. In conclusion, propranolol can displace lidocaine from liver proteins and therefore the co-administration of the two drugs may increase the free fraction of lidocaine excreted by the liver. However, this result arises from an in virro model and thus further investigation is needed.