Workforce Considerations, Training, and Certification of Physicians in Europe.

Following recent geopolitical events and unification of Europe, the European Union (EU) is currently confronted with health care workforce shortage and insufficient uniform access to quality care. Aging population, difficulties with physician retention, and mobility of health care professionals are thought to contribute to this problem. Because of the differences in medical education and residency curriculum across the European countries, there is a need for a standardized training and certification. Current government initiatives are geared toward developing common policies and programs across the EU countries to address health care access.

Oncologic outcomes of surgically treated early-stage oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to characterize oncologic outcomes in early (T1-T2, N0) and intermediate (T1-T2, N1) oropharyngeal squamous cell carcinoma (SCC) after surgery. METHODS: Patients with oropharyngeal SCC treated with surgery were identified from 2 academic institutions. RESULTS: Of 188 patients, 143 met the inclusion criteria. Eighty-six (60%) had T1 to T2 N0 and 57 (40%) had T1 to T2 N1 disease. Sixty-five patients (45%) underwent a robotic-assisted resection, whereas the remaining had transoral (n = 60; 42%), mandible-splitting (n = 11; 8%), or transhyoid approaches (n = 7; 5%). Human papillomavirus (HPV) status was known for 97 patients (68%), and 54 (55%) were HPV positive. Three-year recurrence-free survival (RFS) was 82% (95% confidence interval [CI] = 0.75-0.89). Since 2008, HPV infection was protective of recurrence (log-rank p = .0334). A single node did not increase the risk of recurrence (p = .467) or chance of a second primary (p = .175). CONCLUSION: Complete surgical resection is effective therapy for early and intermediate oropharyngeal SCC. HPV-negative patients were at increased risk for locoregional recurrence or second primary disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1471, 2016.

Early squamous cell carcinoma of the oral tongue: comparing margins obtained from the glossectomy specimen to margins from the tumor bed.

OBJECTIVES: To evaluate the impact of margin sampling on local recurrence in patients with pT1-2 pN0 conventional squamous cell carcinoma of the oral tongue. MATERIALS AND METHODS: Based on margin sampling, 126 cases were divided into group 1 (margins sampled from the glossectomy specimen only), group 2 (with revision of glossectomy margins), and group 3 (margins primarily sampled from the tumor bed). RESULTS: The probability of local progression-free survival at 3years was .90, .76 and .73 (p=.0389) in groups 1, 2, and 3, respectively. Groups differed by frequency of positive glossectomy specimen margins (p=<.0001) and by the average distance from carcinoma to the closest margin (4.5, 2.4, and 3.0mm for Groups 1, 2, and 3, respectively; p=.0009). Tumor bed margin status (positive vs. negative) and other parameters (e.g., pattern and depth of invasion) did not correlate with local recurrence. Status of the glossectomy specimen margins did correlate with outcome. A positive glossectomy margin conferred a relative risk of 2.5 (95% confidence interval, CI, 1 - 6.3) for local recurrence. A proportional hazards regression model for margin width found a hazard ratio of 0.67 (95% CI=.57-.98) comparable to a 33% decrease in risk of local recurrence for an increase of 1mm of margin width (p=.0271). CONCLUSIONS: Status of the glossectomy specimen margins rather than that of tumor bed margins was prognostically relevant. Reliance on tumor bed margins appears to be associated with worse local control, perhaps due to the narrower initial resection.

Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status.

BACKGROUND: Extracapsular spread (ECS) in cervical lymph node metastases from head and neck squamous cell carcinoma (SCC) is regarded as an adverse prognostic factor and is often used to select patients who may benefit from adjuvant therapy. The prognostic value of ECS was evaluated for patients with oropharyngeal SCC (OPC; with known p16/human papillomavirus [HPV] status) and for patients with SCC of the oral cavity (OCC). METHODS: Disease-specific survival (DSS) was assessed among SCC patients with cervical lymph node metastases (n = 347, including 133 patients with OPC and 214 patients with OCC). All patients were treated surgically between 1983 and 2009. ECS status was determined by pathologists at the time of initial pathologic evaluation and confirmed for this study. HPV status of patients with OPC was determined via immunohistochemistry for p16 and in situ hybridization. RESULTS: Among OCC patients, ECS was a significant, independent factor influencing DSS. For OCC patients with ECS, 3-year DSS was 45% (95% confidence interval [CI], 36%-56%); for those without ECS, 3-year DSS was 71% (95% CI, 62%-81%; P = .0018). The effect of ECS was independent of the number of positive lymph nodes as well as other clinical, pathologic, and treatment variables. Of the 133 OPC patients, 76 (57%) were p16-positive and 57 (43%) were p16-negative. ECS status did not correlate with DSS among p16-positive or p16-negative OPC patients. CONCLUSION: ECS was not associated with worse DSS in p16-positive or p16-negative OPC patients. Adverse prognostic value of ECS in OCC patients was confirmed. Cancer 2013;119:3302-8. © 2013 American Cancer Society.

Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer.

BACKGROUND: Natural killer (NK) cells and dendritic cells (DCs) mediate tumor cell apoptosis using tumor necrosis factor superfamily ligands (TNFSFLs). This cytotoxicity is an important anticancer immune defense mechanism. METHODS: We examined TNFSFL expression and apoptotic tumoricidal activity (ATA) of purified NK cells and DCs, and peripheral blood mononuclear leukocytes (PBMLs) of healthy individuals and patients with head and neck cancer (HNC) before and after cancer ablation. RESULTS: PBMLs, NK cells and DCs, but not NK-cell/DC-depleted PBMLs, expressed multiple TNFSFLs and mediated ATA. Both TNFSFL expression and ATA were suppressed in tumor-bearing, and restored in tumor-ablated patients with (HNC) Soluble TNF superfamily receptors (solTNFSFRs) were increasingly bound by PBNLs of tumor-bearing HNC patients. Dissociation of solTNFSFR led to more pronounced increases in TNFSFL expression and ATA of PBMLs of patients with HNC than healthy individuals. CONCLUSION: NK-cell and DC TNFSFL expression and ATA are suppressed in patients with HNC. This suppression is tumor-dependent and possibly mediated by solTNFSFRs.

Cost-identification analysis of total laryngectomy: an itemized approach to hospital costs.

OBJECTIVES: To understand the contribution of intraoperative and postoperative hospital costs to total hospital costs, examine the costs associated with specific hospital services in the postoperative period, and recognize the impact of patient factors on hospital costs. STUDY DESIGN: Case series with chart review. SETTING: Large tertiary care teaching hospital system. SUBJECTS AND METHODS: Using the Pittsburgh Head and Neck Organ-Specific Database, 119 patients were identified as having total laryngectomy with bilateral selective neck dissection and primary closure from 1999 to 2009. Cost data were obtained for 112 patients. Costs include fixed and variable costs, adjusted to 2010 US dollars using the Consumer Price Index. RESULTS: Mean total hospital costs were $29,563 (range, $10,915 to $120,345). Operating room costs averaged 24% of total hospital costs, whereas room charges, respiratory therapy, laboratory, pharmacy, and radiology accounted for 38%, 14%, 8%, 7%, and 3%, respectively. Median length of stay was 9 days (range, 6-43), and median Charlson comorbidity index score was 8 (2-16). Patients with ≥1 day in the intensive care unit had significantly higher hospital costs ($46,831 vs $24,601, P < .01). The authors found no significant cost differences with stratification based on previous radiation therapy ($27,598 vs $29,915 with no prior radiation, P = .62) or hospital readmission within 30 days ($29,483 vs $29,609 without readmission, P = .97). CONCLUSION: This is one of few studies in surgery and the first in otolaryngology to analyze hospital costs for a relatively standardized procedure. Further work will include cost analysis from multiple centers with investigation of global cost drivers.

Prognostic factors in patients with high-risk locally advanced salivary gland cancers treated with surgery and postoperative radiotherapy.

BACKGROUND: This study was designed to identify the factors associated with the outcome after standard treatment with surgery and postoperative radiotherapy (RT) for locally advanced salivary gland cancers. METHODS: We conducted a retrospective review of patients with salivary gland cancers registered in the University of Pittsburgh databases from 1990 to 2006. RESULTS: A total of 74 patients were analyzed. Histologic types included salivary duct carcinoma, 24%; adenoid cystic carcinoma, 23%; and adenocarcinoma, 19%; N2, 39%; N0-1, 58%; and major salivary gland origin, 80%. With a median follow-up of 4.1 years, the 5-year recurrence-free survival (RFS) was 49%, and the 5-year overall survival (OS) was 55%. The 5-year local RFS was 76% and the 5-year distant RFS was 60%. Using Cox-regression analysis, advanced N classification (N2) was the only significant predictor of both RFS and OS. CONCLUSION: The long-term survival of patients with high-risk, locally advanced salivary gland cancers is unsatisfactory. Advanced nodal disease is strongly associated with patient outcome and should be considered as a stratification factor in future trials in locally advanced salivary gland cancers.

Head and neck oncology--2010, part II.

Part II this article reviewed the current state of the art in head and neck oncology. These include very important and stimulating new areas of interest including the marked acceptance of chemoradiation in favor of surgery in patients with cancer of the head and neck. The concept of HPV as a cause of cancer of the oropharynx is relatively new and very important in the epidemiology of these tumors. New modalities such as PET CT scanning and robotic surgery are discussed and appear to be very important in management of cancer of the head and neck. Endoscopic endonasal skull base surgery is another new high technology contribution to the field of head and neck surgery as is the use of endoscopic assisted thyroid surgery. These and other new concepts are discussed in this manuscript.

Head and neck oncology--2010, Part I.

This article reviewed the current state of the art in head and neck oncology. These include very important and stimulating new areas of interest including the marked acceptance of chemoradiation in favor of surgery in patients with cancer of the head and neck. The concept of HPV as a cause of cancer of the oropharynx is relatively new and very important in the epidemiology of these tumors. New modalities such as PET CT scanning and robotic surgery are discussed and appear to be very important in management of cancer of the head and neck. Endoscopic endonasal skull base surgery is another new high technology contribution to the field of head and neck surgery as is the use of endoscopic assisted thyroid surgery. These and other new concepts are discussed in this manuscript.

Polymorphous low-grade adenocarcinoma: the University of Pittsburgh experience.

OBJECTIVE: To reappraise the clinical and histologic variables associated with a more aggressive outcome in polymorphous low-grade adenocarcinoma (PLGA). DESIGN: Retrospective cohort. SETTING: University hospital. PATIENTS: Twenty-four patients with PLGA treated from January 1, 1973, through December 31, 2005. MAIN OUTCOME MEASURE: Analysis of clinical and pathologic variables in 30 biopsy or resection specimens from 24 patients. RESULTS: Only 4 PLGAs were not initially diagnosed as such. However, 8 non-PLGAs (thus excluded) were incorrectly diagnosed as PLGA. Most carcinomas (14 of 24 [58%]) were palatal. Recurrent carcinomas had a significantly higher mitotic rate (2.7 mitoses per 10 high-power fields) compared with primary tumors (1.2 mitoses per high-power fields, P = .046), and 3 of 7 (43%) recurrences showed progression to an intermediate-grade histologic type. No patient died of disease. Median disease-free survival was 12.8 years. Four of 24 patients (17%) had regional lymph node metastases, 3 with carcinomas of the base of the tongue. One PLGA metastasized to the subcutaneous tissue of the face, orbit, and lungs at 19.6 years. An extrapalatal site was the only significant determinant of disease-free survival (P = .03). CONCLUSIONS: Diagnosis of PLGA remains a challenge. Extrapalatal carcinomas appear to behave in a more aggressive fashion than those of the palate, and cancer arising from the base of the tongue frequently metastasizes to the cervical lymph nodes, suggesting a role for neck dissection in these patients. Recurrent cancers show evidence of histologic progression, justifying an aggressive approach to achieving initial complete excision.

Sheddase activity of tumor necrosis factor-alpha converting enzyme is increased and prognostically valuable in head and neck cancer.

Tumor necrosis factor alpha converting enzyme (TACE) is a sheddase overexpressed in cancers that generates cancer cell growth and survival factors, and is implicated in carcinogenesis and tumor growth. This indicates that TACE could be a potentially important cancer biomarker. Unexpectedly, TACE expression in cancer tissues does not correlate with cancer stage or invasiveness. Although TACE sheddase activity is a more direct and potentially better indicator of TACE biology and might be a better cancer biomarker than TACE expression, it has not been studied in cancer tissues. In the present study, we developed a reliable specific assay for quantification of TACE sheddase activity, investigated TACE activity and TACE protein expression in head and neck cancer (HNC) tissues, and examined the correlation of the results with HNC clinical stages and likelihood to recur. We found that HNC cell lines and tissues contained remarkably higher quantities of TACE activity and TACE protein than normal keratinocytes or oral mucosa. siRNA silencing of TACE resulted in the inhibition of release of the tumorogenic factors amphiregulin and transforming growth factor alpha, and tumor protective factors tumor necrosis factor receptors from HNC cells. Importantly, TACE activity, but not TACE protein expression, was significantly higher in large, T3/T4, primary tumors relative to small, T1/T2, primary tumors, and especially in primary tumors likely to recur relative to those unlikely to recur. These data show that increased TACE activity in cancer is biologically and clinically relevant, and indicate that TACE activity could be a significant biomarker of cancer prognosis.

Management of squamous cell carcinoma of the base of tongue with chemoradiation and brachytherapy.

BACKGROUND: Treatment of base of tongue (BOT) squamous cell carcinoma (SCC) has traditionally been associated with poor prognosis and significant morbidity. We report a program consisting of concurrent chemoradiation followed by brachytherapy for these patients. METHODS: We reviewed all patients in our institution with previously untreated BOT SCC (1996-2004) who received this treatment program. RESULTS: In 88 patients (median age, 60.2 years; 37 T1/T2; 51 T3/T4), cervical lymph node metastases were present in 71 patients (80.7%). Six patients had residual/subsequent cervical metastases requiring 7 neck dissections. Local recurrence occurred in 16 patients (18.2%) and distant metastases occurred in 9 patients (10.2%). Median follow-up time was 3.1 years (range, 0.5-7.8 years). Three-year overall survival was 80.9% (95% CI: 69.6% to 88.3%). Locoregional control rate was 79.9% and disease-specific survival was 69.5% at 3 years. CONCLUSIONS: Concurrent chemoradiotherapy followed with brachytherapy is a safe and effective method of treatment of SCC of the BOT.

Incidence and patterns of regional metastasis in early oral squamous cell cancers: feasibility of submandibular gland preservation.

BACKGROUND: We aimed to study the incidence of metastasis to the submandibular gland (SMG) and to establish the oncologic basis of SMG preservation in early-stage cancer of the oral cavity (OSCC). METHODS: This was a retrospective study of 261 patients with OSCC treated primarily with surgery at a tertiary medical center. One hundred thirty-two early-stage (T1-2, N0) OSCCs were further analyzed. RESULTS: The mean age was 59 years with male-to-female sex ratio of 1.4:1. Two hundred sixty-one neck dissections were performed with SMG removal in 253 patients. One patient with an advanced floor of mouth cancer had obvious infiltration of the SMG. Only 2.5% (3 of 116) patients with early-stage OSCC had level I metastasis; none had SMG metastases. CONCLUSION: SMG preservation in early cancers (T1-2, N0) of the oral cavity should be feasible unless there is evidence of direct invasion of the gland or close proximity of the cancer to it.

Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms.

PURPOSE: Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. PATIENTS AND METHODS: Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 microg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. RESULTS: Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). CONCLUSION: Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects.

Ocular outcomes after gold weight placement and facial nerve resection.

OBJECTIVE: To assess the effectiveness of acute gold weight placement after facial nerve resection and to determine the role of concomitant lower eyelid procedures. STUDY DESIGN: Retrospective review. SUBJECTS AND METHODS: Twenty-two patients who received an upper eyelid gold weight at the time of parotidectomy and facial nerve resection were reviewed to assess ocular outcomes. RESULTS: After gold weight placement, twelve patients (12 of 22, 54.5%) subsequently presented with symptomatic ectropion (n = 9) and/or lagophthalmos (n = 5). Nine patients received a lower eyelid procedure (7 tarsal strips only, 1 tarsal strip combined with a lateral tarsorrhaphy, and 1 lateral tarsorrhaphy only). Six patients, in addition to a gold weight, also underwent a static sling to the midface at the time of facial nerve resection. None of these 6 received a subsequent lower eyelid procedure. Two patients required gold weight upsizing. Two patients required weight removal. CONCLUSIONS: Insertion of 1.2 gm upper eyelid weight with placement of midface sling is recommended at the time of facial nerve resection. Due to the need to tighten the lower eyelid in many of these patients, we now also consider performing a tarsal strip procedure at the time of facial nerve resection in any patient with pre-existing lower lid laxity.

Treatment and survival outcomes based on histologic grading in patients with head and neck mucoepidermoid carcinoma.

BACKGROUND: Histopathologic grade of mucoepidermoid carcinoma (MEC) is an established predictor of prognosis and affects treatment protocol. Tumor behavior is more aggressive in high-grade than in low-grade MEC, leading to a more intensive treatment protocol. Outcomes for patients with intermediate-grade MEC are less clear; therefore, the optimal treatment protocol for this group is not well defined. The treatment protocol and survival outcomes of patients treated for MEC of the head and neck was investigated. METHODS: A retrospective clinical review and prospective review of histopathologic grading were undertaken using the most recently established grading system of 50 patients with MEC of the head and neck from 1983 through 2004. RESULTS: As histologic grade increased from low to intermediate to high, overall survival (P < .0001) and disease-free survival (P < .001) were significantly decreased. Overall and disease-free survival were significantly better for patients with intermediate-grade MEC than those with high-grade disease. Overall and disease-free survival were similar for patients with low-grade and intermediate-grade MEC. There was a low rate of disease recurrence in patients with intermediate-grade MEC, but this did not lead to death from disease. Although no patients with low-grade or intermediate-grade MEC died of disease, 52% of patients with high-grade MEC died of disease. Multivariate analysis revealed that histologic grade, age, and surgical margin status significantly predicted prognosis. CONCLUSIONS: These findings suggest that, under the current histopathologic classification system, the behavior of intermediate-grade MEC is comparable to that of low-grade MEC and different from high-grade MEC, allowing for the establishment of an evidence-based treatment protocol.

Chromosomal imbalances in oral squamous cell carcinoma: examination of 31 cell lines and review of the literature.

Classical and molecular cytogenetic analysis, including fluorescence in situ hybridization (FISH) and chromosomal comparative genomic hybridization (CGH), were used to examine genetic changes involved in the development and/or progression of oral squamous cell carcinoma (OSCC). Of 31 OSCC cell lines studied, more than one-third expressed clonal structural abnormalities involving chromosomes 3, 7, 8, 9, and 11. Eleven OSCC cell lines were evaluated using CGH to identify novel genome-wide gains, losses, or amplifications. By CGH, more than half of the cell lines showed loss of 3p, gain of 3q, 8q, and 20q. Further, molecular cytogenetic analyses by FISH of primary tumors showed that the karyotypes of cell lines derived from those tumors correlated with specific gains and losses in the tumors from which they were derived. The most frequent nonrandom aberration identified by both karyotype and CGH analyses was amplification of chromosomal band 11q13 in the form of a homogeneously staining region. Our data suggest that loss of 9p and 11q13 amplification may be of prognostic benefit in the management of OSCC, which is consistent with the literature. The results of this study validate the relationship between these OSCC cell lines and the tumors from which they were derived. The results also emphasize the usefulness of these cell lines as in vitro experimental models and provide important genetic information on these OSCC cell lines that were recently reported in this journal.

Reconstruction of the marginal mandibulectomy defect: an update.

OBJECTIVE: The purpose of this study is to provide an update to the reconstructive management of the marginal mandibulectomy defect. STUDY DESIGN: Twenty-six consecutive patients were retrospectively reviewed. METHODS: Patient and tumor variables were extracted from the medical record. Outcomes that were examined included method of reconstruction, frequency of osteoradionecrosis, and resumption of an oral diet. RESULTS: Fifteen (57.7%), 8 (30.8%), and 3 (11.5%) patients were reconstructed with a skin graft, primary closure, or a radial forearm free flap, respectively. Indications for a radial forearm free flap were reconstruction of an associated subtotal glossectomy defect, a through-and-through cheek defect, and a maxillectomy defect. Five patients reconstructed with a skin graft also received postoperative radiation therapy. One (20%) developed osteoradionecrosis. Excluding patients with recurrent tumors (n = 5) or osteoradionecrosis (n = 1), all patients at last follow-up were maintaining an oral diet. CONCLUSIONS: Skin graft remains a preferred method of reconstruction for the marginal mandibular defect. A free flap is reserved for those marginal defects where additional soft tissue is needed to reconstruct subtotal glossectomy defects or defects of the midface and/or maxilla. Because of the potentially increased risk of osteoradionecrosis, reconstruction with a free flap instead of a skin graft should be considered if a patient will receive postoperative radiation therapy.

The influence of clinical and demographic risk factors on the establishment of head and neck squamous cell carcinoma cell lines.

The purpose of this study was to generate stable cell cultures from head and neck squamous cell carcinomas (HNSCC), and retrospectively analyze the factors associated with successful cell line establishment. Fifty-two HNSCC cell lines were isolated from a series of 199 tumors collected between 1992 and 1997 at the University of Pittsburgh Medical Center. Cell lines were characterized at the molecular and cellular level to determine the features associated with cell line formation. Successful cell line formation was dependent on multiple factors, including gene amplification involving chromosomal band 11q13, local and/or regional involvement of lymph nodes, and alcohol usage. The establishment of HNSCC cell lines enriches the resources available for cancer research. Our findings indicate that generation of stable cell lines from HNSCC is biased towards tumors with a poor prognosis. Our 52 stable lines comprise one of the largest series of HNSCC cell lines in the literature, with complete demographic, histopathologic, clinical, and survival data.