Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Clinicians' Views of Patient-initiated Follow-up in Head and Neck Cancer: a Qualitative Study to Inform the PETNECK2 Trial.

AIMS: Current follow-up for head and neck cancer (HNC) is ineffective, expensive and fails to address patients' needs. The PETNECK2 trial will compare a new model of patient-initiated follow-up (PIFU) with routine scheduled follow-up. This article reports UK clinicians' views about HNC follow-up and PIFU, to inform the trial design. MATERIALS AND METHODS: Online focus groups with surgeons (ear, nose and throat/maxillofacial), oncologists, clinical nurse specialists and allied health professionals. Clinicians were recruited from professional bodies, mailing lists and personal contacts. Focus groups explored views on current follow-up and acceptability of the proposed PIFU intervention and randomised controlled trial design (presented by the study co-chief investigator), preferences, margins of equipoise, potential organisational barriers and thoughts about the content and format of PIFU. Data were interpreted using inductive thematic analysis. RESULTS: Eight focus groups with 34 clinicians were conducted. Clinicians highlighted already known limitations with HNC follow-up - lack of flexibility to address the wide-ranging needs of HNC patients, expense and lack of evidence - and agreed that follow-up needs to change. They were enthusiastic about the PETNECK2 trial to develop and evaluate PIFU but had concerns that PIFU may not suit disengaged patients and may aggravate patient anxiety/fear of recurrence and delay detection of recurrence. Anticipated issues with implementation included ensuring a reliable route back to clinic and workload burden on nurses and allied health professionals. CONCLUSIONS: Clinicians supported the evaluation of PIFU but voiced concerns about barriers to help-seeking. An emphasis on patient engagement, psychosocial issues, symptom reporting and reliable, quick routes back to clinic will be important. Certain patient groups may be less suited to PIFU, which will be evaluated in the trial. Early, meaningful, ongoing engagement with clinical teams and managers around the trial rationale and recruitment process will be important to discourage selective recruitment and address risk-averse behaviour and potential workload burden.

Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study.

AIMS: The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS: Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS: Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION: In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Oropharyngeal Cancers in the East and the West - Implications of Aetiopathogenesis on Prognosis and Research.

There has been a surge in human papillomavirus (HPV)-positive oropharyngeal cancers (OPCs) in the West. Although the prognosis of HPV-positive OPC is good, de-escalation strategies have so far not been able to confirm comparable cancer control. We examine the strategies implemented across the globe to safely reduce toxicities in HPV-positive disease. HPV-negative OPC has a poorer prognosis and is more prevalent in Eastern countries. We outline the intensification strategies currently used in HPV-negative cancers, with an aim to better prognosis. With recent improvements in clinical trial frameworks in Eastern countries such as India, we discuss areas where joint collaborative research between Western and Eastern countries could further improve outcomes in OPC.

Provision of physiotherapy rehabilitation following neck dissection in the UK.

BACKGROUND: Neck dissection is associated with post-operative shoulder dysfunction in a substantial number of patients, affecting quality of life and return to work. There is no current UK national practice regarding physiotherapy after neck dissection. METHOD: Nine regional centres were surveyed to determine their standard physiotherapy practice pre- and post-neck dissection, and to determine pre-emptive physiotherapy for any patients. RESULTS: Eighty-nine per cent of centres never arranged any pre-emptive physiotherapy for any patients. Thirty-three per cent of centres offered routine in-patient physiotherapy after surgery. No centres offered out-patient physiotherapy for all patients regardless of symptoms. Seventy-eight per cent offered physiotherapy for patients with any symptoms, with 11 per cent offering physiotherapy for those with severe dysfunction only. Eleven per cent of centres never offered physiotherapy for any dysfunction. CONCLUSION: The provision of physiotherapy is most commonly reactive rather than proactive, and usually driven by patient request. There is little evidence of pre-arranged physiotherapy for patients to treat or prevent shoulder dysfunction in the UK.

Feasibility of Dose-escalated Hypofractionated Chemoradiation in Human Papilloma Virus-negative or Smoking-associated Oropharyngeal Cancer.

AIMS: Oropharyngeal squamous cell carcinoma (OPSCC) can be divided into favourable and poor prognostic groups by association with human papilloma virus (HPV) and smoking. This study prospectively investigated a dose-intensified schedule in poor/intermediate prognosis OPSCC. MATERIALS AND METHODS: Patients with p16/HPV-negative or p16-positive N2b OPSCC with a greater than 10 pack-year smoking history were eligible. Patients were planned to receive 64 Gy in 25 fractions with cisplatin. The primary end point was absence of grade 3 mucositis at 3 months. RESULTS: Fifteen patients were recruited over 14 months. All patients completed a minimum of 2 years of follow-up. All patients completed full-dose radiotherapy within a median treatment time of 32 days (31-35). Grade 3 mucositis was absent in all patients at 3 months. There was one grade 4 toxicity event due to cisplatin (hypokalaemia). Complete response rates at 3 months were 100% and 93% for local disease and lymph nodes, respectively. One patient developed metastatic disease and subsequently died. Overall survival at 2 years was 93% (95% confidence interval 61-99%). CONCLUSIONS: The schedule of 64 Gy in 25 fractions with concomitant chemotherapy is tolerable in patients with poor and intermediate prognosis OPSCC.

Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer.

BACKGROUND: A recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography-computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective. METHODS: Initial 6-month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality-adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader National Health Service (NHS) and personal social services (PSS) costs on the results. RESULTS: PET-CT management produced an average per-person lifetime cost saving of £1485 and an additional 0.13 QALYs. At a £20,000 willingness-to-pay per additional QALY threshold, there was a 75% probability that PET-CT was cost-effective, and the results remained cost-effective over the majority of sensitivity analyses. When adopting a broader NHS and PSS perspective, PET-CT management produced an average saving of £700 and had an 81% probability of being cost-effective. CONCLUSIONS: This analysis indicates that PET-CT-guided management is cost-effective in the long-term and supports the case for wide-scale adoption.

A Q methodology study to investigate the experiences of head and neck cancer patients from diagnosis to 1 year.

The experiences of disease and treatment for patients diagnosed with head and neck cancer (H&NC) are known to be important indicators of the quality of care but are represented poorly in the literature. Survival is a major outcome measure to which health-related quality of life (HRQoL) adds detail but outcomes are not fully representative of the patients' experiences because quality of care and reality of treatment are overlooked. This study explored the HRQoL, quality of care and reality of treatment themes using a mixed-methods approach, Q Methodology. In total, 18 participants who were at least 12 months post-diagnosis rank-ordered 45 prepared statements to reflect their own experiences of H&NC. After the statements had been sorted, the participants reviewed the order in an interview to clarify experiences. The statements become a way of facilitating the discussion because the participant can explain the position of specific statements that are notable for them. The ranking was factor-analysed case-wise and five factors provided the best conceptual fit: meaning and attachment to illness; overwhelmed by the cancer; surviving or not; change and recovery; and keep control for the greater good of others. The findings suggest there are distinct ways that H&NC patients experience the disease and its treatment. The concept of the experience being different and defined for individuals has practical implications at a clinical level and is a way of ensuring care is truly patient-centred.

Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. There has been significant debate in the management of oropharyngeal cancer in the last decade, especially in light of the increased incidence, clarity on the role of the human papilloma virus in this disease and the treatment responsiveness of the human papilloma virus positive cancers. This paper discusses the evidence base pertaining to the management of oropharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. Recommendations • Cross-sectional imaging is required in all cases to complete assessment and staging. (R) • Magnetic resonance imaging is recommended for primary site and computed tomography scan for neck and chest. (R) • Positron emission tomography combined with computed tomography scanning is recommended for the assessment of response after chemoradiotherapy, and has a role in assessing recurrence. (R) • Examination under anaesthetic is strongly recommended, but not mandatory. (R) • Histological diagnosis is mandatory in most cases, especially for patients receiving treatment with curative intent. (R) • Oropharyngeal carcinoma histopathology reports should be prepared according to The Royal College of Pathologists Guidelines. (G) • Human papilloma virus (HPV) testing should be carried out for all oropharyngeal squamous cell carcinomas as recommended in The Royal College of Pathologists Guidelines. (R) • Human papilloma virus testing for oropharyngeal cancer should be performed within a diagnostic service where the laboratory procedures and reporting standards are quality assured. (G) • Treatment options for T1-T2 N0 oropharyngeal squamous cell carcinoma include radical radiotherapy or transoral surgery and neck dissection (with post-operative (chemo)radiotherapy if there are adverse pathological features on histological examination). (R) • Transoral surgery is preferable to open techniques and is associated with good functional outcomes in retrospective series. (R) • If treated surgically, neck dissection should include levels II-IV and possibly level I. Level IIb can be omitted if there is no disease in level IIa. (R) • If treated with radiotherapy, levels II-IV should be included, and possibly level Ib in selected cases. (R) • Altering the modalities of treatment according to HPV status is currently controversial and should be undertaken only in clinical trials. (R) • Where possible, patients should be offered the opportunity to enrol in clinical trials in the field. (G).

Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. Recurrent cancers present some of the most challenging management issues in head and neck surgical and oncological practice. This is rendered even more complex by the poor evidence base to support management options, the substantial implications that treatments can have on the function and quality of life, and the difficult decision-making considerations for supportive care alone. This paper provides consensus recommendations on the management of recurrent head and neck cancer. Recommendations • Consider baseline and serial scanning with computed tomography and/or magnetic resonance (CT and/or MR) to detect recurrence in high-risk patients. (R) • Patients with head and neck cancer recurrence being considered for active curative treatment should undergo assessment by positron emission tomography combined with computed tomography (PET-CT) scan. (R) • Patients with recurrence should be assessed systematically by a team experienced in the range of management options available for recurrence including surgical salvage, re-irradiation, chemotherapy and palliative care. (R) • Management of patients with laryngeal recurrence should include input from surgeons with experience in transoral surgery and partial laryngectomy for recurrence. (G) • Expertise in transoral surgery and partial laryngectomy for recurrence should be concentrated to a few surgeons within each multidisciplinary teams. (G) • Transoral or open partial laryngectomy should be offered as definitive treatment modality for highly-selected patients with recurrent laryngeal cancer. (R) • Patients with OPC recurrence should have p16 human papilloma virus status assessed. (R) • Patients with OPC recurrence should be considered for salvage surgical treatment by an experienced team, with reconstructive expertise input. (G) • Transoral surgery appears to be an effective alternative to open surgery for the management of OPC recurrence in carefully selected patients. (R) • Consider elective selective neck dissections in patients with recurrent primaries with N0 necks, especially in advanced cases. (R) • Selective neck dissection (with preservation of nodal levels, especially level V, that are not involved by disease) in patients with nodal (N+) recurrence appears to be as effective as modified or radical neck dissections. (R) • Use salivary bypass tubes following salvage laryngectomy. (R) • Use interposition muscle-only pectoralis major or free flap for suture line reinforcement if performing primary closure following salvage laryngectomy. (R) • Use inlaid pedicled or free flap to close wound if there is tension at the anastomosis following laryngectomy. (R) • Perform secondary puncture in post chemoradiotherapy laryngectomy patients. (R) • Triple therapy with platinum, cetuximab and 5-fluorouracil (5-FU) appears to provide the best outcomes for the management of patients with recurrence who have a good performance status and are fit to receive it. If not fit, then combinations of platinum and cetuximab or platinum and 5-FU may be considered. (R) • Patients with non-resectable recurrent disease should be offered the opportunity to participate in phases I-III clinical trials of new therapeutic agents. (R) • Chemo re-irradiation appears to improve locoregional control, and may have some benefit for overall survival, at the risk of considerable acute and late toxicity. Benefit must be weighed carefully against risks, and patients must be counselled appropriately. (R) • Target volumes should be kept tight and elective nodal irradiation should be avoided. (R) • Best supportive care should be offered routinely as part of the management package of all patients with recurrent cancer even in the case of those who are being treated curatively. (R).

Management of neck metastases in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. A rational plan to manage the neck is necessary for all head and neck primaries. With the emergence of new level 1 evidence across several domains of neck metastases, this guideline will identify the evidence-based recommendations for management. Recommendations • Computed tomographic or magnetic resonance imaging is mandatory for staging neck disease, with choice of modality dependant on imaging modality used for the primary site, local availability and expertise. (R) • Patients with a clinically N0 neck, with more than 15-20 per cent risk of occult nodal metastases, should be offered prophylactic treatment of the neck. (R) • The treatment choice of for the N0 and N+ neck should be guided by the treatment to the primary site. (G) • If observation is planned for the N0 neck, this should be supplemented by regular ultrasonograms to ensure early detection. (R) • All patients with T1 and T2 oral cavity cancer and N0 neck should receive prophylactic neck treatment. (R) • Selective neck dissection (SND) is as effective as modified radical neck dissection for controlling regional disease in N0 necks for all primary sites. (R) • SND alone is adequate treatment for pN1 neck disease without adverse histological features. (R) • Post-operative radiation for adverse histologic features following SND confers control rates comparable with more extensive procedures. (R) • Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates. (R) • Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins. (R) • Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered positron emission tomography-computed tomography (PET-CT) scans performed at 10-12 weeks, do not need salvage neck dissection. (R) • Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET-CT. (R).

Reconstructive considerations in head and neck surgical oncology: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. The reconstructive needs following ablative surgery for head and neck cancer are unique and require close attention to both form and function. The vast experience accrued with microvascular reconstructive surgery has meant a significant expansion in the options available. This paper discusses the options for reconstruction available following ablative surgery for head and neck cancer and offers recommendations for reconstruction in the various settings. Recommendations • Microsurgical free flap reconstruction should be the primary reconstructive option for most defects of the head and neck that need tissue transfer. (R) • Free flaps should be offered as first choice of reconstruction for all patients needing circumferential pharyngoesophageal reconstruction. (R) • Free flap reconstruction should be offered for patients with class III or higher defects of the maxilla. (R) • Composite free tissue transfer should be offered as first choice to all patients needing mandibular reconstruction. (R) • Patients undergoing salvage total laryngectomy should be offered vascularised flap reconstruction to reduce pharyngocutaneous fistula rates. (R).

Long-term survival outcomes in patients with surgically treated oropharyngeal cancer and defined human papilloma virus status.

OBJECTIVE: This study investigated long-term survival outcomes in surgically treated oropharyngeal cancer patients with known human papilloma virus status. METHODS: A case note review was performed of all patients undergoing primary surgery for oropharyngeal cancer in a single centre over a 10-year period. Human papilloma virus status was determined via dual modality testing. Associations between clinicopathological variables and survival were identified using a log-rank test. RESULTS: Of the 107 cases in the study, 40 per cent (n = 41) were human papilloma virus positive. The positive and negative predictive values of p16 immunohistochemistry for human papilloma virus status were 57 per cent and 100 per cent, respectively. At a mean follow up of 59.5 months, 5-year overall and disease-specific survival estimates were 78 per cent and 69 per cent, respectively. Human papilloma virus status (p = 0.014), smoking status (p = 0.021) and tumour stage (p = 0.03) were significant prognostic indicators. CONCLUSION: The long-term survival rates in surgically treated oropharyngeal cancer patients were comparable to other studies. Variables including human papilloma virus status and tumour stage were associated with survival in patients treated with primary surgery; however, nodal stage and presence of extracapsular spread were non-prognostic.

Resection of subsequent pulmonary metastases from treated head and neck squamous cell carcinoma: systematic review and meta-analysis.

BACKGROUND: Pulmonary metastasectomy involves the surgical removal of pulmonary nodules. It is a recognised therapeutic modality for the treatment of metastatic disease. There is no consensus as to the role of pulmonary metastasectomy in squamous cell carcinoma of the head and neck. The objective of this study was to determine whether, in selected patients, resection of subsequent pulmonary metastases prolongs survival in patients already treated for head and neck squamous cell carcinoma and to identify independent risk factors that influence 5-year survival of patients undergoing pulmonary metastasectomy. METHODS: A systematic review of English and non-English articles using MEDLINE (1950-present), EMBASE (1980-present), NHS evidence and Cochrane databases. Search terms included but were not limited to: squamous cell carcinoma, pulmonary metastasectomy or resection, head and neck cancer, malignancy or tumour. Studies examining outcomes for patients with head and neck squamous cell carcinoma who underwent pulmonary metastasectomy for metachronous pulmonary metastases were included. Independent data extraction of articles by two trained researchers using predefined data fields was performed. RESULTS: Thirteen of 47 studies (all retrospective) fulfilled eligibility criteria, with a total of 403 patients. In total, 11 papers reported 5-year survival rates (Kaplan-Meier) in 387 patients with head and neck squamous cell carcinoma following pulmonary metastasectomy. Meta-analysis of survival data showed an overall absolute 5-year survival rate of 29.1% for patients undergoing pulmonary metastasectomy for metachronous metastases from head and neck squamous cell carcinoma. Two papers reported significantly worse 5-year survival rates in patients with oral head and neck squamous cell carcinoma compared with other sites (9.2% versus 32.4%, P < 0.001 and 15.4% versus 45.2%, P = 0.01). Two papers reported that the presence of cervical lymph node metastases at diagnosis of the primary tumour significantly worsened 5-year survival rates following pulmonary metastasectomy (13.8% (N+) versus 32% (N0) P = 0.01 and 24% (N+) versus 60% (N0) P = 0.025). Other significant poor prognostic factors included incomplete pulmonary resection and the presence of multiple pulmonary nodules. CONCLUSIONS: This systematic review provides level 2a evidence of the effectiveness of pulmonary metastasectomy for metachronous pulmonary metastases from head and neck squamous carcinoma, which may offer prolonged survival for selected patients. Poor prognostic factors for pulmonary metastasectomy in this cohort of patients include the presence of lymph node metastasis at the diagnosis of the original tumour, squamous cell carcinoma of the oral cavity, incomplete pulmonary resection and the presence of multiple pulmonary nodules.

Tetraspanins CD9 and CD151, epidermal growth factor receptor and cyclooxygenase-2 expression predict malignant progression in oral epithelial dysplasia.

BACKGROUND: Prognostic biomarkers aim to improve on the current inadequate method of histological assessment to identify patients with oral epithelial dysplasia at greatest risk of malignant transformation. We aimed to assess the prognostic ability of six protein biomarkers linked to the epidermal growth factor receptor (EGFR) pathway, including three tetraspanins, in a large multicentre oral dysplasia cohort. METHODS: One hundred and forty-eight cases with varying degrees of epithelial dysplasia underwent immunohistochemical assessment for CD9, CD151, CD82, EGFR, Her-2, and COX-2. Scoring was performed independently by two observers. Univariate analyses using both logistic and Cox regression models and a multivariate regression were performed. RESULTS: Malignant progression was significantly greater in those cases with decreased expression of CD9 (P=0.02), and increased expression of CD151 (P=0.02), EGFR (P=0.04), and COX-2 (P=0.003). Histological grade (P=0.0002) and morphology (P=0.03) were also prognostic, whereas smoking and alcohol were not. The optimal combination by backward-variable selection was of histological grade (hazard ratio (HR) 1.64; 95% CI 1.12, 2.40), COX-2 overexpression (HR 1.12; 1.02, 1.24) and CD9 underexpression (HR 0.88; 0.80, 0.97). CD82 and Her-2 demonstrated no prognostic ability. CONCLUSION: This is the first study of the expression and prognostic potential of the tetraspanins in oral dysplasia. A combination of certain biomarkers with clinical factors appeared to improve the accuracy of determining the risk of malignancy in individuals with oral dysplasia. These findings may also offer potential new therapeutic approaches for this condition.

PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8.

Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.

Dexamethasone reduces pain, vomiting and overall complications following tonsillectomy in adults: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Tonsillectomy is one of the most common surgical procedures, but there is debate whether systemic steroids should be used to reduce pain and post-operative complications. OBJECTIVE OF REVIEW: To determine whether peri-operative steroids reduce post-tonsillectomy pain and complications in adults. TYPE OF REVIEW: Systematic review and meta-analysis of randomised controlled trials. SEARCH STRATEGY: We searched MEDLINE (1950-2010), EMBASE (1980-2010), CINAHL (1981-2010), Web of Science, ProQuest, metaRegister, Conference Proceedings Citation Index, the Cochrane Library and reference lists of relevant studies. EVALUATION METHOD: Two reviewers independently selected trials and extracted data on their quality, characteristics and results. Trials included adults (age >16 years) undergoing elective tonsillectomy where peri-operative steroids were used, and the results were compared with control or placebo. RESULTS: There were seven randomised controlled trials (580 patients) reporting post-operative pain. Meta-analysis demonstrates that dexamethasone in adults reduces the pain level experienced in the first post-tonsillectomy day [standard mean difference (SMD): -0.63, 95% CI: -1.13 to -0.12] with significant heterogeneity (I(2) = 84%, P < 0.00001). Sub-group analysis to explore heterogeneity demonstrated this reduction in pain was mostly with high total dose steroids (total >10 mg over first 24 h post-operatively; SMD: -1.48, 95% CI: -2.17 to -0.79, P < 0.00001), especially when given both intra-operatively and post-operatively. There was no significant effect with low doses (SMD: -0.12, 95% CI: -0.36 to 0.13, P = 0.35). There were three trials (231 patients) that reported post-operative nausea and vomiting, three other trials (270 patients) reporting on bleeding and three trials (401 patients) reporting other complications (infections and odynophagia). There was a significant reduction in post-operative nausea and vomiting (RR: 0.53, 95% CI: 0.36 to 0.80, P = 0.002, I(2) = 26%) and bleeding (RR: 0.45, 95% CI: 0.25 to 0.80, P = 0.007, I(2) = 0%), but the reduction in the other complications did not reach statistical significance (RR: 0.69, 95% CI: 0.48 to 1.01, P = 0.06, I(2) = 0%). Pooling of these complications (post-operative nausea and vomiting, bleeding, infections and odynophagia) shows that in six trials (501 patients), the use of dexamethasone significantly reduced post-operative complications following tonsillectomy in adults (RR: 0.59, 95% CI: 0.49 to 0.71, P < 0.00001, I(2) = 0%), when compared with placebo or control. CONCLUSIONS: Dexamethasone reduces pain, post-operative nausea and vomiting, bleeding and overall post-operative complications in adults undergoing tonsillectomy. However, the effect of the dose of dexamethasone on post-operative pain and whether dexamethasone reduces bleeding require further research.