Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

The effect of Nordic hamstring exercise training volume on biceps femoris long head architectural adaptation.

The aim of this study was to determine the time course of architectural adaptations in the biceps femoris long head (BFLH ) following high or low volume eccentric training. Twenty recreationally active males completed a two week standardized period of eccentric Nordic hamstring exercise (NHE) training, followed by four weeks of high (n = 10) or low volume (n = 10) training. Eccentric strength was assessed pre- and post intervention and following detraining. Architecture was assessed weekly during training and after two and four weeks of detraining. After six weeks of training, BFLH fascicles increased significantly in the high (23% ± 7%, P < .001, d = 2.87) and low volume (24% ± 4%, P < .001, d = 3.46) groups, but reversed following two weeks of detraining (high volume: -17% ± 5%, P < .001, d = -2.04; low volume: -15% ± 3%, P < .001, d = -2.56) after completing the intervention. Both groups increased eccentric strength after six weeks of training (high volume: 28% ± 20%, P = .009, d = 1.55; low volume: 34% ± 14%, P < .001, d = 2.09) and saw no change in strength following a four week period of detraining (high volume: -7% ± 7%, P = .97, d = -0.31; low volume: -2% ± 5%, P = .99, d = -0.20). Both low and high volume NHE training stimulate increases in BFLH fascicle length and eccentric knee flexor strength. Architectural adaptations reverted to baseline levels within two weeks after ceasing training, but eccentric strength was maintained for at least four weeks. These observations provide novel insight into the effects of training volume and detraining on BFLH architecture and may provide guidance for the implementation of NHE programs.

Muscle activation patterns in the Nordic hamstring exercise: Impact of prior strain injury.

This study aimed to determine: (a) the spatial patterns of hamstring activation during the Nordic hamstring exercise (NHE); (b) whether previously injured hamstrings display activation deficits during the NHE; and (c) whether previously injured hamstrings exhibit altered cross-sectional area (CSA). Ten healthy, recreationally active men with a history of unilateral hamstring strain injury underwent functional magnetic resonance imaging of their thighs before and after six sets of 10 repetitions of the NHE. Transverse (T2) relaxation times of all hamstring muscles [biceps femoris long head (BFlh); biceps femoris short head (BFsh); semitendinosus (ST); semimembranosus (SM)] were measured at rest and immediately after the NHE and CSA was measured at rest. For the uninjured limb, the ST's percentage increase in T2 with exercise was 16.8%, 15.8%, and 20.2% greater than the increases exhibited by the BFlh, BFsh, and SM, respectively (P < 0.002 for all). Previously injured hamstring muscles (n = 10) displayed significantly smaller increases in T2 post-exercise than the homonymous muscles in the uninjured contralateral limb (mean difference -7.2%, P = 0.001). No muscles displayed significant between-limb differences in CSA. During the NHE, the ST is preferentially activated and previously injured hamstring muscles display chronic activation deficits compared with uninjured contralateral muscles.

Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC. PATIENTS AND METHODS: Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis. RESULTS: Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression-free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS. CONCLUSIONS: The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum-resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis. CLINICAL TRIAL NUMBER: NCT00942734.

Novel characterization of a breakpoint in F8: an individualized approach to gene analysis when PCR and MLPA results contradict.

Haemophilia A is an X-linked bleeding disorder caused by heterogeneous mutations in the F8 gene. Two inversion hotspots in intron 22 and intron 1, as well as point mutations, small insertions and deletions in the F8 gene account for causal mutations leading to severe haemophilia A. Rarely, novel molecular mechanisms lead to a haemophilia A phenotype which cannot be completely characterized by routine molecular diagnostic methods. Here, we characterized the molecular abnormality in a boy with a severe haemophilia A phenotype. On investigation by PCR and DNA sequencing, exon 18 of F8 repeatedly failed to amplify. However, analysis by multiplex ligation-dependent probe amplification demonstrated the presence of exon 18 sequence, suggesting a more complex rearrangement than a single exon deletion. The analysis of exon 18 and its flanking regions by inverse PCR revealed a complex mutation comprising insertions of extragenic sequences from Xq28 along with a partial duplication of exon 18. Based on the successful analysis and characterization of the familial breakpoint, we developed a PCR-based diagnostic approach to detect this defect in family members in whom no diagnostic test could be offered until this time.

Ultrasound-guided botulinum toxin injection to treat a parotid fistula following gunshot injury.

Parotid fistula is a rare but very distressing sequelum of post-operative or traumatic injuries. The management of these injuries has been reported in the literature previously and techniques employed include pressure dressings, surgery and more recently botulinum toxin A (BTA) injections. We present a patient who developed a parotid fistula as a late complication of an extensive gunshot injury to the face with subsequent successful management with ultrasound-guided intraglandular injections of BTA. This case demonstrates that the BTA injection is an effective and safe method under ultrasound guidance and should considered as a first-line treatment option for the treatment of salivary fistulas.

Reduced biceps femoris myoelectrical activity influences eccentric knee flexor weakness after repeat sprint running.

The aim of this study was to determine whether declines in knee flexor strength following overground repeat sprints were related to changes in hamstrings myoelectrical activity. Seventeen recreationally active men completed maximal isokinetic concentric and eccentric knee flexor strength assessments at 180°/s before and after repeat sprint running. Myoelectrical activity of the biceps femoris (BF) and medial hamstrings (MHs) was measured during all isokinetic contractions. Repeated measures mixed model [fixed factors = time (pre- and post-repeat sprint) and leg (dominant and nondominant), random factor = participants] design was fitted with the restricted maximal likelihood method. Repeat sprint running resulted in significant declines in eccentric, and concentric, knee flexor strength (eccentric = 26 ± 4 Nm, 15% P < 0.001; concentric 11 ± 2 Nm, 10% P < 0.001). Eccentric BF myoelectrical activity was significantly reduced (10%; P = 0.035). Concentric BF and all MH myoelectrical activity were not altered. The declines in maximal eccentric torque were associated with the change in eccentric BF myoelectrical activity (P = 0.013). Following repeat sprint running, there were preferential declines in the myoelectrical activity of the BF, which explained declines in eccentric knee flexor strength.

Expansion of genetic services utilizing a general genetic counseling clinic.

We established a general genetic counseling clinic (GCC) to help reduce long wait times for new patient appointments and to enhance services for a subset of patients. Genetic counselors, who are licensed in Tennessee, were the primary providers and MD geneticists served as medical advisors. This article describes the clinic referral sources, reasons for referral and patient dispositions following their GCC visit(s). We obtained patients by triaging referrals made to our medical genetics division. Over 24 months, our GCC provided timely visits for 321 patients, allowing the MD geneticists to focus on patients needing a clinical exam and/or complex medical management. Following their GCC visit(s), over 80 % of patients did not need additional appointments with an MD geneticist. The GCC allowed the genetic counselor to spend more time with patients than is possible in our traditional medical genetics clinic. Patient satisfaction surveys (n = 30) were very positive overall concerning the care provided. Added benefits for the genetic counselors were increased professional responsibility, autonomy and visibility as health care providers. We conclude that genetic counselors are accepted as health care providers by patients and referring providers for a subset of clinical genetics cases. A GCC can expand genetic services, complement more traditional genetic clinic models and utilize the strengths of the genetic counselor health care provider.

Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis.

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

Antimicrobial activity of cuprous oxide-coated and cupric oxide-coated surfaces.

BACKGROUND: Disease can be spread through contact with contaminated surfaces (fomites). For example, fomites have been implicated in the spread of meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Antimicrobial surface treatments are a potential method of reducing disease transmission from fomites, and broad-spectrum activity is desirable. AIM: To test cuprous oxide (Cu2O) and cupric oxide (CuO) coatings for antimicrobial activity against 12 micro-organisms including bacteria and fungi. METHODS: We fabricated two surface coatings. The Cu2O coating was fabricated in a simple two-step process using polyurethane to bind the active copper oxide particles; CuO was prepared by heat treatment of Cu2O particles in air to produce cupric oxide (CuO) and to cause early-stage sintering to form a continuous coating. The antimicrobial activity was examined with 10 µL of microbial suspension droplets followed by counting cells as colony-forming units (cfu). FINDINGS: The coatings rapidly killed nine different micro-organisms, including Gram-negative and Gram-positive bacteria, mycobacteria and fungi. For example, the Cu2O/PU coating killed 99.9997% of P. aeruginosa and 99.9993% of S. aureus after 1 h. Efficacy was not reduced after weekly cleanings. The antimicrobial activity of the Cu2O coating was unchanged after abrasion treatment, and the coatings were not cytotoxic to human cells. CONCLUSION: The combination of broad-spectrum antimicrobial activity, abrasion resistance, and low toxicity of the Cu2O coating suggests potential use in healthcare settings.

Management of devastating ocular trauma--experience of maxillofacial surgeons deployed to a forward field hospital.

Combat-related eye injuries continue to increase in frequency and are generally secondary to Improvised Explosive Devices. Many ocular injuries are potentially preventable by the wearing of ballistic eye protection. The management of penetrating eye trauma is normally outside the routine practice of maxillofacial surgeons in the UK. The aim of this paper is to describe the surgical techniques used in the modern management of devastating ocular trauma including selected case examples managed by British military maxillofacial surgeons deployed to Afghanistan.

Five months of surgery in the multinational field hospital in Afghanistan with an emphasis on oral and maxillofacial injuries.

The aim of this review was to assess the workload of theatres in the role 3 Multinational Field Hospital in Kandahar, Afghanistan and to identify what period of day most emergency admissions arrived. During the period 05 August 2006 to 21 December 2006, 288 operations were performed on 259 patients and comprised 393 individually quantifiable procedures. 98% of these operations were to treat acute injuries. Oral and Maxillofacial surgeons were involved in 24% of operations. 63% of procedures done at these operations involved upper or lower limbs, 19% the head and neck and 18% involved the torso. An analysis of emergency admissions in November 2006 showed that most occurred between 18.00 and midnight. Although theatre timetabling made provision for this, whenever possible, elective surgery was scheduled for the following morning when emergency injury admissions were at their lowest.

Thyroid function and the natural history of depression: findings from the Caerphilly Prospective Study (CaPS) and a meta-analysis.

OBJECTIVE: Low thyroid function has been associated with depression in clinical populations. We have examined whether thyroid function in the normal range is associated with minor psychiatric morbidity. DESIGN: Prospective cohort study of 2269 middle aged men (45-59 years) with thyroid function (total T(4) only, TSH unavailable) measured between 1979 and 1983 and with repeat measures of minor psychiatric morbidity (GHQ-30) over a mean of 12.3 years follow-up. We also undertook a systematic review and meta-analysis of population-based studies examining thyroid function and mood. RESULTS: There was a positive association between total T(4) and chronic psychiatric morbidity (odds ratio 1.21, 95% CI 1.02-1.43, P= 0.03), but this was consistent with chance after adjusting for social class, alcohol and smoking behaviours. The association with incident and recovery from psychiatric morbidity was weaker and consistent with chance. We identified seven eligible studies, from our systematic review and included six studies, including our own, in a meta-analysis. The pooled estimate showed a positive association (odds ratio 1.12, 95% CI 1.02-1.22, P-value = 0.01) between depression and T(4) and an inverse association with TSH (odds ratio 0.92, 95% CI 0.88-0.97, P= 0.0007) with no evidence of heterogeneity or publication bias. CONCLUSION: The results from CaPS and our meta-analysis are consistent and suggest that, if anything, higher levels of thyroxine in the normal range are associated with increased risk of depression. The effects of thyroid hormone on mood may differ in normal populations and patients with clinical thyroid dysfunction.

Promoting Global Research Excellence in Severe Sepsis (PROGRESS): lessons from an international sepsis registry.

BACKGROUND: The PROGRESS Registry (Promoting Global Research Excellence in Severe Sepsis) was designed to provide comparative data reflecting everyday clinical practice, thereby allowing participating institutions to explore and benchmark medical interventions in severe sepsis. MATERIALS AND METHODS: PROGRESS was an international, noninterventional, prospective, observational registry collecting data that describe the management and outcomes of severe sepsis patients in intensive care units (ICUs). Patients were enrolled who had been diagnosed with severe sepsis (suspected or proven infection and >or= 1 acute sepsis-induced organ dysfunction) at the participating institutions, where de-identified data were entered directly into a secured website. PROGRESS was governed by an independent international medical advisory board. RESULTS: PROGRESS took place in 276 ICUs in 37 countries, and 12,881 patients were identified as having severe sepsis. There was considerable variation among countries in enrollment levels, provision of standard treatment and supportive therapies, and ICU and hospital outcomes. Eight countries accounted for 65.2% of the enrolled patients. Males (59.3%) and Caucasian (48.6%) patients predominated the patient cohort. Diagnosis of severe sepsis was prior to ICU admission in 45.7% of patients, at ICU admission in 29.1% of patients, and after ICU admission in the remainder. Globally, ICU and hospital mortality rates were 39.2% and 49.6%, respectively. The mean length of ICU and hospital stay was 14.6 days and 28.2 days, respectively. CONCLUSIONS: The PROGRESS international sepsis registry demonstrates that a large web-based sepsis registry is feasible. Wide variations in outcomes and use of sepsis therapies were observed between countries. These results also suggest that additional opportunities exist across countries to improve severe sepsis outcomes.

Pleomorphic adenoma arising from accessory parotid tissue presenting as dysphonia.

This article describes an unusual presentation of pleomorphic adenoma arising from accessory parotid tissue. A patient who had recently been diagnosed with Parkinson's disease, presented with worsening dysphonia. Magnetic resonance imaging and ultrasound guided core biopsies confirmed the diagnosis and the mass was removed by extra capsular dissection through a lip split mandibulotomy approach. This case confirms the need for careful examination of the oropharynx in patients with preexisting neurological conditions that develop speech disturbance. It also demonstrates the importance of these imaging techniques in the diagnosis of parapharyngeal lesions.

How phenotype guides management of the neuroendocrine carcinomas of the larynx.

OBJECTIVE: This review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx. METHOD: A PubMed search was performed using the term 'neuroendocrine carcinoma'. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.Results and conclusionWhile many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.

Imaging of Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma is fatal if unresectable. However, improved survival has been reported after gross total resection and multimodality therapy. In this report, we describe the contrast-enhanced high-resolution CT characteristics of anaplastic thyroid carcinoma in 57 patients. Anaplastic thyroid carcinoma presented as a large neck mass with necrosis in 82% of cases. The tumors demonstrated common extrathyroidal extension (91%). Sixty-two percent of tumors demonstrated calcification. Visceral space invasion involved the esophagus (62%), trachea (57%), and larynx (29%). Carotid artery encasement was present in 42%, and 43% involved the internal jugular vein. Sixty-three percent had lateral compartment lymphadenopathy; 58% of these nodes were necrotic, and 11% were cystic. No metastatic nodes had calcification. Central compartment lymphadenopathy was seen in 56% of cases, and lateral retropharyngeal lymphadenopathy was detected in 12%. Knowledge of these imaging features aids in guiding the approach to the initial tissue diagnosis with either fine-needle aspiration or core biopsy, assessing the feasibility of surgical resection, and determining prognosis.

Hypoxic preconditioning of myoblasts implanted in a tissue engineering chamber significantly increases local angiogenesis via upregulation of myoblast vascular endothelial growth factor-A expression and downregulation of miRNA-1, miRNA-206 and angiopoietin-1.

Vascularization is a major hurdle for growing three-dimensional tissue engineered constructs. This study investigated the mechanisms involved in hypoxic preconditioning of primary rat myoblasts in vitro and their influence on local angiogenesis postimplantation. Primary rat myoblast cultures were exposed to 90 min hypoxia at <1% oxygen followed by normoxia for 24 h. Real time (RT) polymerase chain reaction evaluation indicated that 90 min hypoxia resulted in significant downregulation of miR-1 and miR-206 (p < 0.05) and angiopoietin-1 (p < 0.05) with upregulation of vascular endothelial growth factor-A (VEGF-A; p < 0.05). The miR-1 and angiopoietin-1 responses remained significantly downregulated after a 24 h rest phase. In addition, direct inhibition of miR-206 in L6 myoblasts caused a significant increase in VEGF-A expression (p < 0.05), further establishing that changes in VEGF-A expression are influenced by miR-206. Of the myogenic genes examined, MyoD was significantly upregulated, only after 24 h rest (p < 0.05). Preconditioned or control myoblasts were implanted with Matrigel™ into isolated bilateral tissue engineering chambers incorporating a flow-through epigastric vascular pedicle in severe combined immunodeficiency mice and the chamber tissue harvested 14 days later. Chambers implanted with preconditioned myoblasts had a significantly increased percentage volume of blood vessels (p = 0.0325) compared with chambers implanted with control myoblasts. Hypoxic preconditioned myoblasts promote vascularization of constructs via VEGF upregulation and downregulation of angiopoietin-1, miR-1 and miR-206. The relatively simple strategy of hypoxic preconditioning of implanted cells - including non-stem cell types - has broad, future applications in tissue engineering of skeletal muscle and other tissues, as a technique to significantly increase implant site angiogenesis.

"One-stop" clinics in the investigation and diagnosis of head and neck lumps.

This article considers the issues raised by the NICE guidelines "Improving outcomes in head and neck cancers" (2004) with particular emphasis on the guidelines regarding the creation of "one-stop" neck lump assessment clinics. Tissue sampling is an essential function of the clinics and the relative merits of fine needle aspiration cytology (FNAC) and ultrasound-guided core biopsy (US-CB) in the context of a one-stop model are discussed. All cancer service providers in the UK have a duty to implement the NICE guidelines, with the intention of improving cancer services to our patients. The measures against which head and neck cancer teams are to be accredited through the process of peer review will specify such a clinic to be in place. Teams should implement the guidance in such a way that there is a genuine benefit to patients. In many centres this may require clinicians to learn new skills and adopt different ways of working.

Ultrasound-guided core biopsy for the diagnosis of lumps in the neck: results in 82 patients.

Ultrasound-guided core biopsy of nodes (n = 78) and other lumps (n = 4) in the neck allowed a firm histological diagnosis in 76 of 82 patients (93%). Of the remaining six patients, histological examination was equivocal in four and valueless in two. Of 18 patients with a diagnosis of lymphoma only 3 required excision of the node to provide additional information for the planning of treatment.