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

AN OBLIGATORY ROLE OF MIND BOMB-1 IN NOTCH SIGNALING OF MAMMALIAN DEVELOPMENT

Background. The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood. Methodology/Principal Findings. Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2 2/2 mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants. Conclusions/Significance. Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.open117978Nsciescopu

Potential pitfalls in MitoChip detected tumor-specific somatic mutations: a call for caution when interpreting patient data

<p>Abstract</p> <p>Background</p> <p>Several investigators have employed high throughput mitochondrial sequencing array (MitoChip) in clinical studies to search mtDNA for markers linked to cancers. In consequence, a host of somatic mtDNA mutations have been identified as linked to different types of cancers. However, closer examination of these data show that there are a number of potential pitfalls in the detection tumor-specific somatic mutations in clinical case studies, thus urging caution in the interpretation of mtDNA data to the patients. This study examined mitochondrial sequence variants demonstrated in cancer patients, and assessed the reliability of using detected patterns of polymorphisms in the early diagnosis of cancer.</p> <p>Methods</p> <p>Published entire mitochondrial genomes from head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor from clinical patients were examined in a phylogenetic context and compared with known, naturally occurring mutations which characterize different populations.</p> <p>Results</p> <p>The phylogenetic linkage analysis of whole arrays of mtDNA mutations from patient cancerous and non-cancerous tissue confirmed that artificial recombination events occurred in studies of head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor. Our phylogenetic analysis of these tumor and control leukocyte mtDNA haplotype sequences shows clear cut evidence of mixed ancestries found in single individuals.</p> <p>Conclusions</p> <p>Our study makes two prescriptions: both in the clinical situation and in research 1. more care should be taken in maintaining sample identity and 2. analysis should always be undertaken with respect to all the data available and within an evolutionary framework to eliminate artifacts and mix-ups.</p

Towards learning and verifying invariants of cyber-physical systems by code mutation

Cyber-physical systems (CPS), which integrate algorithmic control with physical processes, often consist of physically distributed components communicating over a network. A malfunctioning or compromised component in such a CPS can lead to costly consequences, especially in the context of public infrastructure. In this short paper, we argue for the importance of constructing invariants (or models) of the physical behaviour exhibited by CPS, motivated by their applications to the control, monitoring, and attestation of components. To achieve this despite the inherent complexity of CPS, we propose a new technique for learning invariants that combines machine learning with ideas from mutation testing. We present a preliminary study on a water treatment system that suggests the efficacy of this approach, propose strategies for establishing confidence in the correctness of invariants, then summarise some research questions and the steps we are taking to investigate them.Comment: Short paper accepted by the 21st International Symposium on Formal Methods (FM 2016

Aharonov-Bohm interference in topological insulator nanoribbons

Topological insulators represent novel phases of quantum matter with an insulating bulk gap and gapless edges or surface states. The two-dimensional topological insulator phase was predicted in HgTe quantum wells and confirmed by transport measurements. Recently, Bi2Se3 and related materials have been proposed as three-dimensional topological insulators with a single Dirac cone on the surface and verified by angle-resolved photoemission spectroscopy experiments. Here, we show unambiguous transport evidence of topological surface states through periodic quantum interference effects in layered single-crystalline Bi2Se3 nanoribbons. Pronounced Aharonov-Bohm oscillations in the magnetoresistance clearly demonstrate the coverage of two-dimensional electrons on the entire surface, as expected from the topological nature of the surface states. The dominance of the primary h/e oscillation and its temperature dependence demonstrate the robustness of these electronic states. Our results suggest that topological insulator nanoribbons afford novel promising materials for future spintronic devices at room temperature.Comment: 5 pages, 4 figures, RevTex forma

Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor‐Naïve Advanced Pancreatic Neuroendocrine Tumors

BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3‐kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy. METHODS: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure. RESULTS: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1–NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72–3.25). The most commonly reported all‐grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%). CONCLUSION: BEZ235 treatment in mTOR inhibitor‐naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile

Analysis and Design of a Compact Leaky-Wave Antenna for Wide-Band Broadside Radiation

A low-cost compact planar leaky-wave antenna (LWA) is proposed offering directive broadside radiation over a significantly wide bandwidth. The design is based on an annular metallic strip grating (MSG) configuration, placed on top of a dual-layer grounded dielectric substrate. This defines a new two-layer parallel-plate open waveguide, whose operational principles are accurately investigated. To assist in our antenna design, a method-of-moments dispersion analysis has been developed to characterize the relevant TM and TE modes of the perturbed guiding structure. By proper selection of the MSG for a fabricated prototype and its supporting dielectric layers as well as the practical TM antenna feed embedded in the bottom ground plane, far-field pencil-beam patterns are observed at broadside and over a wide frequency range, i.e., from 21.9 GHz to 23.9 GHz, defining a radiating percentage bandwidth of more than 8.5%. This can be explained by a dominantly excited TM mode, with low dispersion, employed to generate a two-sided far-field beam pattern which combines to produce a single beam at broadside over frequency. Some applications of this planar antenna include radar and satellite communications at microwave and millimeter-wave frequencies as well as future 5G communication devices and wireless power transmission systems

Essential Roles of the Tap42-Regulated Protein Phosphatase 2A (PP2A) Family in Wing Imaginal Disc Development of Drosophila melanogaster

Protein ser/thr phosphatase 2A family members (PP2A, PP4, and PP6) are implicated in the control of numerous biological processes, but our understanding of the in vivo function and regulation of these enzymes is limited. In this study, we investigated the role of Tap42, a common regulatory subunit for all three PP2A family members, in the development of Drosophila melanogaster wing imaginal discs. RNAi-mediated silencing of Tap42 using the binary Gal4/UAS system and two disc drivers, pnr- and ap-Gal4, not only decreased survival rates but also hampered the development of wing discs, resulting in a remarkable thorax cleft and defective wings in adults. Silencing of Tap42 also altered multiple signaling pathways (HH, JNK and DPP) and triggered apoptosis in wing imaginal discs. The Tap42RNAi-induced defects were the direct result of loss of regulation of Drosophila PP2A family members (MTS, PP4, and PPV), as enforced expression of wild type Tap42, but not a phosphatase binding defective Tap42 mutant, rescued fly survivorship and defects. The experimental platform described herein identifies crucial roles for Tap42•phosphatase complexes in governing imaginal disc and fly development

Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

<p>Abstract</p> <p>Background</p> <p>Atrial natriuretic peptide (ANP) and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126) of pro-atrial natriuretic factor (proANF) and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF) have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD), another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma.</p> <p>Methods</p> <p>A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2) through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid.</p> <p>Results</p> <p>pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation.</p> <p>Conclusion</p> <p>VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.</p